RUNX1-BMP2 promotes vasculogenic mimicry in laryngeal squamous cell carcinoma via activation of the PI3K-AKT signaling pathway.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck. Vasculogenic mimicry (VM) is crucial for tumor growth and metastasis and refers to the formation of fluid channels by invasive tumor cells rather than endothelial cells. However, the regulatory mechanisms underlying VM during the malignant progression of LSCC remain largely unknown. METHODS: Gene expression and clinical data for LSCC were obtained from the TCGA and Gene GEO (GSE27020) databases. A risk prediction model associated with VM was established using LASSO and Cox regression analyses. Based on their risk scores, patients with LSCC were categorized into high- and low-risk groups. The disparities in immune infiltration, tumor mutational burden (TMB), and functional enrichment between these two groups were examined. The core genes in LSCC were identified using the machine learning (SVM-RFE) and WGCNA algorithms. Subsequently, the involvement of bone morphogenetic protein 2 (BMP2) in VM and metastasis was investigated both in vitro and in vivo. To elucidate the downstream signaling pathways regulated by BMP2, western blotting was performed. Additionally, ChIP experiments were employed to identify the key transcription factors responsible for modulating the expression of BMP2. RESULTS: We established a new precise prognostic model for LSCC related to VM based on three genes: BMP2, EPO, and AGPS. The ROC curves from both TCGA and GSE27020 validation cohorts demonstrated precision survival prediction capabilities, with the nomogram showing some net clinical benefit. Multiple algorithm analyses indicated BMP2 as a potential core gene. Further experiments suggested that BMP2 promotes VM and metastasis in LSCC. The malignant progression of LSCC is promoted by BMP2 via the activation of the PI3K-AKT signaling pathway, with the high expression of BMP2 in LSCC resulting from its transcriptional activation by runt-related transcription factor 1 (RUNX1). CONCLUSION: BMP2 predicts poor prognosis in LSCC, promotes LSCC VM and metastasis through the PI3K-AKT signaling pathway, and is transcriptionally regulated by RUNX1. BMP2 may be a novel, precise, diagnostic, and therapeutic biomarker of LSCC.

Choanal Polyps With Osseous Metaplasia From the Nasal Septum: A Case Report and the Literature Review.

Choanal polyps belong to a special type of nasal polyps, which are quite uncommon if originating from the nasal septum, especially those with osseous metaplasia. In this article, we report the case of a 63-year-old male patient with persistent nasal obstruction on the right side. An irregular light yellow lobulated mass with smooth surface could be visualized in the nasal cavity through nasal endoscopy, arising from the right nasal septum and extending to the nasopharynx. Computed tomography scan showed a large soft tissue shadow of the nasal meatus, with ossified structure in the center. Histopathological biopsy revealed nasopharyngeal mucositis. The patient underwent functional endoscopic sinus surgery and the polypoidal mass sent for histopathological examination proved to be choanal polyps.

Gene expression analysis of oxidative stress-related genes in the apical, middle, and basal turns of the cochlea.

It can be observed from aminoglycoside-induced hair cell damage that the cochlea basal turn is more susceptible to trauma than the apex. Drug-induced hearing loss is closely related to oxidative damage. The basilar membrane directly exposed to these ototoxic drugs exhibits differences in damage, indicating that there is an inherent difference in the sensitivity to oxidative damage from the apex to the base of the cochlea. It has been reported that the morphology and characteristics of the cochlea vary from the apex to the base. Therefore, we investigated oxidative stress-related gene expression profiles in the apical, middle, and basal turns of the cochlea. The Oxidative Stress RT2 Profiler™ PCR Array revealed that three of the 84 genes (Mb, Mpo, and Ncf1) were upregulated in the middle turn compared to their level in the apical turn. Moreover, eight genes (Mb, Duox1, Ncf1, Ngb, Fmo2, Gpx3, Mpo, and Gstk1) were upregulated in the basal turn compared to their level in the apical turn. The qPCR verification data were similar to that of the PCR Array. We found that MPO was expressed in the rat cochlea and protected against gentamicin-induced hair cell death. This study summarized the data for the gradient of expression of oxidative stress-related genes in the cochlea and found potential candidate targets for prevention of ototoxic deafness, which may provide new insights for cochlear pathology.

Norepinephrine protects against cochlear outer hair cell damage and noise-induced hearing loss via α2A-adrenergic receptor.

BACKGROUND: The cochlear sympathetic system plays a key role in auditory function and susceptibility to noise-induced hearing loss (NIHL). The formation of reactive oxygen species (ROS) is a well-documented process in NIHL. In this study, we aimed at investigating the effects of a superior cervical ganglionectomy (SCGx) on NIHL in Sprague-Dawley rats. METHODS: We explored the effects of unilateral and bilateral Superior Cervical Ganglion (SCG) ablation in the eight-ten weeks old Sprague-Dawley rats of both sexes on NIHL. Auditory function was evaluated by auditory brainstem response (ABR) testing and Distortion product otoacoustic emissions (DPOAEs). Outer hair cells (OHCs) counts and the expression of α2A-adrenergic receptor (AR) in the rat cochlea using immunofluorescence analysis. Cells culture and treatment, CCK-8 assay, Flow cytometry staining and analysis, and western blotting were to explore the mechanisms of SCG fibers may have a protective role in NIHL. RESULTS: We found that neither bilateral nor unilateral SCGx protected the cochlea against noise exposure. In HEI-OC1 cells, H2O2-induced oxidative damage and cell death were inhibited by the application of norepinephrine (NE). NE may prevent ROS-induced oxidative stress in OHCs and NIHL through the α2A-AR. CONCLUSION: These results demonstrated that sympathetic innervation mildly affected cochlear susceptibility to acoustic trauma by reducing oxidative damage in OHCs through the α2A-AR. NE may be a potential therapeutic strategy for NIHL prevention.

Study on characteristics of wideband acoustic immittance in patients with Inner Ear Malformations.

OBJECTIVE: To compare the differences in wideband absorbance and the resonance frequency (RF) between patients with inner ear malformations and normal control, and to explore the auditory diagnostic value of wideband acoustic immittance (WAI). METHODS: A total of 38 patients (59 ears) with enlarged vestibular aqueduct (EVA), 13 patients (14 ears) with incomplete partition type I (IP-I) and 13 patients (26 ears) with incomplete partition type II (IP-II) were included. 50 normal control (100 ears). All subjects underwent WAI tests to compare the absorbance configuration and resonance frequency. RESULTS: All the group showed lower absorbance at ambient pressure than at peak pressure in certain frequencies under 2000Hz. Under 1000Hz, the absorbance of EVA was higher than that of other groups. The average absorbance and highest absorbance of IP-I were the lowest(P＜0.05). However, IP-II and normal group had similarity on some characteristics. The three IEM groups mainly different at low and high frequencies, but not at medium frequencies. The highest absorbance of all the groups were appeared around 3000Hz. The RF of all the groups from low to high were EVA＜IP-II＜normal control＜IP-I, and the lowest was EVA(P＜0.05). CONCLUSION: Inner ear malformations can affect energy absorbance and RF. WAI is sensitive and non-invasive to provide useful information about inner ear status and facilitate detection of ear pathology.

Translocation of telomerase reverse transcriptase coincided with ATP release in postnatal cochlear supporting cells.

The spontaneous bursts of electrical activity in the developing auditory system are derived from the periodic release of adenosine triphosphate (ATP) by supporting cells in the Kölliker's organ. However, the mechanisms responsible for initiating spontaneous ATP release have not been determined. Our previous study revealed that telomerase reverse transcriptase (TERT) is expressed in the basilar membrane during the first postnatal week. Its role in cochlear development remains unclear. In this study, we investigated the expression and role of TERT in postnatal cochlea supporting cells. Our results revealed that in postnatal cochlear Kölliker's organ supporting cells, TERT shifts from the nucleus into the cytoplasm over time. We found that the TERT translocation tendency in postnatal cochlear supporting cells in vitro coincided with that observed in vivo. Further analysis showed that TERT in the cytoplasm was mainly located in mitochondria in the absence of oxidative stress or apoptosis, suggesting that TERT in mitochondria plays roles other than antioxidant or anti-apoptotic functions. We observed increased ATP synthesis, release and activation of purine signaling systems in supporting cells during the first 10 postnatal days. The phenomenon that TERT translocation coincided with changes in ATP synthesis, release and activation of the purine signaling system in postnatal cochlear supporting cells suggested that TERT may be involved in regulating ATP release and activation of the purine signaling system. Our study provides a new research direction for exploring the spontaneous electrical activity of the cochlea during the early postnatal period.

Lysophosphatidic acid exerts protective effects on HEI-OC1 cells against cytotoxicity of cisplatin by decreasing apoptosis, excessive autophagy, and accumulation of ROS.

Lysophosphatidic acid (LPA) is an active phospholipid signaling molecule that binds to six specific G protein-coupled receptors (LPA1-6) on the cell surface and exerts a variety of biological functions, including cell migration and proliferation, morphological changes, and anti-apoptosis. The earliest study from our group demonstrated that LPA treatment could restore cochlear F-actin depolymerization induced by noise exposure, reduce hair cell death, and thus protect hearing. However, whether LPA could protect against cisplatin-induced ototoxicity and which receptors play the major role remain unclear. To this end, we integrated the HEI-OC1 mouse cochlear hair cell line and zebrafish model, and found that cisplatin exposure induced a large amount of reactive oxygen species accumulation in HEI-OC1 cells, accompanied by mitochondrial damage, leading to apoptosis and autophagy. LPA treatment significantly attenuated autophagy and apoptosis in HEI-OC1 cells after cisplatin exposure. Further investigation revealed that all LPA receptors except LPA3 were expressed in HEI-OC1 cells, and the mRNA expression level of LPA1 receptor was significantly higher than that of other receptors. When LPA1 receptor was silenced, the protective effect of LPA was reduced and the proportion of apoptosis cells was increased, indicating that LPA-LPA1 plays an important role in protecting HEI-OC1 cells from cisplatin-induced apoptosis. In addition, the behavioral trajectory and in vivo fluorescence imaging results showed that cisplatin exposure caused zebrafish to move more actively, and the movement speed and distance were higher than those of the control and LPA groups, while LPA treatment reduced the movement behavior. Cisplatin caused hair cell death and loss in zebrafish lateral line, and LPA treatment significantly protected against hair cell death and loss. LPA has a protective effect on hair cells in vitro and in vivo against the cytotoxicity of cisplatin, and its mechanism may be related to reducing apoptosis, excessive autophagy and ROS accumulation.

Cuproptosis-related LINC02454 as a biomarker for laryngeal squamous cell carcinoma based on a novel risk model and in vitro and in vivo analyses.

PURPOSE: Laryngeal squamous cell carcinomas (LSCCs) are aggressive tumors with the second-highest morbidity rate in patients with head and neck squamous cell carcinoma. Cuproptosis is a type of programmed cell death that impacts tumor malignancy and progression. The purpose of this study was to investigate the relationship between cuproptosis-related long non-coding RNAs (crlncRNAs) and the tumor immune microenvironment and chemotherapeutic drug sensitivity in LSCC, and crlncRNA impact on LSCC malignancy. MATERIALS AND METHODS: Clinical and RNA-sequencing data from patients with LSCC were retrieved from the Cancer Genome Atlas. Differentially expressed prognosis-related crlncRNAs were identified based on univariate Cox regression analysis, a crlncRNA signature for LSCC was developed and validated using LASSO Cox regression. Finally, the effect of LINC02454, the core signature crlncRNA, on LSCC malignancy progression was evaluated in vitro and in vivo. RESULTS: We identified a four-crlncRNA signature (LINC02454, AC026310.1, AC090517.2, and AC000123.1), according to which we divided the patients into high- and low-risk groups. The crlncRNA signature risk score was an independent prognostic indicator for overall and progression-free survival, and displayed high predictive accuracy. Patients with a higher abundance of infiltrating dendritic cells, M0 macrophages, and neutrophils had worse prognoses and those in the high-risk group were highly sensitive to multiple chemotherapeutic drugs. Knockdown of LINC02454 caused tumor suppression, via cuproptosis induction. CONCLUSIONS: A novel signature of four crlncRNAs was found to be highly accurate as a risk prediction model for patients with LSCC and to have potential for improving the diagnosis, prognosis, and treatment of LSCC.

Expression and localization of α2A-adrenergic receptor in the rat post-natal developing cochlea.

Lots of adrenergic receptors (ARs) are widely present across the auditory pathways and are positioned to affect auditory and vestibular functions. However, noradrenergic regulation in the cochlea has not been well characterized. In this study, a rat model of noise-induced hearing loss was developed to investigate the expression of α2A-adrenergic receptor (AR) after acoustic trauma, then, we investigated the expression of α2A-AR in the developing rat cochlea using immunofluorescence, qRT-PCR, and Western blotting. We found that the expression of α2A-AR significantly increased in rats exposed to noise compared with controls. Immunofluorescence analysis demonstrated that α2A-AR is localized on hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV) in the postnatal developing cochlea from post-natal day (P) 0 to P28. Furthermore, we observed α2A-AR mRNA reached a maximum level at P14 and P28 when compared with P0, while no significant differences in α2A-AR protein levels at the various stages when compared with P0. This study provides direct evidence for the expression of α2A-AR in HCs, SGNs, and the SV of the cochlea, indicating that norepinephrine might play a vital role in hearing function within the cochlea through α2A-AR.

Comparative Analysis of the Hearing Effects of Partial Ossicular Replacement Prosthesis Versus Conchal Cartilage in Canal Wall Down Mastoidectomy with Type II Tympanoplasty: A Retrospective Case Review Study.

OBJECTIVES: To investigate the effects of titanium partial ossicular replacement prosthesis (PORP) and conchal cartilage for ossiculoplasty on hearing results in single-stage canal wall down (CWD) mastoidectomy surgery with type II tympanoplasty in patients with cholesteatoma. METHODS: The patients were performed surgeries for the first time by a senior otosurgeon from 2009 to 2022 and were performed CWD mastoidectomy with type II tympanoplasty in one stage were enrolled. Patients who could not be followed up were excluded. Titanium PORP or conchal cartilage was used for ossiculoplasty. When the stapes head was intact, a cartilage 1.2-1.5 mm thick was attached directly to the stapes; when the head of the stapes was eroded, a 1 mm high PORP and cartilage of .2-.5 mm thick were placed on the stapes simultaneously. RESULTS: 148 patients were included in the study in total. The titanium PORP and conchal cartilage groups showed no statistically significant differences at 500, 1000, 2000, and 4000 Hz considering the number of decibels of closure of the air-bone gap (ABG) (P > .05) and pure-tone average ABG (PTA-ABG) (P > .05). Meanwhile, the closure of PTA-ABG between the 2 groups showed no statistically significant differences in the overall distribution (P > .05). CONCLUSIONS: For patients with cholesteatoma and mobile stapes who underwent CWD mastoidectomy with type II tympanoplasty in one stage, either PORP or conchal cartilage is a satisfactory material for ossiculoplasty.

PTEN inhibitor bisperoxovanadium protects against noise-induced hearing loss.

Studies have shown that phosphatase and tensin homolog deleted on chromosome ten (PTEN) participates in the regulation of cochlear hair cell survival. Bisperoxovanadium protects against neurodegeneration by inhibiting PTEN expression. However, whether bisperoxovanadium can protect against noise-induced hearing loss and the underlying mechanism remains unclear. In this study, we established a mouse model of noise-induced hearing loss by exposure to 105 dB sound for 2 hours. We found that PTEN expression was increased in the organ of Corti, including outer hair cells, inner hair cells, and lateral wall tissues. Intraperitoneal administration of bisperoxovanadium decreased the auditory threshold and the loss of cochlear hair cells and inner hair cell ribbons. In addition, noise exposure decreased p-PI3K and p-Akt levels. Bisperoxovanadium preconditioning or PTEN knockdown upregulated the activity of PI3K-Akt. Bisperoxovanadium also prevented H2O2-induced hair cell death by reducing mitochondrial reactive oxygen species generation in cochlear explants. These findings suggest that bisperoxovanadium reduces noise-induced hearing injury and reduces cochlear hair cell loss.

NRG1/ErbB2 axis regulated mitochondrial function and antioxidant enzymes of neural stem cells in the cochlear nucleus partially through PGC-1α.

Neuregulin-1 (NRG1)/erythroblastic leukaemia viral oncogene homologues 2 (ErbB2) pathway had been implicated in promoting differentiation and suppressing apoptosis of neuronal stem cells (NSCs) isolated from cochlear nucleus. In the current study, we aimed at determining the effects of NRG1/ErbB2 on mitochondrial (mt) function of NSCs. As expected, NRG1 increased the expression of mitofusin (Mfn) 1 and Mfn2 and decreased the expression of mitochondrial fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1). However, after ErbB2 knockout, Mfn1 and Mfn2 expression decreased while Fis1 and Drp1 increased. Moreover, the increased mtDNA copy number and intracellular ATP level, elevated ATPase activities as well as decreased lactate production induced by NRG1 were partially reversed by ErbB2 knockout. Additionally, NRG1 treatment increased the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and upregulated the protein expression of catalase, manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and transcription factor A, mitochondrial (TFAM), which were also reversed by ErbB2 knockout. Furthermore, PGC-1α overexpression partially reversed the above effects of ErbB2 knockout. In conclusion, these findings suggest that the promotion of mitochondrial function of NRG1/ErbB2 axis is at least in part mediated by PGC-1α in NSCs from cochlear nucleus.

VDR Regulates BNP Promoting Neurite Growth and Survival of Cochlear Spiral Ganglion Neurons through cGMP-PKG Signaling Pathway.

Spiral ganglion neurons (SGNs) are important for hearing, and their peripheral and central processes connect sensory cells of the Corti organ to the central nervous system. The resulting network forms a point-to-point auditory conduction. As a cardiac hormone, brain natriuretic peptide (BNP) binds to natriuretic peptide receptor type A leading to diuresis, vasodilatation, inhibition of renin and aldosterone production, and cardiac and vascular myocyte growth. This study primarily aimed to explore the expression and function of BNP in the rat's inner ear and elucidate its regulatory mechanism. We determined the expression and function of BNP and found that the vitamin D receptor (VDR) could upregulate the expression of BNP and enhance its function. In SGNs of the rat inner ear, BNP promotes neuron survival and prolongs neurite length through the cGMP-PKG signaling pathway, which could be regulated by VDR and provide a novel approach for neuronal regeneration therapy. To the best of our knowledge, this is the first study to report this potential transcriptional regulatory relationship and will act as a reference for research on neuronal regeneration therapy for SGNs injury.

TNN is first linked to auditory neuropathy.

Autosomal recessive nonsyndromic auditory neuropathy is attributed to a genetic etiology. We identified a compound heterozygous missense variant, c.G736A (p.G246S) and c.C2954T (p.T985 M) in TNN of affected patients in a pedigree via candidate gene screening and exome sequencing. To determine the genetic etiology of deafness in the pedigree with a heterozygous missense variant in the gene TNN encoding tenascin-W associated with autosomal recessive nonsyndromic auditory neuropathy, the cochlear expression of tenascin-W was evaluated at mRNA and protein levels in mice, and Tnn knock out mice were generated and utilized to study the function of Tnn in the auditory system. Immunofluorescence stainings showed that tenascin-W was mainly expressed in the somatic cytoplasm of spiral ganglion neurons of mice. Homozygous Tnn knockout was lethal in mice, whereas Tnn heterozygous mice showed decreases in spiral ganglion neuron density and progressive hearing loss. We demonstrate that tenascin-W is expressed in the murine cochleae and is essential for the development of spiral ganglion neurons. An abnormal expression of tenascin-W can influence the development and function of SGNs and affect the function of the auditory system.

Effects of aging on ocular vestibular-evoked myogenic potential using ER-3A insert earphone and B81 bone vibrator.

Purpose: Aging is a process associated with degeneration and dysfunction of peripheral vestibular system or apparatus. This study aimed to investigate the influence of aging on ocular vestibular-evoked myogenic potential (oVEMP) response rates and recording parameters using the B81 bone vibrator and compare them with air conduction stimuli (ACS) oVEMP response characteristics. Methods: In 60 healthy participants aged 10-71 years (mean age 39.9; 29 male participants), the oVEMP response was elicited using a B81 bone vibrator and an ER-3A insert earphone. The effects of age and stimulus on oVEMP response rates and recording parameters were evaluated. Results: Response rates and amplitudes declined with aging using either ACS or bone-conducted vibration (BCV) stimulation, particularly in individuals over 60 years of age, whereas thresholds increased and N1 latencies were prolonged. BCV showed fewer risks of absent oVEMP response than ACS (p = 0.002). BCV acquired higher amplitudes (p < 0.001), lower thresholds, and shorter N1 and P1 latencies (all p < 0.001) than ACS. Conclusions: The absence of an oVEMP response may be attributed to aging rather than a concurrent vestibular disorder. B81-BCV likely produces higher mechanical drives to the vestibular hair cells at safer and non-traumatic levels compared with ACS and therefore may be more likely to evoke a response in the elderly cohort, whose vestibular function and mechanical sensitivity have declined. Thus, B81-BCV stimulation is more effective and safer to elicit oVEMPs, and it should be recommended when ACS fails in the clinic, particularly in the elderly population.

A novel splice site variant c.1183 + 1 G > C in DFNA5 causing autosomal dominant nonsyndromic hearing loss in a Chinese family.

BACKGROUND: The most frequent clinical presentation of autosomal dominant nonsyndromic hearing loss (ADNSHL) is bilateral, symmetrical, postlingual progressive sensorineural hearing loss, which begins with impairment at high frequencies and eventually progresses to hearing loss at all frequencies. Autosomal dominant deafness-5 (DFNA5) is a subtype of ADNSHL caused by heterozygous variants in the gasdermin E (GSDME, also known as DFNA5) gene. METHODS: Deafness gene NGS panel analysis were performed on the proband of a six-generation Chinese family with hearing loss. The co-segregation analysis between the hearing loss and the novel variant was analyzed by Sanger sequencing and pure-tone audiometry. The minigene splicing assay was performed to evaluate the potential effect of the variant on messenger RNA splicing in vitro. RESULTS: The family exhibited autosomal dominant, progressive, postlingual, nonsyndromic sensorineural hearing loss, which was similar to that of the previously reported DFNA5 families. A novel heterozygous splice site variant in GSDME gene intron 8 was identified, which co-segregated with the hearing loss phenotype of the family. The variant caused skipping of exon 8 in the mutant transcript, leading to the direct linking of exons 7 and 9. CONCLUSIONS: We identified a novel GSDME splice site variant c.1183 + 1 G > C in an extended Chinese family, which led to the skipping of exon 8. The results extended the pathogenic variants spectrum of the GSDME gene, provided further support for the 'gain-of-function' mechanism of DFNA5, and afforded a molecular interpretation for these patients with ADNSHL.

[Clinical features, diagnosis and treatment for patients presenting with granulation tissue of the external auditory canal].

Objective:To explore the clinical characteristics and diagnosis and treatment in the patients presenting with granulation tissue of the external auditory canal. Methods:The data of 71 postoperative patients presenting with granulation tissue of the external auditory canal in the Department of Otolaryngology, the First Affiliated Hospital of the Air Force Military Medical University from January 2015 to June 2020 were analyzed retrospectively, including the chief complaint, physical examination, auxiliary examination and preoperative imaging, biopsy was performed when necessary to confirm the diagnosis. Among the 71 patients, 30 cases were diagnosed as chronic otitis media, 19 cases were external auditory canal cholesteatoma, 5 cases were external auditory canal carcinoma, 6 cases were paraganglioma, 1 case was granulomatous hemangioma, 1 case was first branchial cleft fistula, 4 cases were granuloma of the external auditory canal, 4 cases were hemangioma of the external auditory canal, and 1 case was foreign body of the external auditory canal. Individualized treatment plans are made according to the characteristics and extent of the lesions. Results:Postoperative follow-up was 12 to 74 months, with an average of （44±18.1） months. Seventy patients（98.6%） had no complications such as sensorineural deafness, external auditory stenosis or peripheral facial paralysis after surgery, and one patient with paraganglioma had postoperative neurological function grade Ⅱ, and was treated with nutritional nerves, and the postoperative neural function recovered to grade Ⅰ after 3 months. Conclusion:The patients presenting with granulation tissue of the external auditory canal can be diagnosed as various diseases. It is necessary to analyze the patient's medical history in detail, confirm the diagnosis in combination with imaging examination, and formulate an individualized treatment plan to reduce misdiagnosis and missed diagnosis.

A forskolin-loaded nanodelivery system prevents noise-induced hearing loss.

Hearing loss is the most common sensory disorder worldwide and may result from age, drugs, or exposure to excessive noise. Crossing the blood-labyrinth barrier to achieve targeted drug delivery to the inner ear is key to the treatment of hearing loss. We designed a nanoparticle (NP)-based system for targeted drug delivery of forskolin (FSK) to the inner ear, driven by the prestin-targeting peptide LS19 ("ligand-receptor type interaction"). In vivo experiments in developing zebrafish embryos (4-96 h past fertilization) and mice confirmed that LS19-FSK specifically targeted and accumulated in zebrafish lateral line neuromasts and mouse outer hair cells (OHCs). LS19 peptide modification enabled LS19-FSK-NPs to rapidly target OHCs with high specificity. Furthermore, the multifunctional LS19-FSK-NPs were successfully delivered to the OHCs via the round window membrane route and exhibited slow-release properties. The sustained release and intracellular accumulation of FSK inhibited apoptosis of OHCs. Compared with LS19-NPs and FSK-NPs, LS19-FSK-NPs provided significantly stronger protection against noise-induced hearing damage, based on auditory brainstem responses at 4, 8, 16, and 32 kHz. Thus, our specially designed targeted nano-delivery system may serve as a basis for future clinical applications and treatment platforms and has the potential to significantly improve the treatment results of many inner ear diseases.

Heme Oxygenase-1 Protects Hair Cells From Gentamicin-Induced Death.

Gentamicin ototoxicity can generate free radicals within the inner ear, leading to permanent damage to sensory hair cells (HCs) and eventually hearing loss. The following study examined the alterations of oxidative damage-related genes in the cochlea and important molecules responsible for oxidation following gentamicin injury in vitro. The RT2 Profiler polymerase chain reaction (PCR) array was used to screen candidate targets for treatment to prevent hearing loss caused by gentamicin. We found that during gentamicin-induced death in HCs, Heme oxygenase-1 (HO-1) had a high fold change in the HCs of the cochlea. Moreover, the use of CoPPIX to induce HO-1 inhibited gentamicin-induced HC death, while HO-1 inhibitors ZnPPIX after CoPPIX reversed this process. Furthermore, the inhibitors of NF-E2-related factor-2 (Nrf2) reduced the expression of HO-1 and inhibited the protective effect of HO-1 after gentamicin, thus suggesting that the Nrf2/HO-1 axis might regulate gentamicin-associated ototoxicity. We further demonstrated that induction of HO-1 up-regulated the expression of Nrf2 in both cochlear and HEI-OC1 cells. In summary, these findings indicated that HO-1 protects HCs from gentamicin by up-regulating its expression in HCs and interacting with Nrf2 to inhibit reactive oxygen species (ROS).

Expression and distribution of Nob1 in the developing rat cochleae.

BACKGROUND: Mammalian inner ear cells are produced during embryonic development. NIN1/RPN12 binding protein 1 homolog (Nob1), a ribosome assembly factor, is believed to be involved in transcriptional regulation and may play an important role in mediating certain physiological and pathological functions. METHODS: We investigated the expression levels and distribution patterns of Nob1 in rat cochlea at different developmental stages using reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis, and immunofluorescence microscopy (P0, P3, P7, P14, and P30, n = 11 per age group). RESULTS: The expression of Nob1 was gradually upregulated from Postnatal day (P) 0 to P14 and stabilized at P30. Our results analyzing Nob1 expression at P0 and P3 in the rat cochleae revealed expression in the greater epithelial ridge cells, lesser epithelial ridge cells, and spiral ganglion neurons (SGNs), whereas low levels of Nob1 expression were observed in the stria vascularis cells. During the development of the cochlea, the organ of Corti undergoes dramatic architectural remodeling. Nob1 expression was stably detected in supporting cells and hair cells from P7 to P30, and its expression gradually increased in the SGNs. CONCLUSIONS: Thus, the present study revealed that upregulation of Nob1 might explain the maturation of the cytoarchitecture in the cochlea during the postnatal period, and a complete understanding of its function in the mammalian inner ear may help to develop strategies to resolve auditory hair cell loss.