Inhibition of CISD1 attenuates cisplatin-induced hearing loss in mice via the PI3K and MAPK pathways.

Cisplatin is an effective chemotherapeutic drug for different cancers, but it also causes severe and permanent hearing loss. Oxidative stress and mitochondrial dysfunction in cochlear hair cells (HCs) have been shown to be important in the pathogenesis of cisplatin-induced hearing loss (CIHL). CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) plays a critical role in mitochondrial oxidative capacity and cellular bioenergetics. Targeting CISD1 may improve mitochondrial function in various diseases. However, the role of CISD1 in cisplatin-induced ototoxicity is unclear. Therefore, this study was performed to assess the role of CISD1 in cisplatin-induced ototoxicity. We found that CISD1 expression was significantly increased after cisplatin treatment in both HEI-OC1 cells and cochlear HCs. Moreover, pharmacological inhibition of CISD1 with NL-1 inhibited cell apoptosis and reduced mitochondrial reactive oxygen species accumulation in HEI-OC1 cells and cochlear explants. Inhibition of CISD1 with small interfering RNA in HEI-OC1 cells had similar protective effects. Furthermore, NL-1 protected against CIHL in adult C57 mice, as evaluated by the auditory brainstem response and immunofluorescent staining. Mechanistically, RNA sequencing revealed that NL-1 attenuated CIHL via the PI3K and MAPK pathways. Most importantly, NL-1 did not interfere with the antitumor efficacy of cisplatin. In conclusion, our study revealed that targeting CISD1 with NL-1 reduced reactive oxygen species accumulation, mitochondrial dysfunction, and apoptosis via the PI3K and MAPK pathways in HEI-OC1 cell lines and mouse cochlear explants in vitro, and it protected against CIHL in adult C57 mice. Our study suggests that CISD1 may serve as a novel target for the prevention of CIHL.

Aucubin protects mouse cochlear hair cells from cisplatin-induced ototoxicity via activation of the PI3K/AKT/STAT3 pathway.

Cisplatin is commonly used to treat cancers and is associated with a significant risk of irreversible sensorineural hearing loss. However, no effective preventive strategies are available for cisplatin-induced HL. Therefore, significant efforts have been made to discover new drugs protecting cochlear hair cells from cisplatin-induced damage. We found that a new phytochemical, aucubin, attenuated cisplatin-induced apoptosis, the production of reactive oxygen species, and mitochondrial dysfunction in House Ear Institute Organ of Corti 1 cells and cochlear hair cells. Moreover, aucubin attenuated cisplatin-induced sensorineural hearing loss and hair cells loss in vivo. Furthermore, RNA sequencing analysis revealed that the otoprotective effects of aucubin were mainly mediated by increased STAT3 phosphorylation via the PI3K/AKT pathway. Inhibition of the STAT3 signaling pathway with the inhibitor S3I-201 or siRNA disrupted the protective effects of aucubin on cisplatin-induced apoptosis. In conclusion, we identified an otoprotective effect of aucubin. Therefore, aucubin could be used to prevent cisplatin-induced ototoxicity.

[Research progress on non-surgical treatment of vestibular schwannomas].

At present, the main treatment for vestibular schwannomas is surgery. Considering the risk of multiple complications from surgery and the subjective and objective conditions of patients, a non-surgical treatment modality, namely stereotactic radiotherapy, has gradually been included in the treatment of vestibular schwannomas. Studies have shown that Gamma Knife therapy has a more prominent therapeutic effect on smaller tumors and can alleviate facial nerve disorders caused by space occupying of tumor mass. Cyberknife not only has a better effect on tumor control, but also has an ideal retention rate for patients' auditory function. Proton beam therapy has also been gradually applied to the treatment of vestibular schwannomas, but the effect of treatment remains to be further studied. Drug therapy includes a variety of target inhibitors and anti-angiogenic drugs. At present, drug treatment focuses more on preclinical research. This article reviews the clinical research of various radiotherapy and the progress of drug treatment.

The Spectrum of Vestibular Disorders Presenting With Acute Continuous Vertigo.

Objective: To explore the composition of vestibular disorders presenting with the acute vestibular syndrome (AVS). Methods: We performed a case analysis of 209 AVS patients between January 2016 and December 2020. These patients were grouped into different disorder categories according to the relevant diagnostic criteria. Results: We classified the 209 patients into 14 disorder categories, including 110 cases of vestibular neuritis, 30 of idiopathic sudden sensorineural hearing loss with vertigo, 17 of the first attack of continuous vertigo with migraine, 15 of Ramsay Hunt syndrome, 11 of acute labyrinthitis secondary to chronic otitis media, 8 of vestibular schwannoma, 6 of posterior circulation infarction and/or ischemia, 3 of cerebellar abscess secondary to chronic otitis media, 3 of AVS caused by trauma or surgery, 2 of AVS with down-beating nystagmus, 1 of multiple sclerosis of the medulla oblongata, 1 of epidermoid cyst of the posterior cranial fossa, 1 of a probable acute otolithic lesion, and 1 of AVS without measurable vestibular dysfunction. Conclusion: When a group of disorders present with AVS, characteristic clinical manifestations and imaging help with an accurate diagnosis.

Single-Cell RNA-Seq Reveals Heterogeneity of Cell Communications between Schwann Cells and Fibroblasts within Vestibular Schwannoma Microenvironment.

Vestibular schwannomas (VSs), which develop from Schwann cells (SCs) of the vestibular nerve, are the most prevalent benign tumors of the cerebellopontine angle and internal auditory canal. Despite advances in treatment, the cellular components and mechanisms of VS tumor progression remain unclear. Herein, single-cell RNA-sequencing was performed on clinically surgically isolated VS samples and their cellular composition, including the heterogeneous SC subtypes, was determined. Advanced bioinformatics analysis revealed the associated biological functions, pseudotime trajectory, and transcriptional network of the SC subgroups. A tight intercellular communication between SCs and tumor-associated fibroblasts via integrin and growth factor signaling was observed and the gene expression differences in SCs and fibroblasts were shown to determine the heterogeneity of cellular communication in different individuals. These findings suggest a microenvironmental mechanism underlying the development of VS.

Changes of Vestibular Symptoms in Menière's Disease After Triple Semicircular Canal Occlusion: A Long-Term Follow-Up Study.

BACKGROUND: The clinical efficacy of triple semicircular canal occlusion (TSCO) and vestibular nerve resection (VNS) for patients with Ménière's disease has been unclear. OBJECTIVE: To explore changes in vestibular symptoms after TSCO and its advantages compared to the classical operation of VNS in patients with Menière's disease. METHODS: In total, 36 patients with Menière's disease performed TSCO or VNS at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China from May 2005 to July 2021, and all of them were enrolled in our study. Twelve of them underwent TSCO, 23 underwent VNS, and 1 had both treatments. We compared the demographic parameters, clinical symptoms, and selected test results between the two surgical methods. Ten patients each who underwent TSCO and VNS completed the follow-up. We collected and compared data pertaining to changes in vestibular symptoms. RESULTS: No significant difference in demographic parameters, clinical symptoms, or auditory or vestibular test results was detected between the two groups preoperatively. The TSCO group with vertigo as the main complaint experienced less residual paroxysmal dizziness after surgery than the VNS group (P = 0.020). Also, 57% of the patients in the VNS group had unsteadiness after surgery, while no such problems were reported in the TSCO group (P = 0.025). CONCLUSIONS: Our study shows that TSCO controls vertigo in most Menière's disease patients, and also has the advantage of lower rates of postoperative paroxysmal dizziness and unsteadiness than VNS. Thus, TSCO may be an effective surgery for refractory Menière's disease.

Trehalose protects against cisplatin-induced cochlear hair cell damage by activating TFEB-mediated autophagy.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors, but its side effects limit its application. Ototoxicity, a major adverse effect of cisplatin, causes irreversible sensorineural hearing loss. Unfortunately, there are no effective approaches to protect against this damage. Autophagy has been shown to exert beneficial effects in various diseases models. However, the role of autophagy in cisplatin-induced ototoxicity has been not well elucidated. In this study, we aimed to investigate whether the novel autophagy activator trehalose could prevent cisplatin-induced damage in the auditory cell line HEI-OC1 and mouse cochlear explants and to further explore its mechanisms. Our data demonstrated that trehalose alleviated cisplatin-induced hair cell (HC) damage by inhibiting apoptosis, attenuating oxidative stress and rescuing mitochondrial dysfunction. Additionally, trehalose significantly enhanced autophagy levels in HCs, and inhibiting autophagy with 3-methyladenine (3-MA) abolished these protective effects. Mechanistically, we showed that the effect of trehalose was attributed to increased nuclear translocation of transcription factor EB (TFEB), and this effect could be mimicked by TFEB overexpression and inhibited by TFEB gene silencing or treatment with cyclosporin A (CsA), a calcineurin inhibitor. Taken together, our findings suggest that trehalose and autophagy play a role in protecting against cisplatin-induced ototoxicity and that pharmacological enhancement of TFEB-mediated autophagy is a potential treatment for cisplatin-induced damage in cochlear HCs and HEI-OC1 cells.

Essential Role of Sptan1 in Cochlear Hair Cell Morphology and Function Via Focal Adhesion Signaling.

Hearing loss is the most common human sensory deficit. Hearing relies on stereocilia, inserted into the cuticular plate of hair cells (HCs), where they play an important role in the perception of sound and its transmission. Although numerous genes have been associated with hearing loss, the function of many hair cell genes has yet to be elucidated. Herein, we focused on nonerythroid spectrin αII (SPTAN1), abundant in the cuticular plate, surrounding the rootlets of stereocilia and along the plasma membrane. Interestingly, mice with HC-specific Sptan1 knockout exhibited rapid deafness, abnormal formation of stereocilia and cuticular plates, and loss of HCs from middle and apical turns of the cochlea during early postnatal stages. Additionally, Sptan1 deficiency led to the decreased spreading of House Ear Institute-Organ of Corti 1 cells, and induced abnormal formation of focal adhesions and integrin signaling in mouse HCs. Altogether, our findings highlight SPTAN1 as a critical molecule for HC stereocilia morphology and auditory function via regulation of focal adhesion signaling.

Contribution of Audiogram Classification in Evaluating Vestibular Dysfunction in Sudden Sensorineural Hearing Loss With Vertigo.

Object: We aimed to identify the relationship between vertigo symptoms and the involvement of vestibular dysfunction in sudden sensorineural hearing loss (SSNHL) and the contribution of audiogram classification. Methods: A total of 50 patients with unilateral SSNHL were retrospectively divided into the vertigo group and non-vertigo group depending on the presence of vertigo. The involved vestibular end organs (VEOs) were verified by a battery of vestibular function tests including video head impulse test (vHIT), cervical vestibular-evoked myogenic potential (cVEMP), and ocular VEMP (oVEMP). The correlations of audiogram configurations, initial pure-tone average (PTA), number of involved VEOs, prognosis (complete recovery rate), and vestibular functions were analyzed between the two groups. Additionally, the vestibular functions in a subgroup of profound SSNHL patients were further compared within groups with or without vertigo. Results: Significant differences in the initial audiogram configurations (p = 0.033) and the abnormal rates of the posterior semicircular canal (PSC) (p = 0.035) and oVEMP (p = 0.046) were found between the two groups. The number of involved VEOs was related to the initial PTA in the vertigo group (p = 0.002, r = 0.541) and non-vertigo group (p = 0.042, r = 0.446). The prognosis was related to the abnormal rate of cVEMP and the number of involved VEOs in both vertigo group (p = 0.008, r = 0.482; p = 0.039, r = 0.385, respectively) and non-vertigo group (p = 0.016, r = 0.520; p = 0.022, r = 0.495, respectively), and it was especially related to the audiogram configurations in the vertigo group (p < 0.001, r = 0.692). However, after classification by audiogram configurations, there was no statistical difference in the abnormal rates of all vestibular function tests or the number of involved VEOs between the profound SSNHL patients with or without vertigo. Conclusion: The relationship between the involvement of vestibular dysfunction and vertigo symptoms in patients with SSNHL was significantly different before and after audiogram classification. When evaluating the vestibular dysfunction in SSNHL patients, more attention should be paid to the audiogram configuration.

Steroid Administration Approach for Idiopathic Sudden Sensorineural Hearing Loss: A National Survey in China.

OBJECTIVE: To optimize a protocol for the steroid administration approach for idiopathic sudden sensorineural hearing loss (ISSNHL) in China. METHODS: A questionnaire was distributed to otolaryngologists. The data on demographics, indications for first-line and salvage treatment, such as intratympanic administration of steroids (ITS) and postauricular steroids (PAS), and procedures were analyzed. RESULTS: 74 respondents used oral steroids, 112 used intravenous injections, 10 used ITS and 6 used PAS as a monotherapy for first-line treatment, and 135 used ITS or PAS in conjunction with oral or intravenous injection as a first-line treatment. Of the 249 respondents who used ITS, 97.19% adopted it as salvage therapy. The most commonly used steroid was 0.5 ml dexamethasone at 5 mg/ml and the most common side effect was pain. Of the 174 respondents who used PAS, 94.25% used it as salvage therapy. The most commonly used steroid was 0.5 ml methylprednisolone mixed with 0.5 ml lidocaine. CONCLUSIONS: The obtained data suggested that intravenous injection of steroids was the most popular treatment for ISSNHL and that ITS or PAS were used as a salvage treatment in China.

Characteristics of positional nystagmus in patients with horizontal canal canalolithiasis or cupulopathy.

OBJECTIVES: Positional nystagmus can be related to various kinds of disorders. The current study aims to compare the direction-changing horizontal positional nystagmus (DCPN) characteristics in horizontal canal canalolithiasis (HC-canalolithiasis), heavy cupula of the horizontal canal (HC-Hcu), and light cupula of the horizontal canal (HC-Lcu), especially the temporal patterns of positional nystagmus in three disorders. METHODS: 52 patients (22 males, 30 females; mean age, 49.6 years) presenting with geotropic or apogeotropic DCPN were enrolled, and they were divided into HC-canalolithiasis, HC-Hcu, or HC-Lcu groups according their nystagmus characteristics. We compared their latency, time constant, peak slow-phase velocity (SPV), time to reach peak SPV intensity (Tpeak), and time to decay to half-peak intensity (T1/2peak). RESULTS: The time to reach peak SPV did not differ significantly between the HC-Hcu (23.1 ± 8.6 s) and HC-Lcu (24.4 ± 9.9 s) groups (p = 0.733), but was significantly longer than that of the HC-canalolithiasis group (5.4 ± 3.5 s; p ≤ 0.001). The peak intensity did not differ among the canalolithiasis (36.4 ± 20.6º/s), HC-Hcu (30.1 ± 23.6º/s), and HC-Lcu (21.4 ± 12.7º/s) groups (p = 0.133). The onset latency also had no statistical difference among three groups (p = 0.200). The nystagmus patterns of HC-Lcu and HC-Hcu groups were similar, including latency, peak SPV intensity, Tpeak, T1/2peak, and SPV in 20 s, 40 s, 60 s, 80 s. CONCLUSIONS: The nystagmus characteristics of HC-Hcu and HC-Lcu are similar, except for the fact that movement was in opposite directions, suggesting that HC-Hcu and HC-Lcu may result from a similar pathophysiological mechanism (cupulopathy) differing from that underlying canalolithiasis.

Benign paroxysmal positional vertigo in children.

OBJECTIVE: To describe the clinical features of benign paroxysmal positional vertigo (BPPV) in children. DESIGN: A retrospective study. SETTING: Six children diagnosed with BPPV between March 2014 and March 2015 were retrospectively evaluated. BPPV was diagnosed using the Dix-Hallpike and supine roll tests and treated with either the modified Epley particle repositioning procedure or Lempert or Gufoni manoeuvre. Follow-up was performed at 1-week intervals until vertigo and nystagmus disappeared during positional testing. PARTICIPANTS: A total of six children were followed up for a period of 10-22 months. MAIN OUTCOME MEASURES: Clinical features such as history, nystagmus and symptoms of vertigo, dizziness and nausea. RESULTS: Six children were diagnosed with BPPV using positional testing and treated with the modified Epley or Lempert/Gufoni particle repositioning procedures. Four children were diagnosed with posterior canal BPPV, while the remaining two were diagnosed with horizontal canal BPPV. One girl reported a history of head trauma, one girl had a family history of vertigo, and one boy reported hearing loss in the same ear as that affected by BPPV. Overall, 83.33% of children (5/6) were completely relieved of vertigo following one treatment session. The remaining child was asymptomatic after two sessions. No child reported relapse of vertigo during the follow-up period. CONCLUSIONS: BPPV can be diagnosed accurately by taking a detailed medical history and by use of positional testing. BPPV in children can be successfully identified and treated.

Use of the Bárány Society criteria to diagnose benign paroxysmal positional vertigo.

BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is the most common vestibular disorder affecting about 20% of dizzy patients. Early diagnosis and treatment can improve the quality of life for patients. OBJECTIVE: We reviewed the classifications of different subtypes of benign paroxysmal positional vertigo and the problems we encountered using the diagnostic criteria of the Bárány Society. METHODS: Both the Dix-Hallpike maneuver and supine roll test were performed on 568 patients, and diagnoses were made based on patient history and the type of provoked nystagmus (if any). Next, the numbers of patients with each subtype and other parameters, including age and sex, were analyzed. RESULTS: Posterior semicircular canal BPPV (pc-BPPV) accounted for the largest proportion, followed by horizontal semicircular canal BPPV (hc-BPPV). Both anterior canal BPPV and multiple canal lithiasis BPPV were rare, and no patient was diagnosed with cupulolithiasis of the posterior canal. CONCLUSIONS: pc-BPPV, hc-BPPV, and cupulolithiasis of the horizontal canal (hc-BPPV-cu) were the three major subtypes that could be definitively diagnosed, whereas the diagnoses of possible benign paroxysmal positional vertigo (pBPPV) and probable benign paroxysmal positional vertigo [spontaneously resolved] (pBPPVsr) require further investigation, with special attention being paid to appropriate differentiation and repositioning maneuvers.