Relationship of Hearing Loss to Parkinson's Disease, Dementia, and APOE Genotype in Adults.

Background: Hearing loss has been recognized as a risk factor for dementia and non-motor features of Parkinson's disease (PD). The apolipoprotein E (APOE) protein contributes to maintenance and repair of neuronal cell membranes, causing age-related disorders. This study aimed to analyze the impact of hearing loss on cognitive impairment, PD severity, and APOE gene expression in these patients. Methods: A total of 72 out-patients diagnosed with either PD or hearing loss were enrolled in this study. The hearing assessment included pure-tone audiometry, speech reception thresholds, and speech discrimination ability. Dementia was assessed by filling out the Clinical Dementia Rating and Mini-Mental State Examination questionnaires. The severity of PD was assessed using the Modified Hoehn and Yahr scale. Blood samples were tested for the gene expression of APOE. Results: Out of the 72 cases, there were 44 males and 28 females, with an average age of 64.4 ± 9.1 years. A total of 41 out of 72 cases had dementia and had a worse hearing threshold than those without dementia (47.1 ± 24.4 vs. 31.7 ± 22.1 dB, p = 0.006). A total of 58 patients were diagnosed with PD, with 14 of them classified as having severe symptoms (Modified Hoehn and Yahr scale > 2). Patients with severe PD were found to have a worse hearing threshold (49.6 ± 28.3 vs. 30.3 ± 17.8 dB, p = 0.028) and higher prevalence of dementia (12/14 vs. 18/44, p = 0.006). Among 10 individuals with the APOE ε4 gene, the prevalence of dementia was higher than those without the ε4 allele (9/10 vs. 32/62, p = 0.036). Conclusions: Hearing loss is common in severe PD and in dementia patients. Severe PD has a negative impact on the hearing threshold and cognitive dysfunction. Patients with APOE ε4 have a higher prevalence of dementia.

Functional and Molecular Markers for Hearing Loss and Vertigo Attacks in Meniere's Disease.

Meniere's disease (MD) is one of the most complicated diseases in the otologic clinic. The complexity of MD is partially due to the multifactorial etiological mechanisms and the heterogenous symptoms, including episodic vertigo, hearing loss, aural fullness and tinnitus. As a result, the diagnosis of MD and differentiating MD from other diseases with similar symptoms, such as vestibular migraine (VM), is challenging. In addition, it is difficult to predict the progression of hearing loss and the frequency of vertigo attacks. Detailed studies have revealed that functional markers, such as pure tone audiometry (PTA), electrocochleography (ECochG), vestibular evoked myogenic potential (VEMP), caloric test, video head impulse test (vHIT) and magnetic resonance imaging (MRI) could help to evaluate MD with different hearing levels and frequency of vertigo attacks. Investigations of molecular markers such as autoimmunity, inflammation, protein signatures, vasopressin and circadian clock genes in MD are still underway. This review will summarize these functional and molecular markers, address how these markers are associated with hearing loss and vertigo attacks in MD, and analyze the results of the markers between MD and VM.

Hearing Features and Cochlear Implantation Outcomes in Patients With Pathogenic MYO15A Variants: a Multicenter Observational Study.

OBJECTIVES: Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants. DESIGN: This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes. RESULTS: At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation. CONCLUSIONS: The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention.

Constant Light Dysregulates Cochlear Circadian Clock and Exacerbates Noise-Induced Hearing Loss.

Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes Per1, Per2, Rev-erbα, Bmal1, and Clock in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light-dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system.

Ethanolic Extracts of Pluchea indica Induce Apoptosis and Antiproliferation Effects in Human Nasopharyngeal Carcinoma Cells.

Pluchea indica is used in traditional medicine for the treatment of lumbago, ulcer, tuberculosis and inflammation. The anti-cancer activities and the underlying molecular mechanisms of the ethanolic extracts of P. indica root (PIRE) were characterized in the present study. PIRE strongly inhibited the viability of the human nasopharyngeal carcinoma cells (NPC-TW 01 and NPC-TW 04) in a time- and dose-dependent manner. Migration of cancer cells was also suppressed by PIRE. In addition, PIRE significantly increased the occurrence of the cells in sub-G1 phase and the extent of DNA fragmentation in a dose-dependent manner, which indicates that PIRE significantly increased apoptosis in NPC cells. The apoptotic process triggered by PIRE involved up-regulation of pro-apoptotic Bax protein and down-regulation of anti-apoptotic Bcl-2 protein, consequently increasing the ratios of Bax/Bcl-2 protein levels. Moreover, the p53 protein was up-regulated by PIRE in a concentration-dependent manner. Therefore, PIRE could induce the apoptosis-signaling pathway in NPC cells by activation of p53 and by regulation of apoptosis-related proteins.

Variability in Inner Ear Morphology Among a Family With Pendred Syndrome Due to a SLC26A4 Gene Variant.

OBJECTIVES: Pendred syndrome, an autosomal recessive disorder, is often associated with pathogenic variants of the SLC26A4 gene that encodes the pendrin protein. Given its autosomal recessive inheritance, tracing the family history and screening siblings become crucial once a diagnosis of Pendred syndrome is confirmed. This case report aims to underscore the variability in inner ear morphology within a family diagnosed with Pendred syndrome, all carrying the same SLC26A4 gene mutation. METHODS: A chart review and a review of the literature. RESULTS: We present a family of 4, all of whom possess sensorineural hearing loss due to the same homozygous SLC26A4 variant c.919-2A>G. Intriguingly, clinical manifestations, especially inner ear deformities, displayed variability among family members. Notably, 1 family member exhibited a normal cochleovestibular structure morphology, which was rarely reported in the literature. CONCLUSIONS: This report highlights the significance of genetic testing and familial consultation when a proband exhibits typical Pendred syndrome symptoms. It also underscores that the inner ear morphology can exhibit variability among family members, even with the same homozygous SLC26A4 variant.

Association of Autonomic Symptom Burden with Sudden Sensorineural Hearing Loss.

OBJECTIVE: To investigate the autonomic symptom burden in patients with sudden sensorineural hearing loss (SSNHL) and its association with the severity and prognosis. STUDY DESIGN: Observational prospective study. SETTING: Tertiary academic medical center. METHODS: Patients diagnosed with SSNHL at a single medical center completed the COMPASS 31 questionnaire, which assesses dysautonomia across 6 domains with 31 questions. A total COMPASS 31 score was calculated by summing the scores from each weighted domain. The treatment outcome was evaluated by the percentage of recovery, calculated as the hearing gain in pure tone average (PTA) after treatment divided by the pretreatment PTA difference between the 2 ears. We defined poor recovery as a percentage of recovery <80%. RESULTS: A total of 63 SSNHL patients were included. The mean COMPASS 31 score was 23.4 (SD 14). Patients with poor recovery had significantly higher COMPASS 31 scores than those with good recovery (mean 26.4 [SD 14.4] vs 16.9 [SD 10.4]; 95% confidence interval [CI] 2-17). There was a negative association between COMPASS 31 score and both hearing gain (r = -.323, 95% CI -0.082 to -0.529) and percentage of recovery (r = -.365, 95% CI -0.129 to -0.562). Multivariate analyses of independent factors indicate that patients with higher COMPASS 31 scores had a greater risk for poor recovery (OR 1.06 [95% CI 1.003-1.117]). CONCLUSION: This study highlights the association between autonomic symptom burden and poor hearing outcomes in SSNHL patients. The findings underscore the importance of evaluating autonomic function during the treatment of SSNHL.

Human papillomavirus infection and papillary squamous cell carcinoma in the head and neck region.

Papillary squamous cell carcinoma (PSCC) is a rare variant of SCC in the head and neck region. The role of human papillomavirus (HPV) infection in PSCC is still unclear. We retrospectively reviewed 11 PSCCs in our institute over a 21-year period and compared the HPV status of PSCCs with 26 squamous cell papillomas (SCPs). Polymerase chain reaction (PCR) amplification to detect HPV DNA and in situ hybridization (ISH) were performed to analyze the relationship between the papillary lesions and HPV infection. Immunohistochemical (IHC) staining for p16 protein expression was used to analyze the PSCC specimens. Nine of 11 (82 %), eight of 11 (73 %), and eight of 11 (73 %) PSCC samples were found to be HPV positive by PCR, ISH, and IHC staining for p16 protein expression, respectively. PSCC had a significantly higher rate of HPV infection than SCP by PCR (p = 0.002) and ISH (p = 0.001) analysis. This study presents different HPV status in two papillary neoplasms and may help to clarify the unique morphological and biological characteristics of head and neck PSCC.

A Rare Combination of Acquired Lymphangioma of the External Auditory Canal and Cholesteatoma in the Middle Ear Cavity.

Lymphangioma (LM) is a rare but benign tumor derived from lymphatic malformation, which is extremely rare in the auditory canal or middle ear cavity. We presented a case of acquired lymphangioma of the external auditory canal combined with cholesteatoma in the middle ear cavity. To our best knowledge, this is the first case of combined lesions of lymphangioma and cholesteatoma in English literature.

Evaluation of Sinonasal Outcome Test (SNOT-22) Domains in the Assessment of the Quality of Life in Patients with Nasopharyngeal Carcinoma.

Background: Few instruments are available for assessing the otorhinologic-related quality of life (QOL) in nasopharyngeal carcinoma (NPC) patients. Therefore, we evaluated whether the 22-item Sinonasal Outcome Test (SNOT-22) could be applied to these patients. Methods: Patients diagnosed with NPC, who had been treated with standard protocol and followed up in our institute between 2019 and 2022, were invited to join the cross-sectional study during their clinic visits. All participants completed the SNOT-22 and Eustachian Tube Dysfunction Questionnaire-7 once they were recruited. Confirmatory factor analysis (CFA) was performed to decide the most suitable model for the underlying SNOT-22 subdomains, along with various validity and reliability tests. Results: We identified a total of 275 patients, with 84 (30.5%) women and 191 (69.5%) men. The mean age was 54.1 years (standard deviation: 11.2). Among these patients, 171 (62.1%) were in late stages, and 260 (94.5%) received chemoradiotherapy as treatment. The median interval between primary RT treatment and questionnaire completion was 50 months (interquartile range: 29-93). CFA supported a five-factor model for the SNOT-22 for NPC patients, including nasal, ear/facial, sleep, function, and emotion domains. The internal consistency and test-retest reliability of the SNOT-22 domain score were good. In addition, known-group validity was good for the SNOT-22 total score and domain scores according to the disease recurrence status. Conclusion: Psychometric analyses supported the reliability and validity of a five-domain SNOT-22 for assessing otorhinologic-related QOL in NPC patients.

FLJ10540 is associated with tumor progression in nasopharyngeal carcinomas and contributes to nasopharyngeal cell proliferation, and metastasis via osteopontin/CD44 pathway.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is well-known for its highly metastatic characteristics, but little is known of its molecular mechanisms. New biomarkers that predict clinical outcome, in particular the ability of the primary tumor to develop metastatic tumors are urgently needed. The aim of this study is to investigate the role of FLJ10540 in human NPC development. METHODS: A bioinformatics approach was used to explore the potentially important regulatory genes involved in the growth/metastasis control of NPC. FLJ10540 was chosen for this study. Two co-expression strategies from NPC microarray were employed to identify the relationship between FLJ10540 and osteopontin. Quantitative-RT-PCR, immunoblotting, and immunohistochemistry analysis were used to investigate the mRNA and protein expression profiles of FLJ10540 and osteopontin in the normal and NPC tissues to confirm microarray results. TW01 and Hone1 NPC cells with overexpression FLJ10540 or siRNA to repress endogenous FLJ10540 were generated by stable transfection to further elucidate the molecular mechanisms of FLJ10540-elicited cell growth and metastasis under osteopontin stimulation. RESULTS: We found that osteopontin expression exhibited a positive correlation with FLJ10540 in NPC microarray. We also demonstrated comprehensively that FLJ10540 and osteopontin were not only overexpressed in NPC specimens, but also significantly correlated with advanced tumor and lymph node-metastasis stages, and had a poor 5-year survival rate, respectively. Stimulation of NPC parental cells with osteopontin results in an increase in FLJ10540 mRNA and protein expressions. Functionally, FLJ10540 transfectant alone, or stimulated with osteopontin, exhibited fast growth and increased metastasis as compared to vehicle control with or without osteopontin stimulation. Conversely, knockdown of FLJ10540 by siRNA results in the suppression of NPC cell growth and motility. Treatment with anti-CD44 antibodies in NPC parental cells not only resulted in a decrease of FLJ10540 protein, but also affected the abilities of FLJ10540-elicited cell growth and motility in osteopontin stimulated-NPC cells. CONCLUSIONS: These findings suggest that FLJ10540 may be critical regulator of disease progression in NPC, and the underlying mechanism may involve in the osteopontin/CD44 pathway.

Comparison of Mandarin tone and speech perception between advanced combination encoder and continuous interleaved sampling speech-processing strategies in children.

OBJECTIVE: This study was performed to compare cochlear implant (CI) users' performance in Mandarin speech and tone perception between 2 types of speech-processing strategies-advanced combination encoder (ACE) and continuous interleaved sampling (CIS)-under quiet and noisy conditions. METHODS: This study involved 10 congenitally deaf children (age range, 5.7-15.3 years; mean, 9.2 years) who received the Nucleus 24-channel CI system cochlear device (CI24R; Cochlear Ltd, Lane Cove NSW, Australia). The subjects used ACE since switching on their CI devices. Speech and tone perception tests were administered under quiet and noisy (+5 dB signal-to-noise ratio) conditions with ACE and CIS strategies 20 minutes and 2 weeks apart. RESULTS: Regardless of the strategy used, subjects showed significantly higher scores in speech perception than in tone recognition. Under noisy conditions, subjects had significantly higher tone identification scores with the CIS than the ACE strategy (P = .038). There was no significant difference in speech identification score between the strategies. Subjects showed significant higher tone identification and speech perception scores under quiet than noisy (+5 dB signal-to-noise ratio) conditions. Subjectively, 6 subjects preferred the ACE strategy, and the remaining 4 preferred the CIS strategy. The strategy preference of the subjects was related to speech perception performance rather than tone identification. A significant correlation was observed between tone identification and speech recognition, regardless of whether speech was evaluated by consonants (r = 0.669, P < .001), vowels (r = 0.426, P = .001), or sentences (r = 0.294, P = .023). CONCLUSION: There are only 4 patterns of tone in Mandarin, which is far fewer than the number of speech sounds. However, tone identification is poorer than speech perception. The CIS speech-processing strategy may improve tone identification under noisy conditions. Before improved speech strategies to code acoustic characteristics of tone can be developed, it would be worthwhile to try both CIS and ACE for CI users and to select the most suitable speech-processing strategy according to the subjective preference and objective performance.

Expression of circadian clock genes in leukocytes of patients with Meniere's disease.

Objectives: The underlying etiology of Meniere's disease (MD) is not completely clear, but the precipitated triggers may alter the circadian clock in patients with MD. This study aims to survey the expression of circadian clock genes in peripheral blood (PB) leukocytes of MD patients. Methods: We investigated the expression of nine circadian clock genes in the PB leukocytes of patients with MD and normal controls using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Results: We observed significantly lower expression of PER1 gene and higher expression of CLOCK gene in MD patients than those in normal controls (p < 0.05). PER1 did not associate with the degree of dizziness handicap in the patients with MD, but a lower expression of PER1 was significantly correlated with higher pure tone average (PTA) and speech reception threshold of the affected ear (p < 0.05). Patients with PTA > 30 dB had significantly lower PER1 expression than those with PTA ≤30 dB in the affected ear (p < 0.05). Our qRT-PCR result was validated by fewer positively stained leukocytes for PER1 protein in the MD patients using the immunocytochemical study. Conclusion: Our study implies the alteration of the circadian clock in patients with MD. In particular, the downregulation of PER1 correlated with the degree of hearing loss in the affected ear. PER1 in PB leukocytes may be a potential marker for the progression of hearing loss in MD.

Clinical significance of the neural response telemetric thresholds in Mandarin-speaking cochlear implant patients.

BACKGROUND: It is unclear whether neural response telemetric (NRT) thresholds are related to lexical tonal language performance after cochlear implants (CIs). We explored the factors associated with changes in NRT thresholds and postoperative performance of CI patients. METHODS: Patients receiving nucleus 24 CIs in our hospital from November 2010 were enrolled. We analyzed medical records and NRT thresholds. Mandarin speech and tone identification were measured in CI patients for at least 1 year postoperatively. RESULTS: Seventy-two patients with an average age of 16.1 years received CIs. The postoperative NRT threshold was lower than the intraoperative threshold. The NRT threshold was higher in the early- than the late-activation group (mapping within 21 vs >21 days postoperatively, respectively). Lower intraoperative NRT thresholds and curved electrodes were significantly associated with lower postoperative NRT thresholds. In multiple linear regression analysis, only postoperative NRT thresholds significantly affected speech and tone perception, including word recognition scores, tone perception, and comprehension of easy and difficult sentences (all p < 0.05). Other clinical parameters, including age, gender, implant type, and activation timing, were not significantly associated with clinical tone or speech outcomes. CONCLUSION: Curved electrode arrays were associated with lower postoperative NRT thresholds. A lower postoperative NRT threshold might predict better performance of Mandarin-speaking CI patients. Future studies should evaluate factors that affect both postoperative NRT thresholds and lexical tonal language performance.

Comparison of the Functional Success of Fat Myringoplasty and Perifascial Areolar Tympanoplasty in Transcanal Endoscopic Ear Surgery.

OBJECTIVES: We compared the functional outcomes of fat myringoplasty and areolar tympanoplasty through a small postauricular incision in patients who underwent transcanal endoscopic ear surgery (TEES). METHODS: The study included patients who underwent myringoplasty or type I tympanoplasty using TEES in our Department of Otolaryngology between April 2016 and May 2019. The patients were divided into 2 groups according to the type of graft material used, which was selected based on the available amount of subcutaneous fat and the surgeon's experience. RESULTS: In total, 63 patients received fat tissue grafts (group A) and 77 received areolar tissue grafts (group B). The median operative time was significantly longer in group B (132 minutes) than in group A (65 minutes); perforations were significantly larger in group B than in group A (61.0% vs 29.7% of the eardrum surface). The postoperative air conduction threshold, air-bone gap, and speech reception threshold values were significantly lower than the preoperative values in both groups. The graft success rate did not significantly differ between groups A (96.8%, 61/63) and B (96.1%, 74/77). In group A, the perforation was > 35% of the eardrum surface in 27.0% (17/63) of the patients; the graft success rate was 100% (17/17). In the remaining 46 patients (perforation > 35%), the graft success rate was 95.7% (44/46); this difference was not statistically significant. CONCLUSIONS: Transcanal endoscopic ear surgery increases the usefulness of fat myringoplasty for the repair of perforations > 35% of the eardrum surface. Postauricular fatty and areolar tissues are suitable for this simple and rapid technique, which yields excellent outcomes.

Aberrant miR-874-3p/leptin/EGFR/c-Myc signaling contributes to nasopharyngeal carcinoma pathogenesis.

BACKGROUND: Leptin is important in physiological and pathological functions in various cancers, however, the significance and mechanisms of leptin in nasopharyngeal carcinoma remain ambiguous. METHODS: Leptin expression was analyzed by QPCR, immunohistochemistry, Western blotting, and TCGA database. The impact of gain- or loss-of-function of leptin were determined by MTT, colony formation, wound healing, and Transwell assays in NPC cells, and by a xenograft tumor model. Leptin-modulated glucose consumption and lactate production were assessed by ELISA. Furthermore, leptin-regulated signaling pathways were examined by QPCR and Western blotting assays. The immunoprecipitation assay was conducted to determine interaction between leptin and EGFR. In addition, miR-874-3p-regulated leptin expression was evaluated using bioinformatics, QPCR, luciferase assay, AGO2-RIP assay, and Western blotting. RESULTS: In this study, we found that leptin was highly expressed in the sera and tumor tissues of patients with NPC, and elevated leptin expression was associated with advanced clinical features and poor prognosis. Functional assays demonstrated that leptin remarkably promoted NPC cell growth, motility, and glycolysis in vitro and in vivo. Mechanistically, leptin associated with EGFR, resulting in enhanced cell growth through the regulation of cell-cycle related markers, glycolysis-related genes, and EGFR/AKT/c-Myc signaling. Moreover, leptin potentiated the invasive capacity of NPC cells by promoting EMT. We further explored that miR-874-3p influenced leptin-mediated NPC progression. Overexpression of miR-874-3p prevented cell growth, motility, glucose consumption, and lactate production in NPC cells, whereas miR-874-3p inhibition had the opposite effects. AGO-RIP assays confirmed that Argonaute 2 (AGO2), a protein associated with miR-874-3p, regulated leptin expression in NPC cells. The rescue assays indicated that inhibition of leptin suppressed the effects of miR-874-3p inhibitor. In clinical specimens, miR-874-3p was negatively correlated with leptin. CONCLUSIONS: Leptin may serve as a novel prognostic factor and potential therapeutic target for patients with NPC. In addition, a newly discovered regulatory axis of leptin/EGFR/AKT/c-Myc can provide a novel therapeutic strategy for NPC.

Applicability of Oculomotor Tests for Predicting Central Vestibular Disorder Using Principal Component Analysis.

The videonystagmography oculomotor test battery is considered useful method for diagnosing vertigo. However, its role in diagnosing central vestibular disorder has not been clarified due to variations in interpretation. Patients (n = 103) with vertigo or dizziness symptoms undergoing the oculomotor tests and brain MRI within 1 month were analyzed. Two otology specialists retrospectively interpreted the oculomotor tests, and three neurology and neuroradiology specialists determined whether central lesions were present on brain MRI. Multivariable logistic regression analysis was performed to determine the factors contributing to discordant interpretation between oculomotor tests and brain MRI. Oculomotor tests predicting central lesions were assessed using principal component analysis. The intra- and inter-rater reliability in oculomotor test interpretation was moderate to good. Age > 60 years and multiple comorbidities were significant predictors of a discordant interpretation between MRI and oculomotor tests. Positive neurological symptoms and a higher oculomotor index (according to saccade (vertical axis), smooth pursuit (horizontal axis), and gaze-evoked nystagmus (horizontal/vertical axes) tests) significantly predicted central vestibular disorder in vertigo patients. Caution is required when interpreting the results of the oculomotor test battery for diagnosis of central lesions in older patients, as well as in those with multiple comorbidities.

2,3,4',5­Tetrahydroxystilbene­2­O­ß­D­glucoside ameliorates gentamicin­induced ototoxicity by modulating autophagy via Sesn2/AMPK/mTOR signaling.

Gentamicin is an important aminoglycoside antibiotic used in the treatment of gram­negative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5­tetrahydroxystilbene­2­O­ß­D-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC­2. MTT assay demonstrated that gentamicin reduced UB/OC­2 cell viability and western blotting showed that gentamicin upregulated autophagy­related proteins, such as Beclin, autophagy related 5 and LC3­II. THSG significantly attenuated gentamicin­induced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagy­related proteins. Reverse­transcription­quantitative (RT­q) PCR and western blotting showed that THSG against gentamicin­induced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMP­activated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicin­induced ototoxicity in UB/OC­2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.

Fibulin-3 is associated with tumour progression and a poor prognosis in nasopharyngeal carcinomas and inhibits cell migration and invasion via suppressed AKT activity.

Nasopharyngeal carcinoma (NPC) is known for its highly metastatic character. Recent advances in diagnosis and treatment have not improved the high mortality rate that is attributable to early metastasis. Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear. We demonstrate comprehensively that fibulin-3 is down-regulated in NPC. Loss of fibulin-3 expression is significantly correlated with advanced tumour and lymph node-metastasis stages, and indicates a poor 5-year survival rate. Functionally, fibulin-3 has the ability to suppress cell migration and invasion in NPC cancer cells by decreasing the activity of phospho-AKT. Conversely, its depletion by fibulin-3-mediated siRNAs may elevate phospho-AKT activity and significantly enhance the ability of NPC cancer cells to migrate and invade. Consistent with this negative association between fibulin-3 and phospho-AKT, their expression levels are inversely correlated in NPC specimens by immunohistochemical analysis. Thus, lower fibulin-3 expression is an important indicator of poor survival. It may also contribute to the development of new therapeutic strategies to block the PI3K/AKT pathway in NPC cancer cells.

Systemic toll-like receptor 9 agonist CpG oligodeoxynucleotides exacerbates aminoglycoside ototoxicity.

The Toll-like receptor (TLR) signaling pathway is the key regulator of the innate immune system in response to systemic infection. Several studies have reported that the systemic TLR4 agonist lipopolysaccharide exacerbates aminoglycoside ototoxicity, but the influence of virus-associated TLR7 and TLR9 signaling cascades on the cochlea is unclear. The present study aimed to investigate the auditory effects of systemic TLR7 and TLR9 agonists during chronic kanamycin treatment. CBA/CaJ mice received the TLR7 agonist gardiquimod or TLR9 agonist CpG oligodeoxynucleotides (ODN) one day before kanamycin injection and on the 5th and 10th days during a 14-day course of kanamycin treatment. We observed that systemic gardiquimod or CpG ODN alone did not affect the baseline auditory brainstem response (ABR) threshold. Three weeks after kanamycin treatment, gardiquimod did not significantly change ABR threshold shifts, whereas CpG ODN significantly increased kanamycin-induced ABR threshold shifts. Furthermore, outer hair cell (OHC) evaluation revealed that CpG ODN reduced distortion product otoacoustic emission amplitudes and increased kanamycin-induced OHC loss. CpG ODN significantly elevated cochlear Irf-7, Tnf-α, Il-1, and Il-6 transcript levels. In addition, an increased number of Iba-1+ cells, which represented activated macrophages, was observed in the cochlea treated with CpG ODN. Our results indicated that systemic CpG ODN exacerbated kanamycin-induced ototoxicity and increased cochlear inflammation. This study implies that patients with underlying virus infection may experience more severe aminoglycoside-induced hearing loss if it occurs.