Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Involvement of NLRP3-inflammasome pathway in noise-induced hearing loss

The inflammasome is a multiprotein oligomer in the cell cytoplasm and is part of the innate immune system.It plays a crucial role in the pathological process of noise-induced hearing loss(NIHL).However,the mechanisms of NLR family pyrin domain containing 3(NLRP3)inflammasome activation in NIHL have not been clearly demonstrated.In this study,miniature pigs were exposed to white noise at 120 dB(A)and auditory brainstem response measurements were used to measure their hearing function.Immunofluorescence staining,confocal laser scanning microscopy,western blot assay,and quantitative reverse transcription-polymerase chain reaction were used to analyze inflammasome-related protein distribution and expression.NLRP3,interleukin-1β,interleukin-18,and cleaved-caspase-1 were highly expressed in the cochlea after 120 dB(A)white noise exposure.Our findings suggest that NLRP3-inflammasomes in the cochlea may be activated after acoustic trauma,which may be an important mechanism of noise-induced hearing loss.

Otolithic organ function in patients with profound sensorineural hearing loss

Profound sensorineural hearing loss (PSHL) is not uncommonly encountered in otology. In clinics, there is a high incidence of otolithic damage in patients with PSHL, but relevant reports are few. Sharing a continuous membranous structure and similar receptor cell ultrastructures, the cochlea and vestibule may be susceptible to the same harmful factors. Disorders of the inner ear may result in a variety of manifestations, including vertigo, spatial disorientation, blurred vision, impaired articulation, and hearing impairment. Considering the diversity of clinical symptoms associated with PSHL with otolithic dysfunction, it may be frequently misdiagnosed, and objective means of testing the function of otolithic organs should be recommended for hearing-impaired patients. Vestibular-evoked myogenic potentials (VEMPs) via air-conducted sound are of great importance for the diagnosis of otolithic function. Hearing devices such as cochlear implants are commonly accepted treatments for PSHL, and early identification and treatment of vestibular disorders may increase the success rate of cochlear implantation. Therefore, it is necessary to increase awareness of otolithic functional states in patients with PSHL.

A preliminary study of the mechanism of compound hearing loss caused by ototoxic drugs combined with impulse noise

Background:Hearing loss(HL)is becoming increasingly common and is more commonly caused by noise,ototoxic substances,or a combination of ototoxic factors.However,so far,few studies have examined the mechanism by which compound factors cause HL.The only relevant study is about occupational ototoxic substances combined with environmental noise at 85-110 dB SPL.In this study,to address the shortcomings of existing research,we innovatively focused on HL induced by loud noise(impulse noise,>160 dB SPL)combined with common ototoxic drugs.The aim of this study was to establish and validate a mature animal model,and then to compare the characteristics of audiology,pathomorphology and molecular features,and to preliminarily predict pathogenesis in compound HL.Materials and Methods:We selected guinea pigs to construct in vivo HL model groups for different extents of exposure,including a blank control group,a single-drug group,a single-impulse noise group,and a compound group.The animal model of the mature compound HL group was established using gentamicin combined with impulse noise.We then performed audio-logical and pathological verification.We analyzed the auditory brainstem response(ABR),pathological morphology of the cochlea,and molecules(including important self-radicals,cytokines,and apoptosis signal trans-duction pathway proteins in the pathogenesis of drug-and noise-induced HL),compared the effect of different extents of exposure on HL,and preliminarily predict the pathogenic mechanism of compound HL.Results:Four groups of animal models were established successfully and verified by audiology and pathology.Regarding audiology,there were no sig-nificant differences in the ABR thresholds before exposure(p>0.05),but differences emerged among the groups after exposure.Notably,after 3,7,and 14 days of exposure,there were significant differences in the ABR thresholds between the compound group and both the drug and noise groups(p<0.01),and after 14 days,the HL of the compound group was much more severe(greater than the linear sum of single-factor HL group).Regarding the patho-morphology,compared with the control group,the cochleae were damaged to different degrees in the factor exposure groups.The drug group had the least severe HL,the noise group had serious HL(p<0.05),and the compound group had the most severe HL(p<0.01).The compound group's damage was greater than the linear sum of the single-factor group in many ways,such as the loss and damage of hair cells and cilia,disturbed morphology and arrangement of hair cells,protein metabolism,cell function,and structural defects on the epidermal plate(p<0.01).From a molecular perspective,the trend was similar to pathology and audiology,and the synergistic effect of ototoxic drugs and impulse noise significantly increased cytokine levels(IL-6,ICAM-1,8-OHDG,IL-1,and TNF-α),free radicals Malondialdehyde([MDA],▪OH,LPO,O•2ˉ),and the apoptosis signal transduction pathway protein.There were significant differences between the compound group and single-factor groups(p<0.05).Conclusion:Gentamicin,impulse noise,and compound factors were used to induce HL in animal models,which were verified by audiology and pathology,laying a foundation for future studies.After constructing the animal models,we found that 50 mg/kg of gentamicin for 10 days was a subinjury dose,and 50�impulse noise caused partial HL,but the two factors combined had a significant synergistic ototoxicity effect,which increased the level of oxidative stress and the waterfall response of inflammatory cytokines in the cochleae and enhanced the expression of apoptosis-related proteins,resulting in syn-ergistic pathomorphological and audiological injury.We preliminarily analyzed the pathogenic mechanism of compound HL,establishing the basis for further study of the mechanism,prevention,and treatment of this increasing global problem.

Shrinkage of ipsilateral taste buds and hyperplasia of contralateral taste buds following chorda tympani nerve transection

The morphological changes that occur in the taste buds after denervation are not well under- stood in rats, especially in the contralateral tongue epithelium. In this study, we investigated the time course of morphological changes in the taste buds following unilateral nerve transection. The role of the trigeminal component of the lingual nerve in maintaining the structural integrity of the taste buds was also examined. Twenty-four Sprague-Dawley rats were randomly divided into three groups： control, unilateral chorda tympani nerve transection and unilateral chorda tympani nerve transection ＋ lingual nerve transection. Rats were allowed up to 42 days of re- covery before being euthanized. The taste buds were visualized using a cytokeratin 8 antibody. Taste bud counts, volumes and taste receptor cell numbers were quantified and compared among groups. No significant difference was detected between the chorda tympani nerve transection and chorda tympani nerve transection ＋ lingual nerve transection groups. Taste bud counts, volumes and taste receptor cell numbers on the ipsilateral side all decreased significantly compared with control. On the contralateral side, the number of taste buds remained unchanged over time, but they were larger, and taste receptor cells were more numerous postoperatively. There was no evidence for a role of the trigeminal branch of the lingual nerve in maintaining the structural integrity of the anterior taste buds.

Sudden sensorineural hearing loss(SSHL) following a local anesthetic dental procedure

Acute sensorineural hearing loss is an uncommon phenomenon in dentistry.We describe the case of a 79-year-old male who presented with acute sensorineural hearing loss occurring 2 days after a tooth extraction procedure under local anesthesia.Possible mechanisms are discussed.He was treated with vasodilators(Ginaton and Alprostadil Injection)and Mecobalamin injection with benefit.High dose oral steroids(1 mg/kg)and low molecular weight dextran were used.

A hypothesis study on bionic active noise reduction of auditory organs

Background:Noise exposure can lead to hearing loss and multiple system dysfunctions.As various forms of noise exist in our living environments,and our auditory organs are very sensitive to acoustic stimuli,it is a challenge to protect our hearing system in certain noisy environments.Presentation of the hypothesis:Herein,we propose that our hearing organ could serve as a noise eliminator for high intensity noise and enhance acoustic signal processing abilities by increasing the signal-noise ratio.For suprathreshold signals,the hearing system is capable of regulating the middle ear muscles and other structures to actively suppress the sound level to a safe range.Testing the hypothesis:To test our hypothesis,both mathematic model analyses and animal model studies are needed.Based on a digital 3D reconstructed model,every structure in the auditory system can be analyzed and tested for its contribution to the process of noise reduction.Products manufactured by this bionic method could be used and verified in animal models and volunteers.Implications:By mimicking the noise-reduction effect of the sophisticated structures in the hearing system,we may be able to provide a model that establishes a new active-sound-suppression mode.This innovative method may overcome the limited capabilities of current noise protection options and become a promising possibility for noise prevention.

Advantages of Short-term Personalized Vestibular Rehabilitation at Home Guided by Professional Therapist for Treatment of Decompensated Vestibular Vertigo

Objective Patients suffered a lot from decompensated vestibular vertigo.Pharmacotherapy and vestibular rehabilitation training have been proven to be effective in prompting vestibular compensation.Routine rehabilitation training is faced with the challenges of patients’compliance,completion,the average recuperation time and so on.This study is aimed to investigate advantages of short-term personalized vestibular rehabihitation at home guided by professional therapist.Methods A short-term personalized vestibular rehabilitation program(ST-PVR)was designed for patients with decompensated vestibular vertigo in this study.Results Patients experiencing the ST-PVR program showed significant improvement of Self-Rating Anxiety Scale(SAS),Dizziness Handicap Inventory(DHI),Activities-Specific Balance Confidence Scale(ABC)scores by the second follow-up(at 2nd week after treatment,P<0.05).However-improvement in the medication group occurred slightly later,DHI for 1 month and SAS for 2 months after treatment(P<0.05).Also,the improvement in the onset time of unilateral weakness(UW)at 2nd week after treatment in the personalized vestibular rehabilitation(PVR)group was faster than that in the medication group.Conclusion In general,the short-term PVR program showed great advantages by prompting vestibular compensation quickly and putting forward future direction for clinical treatment on decompensated vestibular vertigo.

Mechanism of aseptic inflammation upon the inner ear injury

Many factors can cause inner ear injury,such as noise exposure,chemicals,viral infection,and radiation.The main pathological manifestations of inner ear injury are local hypoxia-ischemia,micro-trauma,and an increased level of reactive oxygen species and inflammatory mediators.The contribution of the inflammatory response to the mediation of cochlear and vestibular pathologies has received increasing attention in recent years.Aseptic inflammation can devastate audition and balance,which can lead to many typical clinical inner ear diseases.In this review,we will discuss the most pertinent and recent research on inflammatory mechanisms in inner ear injury.We will also discuss the pathophysiology of some common and significant ear diseases,such as sudden sensorineural hearing loss,age-related hearing loss,noise-induced hearing loss,and Meniere’s disease.