A Consolidated Understanding of the Contribution of Redox Dysregulation in the Development of Hearing Impairment.

The etiology of hearing impairment is multifactorial, with contributions from both genetic and environmental factors. Although genetic studies have yielded valuable insights into the development and function of the auditory system, the contribution of gene products and their interaction with alternate environmental factors for the maintenance and development of auditory function requires further elaboration. In this review, we provide an overview of the current knowledge on the role of redox dysregulation as the converging factor between genetic and environmental factor-dependent development of hearing loss, with a focus on understanding the interaction of oxidative stress with the physical components of the peripheral auditory system in auditory disfunction. The potential involvement of molecular factors linked to auditory function in driving redox imbalance is an important promoter of the development of hearing loss over time.

Dual red and near-infrared light-emitting diode irradiation ameliorates LPS-induced otitis media in a rat model.

Objective: Otitis media (OM) is an infectious and inflammatory disease of the middle ear (ME) that often recurs and requires long-term antibiotic treatment. Light emitting diode (LED)-based devices have shown therapeutic efficacy in reducing inflammation. This study aimed to investigate the anti-inflammatory effects of red and near-infrared (NIR) LED irradiation on lipopolysaccharide (LPS)-induced OM in rats, human middle ear epithelial cells (HMEECs), and murine macrophage cells (RAW 264.7). Methods: An animal model was established by LPS injection (2.0 mg/mL) into the ME of rats via the tympanic membrane. A red/NIR LED system was used to irradiate the rats (655/842 nm, intensity: 102 mW/m2, time: 30 min/day for 3 days and cells (653/842 nm, intensity: 49.4 mW/m2, time: 3 h) after LPS exposure. Hematoxylin and eosin staining was performed to examine pathomorphological changes in the tympanic cavity of the ME of the rats. Enzyme-linked immunosorbent assay, immunoblotting, and RT-qPCR analyses were used to determine the mRNA and protein expression levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α). Mitogen-activated protein kinases (MAPKs) signaling was examined to elucidate the molecular mechanism underlying the reduction of LPS-induced pro-inflammatory cytokines following LED irradiation. Results: The ME mucosal thickness and inflammatory cell deposits were increased by LPS injection, which were reduced by LED irradiation. The protein expression levels of IL-1ß, IL-6, and TNF-α were significantly reduced in the LED-irradiated OM group. LED irradiation strongly inhibited the production of LPS-stimulated IL-1ß, IL-6, and TNF-α in HMEECs and RAW 264.7 cells without cytotoxicity in vitro. Furthermore, the phosphorylation of ERK, p38, and JNK was inhibited by LED irradiation. Conclusion: This study demonstrated that red/NIR LED irradiation effectively suppressed inflammation caused by OM. Moreover, red/NIR LED irradiation reduced pro-inflammatory cytokine production in HMEECs and RAW 264.7 cells through the blockade of MAPK signaling.

Valproic Acid Inhibits Progressive Hereditary Hearing Loss in a KCNQ4 Variant Model through HDAC1 Suppression.

Genetic or congenital hearing loss still has no definitive cure. Among genes related to genetic hearing loss, the potassium voltage-gated channel subfamily Q member 4 (KCNQ4) is known to play an essential role in maintaining ion homeostasis and regulating hair cell membrane potential. Variants of the KCNQ4 show reductions in the potassium channel activity and were responsible for non-syndromic progressive hearing loss. KCNQ4 has been known to possess a diverse variant. Among those variants, the KCNQ4 p.W276S variant produced greater hair cell loss related to an absence of potassium recycling. Valproic acid (VPA) is an important and commonly used histone deacetylase (HDAC) inhibitor for class I (HDAC1, 2, 3, and 8) and class IIa (HDAC4, 5, 7, and 9). In the current study, systemic injections of VPA attenuated hearing loss and protected the cochlear hair cells from cell death in the KCNQ4 p.W276S mouse model. VPA activated its known downstream target, the survival motor neuron gene, and increased acetylation of histone H4 in the cochlea, demonstrating that VPA treatment directly affects the cochlea. In addition, treatment with VPA increased the KCNQ4 binding with HSP90ß by inhibiting HDAC1 activation in HEI-OC1 in an in vitro study. VPA is a candidate drug for inhibiting late-onset progressive hereditary hearing loss from the KCNQ4 p.W276S variant.

Protective Effect of Avenanthramide-C on Auditory Hair Cells against Oxidative Stress, Inflammatory Cytokines, and DNA Damage in Cisplatin-Induced Ototoxicity.

Cisplatin-induced ototoxicity leads to hearing impairment, possibly through reactive oxygen species (ROS) production and DNA damage in cochlear hair cells (HC), although the exact mechanism is unknown. Avenanthramide-C (AVN-C), a natural, potent antioxidant, was evaluated in three study groups of normal adult C57Bl/6 mice (control, cisplatin, and AVN-C+cisplatin) for the prevention of cisplatin-induced hearing loss. Auditory brainstem responses and immunohistochemistry of outer hair cells (OHCs) were ascertained. Cell survival, ROS production, Phospho-H2AX-enabled tracking of DNA damage-repair kinetics, and expression levels of inflammatory cytokines (TNF-α, IL-1ß, IL6, iNOS, and COX2) were assessed using House Ear Institute-Organ of Corti 1 (HEI-OC1 Cells). In the in vivo mouse model, following cisplatin-induced damage, AVN-C decreased the hearing thresholds and sheltered all cochlear turns' OHCs. In HEI-OC1 cells, AVN-C preserved cell viability and decreased ROS production, whereas cisplatin enhanced both ROS levels and cell viability. In HEI-OC1 cells, AVN-C downregulated IL6, IL-1ß, TNF-α, iNOS, and COX2 production that was upregulated by cisplatin treatment. AVN-C attenuated the cisplatin-enhanced nuclear H2AX activation. AVN-C had a strong protective effect against cisplatin-induced ototoxicity through inhibition of ROS and inflammatory cytokine production and DNA damage and is thus a promising candidate for preventing cisplatin-induced sensorineural hearing loss.

Identification and Characterization of mRNA and lncRNA Expression Profiles in Age-Related Hearing Loss.

OBJECTIVES: Age-related hearing loss (ARHL), or presbycusis, is caused by disorders of sensory hair cells and auditory neurons. Many studies have suggested that the accumulation of mitochondrial DNA damage, the production of reactive oxygen species, noise, inflammation, and decreased antioxidant function are associated with subsequent cochlear senescence in response to aging stress. Long non-coding RNA (lncRNA) has been reported to play important roles in various diseases. However, the function of lncRNA in ARHL remains unclear. In this study, we analyzed the common expression profiles of messenger RNA (mRNA) and lncRNA through ARHL-related RNA-sequencing datasets. METHODS: We selected and downloaded three different sets of RNA-sequencing data for ARHL. We performed differential expression analysis to find common mRNA and lncRNA profiles in the cochleae of aged mice compared to young mice. Gene Ontology (GO) analysis was used for functional exploration. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to validate mRNAs and lncRNAs. In addition, we performed trans target prediction analysis with differentially expressed mRNAs and lncRNAs to understand the function of these mRNAs and lncRNAs in ARHL. RESULTS: We identified 112 common mRNAs and 10 common lncRNAs in the cochleae of aged mice compared to young mice. GO analysis showed that the 112 upregulated mRNAs were enriched in the defense response pathway. When we performed qRT-PCR with 1 mM H2O2-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, the qRT-PCR. RESULTS: were consistent with the RNA-sequencing analysis data. lncRNA-mRNA networks were constructed using the 10 common lncRNAs and 112 common mRNAs in ARHL. CONCLUSION: Our study provides a comprehensive understanding of the common mRNA and lncRNA expression profiles in ARHL. Knowledge of ARHL-associated mRNAs and lncRNAs could be useful for better understanding ARHL and these mRNAs and lncRNAs might be a potential therapeutic target for preventing ARHL.

A novel HDAC6 inhibitor, CKD-504, is effective in treating preclinical models of huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder, of which pathogenesis is caused by a polyglutamine expansion in the amino-terminus of huntingtin gene that resulted in the aggregation of mutant HTT proteins. HD is characterized by progressive motor dysfunction, cognitive impairment and neuropsychiatric disturbances. Histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase, has been shown to induce transport- and release-defect phenotypes in HD models, whilst treatment with HDAC6 inhibitors ameliorates the phenotypic effects of HD by increasing the levels of α-tubulin acetylation, as well as decreasing the accumulation of mutant huntingtin (mHTT) aggregates, suggesting HDAC6 inhibitor as a HD therapeutics. In this study, we employed in vitro neural stem cell (NSC) model and in vivo YAC128 transgenic (TG) mouse model of HD to test the effect of a novel HDAC6 selective inhibitor, CKD-504, developed by Chong Kun Dang (CKD Pharmaceutical Corp., Korea). We found that treatment of CKD-504 increased tubulin acetylation, microtubule stabilization, axonal transport, and the decrease of mutant huntingtin protein in vitro. From in vivo study, we observed CKD-504 improved the pathology of Huntington's disease: alleviated behavioral deficits, increased axonal transport and number of neurons, restored synaptic function in corticostriatal (CS) circuit, reduced mHTT accumulation, inflammation and tau hyperphosphorylation in YAC128 TG mouse model. These novel results highlight CKD-504 as a potential therapeutic strategy in HD. [BMB Reports 2023; 56(3): 178-183].

Hyaluronan Synthase 1: A Novel Candidate Gene Associated With Late-Onset Non-syndromic Hereditary Hearing Loss.

OBJECTIVES: Hyaluronan synthase 1 (HAS1) is a membrane-bound protein that is abundant in the epidermis and dermis, and it is important for skin function. However, its association with hearing loss has not yet been studied. Herein, we sought to evaluate the potential contribution of HAS1: c.1082G>A to genetic hearing loss. METHODS: We used whole-exome sequencing to analyze blood DNA samples of six patients of a family with autosomal dominant familial late-onset progressive hearing loss, which was revealed to be related to a variant of the HAS1 gene. Confirmatory Sanger sequencing was performed with samples from 10 members. A missense variant was detected in HAS1 (c.1082 G>A, p.Cys361Tyr). In silico analyses predicted this variant to result in the functional loss of HAS1. Immunostaining was conducted using wild-type mouse samples to verify HAS1 expression. RESULTS: Has1 was detected in an otocyst at E10.5. In the pup, Has1 expression was localized in the stria vascularis (SV), hair cells, supporting cells of the organ of Corti, and some spiral ganglion neurons. SV marginal cells markedly expressed Has1 in the adult stage. The hearing threshold in the Has1-depleted condition was investigated by accessing the International Mouse Phenotyping Consortium's Auditory Brainstem Response (ABR) data. ABR of Has1 knock-out mice showed threshold elevations at 6, 12, and 18 kHz in young male adults. CONCLUSION: HAS1 may have a close relationship with auditory function and genetic hearing loss. Further investigation is needed to reveal the precise role of HAS1 in the auditory system. HAS1 is a candidate gene for future hereditary hearing loss genetic testing.

Efficiency of antioxidant Avenanthramide-C on high-dose methotrexate-induced ototoxicity in mice.

Methotrexate (MTX) has been used in treating various types of cancers but can also cause damage to normal organs and cell types. Folinic acid (FA) is a well-known MTX antidote that protects against toxicity caused by the drug and has been used for decades. Since hearing loss caused by MTX treatment is not well studied, herein we aimed to investigate the efficiency of the antioxidant Avenanthramide-C (AVN-C) on high-dose MTX (HDMTX) toxicity in the ear and provide insights into the possible mechanism involved in MTX-induced hearing loss in normal adult C57Bl/6 mice and HEI-OC1 cells. Our results show that the levels of MTX increased in the serum and perilymph 30 minutes after systemic administration. MTX increased hearing thresholds in mice, whereas AVN-C and FA preserved hearing within the normal range. MTX also caused a decrease in wave I amplitude, while AVN-C and FA maintained it at higher levels. MTX considerably damaged the cochlear synapses and neuronal integrity, and both AVN-C and FA rescued the synapses. MTX reduced the cell viability and increased the reactive oxygen species (ROS) level in HEI-OC1 cells, but AVN-C and FA reversed these changes. Apoptosis- and ROS-related genes were significantly upregulated in MTX-treated HEI-OC1 cells; however, they were downregulated by AVN-C and FA treatment. We show that MTX can cause severe hearing loss; it can cross the blood-labyrinth barrier and cause damage to the cochlear neurons and outer hair cells (OHCs). The antioxidant AVN-C exerts a strong protective effect against MTX-induced ototoxicity and preserved the inner ear structures (synapses, neurons, and OHCs) from MTX-induced damage. The mechanism of AVN-C against MTX suggests that ROS is involved in HDMTX-induced ototoxicity.

Confirmation and variability of the Allee effect inDictyostelium discoideumcell populations, possible role of chemical signaling within cell clusters.

In studies of the unicellular eukaryoteDictyostelium discoideum, many have anecdotally observed that cell dilution below a certain 'threshold density' causes cells to undergo a period of slow growth (lag). However, little is documented about the slow growth phase and the reason for different growth dynamics below and above this threshold density. In this paper, we extend and correct our earlier work to report an extensive set of experiments, including the use of new cell counting technology, that set this slow-to-fast growth transition on a much firmer biological basis. We show that dilution below a certain density (around 104cells ml-1) causes cells to grow slower on average and exhibit a large degree of variability: sometimes a sample does not lag at all, while sometimes it takes many moderate density cell cycle times to recover back to fast growth. We perform conditioned media experiments to demonstrate that a chemical signal mediates this endogenous phenomenon. Finally, we argue that while simple models involving fluid transport of signal molecules or cluster-based signaling explain typical behavior, they do not capture the high degree of variability between samples but nevertheless favor an intra-cluster mechanism.

Development of PUFF-Gaussian dispersion model for the prediction of atmospheric distribution of particle concentration.

Mt. Baekdu's eruption precursors are continuously observed and have become a global social issue. Volcanic activities in neighboring Japan are also active. There are no direct risks of proximity-related disasters in South Korea from the volcanic eruptions at Japan or Mt. Baekdu; however, severe impacts are expected from the spread of volcanic ash. Numerical analysis models are generally used to predict and analyze the diffusion of volcanic ash, and each numerical analysis model has its own limitations caused by the computational algorithm it employs. In this study, we analyzed the PUFF-UAF model, an ash dispersion model based on the Lagrangian approach, and observed that the number of particles used in tracking substantially affected the results. Even with the presence of millions of particles, the concentration of ash predicted by the PUFF-UAF model does not accurately represent the dispersion. To overcome this deficit and utilize the computational efficiency of the Lagrangian model, we developed a PUFF-Gaussian model to consider the dispersive nature of ash by applying the Gaussian dispersion theory to the results of the PUFF-UAF model. The results of the proposed method were compared with the field measurements from actual volcanic eruptions, and the comparison showed that the proposed method can produce reasonably accurate predictions for ash dispersion.

Scar Formation and Debris Elimination during Hair Cell Degeneration in the Adult DTR Mouse.

The auditory sensory epithelium of the mammalian inner ear is a highly organized structure that contains sensory hair cells (HCs) and non-sensory supporting cells (SCs). Following the partial loss of HCs after cochlear insults such as overstimulation or ototoxic drugs, SCs seal the luminal epithelial surface (reticular lamina) and reorganize its cellular pattern. Here we investigated the changes in the sensory epithelium following a rapid and severe cochlear insult in the diphtheria toxin receptor (DTR) mouse, where diphtheria toxin (DT) injection leads to a HC-specific lesion resulting in a complete HC loss. We found that DT-induced selective HC ablation could lead to a pattern of scar formation and apical cell-cell adherens and tight junction reorganization similar to that occurring after other types of cochlear insult. Prestin, an outer HC-specific protein, was present in amorphous clumps at the sites where SCs had expanded to fill the spaces vacated by the dead HCs for up to 2 months after the DT induced lesion. Many of the prestin clumps appeared to occupy spaces within SCs, suggesting that SCs participate in the removal process of HC corpses in the DTR deafness model. Prestin clumps could be seen in different areas all along the length of the SCs, and appeared to be inside the SCs as well as in the inter-cellular spaces between SCs. The findings suggest that HC elimination in the DTR deafness model follows a mechanism similar to that in overstimulation or ototoxicity models, making the DTR mouse useful for understanding the process underlying HC elimination and the role of SCs in this process.

Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea.

Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor Atoh1, but to date this approach has yielded low and variable efficiency of HC production. Gfi1 is a transcription factor important for HC development and survival. We evaluated the combinatorial effects of Atoh1 and Gfi1 over-expression on HC regeneration using gene transfer methods in neonatal cochlear explants, and in vivo in adult mice. Adenoviral over-expression of Atoh1 and Gfi1 in cultured neonatal cochlear explants resulted in numerous ectopic HC-like cells (HCLCs), with significantly more cells in Atoh1 + Gfi1 cultures than Atoh1 alone. In vitro, ectopic HCLCs emerged in regions medial to inner HCs as well as in the stria vascularis. In vivo experiments were performed in mature Pou4f3DTR mice in which HCs were completely and specifically ablated by administration of diphtheria toxin. Adenoviral expression of Atoh1 or Atoh1 + Gfi1 in cochlear supporting cells induced appearance of HCLCs, with Atoh1 + Gfi1 expression leading to 6.2-fold increase of new HCLCs after 4 weeks compared to Atoh1 alone. New HCLCs were detected throughout the cochlea, exhibited immature stereocilia and survived for at least 8 weeks. Combinatorial Atoh1 and Gfi1 induction is thus a promising strategy to promote HC regeneration in the mature mammalian cochlea.

Near-infra-red fluorescent chitosan oligosaccharide lactate for targeted cancer imaging and photothermal therapy.

Photothermal therapy (PTT) is a promising approach for effective cancer treatment because of its non-invasive procedure, low toxicity to normal tissues, and high tumour ablation efficiency. Developing a PTT agent with precise tumour imaging capabilities is an essential prerequisite for effective PTT. In this study, we developed a bifunctional near-infra-red (NIR) fluorescent conjugate consisting of chitosan oligosaccharide lactate (COL) and the ZW800-1 NIR fluorophore (COL-ZW). We demonstrate that this conjugate is easy to use and that it is an effective theranostic agent for fluorescence-guided photothermal treatment. The temperature of COL-ZW increased by 62.3 °C after NIR laser irradiation (1.1 W/cm2) for 5 min in HT-29 tumour-bearing mice. The HT-29 tumours targeted by COL-ZW showed a remarkable decrease in tumour volume until a week after photothermal treatment. These in vivo results demonstrate that the bifunctional COL-ZW generates strong fluorescence and light-triggered PTT in tumour sites, indicating successful fluorescence-guided PTT. Importantly, no tumour recurrence or treatment-induced toxicity was observed after a single dose of COL-ZW with laser irradiation. Therefore, a combinatorial treatment with COL-ZW and NIR laser irradiation could serve as a promising strategy for photothermal cancer therapy.

Practical aspects of inner ear gene delivery for research and clinical applications.

The application of gene therapy is widely expanding in research and continuously improving in preparation for clinical applications. The inner ear is an attractive target for gene therapy for treating environmental and genetic diseases in both the auditory and vestibular systems. With the lack of spontaneous cochlear hair cell replacement, hair cell regeneration in adult mammals is among the most important goals of gene therapy. In addition, correcting gene defects can open up a new era for treating inner ear diseases. The relative isolation and small size of the inner ear dictate local administration routes and carefully calculated small volumes of reagents. In the current review, we will cover effective timing, injection routes and types of vectors for successful gene delivery to specific target cells within the inner ear. Differences between research purposes and clinical applications are also discussed.

Development of Sound Field Audiometry System for Small Audiometric Booths and Comparison of Its Equivalence With Traditional System.

OBJECTIVES: Sound field (SF) audiometry tests are usually conducted in audiometric booths measuring greater than 2×2 m in size. However, most private ENT clinics carry about 1×1-m-sized audiometric booths, making SF audiometry testing difficult to perform. The aims of this study were to develop an SF audiometry system for use in smaller audiometric booths and compare its performance with traditional system. METHODS: The newly developed SF audiometry system can yield an SF signal at a distance of about 30 cm from the subject's ears. Its height can be adjusted according to the subject's head height. We compared SF hearing results between the new SF system and the traditional SF audiometry system in 20 adults with normal hearing (40 ears) and 24 adults with impaired hearing levels (38 ears) who wore hearing aids. Comparative parameters included warble tone audiometry threshold, a speech reception threshold (SRT), and a speech discrimination score (SDS). For statistical analysis, paired t-test was used. The equivalence of both SF systems was tested using two one-sided test (TOST) with a margin of 5 dB (normal hearing participants) and 10 dB (hearing aids wearing participants). RESULTS: Among participants with normal hearing, warble tone hearing thresholds of 0.5, 1, 2, and 4 kHz, average values of these four frequencies, and SRT were similar between the two systems (all P>0.05). Participants with hearing aids showed similar warble tone threshold and SRT (P>0.05) in both systems except for threshold of 4 kHz (P=0.033). SDS was significantly higher in the newly developed system (P<0.05). TOST results showed equivalent SF audiometry results using either system. CONCLUSION: Audiometric results of the newly developed SF audiometry system were equivalent to those of a traditional system. Therefore, the small SF audiometry system can be used at small audiometric booths present in most private ENT clinics.

Transcanal Endoscopic Tympanoplasty for Pediatric Patients Under 15 Years of Age With Chronic Otitis Media.

OBJECTIVES: To evaluate the results of transcanal endoscopic tympanoplasty for pediatric patients with chronic otitis media (COM) and compare them to that of the previously standard microscopic assisted tympanoplasty technique. METHODS: The patients were divided into two groups based on the operative method. Group 1 underwent tympanoplasty with a totally endoscopic assisted technique (n=21, 24 ears), and group 2 underwent tympanoplasty with the conventional microscopic technique (n=14, 15 ears). We used a transcanal approach in group 1 and a postauricular approach in group 2. In group 1, there were 15 cases of simple COM and nine cases of adhesive otitis media. In group 2, only 15 cases of simple COM were present. We analyzed the outcomes in terms of the hearing gain according to the surgical method and COM type, operation time, hospital stay after surgery, and graft success rate. RESULTS: Postoperative hearing gain results including air conduction (AC) thresholds and air-bone gap (ABG) were not significantly different between the two groups (P>0.05). In both the groups, significant improvement in the postoperative AC and ABG was observed compared to the preoperative hearing. The hospital stay after surgery was significantly shorter in group 1 than the group 2: 2.1±0.4 days and 4.8±0.9 days (P<0.001), respectively. The intact graft success rate was 91.6% in group 1 and 93% in group 2; the values were not significantly different (P>0.05). There was neither intra- nor postoperative complications. CONCLUSION: Transcanal endoscopic ear surgery technique is more conservative than microscopic approach and can be performed in pediatric patients under 15 years of age with COM. Moreover, it offers similar surgical results compared to traditional microscopic technique, and a shorter operative time and hospital stay after surgery are the advantages of this technique.

Near-Infrared Fluorescent Sorbitol Probe for Targeted Photothermal Cancer Therapy.

Abstract: Photothermal therapy (PTT) using a near-infrared (NIR) heptamethine cyanine fluorophore has emerged as an alternative strategy for targeted cancer therapy. NIR fluorophores showing a high molar extinction coefficient and low fluorescence quantum yield have considerable potential applications in photothermal cancer therapy. In this study, a bifunctional sorbitol-ZW800 conjugate was used as an advanced concept of photothermal therapeutic agents for in vivo cancer imaging and therapy owing to the high tumor targetability of the sorbitol moiety and excellent photothermal property of NIR heptamethine cyanine fluorophore. The sorbitol-ZW800 showed an excellent photothermal effect increased by 58.7 °C after NIR laser irradiation (1.1 W/cm2) for 5 min. The HT-29 tumors targeted by sorbitol-ZW800 showed a significant decrease in tumor volumes for 7 days after photothermal treatment. Therefore, combining the bifunctional sorbitol-ZW800 conjugate and NIR laser irradiation is an alternative way for targeted cancer therapy, and this approach holds great promise as a safe and highly efficient NIR photothermal agent for future clinical applications.

Avenanthramide-C prevents noise- and drug-induced hearing loss while protecting auditory hair cells from oxidative stress.

Noise exposure or ototoxic drugs instigate various types of damage to the cochlea, resulting in hearing loss (HL). While the incidence of HL is growing continuously, there are, so far, no adequate drugs to prevent or treat HL. Avenanthramide (AVN), a natural product extracted from oats, has been reported to possess anti-oxidant/inflammatory properties, and protect several types of cells. In this study, we investigated whether AVN-C can protect auditory hair cells, and preserve hearing from noise trauma and ototoxic drugs. Wild-type C57BL/6 mice were used to generate several HL models. Serum and perilymphatic fluid samples were analyzed using mass spectrophotometry to detect AVN-C. AVN-C crossed the blood-labyrinth barrier, and was detected in the perilymph after systemic injection. Pretreatment by AVN-C 24 h before exposure to temporary threshold shift noise contributed to the preserving hearing. Moreover, in the case of permanent threshold shift, AVN-C provided significant protection from noise. AVN-C also strongly protected against deterioration in hearing due to kanamycin and furosemide (K + F). According to the results of our scanning electron microscopy analysis, many outer hair cells (OHCs) were destroyed by noise trauma, while AVN-C prevented these losses. OHC loss due to K + F was even more severe, even affecting the apex. Strikingly, AVN-C treatment maintained OHCs at a level comparable to normal cochlea. AVN-C reduced the dichlorofluorescin (DCF)-positive population in gentamicin-treated HEI-OC1 in vitro. The expressions of TNF-a, BAK, IL-1b, and Bcl-2 were attenuated by AVN-C, revealing its antioxidant effects. The results of this study show that AVN-C crosses the blood-labyrinth barrier and provide a significant protection against noise- and drug-induced ototoxicity. Hence, AVN-C is a good candidate for future therapy aimed at protecting against sensorineural HL.

The Effect of Polydeoxyribonucleotide Extracted from Salmon Sperm on the Restoration of Bisphosphonate-Related Osteonecrosis of the Jaw.

Bisphosphonates (BPs) used for treating skeletal diseases can induce bisphosphonate-related osteonecrosis of the jaw (BRONJ). Despite much effort, effective remedies are yet to be established. In the present study, we investigated the feasibility of polydeoxyribonucleotide (PDRN) extracted from salmon sperm for the treatment of BRONJ, in a BRONJ-induced rat model. Compared with BRONJ-induced samples, PDRN-treated samples exhibited lower necrotic bone percentages and increased numbers of blood vessels and attached osteoclast production. Moreover, local administration of PDRN at a high concentration (8 mg/kg) remarkably resolved the osteonecrosis. Findings from this study suggest that local administration of PDRN at a specific concentration may be considered clinically for the management of BRONJ.

Auditory Evoked Potential Inconsistency in Sudden Unilateral Hearing Loss with Multiple Sclerosis.

Sudden sensorineural hearing loss is a well-recognized clinical symptom in multiple sclerosis (MS). Acute inflammatory demyelination in the cochlear nerve or more central auditory tracts may cause sudden retrocochlear hearing loss. A 28-year-old male patient who was confirmed as having MS presented with suffering from dizziness as well as ongoing right-side hearing loss. We performed audiological tests, such as pure tone audiometry (PTA), otoacoustic emission, auditory brainstem response (ABR), and auditory steady-state response (ASSR). His clinical and audiological abnormalities disappeared with steroid therapy. However, each test showed different time courses of improvement. Although the results of the PTA and ASSR tests improved in exactly 1 month after the first attack, the results of the ABR reached 3 months to return to normal. To the best of our knowledge, this is the first case report of the time difference of hearing improvement shown in PTA, ASSR, and ABR tests.