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Our study aimed to investigate the role of ferroptosis in sevoflurane-induced hearing impairment and explore the mechanism of the microRNA-182-5p (miR-182-5p)/Glutathione Peroxidase 4 (GPX4) pathway in sevoflurane-induced ototoxicity. Immunofluorescence staining was performed using myosin 7a and CtBP2. Cell viability was assessed using the CCK-8 kit. Fe2+ concentration was measured using FerroOrange and Mi-to-FerroGreen fluorescent probes. The lipid peroxide level was assessed using BODIPY 581/591 C11 and MitoSOX fluorescent probes. The auditory brainstem response (ABR) test was conducted to evaluate the hearing status. Bioinformatics tools and dual luciferase gene reporter analysis were used to confirm the direct targeting of miR-182-5p on GPX4 mRNA. GPX4 and miR-182-5p expression in cells was assessed by qRT-PCR and Western blot. Ferrostatin-1 (Fer-1) pretreatment significantly improved hearing impairment and damage to ribbon synapses in mice caused by sevoflurane exposure. Immunofluorescence staining revealed that Fer-1 pretreatment reduced intracellular and mitochondrial iron overload, as well as lipid peroxide accumulation. Our findings indicated that miR-182-5p was upregulated in sevoflurane-exposed HEI-OC1 cells, and miR-182-5p regulated GPX4 expression by binding to the 3′UTR of GPX4 mRNA. The inhibition of miR-182-5p attenuated sevoflurane-induced iron overload and lipid peroxide accumulation. Our study elucidated that the miR-182-5p/GPX4 pathway was implicated in sevoflurane-induced ototoxicity by promoting ferroptosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cisplatin-based chemoradiation is the standard of care for patients with squamous cell carcinomas of the head and neck area. Recent data from randomized phase 3 studies showed that weekly cisplatin has the same oncological outcomes as high-dose triweekly cisplatin when combined with definitive radiation. In this study, audiologic data were prospectively collected before, during, and after treatment completion. Standard audiogram evaluation was used in all cases. The primary endpoint was a hearing change grade of ≥3 (CTCAE v5.0) after completion of chemoradiation. The high-dose cisplatin regimen significantly increased the ≥grade 3 severe irreversible ototoxicity risk compared to the low-dose weekly regimen, irrespective of cumulative cisplatin dose, even with the use of cochlear-sparing intensity-modulated radiation therapy. No significant difference in oncologic outcomes was observed between the two schedules. These findings should be validated in a larger prospective multi-institutional study. Cisplatin, one of the most ototoxic anti-neoplastic agents, causes permanent hearing loss in up to 90% of patients. We assessed ototoxicity rates and prospectively collected audiologic outcomes of patients receiving low-dose or high-dose cisplatin with concurrent cochlear-sparing intensity-modulated radiation therapy (IMRT). Patients with head and neck squamous cell carcinoma (HNSCC) receiving definitive or adjuvant cisplatin-based chemoradiotherapy (CRT) were analyzed. Cisplatin was administered either in low doses weekly (40 mg/m2) for up to seven doses or in high doses triweekly (100 mg/m2) for up to three doses. Cochlear-sparing IMRT was delivered in all cases. Audiologic data were prospectively collected before, during, and after treatment completion. The primary endpoint was a hearing change grade of ≥3 after CRT completion. Of the 96 HNSCC patients evaluated, 69 received weekly cisplatin and 58 received definitive CRT. Of patients receiving weekly cisplatin, 13% developed ≥G3 ototoxicity vs. 56% of patients who received triweekly cisplatin (p < 0.001). In multivariable modeling, the cisplatin dose schedule remained significant (OR: 8.4, 95%CI: 2.8–27.8, p < 0.001) for risk of severe irreversible ototoxicity. Triweekly cisplatin CRT significantly increased the ≥G3 severe irreversible ototoxicity risk compared to low-dose weekly cisplatin, irrespective of the cumulative cisplatin dose, even with the use of cochlear-sparing IMRT. No significant difference in oncologic outcomes was observed between the two schedules. [ABSTRACT FROM AUTHOR]

Background: Ototoxicity is a major side effect of many broadly used aminoglycoside antibiotics (AGs) and no FDA-approved otoprotective drug is available currently. The zebrafish has recently become a valuable model to investigate AG-induced hair cell toxicity and an expanding list of otoprotective compounds that block the uptake of AGs have been identified from zebrafish-based screening; however, it remains to be established whether inhibiting intracellular cell death pathway(s) constitutes an effective strategy to protect against AG-induced ototoxicity. Results: We used the zebrafish model as well as in vitro cell-based assays to investigate AG-induced cell death and found that ferroptosis is the dominant type of cell death induced by neomycin. Neomycin stimulates lipid reactive oxygen species (ROS) accumulation through mitochondrial pathway and blocking mitochondrial ferroptosis pathway effectively protects neomycin-induced cell death. We screened an alkaloid natural compound library and identified seven small compounds that protect neomycin-induced ototoxicity by targeting ferroptosis pathway: six of them are radical-trapping agents (RTAs) while the other one (ellipticine) regulates intracellular iron homeostasis, which is essential for the generation of lipid ROS to stimulate ferroptosis. Conclusions: Our study demonstrates that blocking intracellular ferroptosis pathway is an alternative strategy to ameliorate neomycin-induced ototoxicity and provides multiple hit compounds for further otoprotective drug development. [ABSTRACT FROM AUTHOR]

(1) Background: Antimicrobial resistance is growing at an extreme pace and has proven to be an urgent topic, for research into alternative treatments. Such a prospective possibility is hidden in antimicrobial peptides because of their low to no toxicity, effectiveness at low concentrations, and most importantly their ability to be used for multiple treatments. This work was focused on the study of the effect of the modification in position 7 of Temporin A on its biological activity; (2) Methods: The targeted peptides were synthesized using Fmoc/Ot-Bu SPPS. The antibacterial activity of the analogs was determined using the broth microdilution method and disk-diffusion method. In vitro tests were performed to determine the cytotoxicity, phototoxicity, and antiproliferative activity of the peptide analogs on a panel of tumor and normal cell lines; (3) Results: All analogs except DTCit showed good antibacterial activity, with DTDab having the best activity according to the disk-diffusion method. However, DTCit had an acceptable cytotoxicity, combined with good selectivity against the test MCF-7 cell line; (4) Conclusions: The obtained results revealed the importance of the basicity and length of the side chain at position 7 in the Temporin A sequence for both tested activities. [ABSTRACT FROM AUTHOR]

Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and hearing loss. Currently, there is no targeted therapy for aminoglycoside ototoxicity, since the underlying mechanisms of aminoglycoside-induced hearing impairments are not fully defined. This study aimed to investigate whether the calcium channel blocker verapamil and changes in intracellular & extracellular calcium could ameliorate aminoglycoside-induced ototoxicity in zebrafish. The present findings showed that a significant decreased number of neuromasts in the lateral lines of zebrafish larvae at 5 days' post fertilization after neomycin (20 μM) and gentamicin (20 mg/mL) exposure, which was prevented by verapamil. Moreover, verapamil (10–100 μM) attenuated aminoglycoside-induced toxic response in different external calcium concentrations (33–3300 μM). The increasing extracellular calcium reduced hair cell loss from aminoglycoside exposure, while lower calcium facilitated hair cell death. In contrast, calcium channel activator Bay K8644 (20 μM) enhanced aminoglycoside-induced ototoxicity and reversed the protective action of higher external calcium on hair cell loss. However, neomycin-elicited hair cell death was not altered by caffeine, ryanodine receptor (RyR) agonist, and RyR antagonists, including thapsigargin, ryanodine, and ruthenium red. The uptake of neomycin into hair cells was attenuated by verapamil and under high external calcium concentration. Consistently, the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin was also reduced by verapamil and high external calcium. Significantly, zebrafish larvae when exposed to neomycin exhibited decreased swimming distances in reaction to droplet stimulus when compared to the control group. Verapamil and elevated external calcium effectively protected the impaired swimming ability of zebrafish larvae induced by neomycin. These data imply that prevention of hair cell damage correlated with swimming behavior against aminoglycoside ototoxicity by verapamil and higher external calcium might be associated with inhibition of excessive ROS production and aminoglycoside uptake through cation channels. These findings indicate that calcium channel blocker and higher external calcium could be applied to protect aminoglycoside-induced listening impairments. [ABSTRACT FROM AUTHOR]

Objectives: Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity. Methods: RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC50). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay. Results: The LC50 dose of cisplatin was determined to be 3.76 µM (p = 2.2 x 10-16). When co-dosed with cisplatin and a therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone. Conclusion: RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatininduced ototoxicity. [ABSTRACT FROM AUTHOR]

Background: Norway spruce (Picea abies) resin‐based products are used in human medicine. A resin‐based otic rinse also could be useful in supportive care of canine otitis externa (COE), yet information on its antimicrobial effect against canine pathogens or ototoxicity is lacking. Objectives: To investigate the antimicrobial properties and ototoxicity of a commercial resin‐based otic product. Materials and Methods: Antimicrobial effect was evaluated using a standardised challenge test on Staphylococcus pseudintermedius, Corynebacterium auriscanis, Pseudomonas aeruginosa, Escherichia coli, Malassezia pachydermatis, and Streptococcus halichoeri strains to measure reduction in growth after 24 h exposure to the product. Effect on cell morphology was investigated by exposing S. pseudintermedius, C. auriscanis, P. aeruginosa and M. pachydermatis to the product in 20% and 100% (v/v) concentrations for 6, 24 and 48 h, and evaluating cells by transmission (TEM) and scanning (SEM) electron microscopy. An in vitro microbial kill–rate assay also was performed. Auditory brain stem response test, clinical evaluation and postmortem histological evaluation of ear canals were undertaken on experimental guinea pigs treated with the test product or saline controls. Results: The product showed >log 5 growth reduction for all strains in the challenge test. TEM and SEM images showed clear changes in the cells' inner structures and deterioration of cells, and 100% (v/v) test product exposure induced microbial killing in 1–2 h. Ototoxicity was not detected in guinea pigs. Conclusions and Clinical Relevance: The product may be an option in supportive care of COE because of antimicrobial effects and lack of ototoxic properties in a guinea pig model. [ABSTRACT FROM AUTHOR]

Neonates face heightened susceptibility to drug toxicity, often exposed to off-label medications with dosages extrapolated from adult or pediatric studies. Premature infants in Neonatal Intensive Care Units (NICUs) are particularly at risk due to underdeveloped pharmacokinetics and exposure to multiple drugs. The study aimed to survey commonly used medications with a higher risk of ototoxicity and nephrotoxicity in Spanish and Italian neonatal units. A prospective cross-sectional study was conducted in Italian and Spanish neonatal units using a web-based survey with 43 questions. A modified Delphi method involved experts refining the survey through online consensus. Ethical approval was obtained, and responses were collected from January to July 2023. The survey covered various aspects, including drug-related ototoxic and nephrotoxic management, hearing screening, and therapeutic drug monitoring. Responses from 131 participants (35.9% from Spain and 64.1% from Italy) revealed awareness of drug toxicity risks. Varied practices were observed in hearing screening protocols, and a high prevalence of ototoxic and nephrotoxic drug use, including aminoglycosides (100%), vancomycin (70.2%), loop diuretics (63.4%), and ibuprofen (62.6%). Discrepancies existed in guideline availability and adherence, with differences between Italy and Spain in therapeutic drug monitoring practices. Conclusions:The study underscores the need for clinical guidelines and uniform practices in managing ototoxic and nephrotoxic drugs in neonatal units. Awareness is high, but inconsistencies in practices indicate a necessity for standardization, including the implementation of therapeutic drug monitoring and the involvement of clinical pharmacologists. Addressing these issues is crucial for optimizing neonatal care in Southern Europe. What is Known: • Neonates in intensive care face a high risk of nephrotoxicity and ototoxicity from drugs like aminoglycosides, vancomycin, loop diuretics, and ibuprofen. • Therapeutic drug monitoring is key for managing these risks, optimizing dosing for efficacy and minimizing side effects. What is New: • NICUs in Spain and Italy show high drug toxicity awareness but differ in ototoxic/nephrotoxic drug management. • Urgent need for standard guidelines and practices to address nephrotoxic risks from aminoglycosides, vancomycin, loop diuretics, and ibuprofen. [ABSTRACT FROM AUTHOR]

Melanin, particularly eumelanin, is commonly viewed as an efficient antioxidant and photoprotective pigment. Nonetheless, the ability of melanin to photogenerate reactive oxygen species and sensitize the formation of cyclobutane pyrimidine dimers may contribute to melanin‐dependent phototoxicity. The phototoxic potential of melanin depends on a variety of factors, including molecular composition, redox state, and degree of aggregation. Using complementary spectroscopic and analytical methods we analyzed the physicochemical properties of Dopa‐melanin, a synthetic model of eumelanin, subjected to oxidative degradation induced by aerobic photolysis or exposure to 0.1 M hydrogen peroxide. Both modes of oxidative degradation were accompanied by dose‐dependent bleaching of melanin and irreversible modifications of its paramagnetic, ion‐ and electron‐exchange and antioxidant properties. Bleached melanin exhibited enhanced efficiency to photogenerate singlet oxygen in both UVA and short‐wavelength visible light. Although chemical changes of melanin subunits, including a relative increase of DHICA content and disruption of melanin polymer induced by oxidative degradation were considered, these two mechanisms may not be sufficient for a satisfactory explanation of the elevated photosensitizing ability of the bleached eumelanin. This study points out possible adverse changes in the photoprotective and antioxidant properties of eumelanin that could occur in pigmented tissues after exposure to high doses of intense solar radiation. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) signaling plays a significant role in multiple biological processes, including inflammation, immunity, and cell death. However, its specific impact on the cochlea remains unclear. In this study, we aimed to investigate the effects of TGF-β signaling suppression on auditory function and cochlear pathology in mice with kanamycin-induced ototoxicity. Kanamycin and furosemide (KM-FS) were systemically administered to 8-week-old C57/BL6 mice, followed by immediate topical application of a TGF-β receptor inhibitor (TGF-βRI) onto the round window membrane. Results showed significant TGF-β receptor upregulation in spiral ganglion neurons (SGNs) after KM-FA ototoxicity, whereas expression levels in the TGF-βRI treated group remained unchanged. Interestingly, despite no significant change in cochlear TGF-β expression after KM-FS ototoxicity, TGF-βRI treatment resulted in a significant decrease in TGF-β signaling. Regarding auditory function, TGF-βRI treatment offered no therapeutic effects on hearing thresholds and hair cell survival following KM-FS ototoxicity. However, SGN loss and macrophage infiltration were significantly increased with TGF-βRI treatment. These results imply that inhibition of TGF-β signaling after KM-FS ototoxicity promotes cochlear inflammation and SGN degeneration. [ABSTRACT FROM AUTHOR]

Fluorescence microscopy is a powerful tool used in scientific and medical research, but it is inextricably linked to phototoxicity. Neglecting phototoxicity can lead to erroneous or inconclusive results. Recently, several reports have addressed this issue, but it is still underestimated by many researchers, even though it can lead to cell death. Phototoxicity can be reduced by appropriate microscopic techniques and carefully designed experiments. This review focuses on recent strategies to reduce phototoxicity in microscopic imaging of living cells and tissues. We describe digital image processing and new hardware solutions. We point out new modifications of microscopy methods and hope that this review will interest microscopy hardware engineers. Our aim is to underscore the challenges and potential solutions integral to the design of microscopy systems. Simultaneously, we intend to engage biologists, offering insight into the latest technological advancements in imaging that can enhance their understanding and practice. [ABSTRACT FROM AUTHOR]

The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise‐and‐test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well‐tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure–activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi‐automated synthesise‐and‐test protocol to obtain multiplex data within 72 hours. [ABSTRACT FROM AUTHOR]

The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise‐and‐test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well‐tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure–activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi‐automated synthesise‐and‐test protocol to obtain multiplex data within 72 hours. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to identify and clinically characterize patients treated in an Otoneurology Unit who experienced vestibular ototoxicity as a result of using aminoglycoside ear drops during outbreaks of superinfection in chronic otitis media. Material and Methods: An observational retrospective study was conducted, including patients with perforated eardrums who developed vestibular ototoxicity within the past 10 years following the application of topical ear aminoglycosides in a tertiary referral center. The study encompassed the assessment of the clinical presentation, treatment, quality of life, and evolution after treatment of the identified individuals. Results: During the study period, 6 patients, aged between 33 and 71 years, developed vestibular ototoxicity following the use of topical aminoglycoside drops due to infection flares in chronic otitis media. All cases involved the use of gentamicin. Two cases were unilateral, and 4 were unilateral. The onset of symptoms occurred within one to four weeks of using the drops, resulting in all patients experiencing instability without vertigo attacks. After discontinuing the drops and undergoing vestibular rehabilitation, 4 patients experienced sequelae, with 2 patients (both with bilateral vestibular hypofunction) suffering significant impairment in their quality of life. Conclusions: Vestibular ototoxicity due to the topical application of aminoglycosides during acute exacerbations of chronic otitis media is a rare occurrence. However, given its potential for severe consequences and the fact that we are still encountering patients with this condition, healthcare professionals should explore alternative antibacterial agents that offer similar efficacy. [ABSTRACT FROM AUTHOR]

Aminoglycoside antibiotics were historically a cornerstone of antimicrobial therapy for many bacterial infections but as the threat of antimicrobial resistance continues to rise, the once broad-spectrum activity of these agents grows smaller. They are also plagued with the potential for severe adverse events such as nephrotoxicity and ototoxicity, and emerging evidence suggests that these risks may outweigh their benefit in many cases. With the recent introduction of newer and likely safer broad-spectrum antibiotics, do aminoglycosides still have a place in therapy in modern medicine? [ABSTRACT FROM AUTHOR]

Introduction: Due to the growing burden of disease in South Africa, encompassing conditions such as tuberculosis, human immunodeficiency virus, and cancer, the holistic management of affected patients incorporating ototoxicity monitoring is a necessity. However, ototoxicity monitoring in developing countries may be limited due to a lack of resources and inadequate healthcare facilities. Subsequently, the use of tele-audiology may be a revolutionary technique with the potential to provide audiology services to under-served populations with limited access. Methods: The study aimed to describe the use of tele-audiology services in ototoxicity monitoring through a scoping review of English peer-reviewed articles from June 2009 to June 2020. Seventeen articles were purposively selected from the following databases: PubMed, Science Direct, Taylor and Francis Online, WorldCat, and Google Scholar. Data was extracted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram and results were analyzed using deductive thematic analysis. Results and discussion: While a minority of the studies indicated that the cost of implementation and network connectivity within a South African context pose as barriers, most researchers reported that tele-audiology provides a reliable, time-efficient, cost-effective, and easily accessible alternative for ototoxicity monitoring. Hardware including the WAHTS, KUDUwave, and OtoID, along with software such as the TabSINT, Otocalc, uHear, and the hearTest, have proven to be useful for ototoxicity monitoring. A need for further investigations regarding the feasibility of tele-audiology implementation in South Africa is evident. Despite this, it provides audiologists with an opportunity to offer contact-less services during COVID-19, thus, confirming its versatility as an augmentative method for ototoxicity monitoring. [ABSTRACT FROM AUTHOR]

Background and Objectives: Chloroquine and its analog hydroxychloroquine are derivatives of 4-aminoquinoline and are regularly used in the treatment of malaria and autoimmune diseases. Among the side effects of these drugs, alterations associated with the auditory system are frequently mentioned. Thus, the aim of this systematic review is to systematically review publications on hearing disorders and chloroquine or hydroxychloroquine use. Materials and Methods: Inclusion criteria were observational or interventional studies on audiological assessment in participants who were using chloroquine or hydroxychloroquine. The methodological quality was independently assessed by two reviewers using the Meta-Analysis of Statistics: assessment and review Instrument. The certainty of the evidence was assessed using the GRADE tool. Results: A total of 1,372 non-duplicate papers were screened, out of which 17 were included in the final qualitative synthesis, and 5 studies in the meta-analysis. The odds ratio for the two subgroups evaluated did not show significance with no heterogeneity between the effects observed between the different diseases (I²=0%) and obtaining the global estimate of 0.76 (95% confidence interval [CI]=0.41-1.39; p>0.05). Despite the inclusion of papers with different disease samples, the heterogeneity observed in the analysis was low (I²= 0%) and prediction interval (95% PI=0.32-1.80; p>0.05) remained close to that estimated by the CI (95% CI=0.41-1.39; p>0.05). The certainty of the evidence assessed by the GRADE tool was considered very low due to the risk of bias, indirect evidence, and imprecision. Conclusions: The findings of this study suggest that the use of chloroquine/hydroxychloroquine is not associated with hearing disorders. [ABSTRACT FROM AUTHOR]

Background: Management outcomes of drug-resistant (DR) osteoarticular tuberculosis (OATB) is dismal as in pre-ATT era (1905). The studies documenting treatment outcome of DR-OATB are scarce; hence, present retrospective analysis was conducted to evaluate outcome of consecutive cases of DR-OATB. Methods: 45 consecutive patients of suspected DR-OATB were treated from 2010 onwards. Tissue samples were submitted for AFB smear, cytology/histology, liquid culture, CBNAAT/LPA besides gram's staining and aerobic/anaerobic culture. Patients were treated by individualized second-line ATT till documenting healed status by contrast MRI/PET. The changes in neurological deficit, deformities, and drug-induced adverse events were documented. Results: 37/45 patients, 15 males and 22 females, mean age 26.89 years were followed. DR was suspected observing poor clinico-radiological response/appearance of fresh lesions on ATT. All showed no growth on aerobic/anaerobic pyogenic culture. 29 (78%) had microbiologically proven drug resistance and 8 (22%) were labeled as clinical drug resistance (CDR). 18/29 had multi-drug resistance. Mean prior ATT intake was 12.03 months 15 (40%) underwent surgical decompression. Mean duration of second-line ATT was 22.5 months (9–36 months). All patients achieved healed status with 8 (21%) developed side effects, most commonly hepatotoxicity, ototoxicity, and psychiatric disturbances. Average follow-up after completion of ATT was 40.5 months. Conclusion: We report a large series where patients of DR-OATB were suspected on clinical criteria, investigated by DST, and treated. Patients with proven drug resistance were treated by individualized second-line ATT. CDR cases were treated by MDR protocol. Genotypic DST (CBNAAT/LPA) improved demonstration of DR. We demonstrated healed status on MRI/PET with no recurrence at minimum 2-year follow-up. [ABSTRACT FROM AUTHOR]

Cisplatin (Cis Pt)-induced ototoxicity (CIO) is delineated as a consequence of Cis Pt-induced intracellular generation of reactive oxygen species (ROS) which can be circumvented by Bucillamine (BUC; an antioxidant drug with sulfhydryl groups) and Diltiazem (DLT, L-type calcium channel blocker). However, its effective accumulation in the Organ of Corti and cell cytoplasm is desired. Therefore, a biocompatible BUC- and DLT-nanoparticles (NPs)-impregnated dual stimuli-responsive formulation (NanoSensoGel) presented here with ROS- and thermo-responsive properties for the sustained and receptive delivery of drugs. The ROS-responsive polypropylene sulfide- methyl polyethylene glycol-2000 (PPS-mPEG 2000) polymer was rationally designed, synthesized, and characterized to fabricate BUC- and DLT-loaded PPS-mPEG 2000 -NPs (BUC- and DLT-NPs). The fabricated BUC- and DLT-NPs showed efficient cellular uptake, intracellular delivery, ROS responsiveness, and cytoprotective effect which was characterized using cellular internalization, intracellular ROS, mitochondrial superoxide, and Caspase 3/7 assays on the House Ear Institute-Organ of Corti-1 (HEI-OC1) cells. The composite NanoSensoGel (i.e. , ROS-responsive BUC- and DLT-NPs suspended in the thermo-responsive hydrogel) present in a sol state at room temperature and turned to gel above 33°C, which could be essential for retaining the formulation at the target site for long-term release. The NanoSensoGel showed sustained release of BUC and DLT following Fickian release diffusion kinetics. Overall, a novel NanoSensoGel formulation developed in this study has demonstrated its great potential in delivering therapeutics in the inner ear for prophylactic treatment of CIO, and associated hearing loss. Development of dual stimuli-responsive and dual drug-loaded nanoparticle-based composite NanoSensoGel formulation for local delivery to the inner ear via intratympanic route, and the corresponding mechanism of action of the inhibition of reactive oxygen species (ROS)-associated apoptotic cell death of the iner ear hair cells and subsequent hearing loss. [Display omitted] [ABSTRACT FROM AUTHOR]

The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. A total of 42 adult TDT patients (18 male, 24 female; age range: 41–55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gentamicin is a commonly used medication in NICUs. It is known to have ototoxic & nephrotoxic side effects. To date there is no consensus about dosing regimen in different institutions. Our study aims to evaluate the Neofax® dosing regimen for gentamicin in neonatal early onset sepsis in relation to trough level before the second dose and its association with the incidence of gentamicin side effects, namely hearing impairment/loss and acute kidney injury. METHODS: Retrospective chart review of newborns admitted to Tawam hospital NICU (June 2019–May 2020) who received gentamicin for early onset sepsis (≤72 hours old). Trough levels before the second dose at 24,36 and 48 hours were reviewed (≥1 mg/L is high). Excluded patients with renal risk factors. Side effects (hearing impairment, acute renal injury) were also assessed. RESULTS: Total of 265 infants were included, among whom 149 patients received gentamicin at 24 hours interval, 99 at 36 and 17 at 48 hours interval. Trough level was high in 76% (P = 0.022), 65% (P = 0.127), and 53% (P = 0.108) of patients who received gentamicin at 24, 36, and 48 hours, respectively. Hearing screening was normal in 99.2% of patients, while 2 patients failed the test (Both with normal trough levels). No patients in our study developed renal injury related to gentamicin use. CONCLUSION: Neofax® gentamicin dosing often results in high trough levels, especially in late preterm/term infants. This study found no correlation between high trough levels and hearing impairment upon discharge or acute kidney injury. Further studies with larger sample size are recommended. [ABSTRACT FROM AUTHOR]

Purpose: Persons with cystic fibrosis (PwCF) are at high risk for ototoxicity due to the routine use of intravenous aminoglycoside (IV-AG) antibiotics in respiratory infection management. Additionally, factors that contribute to ototoxicity-related symptom development and severity in PwCF are unknown. Given the increased risk of ototoxicity in people with diabetes, we explored the association between cystic fibrosis--related diabetes (CFRD) and self-reported ototoxicity symptoms (tinnitus and vestibular problems) in PwCF treated with aminoglycosides. Method: PwCF (N = 39; 25 females, 14 males; Mage = 30.1 years, SD = 10.3) were recruited from the Cystic Fibrosis Care Center at Oregon Health & Science University. Patients completed the validated questionnaires to ascertain their experiences with ototoxicity-related symptoms of tinnitus and balance function. The diagnosis of CFRD, including oral glucose tolerance testing (OGTT), insulin treatment, hemoglobin A1c, and cumulative IV-AG treatment history, was obtained through a medical chart review. Participants were classified into three groups based on their medical diagnoses via OGTT: normal glucose tolerance (NGT; control; n = 16), abnormal glucose tolerance (AGT; n = 9), and CFRD (n = 14). Participants in each group were further classified based on survey outcomes for ototoxicity-related symptoms. Results: There was a trend toward a higher proportion of patients with CFRD reporting tinnitus compared to the AGT and NGT groups, but did not meet statistical significance (§² = 2.24, p = .13). Approximately, 43% of patients with CFRD reported experiencing clinically significant tinnitus lasting > 3 min compared to 11% in the AGT group and 13% in the NGT group (§² = 3.751, p = .05). Cumulative IV-AG exposure tended to be higher in CFRD compared to other groups. High balance function was generally reported in all groups. Conclusions: Patients with CFRD have greater ototoxicity-related symptoms. Further investigation of the relationship between CF-related comorbidities and the risk of developing ototoxicity-related symptoms is warranted to improve the detection and management of ototoxicity in PwCF. [ABSTRACT FROM AUTHOR]

Introduction: Streptomycin and kanamycin are aminoglycosides that are toxic to the cochlea vestibular system, can causing hearing loss. This antibiotic is used for the treatment of tuberculosis and its ototoxicity occurs in 20% of tuberculosis patients. Spirulina is a cyanobacterial species that is used as a dietary supplement and contains phycocyanin compounds that function as antioxidants and anti-inflammatory. The aim of this study was to determine the effect of spirulina on histopathological changes in the cochlea in Wistar rats after kanamycin induction. Methods: this study is a form of posttest-only controlled group design research with a sample of 24 wistar rats divided into 4 groups, namely negative control group, positive control group, treatment group 1 and treatment group 2. Observations of the study took place in November-December 2021. Histopathological measurements in hair cells, macrophages and cochlear vasculature. The analysis used non-parametric Kruskal-Wallis and post-hoc Mann-Whitney tests. Results: There were more hair cell damage, macrophage cell count, and significant vascular dilatation in the kanamycin group than in the without kanamycin group with the value p=0.001. There was significantly less number of hair cell damage in the kanamycin group with spirulina at a dose of 1000 mg than in the kanamycin group with spirulina at a dose of 400 mg p=0.045. Conclusion: There was a significant effect on the administration of spirulina on histopathological changes in the cochlea of rats. [ABSTRACT FROM AUTHOR]

Hypertension is known to be a multifactorial disease associated with abnormalities in neuroendocrine, metabolic, and hemodynamic systems. Poorly controlled hypertension causes more than one in eight premature deaths worldwide. Hydrochlorothiazide (HCT) and furosemide (FUR), being first-line drugs in the treatment of hypertension, are among others the most frequently prescribed drugs in the world. Currently, many pharmacoepidemiological data associate the use of these diuretics with an increased risk of adverse phototoxic reactions that may induce the development of melanoma and non-melanoma skin cancers. In this study, the cytotoxic and phototoxic potential of HCT and FUR against skin cells varied by melanin pigment content was assessed for the first time. The results showed that both drugs reduced the number of metabolically active normal skin cells in a dose-dependent manner. UVA irradiation significantly increased the cytotoxicity of HCT towards fibroblasts by approximately 40% and melanocytes by almost 20% compared to unirradiated cells. In the case of skin cells exposed to FUR and UVA radiation, an increase in cytotoxicity by approximately 30% for fibroblasts and 10% for melanocytes was observed. Simultaneous exposure of melanocytes and fibroblasts to HCT or FUR and UVAR caused a decrease in cell viability, and number, which was confirmed by microscopic assessment of morphology. The phototoxic effect of HCT and FUR was associated with the disturbance of redox homeostasis confirming the oxidative stress as a mechanism of phototoxic reaction. UVA-irradiated drugs increased the generation of ROS by 10–150%, and oxidized intracellular thiols. A reduction in mitochondrial potential of almost 80% in melanocytes exposed to HCT and UVAR and 60% in fibroblasts was found due to oxidative stress occurrence. In addition, HCT and FUR have been shown to disrupt the cell cycle of normal skin cells. Finally, it can be concluded that HCT is the drug with a stronger phototoxic effect, and fibroblasts turn out to be more sensitive cells to the phototoxic effect of tested drugs. [ABSTRACT FROM AUTHOR]

Aim: Cinchonine (CN) and its isomer cinchonidine (CD), two of the common cinchona alkaloids, are wildly used as antimalarial drugs. However, the effects of CN and CD on the auditory system are unknown. Methods: Molecular docking and molecular dynamics (MD) simulation were used for predicting effective drugs. The CCK‐8 assay was conducted for assessing cell viability in House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells. MitoSox Red staining revealed reactive oxygen species (ROS) amounts. TMRM staining was used to assess the mitochondrial membrane potential (ΔΨm). Immunofluorescence staining of myosin 7a was used to examine hair cells (HCs) in cisplatin‐treated neonatal mouse cochlear explants, while TUJ‐1 immunostaining was used for the detection of spiral ganglion neurons (SGNs). Cleaved caspase‐3 and TUNEL immunostaining were utilized for apoptosis assessment. Immunoblot was carried out to detect PI3K‐AKT signaling effectors. Results: Pretreatment with CN or CD significantly increased cell viability and reduced mitochondrial dysfunction and ROS accumulation in cisplatin‐treated HEI‐OC1 cells. Immunofluorescent staining of cochlear explants showed that CN and CD attenuated cisplatin‐induced damage to SGNs and HCs. Immunoblot revealed that CN and CD downregulated the expression of cleaved caspase‐3 and activated PI3K‐AKT signaling in cisplatin‐injured HEI‐OC1 cells. Conclusion: CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin‐associated hearing loss. [ABSTRACT FROM AUTHOR]

Two novel cyclometallated iridium(III) complexes have been prepared with one bidentate or two monodentate imidazole-based ligands, 1 and 2, respectively. The complexes showed intense emission with long lifetimes of the excited state. Femtosecond transient absorption experiments established the nature of the lowest excited state as 3IL state. Singlet oxygen generation with good yields (40% for 1 and 82% for 2) was established by detecting 1O2 directly, through its emission at 1270 nm. Photostability studies were also performed to assess the viability of the complexes as photosensitizers (PS) for photodynamic therapy (PDT). Complex 1 was selected as a good candidate to investigate light-activated killing of cells, whilst complex 2 was found to be toxic in the dark and unstable under light. Complex 1 demonstrated high phototoxicity indexes (PI) in the visible region, PI > 250 after irradiation at 405 nm and PI > 150 at 455 nm, in EJ bladder cancer cells. [ABSTRACT FROM AUTHOR]

AIM: To study whether glycyrrhizic acid (GL) can resist the ototoxicity of cisplatin( CDDP) in mice and its molecular mechanism. METHODS： Male C57BL/6J mice were divided into 5 groups： control group, DMSO(5%) group, CDDP(4 mg/kg) group, CDDP+low-dose(50 mg/kg) GL group, and CDDP+high-dose(100 mg/kg) GL group(n=14) . Auditory brainstem response(ABR) was used to detect hearing changes of mice. HE staining was used to observe the morphological change of cochlear stria vascular in mice. Evans blue(EB) staining was used to observe the per meability change of the blood-labyrinth barrier (BLB) . Immunohistochemical technique was used to detect the expression and distribution of adhesion protein VE-cadherin and tight junction protein ZO-1 on the cochlear stria. ELISA assay and immunofluorescence technology were employed to detect the expression of tumor necrosis factor-α( TNF-α) and interleu kin-1β( 1L-1β) . RESULTS： In CDDP group, ABR waveforms of all frequencies were disturbed, the hearing threshold was significantly increased, and I wave latency was prolonged (P<0. 05) . In CDDP+GL group, ABR waveforms of various frequencies were well differentiated, the hearing threshold was significantly decreased, and the latency of I-wave was shortened(P<0. 01) . The disordered morphology and more vacuoles in the stria vascularis were observed by HE staining in CDDP group. The GL alleviated CDDP-induced damage in the stria vascularis. In EB staining, CDDP caused an increase in per meability of BLB(P<0. 01), which was improved by GL treatment (P<0. 01) . Immunohistochemical results showed that the expression of VE-cadherin and ZO-1 in CDDP group were decreased (P<0. 01), which was restored in CDDP+GL group(P<0. 01) . The ELISA and immunofluorescence results showed that the expression of IL-1β and TNF-α was increased after CDDP treatment(P<0. 01), which was restored in CDDP+GL group(P<0. 01) . CONCLUSION: The GL alleviates CDDP-induced hearing loss in mice by inhibiting CDDP-induced inflammation and reducing the permeability of BLB. [ABSTRACT FROM AUTHOR]

Fluorescence microscopy is essential for studying living cells, tissues and organisms. However, the fluorescent light that switches on fluorescent molecules also harms the samples, jeopardizing the validity of results - particularly in techniques such as super-resolution microscopy, which demands extended illumination. Artificial intelligence (AI)-enabled software capable of denoising, image restoration, temporal interpolation or cross-modal style transfer has great potential to rescue live imaging data and limit photodamage. Yet we believe the focus should be on maintaining light-induced damage at levels that preserve natural cell behaviour. In this Opinion piece, we argue that a shift in role for AIs is needed - AI should be used to extract rich insights from gentle imaging rather than recover compromised data from harsh illumination. Although AI can enhance imaging, our ultimate goal should be to uncover biological truths, not just retrieve data. It is essential to prioritize minimizing photodamage over merely pushing technical limits. Our approach is aimed towards gentle acquisition and observation of undisturbed living systems, aligning with the essence of live-cell fluorescence microscopy. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a two-stage treatment that implies the use of light energy, oxygen, and light-activated compounds (photosensitizers) to elicit cancerous and precancerous cell death after light activation (phototoxicity). The biophysical, bioengineering aspects and its combinations with other strategies are highlighted in this review, both conceptually and as they are currently applied clinically. We further explore the recent advancements of PDT with the use of nanotechnology, including quantum dots as innovative photosensitizers or energy donors as well as the combination of PDT with radiotherapy and immunotherapy as future promising cancer treatments. Finally, we emphasize the potential significance of organoids as physiologically relevant models for PDT. [ABSTRACT FROM AUTHOR]

Our study investigated the embryo-ototoxic effects of deodorant2 (DA2) on zebrafish embryos, which serve as valuable model organisms due to genetic and physiological similarities to humans. We focused on understanding DA2's impact on zebrafish hair cells, which are vital for sensory perception and balance regulation. DA2, provided by the Ministry of Environment, Republic of Korea, was used at 460 μg/mL in dimethyl sulfoxide (DMSO), with a 0.43% DMSO solvent control group. Three experiments, each using 10 zebrafish specimens from each group, showed an initial 13% hair cell count reduction in the DA2-exposed group. Subsequent experiments demonstrated reductions of 37% and 22%, each with one mortality case. Statistical analysis revealed a significant 24% hair cell count reduction in the DA2-exposed group. We also assessed DA2's impact on zebrafish behavior. Although not statistically significant, differences in distances traveled (0.33–0.39, 95% confidence interval: −0.46–1.1, p = 0.2033) and latencies (−0.016–0.018, 95% confidence interval: −0.052–0.021, p = 0.1917) hinted at negative effects. These results highlight DA2's ototoxic properties affecting zebrafish auditory systems and behavior. Further investigation into DA2's effects on aquatic organisms and potential mitigation strategies are essential. These findings contribute to understanding DA2's safety profile, benefiting aquatic ecosystems and human health assessments. [ABSTRACT FROM AUTHOR]

Timolol (TIM) is a non-selective ß-adrenergic receptor antagonist used orally for the treatment of hypertension and heart attacks, and topically for treating glaucoma; lately, it has also been used in some specific dermatological problems. In the present study, its photodegradation and potential risk of phototoxicity were examined using chemical, in silico and in vitro methods. The UV/VIS irradiated solutions of TIM at pH 1–13 were subjected to LC-UV and UPLC-HRMS/MS analyses showing pseudo first-order kinetics of degradation and several degradation products. The structures of these photodegradants were elucidated by fragmentation path analysis based on high resolution (HR) fragmentation mass spectra, and then used for toxicity evaluation using OSIRIS Property Explorer and Toxtree. Potential risk of phototoxicity was also studied using chemical tests for detecting ROS under UV/VIS irradiation and in vitro tests on BALB/c 3T3 mouse fibroblasts (MTT, NRU and Live/Dead tests). TIM was shown to be potentially phototoxic because of its UV/VIS absorptive properties and generation ROS during irradiation. As was observed in the MTT and NRU tests, the co-treatment of fibroblasts with TIM and UV/VIS light inhibited cell viability, especially when concentrations of the drug were higher than 50 µg/mL. [ABSTRACT FROM AUTHOR]

Continuous exposure of human skin to air pollution can result in a range of undesirable skin conditions. In our recent study, UV and visible light were found to increase cytotoxicity of fine particulate matter (PM2.5) against human keratinocytes. Since it is impossible to avoid exposure of human skin to PM2.5, effective strategies are needed to reduce their damaging effects. l‐ascorbic acid and resveratrol were tested as potential topical agents against pollution‐related skin impairment. Although these agents were previously found to ameliorate PM‐dependent damage, the effect of light and seasonal variation of particles were not previously studied. EPR spin‐trapping, DPPH assay, and singlet oxygen phosphorescence were used to determine the scavenging activities of the antioxidants. MTT, JC‐10 and iodometric assays were used to analyze the effect on PM2.5‐induced cytotoxicity, mitochondrial damage and oxidation of lipids. Live‐cell imaging was employed to examine wound‐healing properties of cells. Light‐induced, PM2.5‐mediated oxidative damage was examined by immunofluorescent staining. Both antioxidants effectively scavenged free radicals and singlet oxygen produced by PM2.5, reduced cell death and prevented oxidative damage to HaCaT cells. l‐ascorbic acid and resveratrol, especially when applied in combination, can protect HaCaT cells against the dark and light induced toxicity of PM2.5. [ABSTRACT FROM AUTHOR]

Synthetic cosmetics, particularly hair dyes, are becoming increasingly popular among people of all ages and genders. 2,4,5,6-tetraaminopyrimidine sulfate (TAPS) is a key component of oxidative hair dyes and is used as a developer in several hair dyes. TAPS has previously been shown to absorb UVB strongly and degrade in a time-dependent manner, causing phototoxicity in human skin cells. However, the toxic effects of UVB-degraded TAPS are not explored in comparison to parent TAPS. Therefore, this research work aims to assess the toxicity of UVB-degraded TAPS than TAPS on two different test systems, that is, HaCaT (mammalian cell) and Staphylococcus aureus (a bacterial cell). Our result on HaCaT has illustrated that UVB-degraded TAPS is less toxic than parent TAPS. Additionally, UVB-exposed TAPS and parent TAPS were given to S. aureus, and the bacterial growth and their metabolic activity were assessed via CFU and phenotype microarray. The findings demonstrated that parent TAPS reduced bacterial growth via decreased metabolic activity; however, bacteria easily utilized the degraded TAPS. Thus, this study suggests that the products generated after UVB irradiation of TAPS is considered to be safer than their parent TAPS. Graphical Abstract [ABSTRACT FROM AUTHOR]

Photosensitization, occurring as a result of drug treatment, represents 8% of all drug-induced skin adverse reactions. The drug photosensitization reaction is unpredictable and every patient can be affected, as it can occur at any age and can be caused by numerous drugs. Currently, two types of photosensitization reactions are known, namely: phototoxic and photoallergic reactions. Phototoxicity reactions are manifested by a direct action of cellular destruction, are not immune-mediated, are dose-dependent, and can occur at first exposure in most individuals receiving photosensitizing drugs. Photoallergic reactions are immune-mediated, not dose-dependent, occur only in sensitized individuals, and are characterized by cross-reactions between related compounds. There are a lot of photosensitizing drugs such as: antibiotics, sulfanilamides, fluoroquinolones, nonsteroidal anti-inflammatory drugs, diuretics, hormonal contraceptives, retinoids, etc. Some drugs cause only one type of reaction, while others may cause both. In general, the prognosis of drug photosensitization reactions is a good one, if certain rules are followed, such as the use of protective creams, clothing and protective glasses together with the drugs, as well as the doctor’s supervision of the treatment evolution. [ABSTRACT FROM AUTHOR]

Ototoxicity is a major side effect of aminoglycosides, which can cause irreversible hearing loss. Previous studies on aminoglycoside-induced ototoxicity have primarily focused on the loss of sensory hair cells. Recent investigations have revealed that aminoglycosides can also lead to the loss of ribbon synapses in inner hair cells (IHCs). However, the functional implications of ribbon synapse loss and the underlying mechanisms remain unclear. In this study, we intraperitoneally injected C57BL/6 J mice with 300 mg/kg gentamicin once daily for 3, 10, and 20 days. Then, we performed immunofluorescence staining, patch-clamp recording, proteomics analysis and western blotting to characterize the changes in ribbon synapses in IHCs and the associated mechanisms. After gentamicin treatment, the auditory brainstem response (ABR) threshold was elevated, and the ABR wave I amplitude was decreased. We also observed loss of ribbon synapses in IHCs. Interestingly, ribbon synapse loss occurred on both the modiolar and pillar sides of IHCs. Whole-cell patch-clamp recordings in IHCs revealed a reduction in the calcium current amplitude, along with a shifted half-activation voltage and altered calcium voltage dependency. Moreover, exocytosis of IHCs was reduced, consistent with the reduction in the ABR wave I amplitude. Through proteomic analysis, western blotting, and immunofluorescence staining, we found that gentamicin treatment resulted in downregulation of myosin VI, a protein crucial for synaptic vesicle recycling and replenishment in IHCs. Furthermore, we evaluated the kinetics of endocytosis and found a significant reduction in IHC exocytosis, possibly reflecting the impact of myosin VI downregulation on synaptic vesicle recycling. In summary, our findings demonstrate that gentamicin treatment leads to synaptic dysfunction in IHCs, highlighting the important role of myosin VI downregulation in gentamicin-induced synaptic damage. [Display omitted] • Gentamicin leads to a loss of ribbons on both the modiolar and pillar sides of the inner hair cells. • Gentamicin leads to a reduction in calcium currents and a decrease in endocytosis and exocytosis in inner hair cells. • Downregulation of myosin VI is involved in gentamicin-induced cochlear synaptopathy. [ABSTRACT FROM AUTHOR]

The photochemical behavior of the phototoxic antidepressant drug venlafaxine (VLF, 1) was studied under aerobic conditions in UV-A light. Irradiation of a phosphate buffer solution of the drug produces N-Demethylated (2) and O-Demethylated (3) as two major photoproducts. The formation of photoproducts (2) and (3) occurs through a singlet oxygen-mediated mechanism, i.e., type-II photodynamic action, involving an irreversible trapping of the self-photogenerated singlet molecular oxygen (1O2) and through free radical-mediated mechanism, i.e., type 1 photodynamic action, respectively. The generation of singlet oxygen and free radicals during photolysis was confirmed by singlet oxygen scavenger sodium azide (NaN3) and free radical scavenger reduced glutathione (GSH). In addition, the comparative antioxidant potentials of the parent drug and its photoproducts were examined utilizing in-silico molecular docking against tyrosinase to better understand the in vivo relevance of drug pharmacological action as a result of drug-light interaction. Photoproduct (2) exhibited less activity as compared to the parent drug, VLF (1), whereas photoproduct (3) formed a stable protein–ligand complex. In order to determine the nature of stability of complex between protein and ligand, further, molecular dynamics (MD) simulation on photoproduct (3) was performed for 100 ns, and the results were analyzed by monitoring root mean square deviations (RMSD), the radius of gyration (Rg), and solvent accessible surface area (SASA). The results proved the formation of a better protein–ligand complex with photoproduct (3). These findings imply that drug users should avoid their exposure to light (natural or artificial) to prevent drug-induced photosensitivity. This study also opens new vistas for the development of novel drugs with desired tyrosinase binding affinity, improved biological features, and low phototoxic manifestations. [ABSTRACT FROM AUTHOR]

Exposure to loud noise or chemical agents may cause hearing disorders such as tinnitus and recruitment, known as an increase in the perception of loudness in addition to hearing loss. Our study aims to evaluate the hearing abilities of hairdressers exposed to noise and chemical agents in the working environment. The study included one hundred hairdressers and one hundred participants who do not work as hairdressers or are nonworkers. The participants' demographic characteristics, working conditions, and auditory complaints were questioned, and each participant completed the Speech, Spatial, and Qualities of Hearing Scale (SSQ). A statistically significant difference was found between the two groups in speech perception, spatial perception, hearing quality, and general SSQ scores. Hairdressers' SSQ scores were significantly lower in all sub-dimensions and general scale scores (p < 0.001). The auditory complaints of the hairdressers and the low SSQ scores indicate that exposure to noise and chemical agents affects the hairdressers' hearing system. [ABSTRACT FROM AUTHOR]

To better characterize the frequency and patterns of hearing dysfunction in patients who have received teprotumumab to treat thyroid eye disease. Noncomparative case series. Patients who underwent audiology testing before and after completion of teprotumumab infusions. A review of patients who underwent audiology testing before and after completion of teprotumumab infusions was carried out. Additional audiogram testing during treatment was included when available. Hearing function was analyzed using audiogram data measuring threshold hearing levels at specific frequencies. Basic demographic data as well as information regarding otologic symptoms also were obtained and analyzed. Hearing loss demonstrated by a significant change in decibel hearing thresholds or that meets criteria for ototoxicity. Twenty-two patients (44 ears) were included in the study, with baseline and most recent audiology testing after treatment ranging from 84 days before to 496 days after treatment. Fifteen patients (30 ears) also underwent testing during treatment starting after the second infusion up until the day of, but before, the eighth infusion. Hearing loss after treatment met criteria for ototoxicity in 17 of the 44 ears (38.6%), with 11 of the 22 patients (50.0%) meeting criteria in at least 1 ear. The pure-tone average decibel hearing levels (HLs) across all 44 ears demonstrated hearing loss after treatment (P = 0.0029), specifically at high (P = 0.0008) and middle frequencies (P = 0.0042), but not at low frequencies (P = 0.8344). Patients who were older also were more likely to experience hearing loss after treatment (P = 0.0048). Audiometric data demonstrate that teprotumumab influences hearing function, most significantly at higher frequencies and in older patients. Audiometric testing is critical for counseling patients regarding teprotumumab treatment. A protocol for monitoring hearing during treatment is needed to detect and manage hearing changes associated with teprotumumab use. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results. [ABSTRACT FROM AUTHOR]

Objectives: Ototoxicity is a common disabling side effect of platinum‐based chemotherapy. This study aimed to assess the evidence on the management of platinum‐induced ototoxicity in adult cancer patients. Methods: Four databases were searched up to 1 November 2022. Original studies were included if they reported on a pharmacologic or non‐pharmacologic intervention to prevent or treat platinum ototoxicity in adults. The articles' quality was assessed via two grading scales. Results: Nineteen randomised controlled trials and five quasi‐experimental studies with 1673 patients were analysed. Eleven interventions were identified, nine pharmacological and two non‐pharmacological. Six of the interventions (sodium thiosulphate, corticoids, sertraline, statins, multivitamins and D‐methionine) showed mild benefits in preventing cisplatin‐induced ototoxicity. Only one trial assessed corticoids as a potential treatment. Overall, only six trials were deemed with a low risk of bias. The majority of studies inadequately documented intervention‐related adverse effects, thereby limiting safety conclusions. Conclusions: Current interventions have mild benefits in preventing cisplatin‐induced ototoxicity in adult cancer patients. Sodium thiosulphate is the most promising intervention as a preventive strategy. Rigorous, high‐quality research is warranted, encompassing an evaluation of all potential symptoms and innovative treatment modalities. [ABSTRACT FROM AUTHOR]

Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in clinical settings is limited due to anatomical barriers in the inner ear and pharmacokinetic instability. To address this issue, we developed an injectable hydrogel called RADA 32 -HRN-dexamethasone (RHD). The RHD hydrogel possesses self-anti-inflammatory properties and can self-assemble into nanofibrous structures, ensuring controlled and sustained release of dexamethasone in the local region. Flow cytometry analysis revealed that the uptake of FITC-conjugated RHD gel by hair cells increased in a time-dependent manner. Compared to free dexamethasone solutions, dexamethasone-loaded RHD gel achieved a longer and more controlled release profile of dexamethasone. Additionally, RHD gel effectively protected against the inflammatory response, reduced excessive reactive oxygen species production, and reversed the decline in mitochondrial membrane potentials induced by ionizing radiation, leading to attenuation of apoptosis and DNA damage. Moreover, RHD gel promoted the recovery of outer hair cells and partially restored auditory function in mice exposed to ionizing radiation. These findings validated the protective effects of RHD gel against radiation-induced ototoxicity in both cell cultures and animal models. Furthermore, RHD gel enhanced the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which was inhibited by ionizing radiation, thereby promoting the survival of hair cells. Importantly, intratympanic injections of RHD gel exhibited excellent biosafety and do not interfere with the anti-tumor effects of radiotherapy. In summary, our study demonstrates the therapeutic potential of injectable dexamethasone-loaded RHD hydrogel for the treatment of radiation-induced hearing loss by regulating the mTOR signaling pathway. Synthesis and schematic illustration of RHD gel for radiation-induced ototoxicity. (A) Schematic diagram of the synthesis of RHD gel. (B) Intratympanic injections of RHD gel. (C) Schematic diagram of animal experimentation. (D) Schematic diagram of RHD gel regulating ROS/mTOR signaling pathway for protecting against radiation-induced hearing loss. [Display omitted] • Intratympanic injection of hydrogel is a safe and effective way to deliver drugs. • RHD peptide gel may affect the mTOR pathway by decreasing ROS levels, protecting against radiation-induced ototoxicity. • RHD gel demonstrates biocompatibility and does not compromise the anti-tumor efficacy of radiotherapy. [ABSTRACT FROM AUTHOR]

• In the cochlea, sound detection highly relies on the extracellular matrix (ECM) integrity, and hereditary deafness in humans is caused by mutations in numerous ECM-related genes. • Cochlear matrisome plays an active role during the development of the hearing organ and the establishment of its unique architecture. • Cochlear matrisome changes with ageing and in response to cochlear insults, such as noise exposure, ototoxic drug administration and insertion of cochlear implants. • ECM remodeling exerts protective functions or improves tissue repair after injury but may also exacerbate cochlear damage. Deciphering the role of individual ECM components and regulators might provide valuable therapeutic targets for hearing preservation. The extracellular matrix (ECM) consists in a complex meshwork of collagens, glycoproteins, and proteoglycans, which serves a scaffolding function and provides viscoelastic properties to the tissues. ECM acts as a biomechanical support, and actively participates in cell signaling to induce tissular changes in response to environmental forces and soluble cues. Given the remarkable complexity of the inner ear architecture, its exquisite structure-function relationship, and the importance of vibration-induced stimulation of its sensory cells, ECM is instrumental to hearing. Many factors of the matrisome are involved in cochlea development, function and maintenance, as evidenced by the variety of ECM proteins associated with hereditary deafness. This review describes the structural and functional ECM components in the auditory organ and how they are modulated over time and following injury. [ABSTRACT FROM AUTHOR]

The Kir4.1 channel, an inwardly rectifying potassium ion (K+) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria vascularis. The Kir4.1 channel has a crucial role in the generation of endolymphatic potential and maintenance of the resting membrane potential. However, the role and functions of the Kir4.1 channel in the progenitor remain undescribed. To observe the role of Kir4.1 in the progenitor treated with the one-shot ototoxic drugs (kanamycin and furosemide), we set the proper condition in culturing Immortomouse-derived HEI-OC1 cells to express the potassium-related channels well. And also, that was reproduced in mice experiments to show the important role of Kir4.1 in the survival of hair cells after treating the ototoxicity drugs. In our results, when kanamycin and furosemide drugs were cotreated with HEI-OC1 cells, the Kir4.1 channel did not change, but the expression levels of the NKCC1 cotransporter and KCNQ4 channel are decreased. This shows that inward and outward channels were blocked by the two drugs (kanamycin and furosemide). However, noteworthy here is that the expression level of Kir4.1 channel increased when kanamycin was treated alone. This shows that Kir4.1, an inwardly rectifying potassium channel, acts as an outward channel in place of the corresponding channel when the KCNQ4 channel, an outward channel, is blocked. These results suggest that the Kir4.1 channel has a role in maintaining K+ homeostasis in supporting cells, with K+ concentration compensator when the NKCC1 cotransporter and Kv7.4 (KCNQ4) channels are deficient. [ABSTRACT FROM AUTHOR]

Cisplatin is a chemotherapeutic drug for the treatment of several solid tumors, whose use is limited by its nephrotoxicity, neurotoxicity, ototoxicity, and development of resistance. The toxicity is caused by DNA cross-linking, increase in reactive oxygen species and/or depletion of cell antioxidant defenses. The aim of the work was to study the effect of antioxidant compounds (Lisosan G, Taurisolo®) or hydrogen sulfide (H2S)-releasing compounds (erucin) in the auditory HEI-OC1 cell line treated with cisplatin. Cell viability was determined using the MTT assay. Caspase and sphingomyelinase activities were measured by fluorometric and colorimetric methods, respectively. Expression of transcription factors, apoptosis hallmarks and genes codifying for antioxidant response proteins were measured by Western blot and/or RT-qPCR. Lisosan G, Taurisolo® and erucin did not show protective effects. Sodium hydrosulfide (NaHS), a donor of H2S, increased the viability of cisplatin-treated cells and the transcription of heme oxygenase 1, superoxide dismutase 2, NAD(P)H quinone dehydrogenase type 1 and the catalytic subunit of glutamate-cysteine ligase and decreased reactive oxygen species (ROS), the Bax/Bcl2 ratio, caspase-3, caspase-8 and acid sphingomyelinase activity. Therefore, NaHS might counteract the cytotoxic effect of cisplatin by increasing the antioxidant response and by reducing ROS levels and caspase and acid sphingomyelinase activity. [ABSTRACT FROM AUTHOR]

High energy visible (HEV) blue light is an increasing source of concern for visual health. Polycyclic aromatic hydrocarbons (PAH), a group of compounds found in high concentrations in smokers and polluted environments, accumulate in the retinal pigment epithelium (RPE). HEV absorption by indeno [1,2,3-cd]pyrene (IcdP), a common PAH, synergizes their toxicities and promotes degenerative changes in RPE cells comparable to the ones observed in age-related macular degeneration. In this study, we decipher the processes underlying IcdP and HEV synergic toxicity in human RPE cells. We found that IcdP-HEV toxicity is caused by the loss of the tight coupling between the two metabolic phases ensuring IcdP efficient detoxification. Indeed, IcdP/HEV co-exposure induces an overactivation of key actors in phase I metabolism. IcdP/HEV interaction is also associated with a downregulation of proteins involved in phase II. Our data thus indicate that phase II is hindered in response to co-exposure and that it is insufficient to sustain the enhanced phase I induction. This is reflected by an accelerated production of endogenous reactive oxygen species (ROS) and an increased accumulation of IcdP-related bulky DNA damage. Our work raises the prospect that lifestyle and environmental pollution may be significant modulators of HEV toxicity in the retina. [ABSTRACT FROM AUTHOR]

Background: High‐dose carboplatin is an essential part of curative high‐dose chemotherapy (HDCT) for patients with previously treated germ cell tumors (GCTs). Although hearing loss (HL) is a known side effect of HDCT, data on its severity and characteristics are limited. Methods: Eligible patients received HDCT for GCTs from 1993 to 2017 and had audiograms before and after HDCT. HL severity was classified by American Speech‐Language‐Hearing Association criteria, and mean change in hearing threshold at each frequency (0.25–8 kHz) was estimated from pre‐ to post‐HDCT and between HDCT cycles. Results: Of 115 patients (median age, 32 years), 102 (89%) received three cycles of HDCT. Of 106 patients with normal hearing to mild HL in the speech frequencies (0.5–4 kHz) before HDCT, 70 (66%) developed moderate to profound HL in the speech frequencies after HDCT. Twenty‐five patients (22%) were recommended for hearing aids after HDCT. Patients with moderate to profound HL isolated to the higher frequencies (6–8 kHz) before HDCT were more likely to develop moderate to profound HL in the speech frequencies after HDCT (94% vs. 61%; p =.01) and to be recommended for hearing aids (39% vs. 18%; p =.05). Conclusions: HL was frequent after HDCT for GCTs, with most patients developing at least moderate HL in the speech frequencies and approximately one in five recommended for hearing aids. Moderate to profound HL isolated to high frequencies at baseline was predictive of more clinically significant hearing impairment after HDCT. Plain Language Summary: Some patients with germ cell tumors, the most common malignancy in adolescent and young adult men, are not cured with standard‐dose chemotherapy and require high‐dose chemotherapy (HDCT).Using detailed hearing assessments of patients receiving HDCT, we found that most patients developed significant hearing loss and that one in five needed hearing aids.Thus, strategies to reduce this side effect are urgently needed, and all patients receiving HDCT should have a hearing test after therapy. High‐dose carboplatin for relapsed or refractory germ cell tumors has a profound impact on patients' hearing. Strategies to reduce this ototoxicity are urgently needed, and management of patients receiving high‐dose carboplatin should include routine posttreatment audiometric assessment. [ABSTRACT FROM AUTHOR]

Cisplatin-based therapies are standard-of-care for advanced-stage head and neck squamous cell carcinoma (HNSCC). Treatment regimens include 3 weeks of high-dose bolus cisplatin or 6–7 weeks of low-dose weekly cisplatin, both with concurrent radiation. The effects of cisplatin dosage on swallowing function warrant further study. A 237-patient cohort treated for HNSCC at a single center were studied retrospectively. Gastrostomy tube dependence served as the primary endpoint. Secondary endpoints included weight changes, esophageal stricture, and lymphedema. The primary/secondary outcomes were not statistically significant; however, ototoxicity and renal toxicity were significantly higher in the high-dose group. These findings add insight into cisplatin dose-based functional outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors (ICIs) are related to various immune-related adverse events (irAEs). However, the knowledge is limited with rare irAEs like hearing loss. Therefore, we evaluated the characteristics, presentation, and treatment of ICI-related hearing loss by reviewing the individual patient data from the previous studies. Methods: We conducted a systematic search of the Web of Science, PubMed, and Embase databases for studies published until 17 November 2022. The selected MeSH search terms were “hearing loss” OR “hearing impairment” OR “ototoxicity” OR “vestibular toxicity” OR “audiovestibular toxicity” AND “immune checkpoint inhibitor” OR “immunotherapy.” Results: A total of 38 patients were included. Melanoma was the most frequent diagnosis (73.7%). The median time from ICI initiation to hearing loss development was 3 months. The hearing impairment was secondary to bilateral sensorineural hearing loss (SNHL) in 24 (68.6%) patients, and at least one other irAE accompanied the hearing loss in 24 patients. Hearing loss significantly improved in 45.7% of the patients. The overall response rate and disease control rate were 67.6% and 85.3%, respectively. Conclusion: We observed that most cases of ICI-related hearing loss were reversible, observed in patients with melanoma, accompanied by other irAEs, and associated with a high response rate to ICIs. With the expanded use of ICIs in the earlier treatment lines and adjuvant settings, the number of survivors with ICI-related hearing loss is expected to increase. Further research is needed to define the true prevalence of ICI-related hearing loss, optimal diagnosis, and management. [ABSTRACT FROM AUTHOR]

Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about the protective mechanisms of E2 against cisplatin-induced ototoxicity. In this study, we investigated the effect of E2 on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated hair cell protection using the organ of Corti isolated from mice. The organ of Corti collected from C57BL/6 mice at 3–5 postnatal days was used in all experiments. The organ of Corti was exposed to 20 μM cisplatin with/without 100 nM E2 to examine the effect of E2 on cisplatin-induced hair cell loss. The mRNA expression of Nrf2 and the phase II detoxification gene after E2 and cisplatin treatment was analyzed using quantitative real-time PCR. E2 significantly reduces cisplatin-induced cochlear hair cell death. In addition, 100 nM E2 increased the mRNA expression of Nrf2 and phase II detoxification genes in the organ of Corti under cisplatin treatment. Our results suggest that E2 activates Nrf2, phase II detoxification enzymes and exerts a protective effect against cisplatin-induced ototoxicity. [ABSTRACT FROM AUTHOR]

Background and Aims: Cisplatin is currently one of the most widely used anticancer drugs in the world. However, its clinical usefulness has frequently been limited by severe side effects, such as nephrotoxicity, ototoxicity and neurotoxicity. Therefore, platinum(II) oxalato complexes with substitute imidazole or benzimidazole carrier ligands were synthesized and their cytotoxic effects were investigated against non-small cell lung cancer (H1299) and human colon adenocarcinoma (CaCo-2), and mouse fibroblast cells lines (L929). Methods: Four platinum(II) complexes, [Pt(L1-L4)2(oxalate)] were synthesized and characterized by FT-IR, 1H NMR and elemental analyses. The MTT method was used to determine the potential antiproliferative effect of synthesized platinum(II) complexes and positive controls. Results: In this study, the cytotoxic activity of platinum(II) complexes against tested cell lines was assessed, with moderate IC50 values. According to IC50 values, Complex 5 with 2-ethylbenzimidazole ligand was found to be the most active complex against H1299 and CaCo-2 cell lines. In general, the compounds are also promising drug candidates for H1299 cell lines with very low activity against the CaCo-2 cell lines. Conclusion: Further modification and development of Complex 4 and 5 derivatives and in vitro cytotoxic activity studies against different cancer cell lines may lead to the emergence of new anticancer agents in the near future. [ABSTRACT FROM AUTHOR]