Although cisplatin is a widely used chemotherapeutic agent, it is severely toxic and causes irreversible hearing loss, restricting its application in clinical settings. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. Here, we established in vitro and in vivo ototoxicity models of cisplatin-induced hair cell loss, and our results showed that reducing STING levels decreased inflammatory factor expression and hair cell death. In addition, we found that cisplatin-induced mitochondrial dysfunction was accompanied by cytosolic DNA, which may act as a critical linker between the cyclic GMP-AMP synthesis-stimulator of interferon genes (cGAS-STING) pathway and the pathogenesis of cisplatin-induced hearing loss. H-151, a specific inhibitor of STING, reduced hair cell damage and ameliorated the hearing loss caused by cisplatin in vivo. This study underscores the role of cGAS-STING in cisplatin ototoxicity and presents H-151 as a promising therapeutic for hearing loss.

Cisplatin causes permanent hearing loss or cisplatin-induced ototoxicity in over 50% of treated patients with cancer, leading to significant social and functional limitations. Interindividual variability in developing hearing loss suggests the role of genetic predispositions to cisplatin-induced hearing loss. We investigated genetic associations between cisplatin-induced ototoxicity and toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin. Using a case-control candidate gene approach, we identified 20 single nucleotide polymorphisms at the TLR4 locus with significant protection against ototoxicity in a cohort of 213 adult patients, followed by an independent pediatric patient cohort (n = 357). Combined cohort analysis demonstrated a significant association between cisplatin-induced ototoxicity protection and a single variant in the TLR4 promoter, rs10759932. We showed that rs10759932 downregulated TLR4 expression that is normally induced by cisplatin. This work provides pharmacogenetic and functional evidence to implicate TLR4 with cisplatin-induced hearing loss in patients. SIGNIFICANCE STATEMENT: Adult and pediatric patients carrying toll-like receptor 4 (TLR4) genetic variants were protected against developing cisplatin-induced hearing loss following cisplatin treatment. Important variants in the TLR4 promoter disrupted a drug-gene interaction between cisplatin and TLR4, mirroring the protective effect conferred by genetic inhibition of TLR4. These variants have the potential to improve the prediction of cisplatin toxicity, allowing for more precise chemotherapy treatment.

Cisplatin-induced sensorineural hearing loss is a significant clinical challenge. Although the potential effects of brain-derived neurotrophic factor (BDNF) have previously been investigated in some ototoxicity models, its efficacy in cisplatin-induced hearing loss remains uncertain. This study aimed to investigate the therapeutic potential of recombinant human BDNF (rhBDNF) in protecting cells against cisplatin-induced ototoxicity.

Using an in vivo model of cisplatin-induced hearing loss, we investigated the beneficial effects of transtympanic administration of rhBDNF in a thermogel solution on hearing function and cochlear injury, using electrophysiological, morphological, immunofluorescence and molecular analyses.

Our data showed that local rhBDNF treatment counteracted hearing loss in rats receiving cisplatin by preserving synaptic connections in the cochlear epithelium and protecting hair cells (HCs) and spiral ganglion neurons (SGNs) against cisplatin-induced cell death. Specifically, rhBDNF maintains the balance of its receptor levels (pTrkB and p75), boosting TrkB-CREB pro-survival signalling and reducing caspase 3-dependent apoptosis in the cochlea. Additionally, it activates antioxidant mechanisms while inhibiting inflammation and promoting vascular repair.

Collectively, we demonstrated that early transtympanic treatment with rhBDNF plays a multifaceted protective role against cisplatin-induced ototoxicity, thus holding promise as a novel potential approach to preserve hearing in adult and paediatric patients undergoing cisplatin-based chemotherapy.

Oral squamous cell carcinoma (OSCC) is a common malignancy often associated with poor prognosis due to chemoresistance. In this study, we investigated whether arecoline, a major alkaloid in betel nuts, can stimulate aldo-keto reductase family 1 member B10 (AKR1B10) levels in OSCC, promoting cancer stemness and leading to resistance to cisplatin (CDDP)-based chemotherapy.

Gain- and Loss- of AKR1B10 functions were analyzed using WB and q-PCR of OSCC cells. Stemness, epithelial mesenchymal transition (EMT) markers, and CDDP drug resistance in overexpressed AKR1B10 were also identified.

Upregulated AKR1B10 in OSCC significantly increased cell motility and aggregation. The results also showed that the canonical TGF-β1-Smad3 pathway was involved in arecoline-induced AKR1B10 expression, further increasing cancer stemness with CDDP resistance via the Snail-dependent EMT pathway. Moreover, oleanolic acid (OA) and ROS/RNS (reactive oxygen/nitrogen species) inhibitors effectively reversed AKR1B10-induced CDDP-resistance.

Arecoline-induced ROS/RNS to hyper-activate AKR1B10 in tumor sphere cells via the TGF-β1-Smad3 pathway. Furthermore, AKR1B10 enhanced CDDP resistance in OSCC cells via EMT-inducing markers. Finally, Finally, OA may efficiently target CDDP resistance, reverse stemness in OSCC cells, and have the potential as a novel anticancer drug.

Sensorineural hearing loss (SNHL) is a prevalent clinical condition primarily attributed to dysfunction within various components of the auditory pathway, spanning from the inner ear to the auditory cortex. Recent research has illuminated immune and inflammation-mediated disorders of the inner ear as critical contributors to SNHL. Disruptions in the equilibrium of inflammatory mediators, chemokines, the complement system, and inflammatory vesicles within the cochlea provoke aberrations in immune cell activity, fostering a chronic pro-inflammatory milieu that detrimentally affects the structural and functional integrity of the inner ear, culminating in hearing impairment. Specific genetic mutations, especially those affecting auditory structures, play an important role in SNHL. These mutations regulate inflammatory mediators and cellular responses, thereby altering the inflammatory dynamics within the cochlea. This review delves into the pathogenesis of sensorineural hearing loss, emphasizing the impact of genetic alterations, immune responses within the inner ear, and inflammatory mediators on auditory function. It highlights the significance of Transmembrane Serine Protease 3 (TMPRSS3) and connexin gene mutations as pivotal genetic elements in SNHL, underscoring the central role of inflammatory responses in cochlear damage. Furthermore, the paper discusses the promise of gene therapy and targeted molecular interventions, underscoring the necessity for continued exploration into the specific actions of various inflammatory agents to refine personalized therapeutic strategies.

In vivo implantation of microelectrodes opens the door to studying neural circuits and restoring damaged neural pathways through direct electrical stimulation and recording. Although some neuroprostheses have achieved clinical success, electrode material properties, inflammatory response, and glial scar formation at the electrode-tissue interfaces affect performance and sustainability. Those challenges can be addressed by improving some of the materials' mechanical, physical, chemical, and electrical properties. This paper reviews materials and designs of current microelectrodes and discusses perspectives to advance neuroprosthetics performance.

Sensorineural hearing loss (SNHL) constitutes a major global health challenge, affecting millions of individuals and substantially impairing social integration and quality of life. The complexity of the auditory system and the multifaceted nature of SNHL necessitate advanced methodologies to understand its etiology, progression, and potential therapeutic interventions. This review provides a comprehensive overview of the current animal models used in SNHL research, focusing on their selection based on specific characteristics and their contributions to elucidating pathophysiological mechanisms and evaluating novel treatment strategies. It discusses the most commonly used rodent models in hearing research, including mice, rats, guinea pigs, Mongolian gerbils, and chinchillas. Through a comparative analysis, this review underscores the importance of selecting models that align with specific research objectives in SNHL studies, discussing the advantages and limitations of each model. By advocating for a multidisciplinary approach that leverages the strengths of various animal models with technological advancements, this review aims to facilitate significant advancements in the prevention, diagnosis, and treatment of sensorineural hearing loss.

Stress granules (SGs) are highly dynamic micromolecular membraneless condensates that generate in cells subjected to stress. Formed from pools of untranslating messenger ribonucleoproteins (RNP), SGs dynamics constitute vital processes essential for cell survival. Here, we investigate whether established cytotoxic agents, such as the platinum-based chemotherapeutic agent cisplatin and the aminoglycoside antibiotic gentamicin, elicit SG formation in the House Ear Institute-Organ of Corti-1 (HEI-OC1) auditory cell line, H4 human neuroglioma cells and HEK-293T human embryonic kidney cells. Cells were treated with cisplatin or gentamicin for specific durations at designated concentrations. SG formation was assessed using immunocytochemistry and live cell imaging. Levels of essential proteins involved in SG assembly were evaluated using immunoblotting. We observed cisplatin-associated SG assembly in HEI-OC1 and H4 cells via confocal microscopy through antibody colabeling of G3BP1 with PABP or Caprin1. While maintaining an unchanged pattern of expression of main constituent SG proteins, cisplatin-related SGs in H4 cells persisted for at least 12 h after drug removal. Cells subjected to gentamicin exposure did not exhibit SGs. Our findings offer insights into subcellular mechanisms related to cisplatin-associated cytotoxicity, highlighting the need for future studies to further investigate this stress-response mechanism.

Ototoxicity is an often-underestimated sequela for cancer patients undergoing chemotherapy, with an incidence rate exceeding 50%, affecting approximately 4 million individuals worldwide each year. Despite the nearly 2,000 publications on chemotherapy-related ototoxicity in the past decade, the understanding of its prevalence, mechanisms, and preventative or therapeutic measures remains ambiguous and subject to debate. To date, only one drug, sodium thiosulfate, has gained FDA approval for treating ototoxicity in chemotherapy. However, its utilization is restricted. This review aims to offer clinicians and researchers a comprehensive perspective by thoroughly and carefully reviewing available data and current evidence. Chemotherapy-induced ototoxicity is characterized by four primary symptoms: hearing loss, tinnitus, vertigo, and dizziness, originating from both auditory and vestibular systems. Hearing loss is the predominant symptom. Amongst over 700 chemotherapeutic agents documented in various databases, only seven are reported to induce hearing loss. While the molecular mechanisms of the hearing loss caused by the two platinum-based drugs are extensively explored, the pathways behind the action of the other five drugs are primarily speculative, rooted in their therapeutic properties and side effects. Cisplatin attracts the majority of attention among these drugs, encompassing around two-thirds of the literature regarding ototoxicity in chemotherapy. Cisplatin ototoxicity chiefly manifests through the loss of outer hair cells, possibly resulting from damages directly by cisplatin uptake or secondary effects on the stria vascularis. Both direct and indirect influences contribute to cisplatin ototoxicity, while it is still debated which path is dominant or where the primary target of cisplatin is located. Candidates for hearing protection against cisplatin ototoxicity are also discussed, with novel strategies and methods showing promise on the horizon.

Hearing loss is one of the most common types of disability; however, there is only one FDA-approved drug to prevent any type of hearing loss. Treatment with the highly effective chemotherapy agent, cisplatin, and exposure to high-decibel noises are two of the most common causes of hearing loss. The mitogen-activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting of RAF, MEK1/2, and ERK1/2, has been implicated in both types of hearing loss. Pharmacologically inhibiting BRAF or ERK1/2 is protective against noise- and cisplatin-induced hearing loss in multiple mouse models. Trametinib, a MEK1/2 inhibitor, protects from cisplatin-induced outer hair cell death in mouse cochlear explants; however, to the best of our knowledge, inhibiting MEK1/2 has not yet been shown to be protective against hearing loss in vivo. In this study, we demonstrate that trametinib protects against cisplatin-induced hearing loss in a translationally relevant mouse model and does not interfere with cisplatin's tumor-killing efficacy in cancer cell lines. Higher doses of trametinib were toxic to mice when combined with cisplatin, but lower doses of the drug were protective against hearing loss without any known toxicity. Trametinib also protected mice from noise-induced hearing loss and synaptic damage. This study shows that MEK1/2 inhibition protects against both insults of hearing loss, as well as that targeting all three kinases in the MAPK pathway protects mice from cisplatin- and noise-induced hearing loss.

Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs.

Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin.

Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs.

Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

Hearing loss is one of the most common types of disability; however, there is only one FDA-approved drug to prevent any type of hearing loss. Treatment with the highly effective chemotherapy agent, cisplatin, and exposure to high decibel noises are two of the most common causes of hearing loss. The mitogen activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting of RAF, MEK1/2, and ERK1/2, has been implicated in both types of hearing loss. Pharmacologically inhibiting BRAF or ERK1/2 is protective from noise and cisplatin-induced hearing loss in multiple mouse models. Trametinib, a MEK1/2 inhibitor, protects from cisplatin induced outer hair cell death in mouse cochlear explants; however, to the best of our knowledge, inhibiting MEK1/2 has not yet been shown to be protective from hearing loss in vivo. In this study, we demonstrate that trametinib protects from cisplatin-induced hearing loss in a translationally relevant mouse model and does not interfere with cisplatin's tumor killing efficacy in cancer cell lines. Higher doses of trametinib were toxic to mice when combined with cisplatin but lower doses of the drug were protective from hearing loss without any known toxicity. Trametinib also protected mice from noise-induced hearing loss and synaptic damage. This study shows that MEK1/2 inhibition protects from both insults of hearing loss and that targeting all three kinases in the MAPK pathway protect from cisplatin and noise-induced hearing loss in mice.

Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric patients. Here, we performed an unbiased screen of 1,300 FDA-approved drugs for protection against cisplatin-induced cell death in an inner ear cell line, and identified oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, as a top candidate. Oseltamivir phosphate was found to be otoprotective by oral delivery in multiple established cisplatin and noise exposure mouse models. The drug conferred permanent hearing protection of 15-25 dB SPL for both female and male mice. Oseltamivir treatment reduced in mice outer hair cells death after cisplatin treatment and mitigated cochlear synaptopathy after noise exposure. A potential binding protein, ERK1/2, associated with inflammation, was shown to be activated with cisplatin treatment and reduced by oseltamivir cotreatment in cochlear explants. Importantly, the number of infiltrating immune cells to the cochleae in mice post noise exposure, were significantly reduced with oseltamivir treatment, suggesting an anti-inflammatory mechanism of action. Our results support oseltamivir, a widespread drug for influenza with low side effects, as a promising otoprotective therapeutic candidate in both cisplatin chemotherapy and traumatic noise exposure.

There is a substantial need of effective drugs for the treatment of hearing loss, which affects nearly 500 million individuals globally. Hearing loss can be the result of intense or prolonged noise exposure, ototoxic drugs, infections, and trauma, which trigger inflammatory signaling cascades that lead to irreversible damage to cochlear structures. To address this, we developed and characterized a series of covalent conjugates of anti-inflammatory drugs to hyaluronic acid (HA), for potential use as topical ototherapeutics. These conjugates were tested in in vitro assays designed to mirror physiological processes typically observed with acoustic trauma. Intense noise exposure leads to macrophage recruitment to the cochlea and subsequent inflammatory damage to sensory cells. We therefore first tested our conjugates' ability to reduce the release of inflammatory cytokines in macrophages. This anti-inflammatory effect on macrophages also translated to increased cochlear cell viability. In our initial screening, one conjugate, ibuprofen-HA, demonstrated significantly higher anti-inflammatory potential than its counterparts. Subsequent cytokine release profiling of ibuprofen-HA further confirmed its ability to reduce a wider range of inflammatory markers, to a greater extent than its equivalent unconjugated drug. The conjugate's potential as a topical therapeutic was then assessed in previously developed tympanic and round window membrane tissue permeation models. As expected, our data indicate that the conjugate has limited tympanic membrane model permeability; however, it readily permeated the round window membrane model and to a greater extent than the unconjugated drug. Interestingly, our data also revealed that ibuprofen-HA was well tolerated in cellular and tissue cytocompatibility assays, whereas the unconjugated drug displayed significant cytotoxicity at equivalent concentrations. Moreover, our data highlighted the importance of chemical conjugation of ibuprofen to HA; the conjugate had improved anti-inflammatory effects, significantly reduced cytotoxicity, and is more suitable for therapeutic formulation. Overall, this work suggests that ibuprofen-HA could be a promising safe and effective topical ototherapeutic for inflammation-mediated cochlear damage.

Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH oxidases (Nox) as a whole enzyme family that only produce this harmful group of molecules was surprising. After intensive research, seven Nox isoforms were discovered, described and extensively studied. Among them, the NADPH oxidase 3 is the perhaps most underrated Nox isoform, since it was firstly discovered in the inner ear. This stigma of Nox3 as "being only expressed in the inner ear" was also used by me several times. Therefore, the question arose whether this sentence is still valid or even usable. To this end, this review solely focuses on Nox3 and summarizes its discovery, the structural components, the activating and regulating factors, the expression in cells, tissues and organs, as well as the beneficial and detrimental effects of Nox3-mediated ROS production on body functions. Furthermore, the involvement of Nox3-derived ROS in diseases progression and, accordingly, as a potential target for disease treatment, will be discussed.

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.

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.

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.

CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin-associated hearing loss.

Macrophages are essential components of the innate immune system and constitute a non-specific first line of host defense against pathogens and inflammation. Mitochondria regulate macrophage activation and innate immune responses in various inflammatory diseases, including cochlear inflammation. The distribution, number, and morphological characteristics of cochlear macrophages change significantly across different inner ear regions under various pathological conditions, including noise exposure, ototoxicity, and age-related degeneration. However, the exact mechanism underlying the role of mitochondria in macrophages in auditory function remains unclear. Here, we summarize the major factors and mitochondrial signaling pathways (e.g., metabolism, mitochondrial reactive oxygen species, mitochondrial DNA, and the inflammasome) that influence macrophage activation in the innate immune response. In particular, we focus on the properties of cochlear macrophages, activated signaling pathways, and the secretion of inflammatory cytokines after acoustic injury. We hope this review will provide new perspectives and a basis for future research on cochlear inflammation.

Ototoxicity is one of the major adverse effects of cisplatin therapy which restrict its clinical application. Alpha-lipoic acid administration may mitigate cisplatin-induced ototoxicity. In the present study, we reviewed the protective potentials of alpha-lipoic acid against the cisplatin-mediated ototoxic adverse effects.

Based on the PRISMA guideline, we performed a systematic search for the identification of all relevant studies in various electronic databases up to June 2022. According to the inclusion and exclusion criteria, the obtained articles (n=59) were screened and 13 eligible articles were finally included in the present study.

The findings of in-vitro experiments showed that cisplatin treatment significantly reduced the auditory cell viability in comparison with the control group; nevertheless, the alpha-lipoic acid co-administration protected the cells against the reduction of cell viability induced by cisplatin treatment. Moreover, the in-vivo results of the auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) tests revealed a decrease in DPOAE and an increase in ABR threshold of cisplatin-injected animals; however, it was shown that alpha-lipoic acid co-treatment had an opposite pattern on the evaluated parameters. Other findings demonstrated that cisplatin treatment could significantly induce the biochemical and histopathological alterations in inner ear cells/tissue; in contrast, alpha-lipoic acid co-treatment ameliorated the cisplatin-mediated biochemical and histological changes.

The findings of audiometry, biochemical parameters, and histological evaluation showed that alpha-lipoic acid co-administration alleviates the cisplatin-induced ototoxicity. The protective role of alpha-lipoic acid against the cisplatin-induced ototoxicity can be due to different mechanisms of anti-oxidant, anti-apoptotic, anti-inflammatory activities, and regulation of cell cycle progression.

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.

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

Cisplatin is a widely used and highly effective anti-cancer drug with significant side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced ototoxicity and nephrotoxicity, we used PLX3397, an FDA-approved inhibitor of the colony-stimulating factor 1 receptor (CSF1R), to eliminate tissue-resident macrophages during the course of cisplatin administration. Mice treated with cisplatin alone (cisplatin/vehicle) had significant hearing loss (ototoxicity) as well as kidney injury (nephrotoxicity). Macrophage ablation using PLX3397 resulted in significantly reduced hearing loss measured by auditory brainstem responses (ABR) and distortion-product otoacoustic emissions (DPOAE). Sensory hair cells in the cochlea were protected against cisplatin-induced death in mice treated with PLX3397. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis as well as reduced plasma blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together our data indicate that ablation of tissue-resident macrophages represents a novel strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.

The most common cause of sensorineural hearing loss is damage of auditory hair cells. Tumor necrosis factor-alpha (TNF-α) is closely associated with sensorineural hearing loss. The present study examined the preconditioning effect of dexamethasone (DEX) on TNF-α-induced ototoxicity in mouse auditory hair cells (HEI-OC1) and cochlear explants. Treatment of HEI-OC1 with 10 ng/ml TNF-α for 24 h decreased cell viability, increased the accumulation of reactive oxygen species (ROS), and induced caspase-mediated apoptotic signaling pathways. Pretreatment with 10 nM DEX for 6 h before TNF-α exposure restored cell viability, decreased ROS accumulation, and attenuated apoptotic signaling activation induced by TNF-α. Incubation of cochlear explants with 20 ng/ml TNF-α for 24 h resulted in significant loss of both inner hair cells (IHCs) and outer hair cells (OHCs) and an increase in apoptotic activation accessed by annexin V staining. The cochlear explants pre-incubated with 10 nM DEX attenuated TNF-α ototoxicity in both IHCs and OHCs and apoptotic cell death. These results indicated that DEX plays a protective role in ototoxicity induced by TNF-α through attenuation of caspase-dependent apoptosis signaling pathway and ROS accumulation.

The ototoxic side effect of cisplatin is a main cause of sensorineural hearing loss. This side effect limits the clinical application of cisplatin and affects patients' quality of life. This study was designed to investigate the effect of apelin-13 on cisplatin-induced C57BL/6 mice hearing loss model and explore the potential underlying molecular mechanisms. Mice were intraperitoneally injected with 100 μg/kg apelin-13 2 h before 3 mg/kg cisplatin injection for 7 consecutive days. Cochlear explants cultured in vitro were pretreated with 10 nM apelin-13 2 h prior to 30 μM cisplatin treatment for another 24 h. Hearing test and morphology results showed that apelin-13 attenuated cisplatin-induced mice hearing loss and protected cochlear hair cells and spiral ganglion neurons from damage. In vivo and in vitro experimental results showed that apelin-3 reduced cisplatin-induced apoptosis of hair cells and spiral ganglion neurons. In addition, apelin-3 preserved mitochondrial membrane potential and inhibited ROS production in cultured cochlear explants. Mechanistic studies showed that apelin-3 decreased cisplatin-induced cleaved caspase 3 expression but increased Bcl-2; inhibited the expression of pro-inflammatory factors TNF-a and IL-6; and increased STAT1 phosphorylation but decreased STAT3 phosphorylation. In conclusion, our results indicate that apelin-13 could be a potential otoprotective agent to prevent cisplatin-induced ototoxicity by inhibiting apoptosis, ROS production, TNF-α and IL-6 expression, and regulating phosphorylation of STAT1 and STAT3 transcription factors.

The cause of Ludwig van Beethoven's health deterioration, i.e., hearing loss and cirrhosis, have been subject to various studies. The genomic analysis of his hair indicates infection with the hepatitis B virus (HBV) at least 6 months prior to death. However, considering his first documented case of jaundice in the summer of 1821, second jaundice months prior to his death, and increased risk of hearing loss in HBV-infected patients, we offer an alternative hypothesis of chronic HBV infection as a cause of deafness and cirrhosis. According to it, HBV was acquired early, progressed from immune-tolerant to an immune-reactive phase, and triggered Beethoven's hearing issues when aged 28. Later, HBV infection entered the non-replication phase with at least two episodes of reactivation in the fifth decade of life accompanied by jaundice. More studies examining hearing loss in patients with chronic HBV infection are encouraged to better understand their potential otologic needs.

Humans have six members of the ferlin protein family: dysferlin, myoferlin, otoferlin, fer1L4, fer1L5, and fer1L6. These proteins share common features such as multiple Ca2+-binding C2 domains, FerA domains, and membrane anchoring through their single C-terminal transmembrane domain, and are believed to play a key role in calcium-triggered membrane fusion and vesicle trafficking. Otoferlin plays a crucial role in hearing and vestibular function. In this review, we will discuss how we see otoferlin working as a Ca2+-dependent mechanical sensor regulating synaptic vesicle fusion at the hair cell ribbon synapses. Although otoferlin is also present in the central nervous system, particularly in the cortex and amygdala, its role in brain tissues remains unknown. Mutations in the OTOF gene cause one of the most frequent genetic forms of congenital deafness, DFNB9. These mutations produce severe to profound hearing loss due to a defect in synaptic excitatory glutamatergic transmission between the inner hair cells and the nerve fibers of the auditory nerve. Gene therapy protocols that allow normal rescue expression of otoferlin in hair cells have just started and are currently in pre-clinical phase. In parallel, studies have linked ferlins to cancer through their effect on cell signaling and development, allowing tumors to form and cancer cells to adapt to a hostile environment. Modulation by mechanical forces and Ca2+ signaling are key determinants of the metastatic process. Although ferlins importance in cancer has not been extensively studied, data show that otoferlin expression is significantly associated with survival in specific cancer types, including clear cell and papillary cell renal carcinoma, and urothelial bladder cancer. These findings indicate a role for otoferlin in the carcinogenesis of these tumors, which requires further investigation to confirm and understand its exact role, particularly as it varies by tumor site. Targeting this protein may lead to new cancer therapies.

Astrocyte dysfunction has previously been linked to multiple neurodegenerative disorders including Parkinson's disease (PD). Among their many roles, astrocytes are mediators of the brain immune response, and astrocyte reactivity is a pathological feature of PD. They are also involved in the formation and maintenance of the blood-brain barrier (BBB), but barrier integrity is compromised in people with PD. This study focuses on an unexplored area of PD pathogenesis by characterizing the interplay between astrocytes, inflammation and BBB integrity, and by combining patient-derived induced pluripotent stem cells with microfluidic technologies to generate a 3D human BBB chip. Here we report that astrocytes derived from female donors harboring the PD-related LRRK2 G2019S mutation are pro-inflammatory and fail to support the formation of a functional capillary in vitro. We show that inhibition of MEK1/2 signaling attenuates the inflammatory profile of mutant astrocytes and rescues BBB formation, providing insights into mechanisms regulating barrier integrity in PD. Lastly, we confirm that vascular changes are also observed in the human postmortem substantia nigra of both males and females with PD.

Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors' long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93-10.18, P = 9.51 × 10^-08). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals' identification for personalized prevention and treatment.

Cisplatin appears to enter the cochlear cells through the organic cation transporter 2 (OCT2). There is recent evidence that multidrug and toxin extrusion protein 1 (MATE1) is involved in cisplatin-induced nephrotoxicity. Its presence and role in the ear are unknown.

Evaluate the presence and localization of MATE1, and determine the localization of OCT2, in the cochlea. Evaluate cisplatin uptake with regard to MATE1 and OCT2 expression.

Murine cochlear explants and paraffin-embedded cochleae were evaluated with immunohistochemistry for OCT2 and MATE1. Explant cultures were also treated with Texas Red cisplatin to determine their cellular uptake.

MATE1 is present in the cochlea. Most intense labeling of MATE1 and OCT2 was seen in the outer hair cells (OHCs) and pillar cells, respectively. Both transporters were observed in the spiral ganglion neurons and stria vascularis. Expression levels of OCT2 and MATE1 decreased following cisplatin exposure. Texas Red cisplatin staining was strong in OHCs and pillar cells.

To the best of our knowledge, this is the first study demonstrating the presence and localization of MATE1 in the cochlea. OCT2 labeling was seen in pillar cells. Consistently, OHCs and pillar cells uptake Texas Red cisplatin.

Cisplatin is an effective chemotherapeutic agent, yet its use is limited by several adverse drug reactions, known as cisplatin-induced toxicities (CITs). We recently demonstrated that cisplatin could elicit proinflammatory responses associated with CITs through Toll-like receptor 4 (TLR4). TLR4 is best recognized for binding bacterial lipopolysaccharide (LPS) via its coreceptor, MD-2. TLR4 is also proposed to directly bind transition metals, such as nickel. Little is known about the nature of the cisplatin-TLR4 interaction. Here, we show that soluble TLR4 was capable of blocking cisplatin-induced, but not LPS-induced, TLR4 activation. Cisplatin and nickel, but not LPS, were able to directly bind soluble TLR4 in a microscale thermophoresis binding assay. Interestingly, TLR4 histidine variants that abolish nickel binding reduced, but did not eliminate, cisplatin-induced TLR4 activation. This was corroborated by binding data that showed cisplatin, but not nickel, could directly bind mouse TLR4 that lacks these histidine residues. Altogether, our findings suggest that TLR4 can directly bind cisplatin in a manner that is enhanced by, but not dependent on, histidine residues that facilitate binding to transition metals. SIGNIFICANCE STATEMENT: This work describes how the xenobiotic cisplatin interacts with Toll-like receptor 4 (TLR4) to initiate proinflammatory signaling that underlies cisplatin toxicities, which are severe adverse outcomes in cisplatin treatment. Here, this study provides a mechanistic bridge between cisplatin extracellular interactions with TLR4 and previous observations that genetic and chemical inhibition of TLR4 mitigates cisplatin-induced toxicity.

Exposure to heavy metals has been shown to cause damage to a variety of different tissues and cell types including hair cells, the sensory cells of our inner ears responsible for hearing and balance. Elevated levels of one such metal, cadmium, have been associated with hearing loss and shown to cause hair cell death in multiple experimental models. While the mechanisms of cadmium-induced cell death have been extensively studied in other cell types they remain relatively unknown in hair cells. We have found that calcium signaling, which is known to play a role in cadmium-induced cell death in other cell types through calmodulin and CaMKII activation as well as IP3 receptor and mitochondrial calcium uniporter mediated calcium flow, does not appear to play a significant role in cadmium-induced hair cell death. While calmodulin inhibition can partially protect hair cells this may be due to impacts on mechanotransduction activity. Removal of extracellular calcium, and inhibiting CaMKII, the IP3 receptor and the mitochondrial calcium uniporter all failed to protect against cadmium-induced hair cell death. We also found cadmium treatment increased pAkt levels in hair cells and pERK levels in supporting cells. This activation may be protective as inhibiting these pathways enhances cadmium-induced hair cell death rather than protecting cells. Thus cadmium-induced hair cell death appears distinct from cadmium-induced cell death in other cell types where calcium, Akt and ERK signaling all promote cell death.

Insulin-like growth factor 1 (IGF-1) is a trophic factor for the nervous system where it exerts pleiotropic effects, including the regulation of metabolic homeostasis. IGF-1 deficiency induces morphological alterations in the cochlea, apoptosis and hearing loss. While multiple studies have addressed the role of IGF-1 in hearing protection, its potential function in the modulation of otic metabolism remains unclear. Here, we report that "House Ear Institute-organ of Corti 1" (HEI-OC1) auditory cells express IGF-system genes that are regulated during their differentiation. Upon binding to its high-affinity receptor IGF1R, IGF-1 activates AKT and mTOR signaling to stimulate anabolism and, concomitantly, to reduce autophagic catabolism in HEI-OC1 progenitor cells. Notably, IGF-1 stimulation during HEI-OC1 differentiation to mature otic cells sustained both constructive metabolism and autophagic flux, possibly to favor cell remodeling. IGF1R engagement and downstream AKT signaling promoted HEI-OC1 cell survival by maintaining redox balance, even when cells were challenged with the ototoxic agent cisplatin. Our findings establish that IGF-1 not only serves an important function in otic metabolic homeostasis but also activates antioxidant defense mechanisms to promote hair cell survival during the stress response to insults.

The cochlea encodes sound stimuli and transmits them to the central nervous system, and damage to sensory cells and synapses in the cochlea leads to hearing loss. The inner ear was previously considered to be an immune privileged organ to protect the auditory organ from reactions with the immune system. However, recent studies have revealed the presence of resident macrophages in the cochlea, especially in the spiral ligament, spiral ganglion, and stria vascularis. The tissue-resident macrophages are responsible for the detection, phagocytosis, and clearance of cellular debris and pathogens from the tissues, and they initiate inflammation and influence tissue repair by producing inflammatory cytokines and chemokines. Insult to the cochlea can activate the cochlear macrophages to initiate immune responses. In this review, we describe the distribution and functions of cochlear macrophages in noise-induced hearing impairment and age-related hearing disabilities. We also focus on potential therapeutic interventions concerning hearing loss by modulating local immune responses.

Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss. The main etiologies are stria vascularis injury, spiral ganglion degeneration, and hair cell death. Over several decades, the research scope of cisplatin-induced ototoxicity has expanded with the discovery of the molecular mechanism mediating inner ear cell death, highlighting the roles of reactive oxygen species and transport channels for cisplatin uptake into inner ear cells. Upon entering hair cells, cisplatin disrupts organelle metabolism, induces oxidative stress, and targets DNA to cause intracellular damage. Recent studies have also reported the role of inflammation in cisplatin-induced ototoxicity. In this article, we preform a narrative review of the latest reported molecular mechanisms of cisplatin-induced ototoxicity, from extracellular to intracellular. We build up a signaling network starting with cisplatin entering into the inner ear through the blood labyrinth barrier, disrupting cochlear endolymph homeostasis, and activating inflammatory responses of the outer hair cells. After entering the hair cells, cisplatin causes hair cell death via DNA damage, redox system imbalance, and mitochondrial and endoplasmic reticulum dysfunction, culminating in programmed cell death including apoptosis, necroptosis, autophagic death, pyroptosis, and ferroptosis. Based on the mentioned mechanisms, prominent therapeutic targets, such as channel-blocking drugs of cisplatin transporter, construction of cisplatin structural analogues, anti-inflammatory drugs, antioxidants, cell death inhibitors, and others, were collated. Considering the recent research efforts, we have analyzed the feasibility of the aforementioned therapeutic strategies and proposed our otoprotective approaches to overcome cisplatin-induced ototoxicity.

Background: Aging is the main negative prognostic factor for various chronic diseases, such as liver fibrosis, and clinical disorders such as hearing loss. This study aimed to investigate the association between age-related hearing loss (ARHL) and age-related central auditory processing disorder (CAPD), and the risk for liver fibrosis in a cross-sectional study on an aging population. Methods: Liver fibrosis risk was judged on the fibrosis-4 (FIB-4) score. Peripheral ARHL was evaluated with pure tone audiometry using a calibrated audiometer. The pure tone average (PTA), calculated as a threshold ≤ 40 dB (HL) in the better ear, was measured at the frequencies 0.5−4 kHz. For age-related CAPD assessment, we employed the Synthetic Sentence Identification with an Ipsilateral Competitive Message test (SSI-ICM). General linear Logistic regression models were used to estimate the association. Results: The increase in the PTA 0.5−2 kHz (coefficient: 0.02, SE: 0.01, CI 95%: 0.01 to 0.03) was directly associated with a higher risk of liver fibrosis (FIB-4 ≥ 2.67). Moreover, the reduction in SSI (coefficient: −0.02, SE: 0.01, CI 95%: −0.03 to −0.01) was inversely associated with FIB-4 values < 2.67. Conclusion: Our results show an association between liver fibrosis and both ARHL and CAPD, linked by the typical consequence of aging. We also assume a role of inflammatory responses and oxidative stress.

The present study investigated the potential protective effect of a selective Cannabinoid-2 (CB2) receptor agonist, 1-phenylisatin, in acute nephrotoxicity induced by cisplatin.

Animals were arranged into 5 groups. Group I; normal saline, group II; 1-phenylisatin for 7 days, group III: received a single injection of cisplatin (20 mg/kg, i.p.) on day 5, group IV: 1-phenylisatin for 7 days and cisplatin on day 5 and group V: AM630, CB2 antagonist, 15 min before 1-phenylisatin for 7 days and a single injection of cisplatin on day 5. Mice were sacrificed 72 h after cisplatin injection. Kidneys were isolated for histopathological and biochemical analyses. Nephrotoxicity parameters including serum creatinine and urea were assessed as well as histopathological examination was done. Also, Oxidative stress markers; MDA and GSH, inflammatory markers; TNF-α, NF-κB (p65), MCP-1, MIP-2, and ICAM-1, along with apoptotic markers, Bax, Bcl2, and caspase-3 were studied. Further, CB2 receptor expression was investigated.

Cisplatin injection increased serum creatinine and urea levels, and increased lipid peroxidation, decreased glutathione level and increased the renal expression of pro-inflammatory markers, TNF-α, NF-κB, MCP-1, MIP-2, and ICAM-1, along with increased apoptotic markers and significantly reduced the expression of the anti-apoptotic Bcl2. Pretreatment with 1-phenylisatin significantly counteracted these effects. The CB2 receptor antagonist; AM630, increased the renal expression of caspase-3 and Bax whereas Bcl2 expression decreased.

1-Phenylisatin protected against cisplatin-induced nephrotoxicity owing to its anti-apoptotic, anti-inflammatory, and antioxidant effects. These actions were mostly mediated through CB2 receptor.

Keap1 mutations regulate Nrf2 activity and lead to chemoresistance in cancers. Yet the underlying molecular mechanisms of chemoresistance are poorly explored. By focusing and genotyping head and neck squamous cell carcinoma (HNSCC) that had available pathologic and clinical data, we provide evidence that Keap1 displays frequent alterations (17%) in HNSCC. Functional loss of Keap1 results in significant activation of Nrf2 and promotes cancer cell growth, proliferation, and elevated cancer stem cell (CSCs) self-renewal efficiency and resistance to oxidative stress. Furthermore, decreased Keap1 activity in these cells increased nuclear accumulation of Nrf2 and activation of the Notch pathway, causing enhanced transcriptional alterations of antioxidants, xenobiotic metabolism enzymes, and resistance to chemotherapeutic treatment. Limiting the Nrf2 activity by either Keap1 complementation or by Nrf2 silencing increased the sensitivity to chemotherapy in Keap1-mutated cells and repressed the CSC self-renewal activity. Our findings suggest that Keap1 mutations define a distinct disease phenotype and the Keap1-Nrf2 pathway is one of the leading molecular mechanisms for clinical chemotherapeutic resistance. Targeting this pathway may provide a potential and attractive personalized treatment strategy for overcoming chemotherapeutic resistance conferred by Keap1 mutations.

Chemotherapeutic agents may adversely affect the nervous system, including the neural precursor cells as well as the white matter. Although the mechanisms are not completely understood, several hypotheses connecting inflammation and oxidative stress with neurotoxicity are now emerging. The proposed mechanisms differ depending on the class of drug. For example, toxicity due to cisplatin occurs due to activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which alters hippocampal long-term potentiation. Free radical injury is also involved in the cisplatin-mediated neurotoxicity as dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been seen which protects against the free radical injury by regulating glutathione S-transferases and hemeoxygenase-1 (HO-1). Thus, correcting the imbalance between NF-κB and Nrf2/HO-1 pathways may alleviate cisplatin-induced neurotoxicity. With newer agents like bortezomib, peripheral neuropathy occurs due to up-regulation of TNF-α and IL-6 in the sensory neurons. Superoxide dismutase dysregulation is also involved in bortezomib-induced neuropathy. This article reviews the available literature on inflammation and oxidative stress in neurotoxicity caused by various classes of chemotherapeutic agents. It covers the conventional medicines like platinum compounds, vinca alkaloids, and methotrexate, as well as the newer therapeutic agents like immunomodulators and immune checkpoint inhibitors. A better understanding of the pathophysiology will lead to further advancement in strategies for management of chemotherapy-induced neurotoxicity.

This study aimed to explore the mechanisms of action of a sulindac acetohydrazide derivative, N'-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide, against anticancer drug cisplatin induced organ damage. Using a rodent model, various markers of organ function and signaling pathways were examined and validated by molecular docking studies. The study involves five groups of animals: control, DMSO, CDDP, CDDP + DMFM, and DMFM. Biochemical enzyme activity, histopathology, tissue antioxidant, and oxidative stress markers were examined. RT-PCR and western blot analyses were conducted for the expression of inducible cyclooxygenase enzyme (COX-2), nuclear factor kappa beta (NF-κB), p65, IL-1, TNF-α, and inducible nitric oxide synthase (iNOS). Flow cytometry analysis of CD4 + TNF-α, CD4 + COX-2, and CD4 + STAT-3 cells in whole blood was performed. Structural and dynamic behavior of DMFM upon binding with receptor molecule molecular docking and dynamic simulations were performed using bioinformatics tools and software. Treatment with DMFM reversed cisplatin-induced malondialdehyde (MDA) and nitric oxide (NO) induction, whereas the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) in the kidney, heart, liver, and brain tissues were increased. DMFM administration normalized plasma levels of biochemical enzymes. We observed a marked decline in CD4 + STAT3, TNF-α, and COX2 cell populations in whole blood after treatment with DMFM. DMFM downregulated the expression factors related to inflammation at the mRNA and protein levels, i.e., IL-1, TNF-α, iNOS, NF-κB, STAT-3, and COX-2. Dynamic simulations and in silico docking data supports the experimental findings. Our experimental and in silico results illustrated that DMFM may affect protective action against cisplatin-induced brain, heart, liver, and kidney damage via reduction of inflammation and ROS.

Cisplatin is a platinum-based chemotherapeutic that has long since been effective against a variety of solid-cancers, substantially improving the five-year survival rates for cancer patients. Its use has also historically been limited by its adverse drug reactions, or cisplatin-induced toxicities (CITs). Of these reactions, cisplatin-induced nephrotoxicity (CIN), cisplatin-induced peripheral neuropathy (CIPN), and cisplatin-induced ototoxicity (CIO) are the three most common of several CITs recognised thus far. While the anti-cancer activity of cisplatin is well understood, the mechanisms driving its toxicities have only begun to be defined. Most of the literature pertains to damage caused by oxidative stress that occurs downstream of cisplatin treatment, but recent evidence suggests that the instigator of CIT development is inflammation. Cisplatin has been shown to induce pro-inflammatory signalling in CIN, CIPN, and CIO, all of which are associated with persisting markers of inflammation, particularly from the innate immune system. This review covered the hallmarks of inflammation common and distinct between different CITs, the role of innate immune components in development of CITs, as well as current treatments targeting pro-inflammatory signalling pathways to conserve the use of cisplatin in chemotherapy and improve long-term health outcomes of cancer patients.

Significance: Sensorineural hearing loss has significant implications for quality of life and risk for comorbidities such as cognitive decline. Noise and ototoxic drugs represent two common risk factors for acquired hearing loss that are potentially preventable. Recent Advances: Numerous otoprotection strategies have been postulated over the past four decades with primary targets of upstream redox pathways. More recently, the application of mild therapeutic hypothermia (TH) has shown promise for otoprotection for multiple forms of acquired hearing loss. Critical Issues: Systemic antioxidant therapy may have limited application for certain ototoxic drugs with a therapeutic effect on redox pathways and diminished efficacy of the primary drug's therapeutic function (e.g., cisplatin for tumors). Future Directions: Mild TH likely targets multiple mechanisms, contributing to otoprotection, including slowed metabolics, reduced oxidative stress, and involvement of cold shock proteins. Further work is needed to identify the mechanisms of mild TH at play for various forms of acquired hearing loss.

This review aims to provide a conceptual and theoretical overview of the association between gut dysbiosis and hearing loss. Hearing loss is a global health issue; the World Health Organisation (WHO) estimates that 2.5 billion people will be living with some degree of hearing loss by 2050. The aetiology of sensorineural hearing loss (SNHL) is complex and multifactorial, arising from congenital and acquired causes. Recent evidence suggests that impaired gut health may also be a risk factor for SNHL. Inflammatory bowel disease (IBD), type 2 diabetes, diet-induced obesity (DIO), and high-fat diet (HFD) all show links to hearing loss. Previous studies have shown that a HFD can result in microangiopathy, impaired insulin signalling, and oxidative stress in the inner ear. A HFD can also induce pathological shifts in gut microbiota and affect intestinal barrier (IB) integrity, leading to a leaky gut. A leaky gut can result in chronic systemic inflammation, which may affect extraintestinal organs. Here, we postulate that changes in gut microbiota resulting from a chronic HFD and DIO may cause a systemic inflammatory response that can compromise the permeability of the blood-labyrinth barrier (BLB) in the inner ear, thus inducing cochlear inflammation and hearing deficits.