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BMC Genomics Feb 2024The stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required...
BACKGROUND
The stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required for sound wave conduction. The pathogenesis of a number of human inheritable deafness syndromes, age related hearing loss, drug-induced ototoxicity and noise-induced hearing loss results from the morphological changes and functional impairments in the development of the SV. In this study, we investigate the implications of intercellular communication within the SV in the pathogenesis of sensorineural hearing loss (SNHL). We aim to identify commonly regulated signaling pathways using publicly available single-cell transcriptomic sequencing (scRNA-seq) datasets.
METHODS
We analyzed scRNA-seq data, which was derived from studying the cochlear SV in mice with SNHL compared to normal adult mice. After quality control and filtering, we obtained the major cellular components of the mouse cochlear SV and integrated the data. Using Seurat's FindAllMarkers and FindMarkers packages, we searched for novel conservative genes and differential genes. We employed KEGG and GSEA to identify molecular pathways that are commonly altered among different types of SNHL. We utilized pySCENIC to discover new specific regulatory factors in SV subpopulation cells. With the help of CellChat, we identified changes in subpopulation cells showing similar trends across different SNHL types and their alterations in intercellular communication pathways.
RESULTS
Through the analysis of the integrated data, we discovered new conserved genes to SV specific cells and identified common downregulated pathways in three types of SNHL. The enriched genes for these pathways showing similar trends are primarily associated with the Electron Transport Chain, related to mitochondrial energy metabolism. Using the CellChat package, we further found that there are shared pathways in the incoming signaling of specific intermediate cells in SNHL, and these pathways have common upstream regulatory transcription factor of Nfe2l2. Combining the results from pySCENIC and CellChat, we predicted the transcription factor Nfe2l2 as an upstream regulatory factor for multiple shared cellular pathways in IC. Additionally, it serves as an upstream factor for several genes within the Electron Transport Chain.
CONCLUSION
Our bioinformatics analysis has revealed that downregulation of the mitochondrial electron transport chain have been observed in various conditions of SNHL. E2f1, Esrrb, Runx1, Yy1, and Gata2 could serve as novel important common TFs regulating the electron transport chain. Adm has emerged as a potential new marker gene for intermediate cells, while Itgb5 and Tesc show promise as potential new marker genes for marginal cells in the SV. These findings offer a new perspective on SV lesions in SNHL and provide additional theoretical evidence for the same drug treatment and prevention of different pathologies of SNHL.
Topics: Adult; Humans; Animals; Mice; Stria Vascularis; Single-Cell Gene Expression Analysis; Hearing Loss, Sensorineural; Cochlea; Transcription Factors
PubMed: 38413848
DOI: 10.1186/s12864-024-10122-7 -
Antioxidants (Basel, Switzerland) Feb 2024Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH... (Review)
Review
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.
PubMed: 38397817
DOI: 10.3390/antiox13020219 -
Antioxidants (Basel, Switzerland) Jan 2024The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN)...
The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss). It has been suggested that glutamate excitotoxicity may be an inciting element in the degenerative cascade observed in these pathological cochlear conditions. Moreover, oxidative damage induced by free hydroxyl radicals and nitric oxide may dramatically enhance cochlear damage induced by glutamate excitotoxicity. To investigate the underlying molecular mechanisms involved in cochlear excitotoxicity, we examined the molecular basis responsible for kainic acid (KA, a full agonist of AMPA/KA-preferring glutamate receptors)-induced IHC synapse loss and degeneration of the terminals of the type I spiral ganglion afferent neurons using a cochlear explant culture from P3 mouse pups. Our results demonstrated that disruption of the synaptic connection between IHCs and SGNs induced increased levels of oxidative stress, as well as altered both mitochondrial function and neurotrophin signaling pathways. Additionally, the application of exogenous antioxidants and neurotrophins (NT3, BDNF, and small molecule TrkB agonists) clearly increases synaptogenesis. These results suggest that understanding the molecular pathways involved in cochlear excitotoxicity is of crucial importance for the future clinical trials of drug interventions for auditory synaptopathies.
PubMed: 38397748
DOI: 10.3390/antiox13020149 -
Journal of Audiology & Otology Apr 2024Chloroquine and its analog hydroxychloroquine are derivatives of 4-aminoquinoline and are regularly used in the treatment of malaria and autoimmune diseases. Among the...
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.
PubMed: 38382520
DOI: 10.7874/jao.2023.00157 -
PloS One 2024American Tegumentary Leishmaniasis (ATL) treatment is based on pentavalent antimonials (Sb5+), but these drugs have been associated to several adverse effects. Hearing...
INTRODUCTION
American Tegumentary Leishmaniasis (ATL) treatment is based on pentavalent antimonials (Sb5+), but these drugs have been associated to several adverse effects. Hearing loss and tinnitus during treatment with meglumine antimoniate (MA) have already been reported. This study aimed to describe the usefulness of self-reporting of hearing loss and tinnitus in diagnosing MA-induced ototoxicity.
METHODS
A prospective longitudinal study was conducted with 102 patients with parasitological diagnosis of ATL, treated with different MA schemes. The presence of clinical auditory toxicity was defined as the emergence or worsening of self-reporting hearing loss and/or tinnitus during monitoring. Measures of sensitivity, specificity, and the positive and negative predictive value of the patient's self-reporting of hearing loss and tinnitus in relation to the result of the audiometric test (considered the gold standard) were calculated.
RESULTS
The age of the evaluated patients ranged from 15 to 81 years, with a median of 41 years, and most were male (73.5%). Seventy-five patients (73.5%) had cutaneous leishmaniasis and 27 (26.5%) mucosal leishmaniasis. Eighty-six patients (84.3%) received intramuscular (IM) treatment and 16 (15.7%) were treated with intralesional MA. During treatment, 18 (17,6%) had tinnitus and 7 (6,9%) had complaint of hearing loss. 53 (52%) patients had cochlear toxicity confirmed by tone threshold audiometry and high frequency audiometry, from which 60% received a dose of 20 mg Sb5+/kg/day (p = 0.015) and 96.2% were treated with IM MA (p = 0.001). Tinnitus has greater specificity and positive predictive value than hearing loss, with a low number of false positives, but with a high false negative value.
CONCLUSION
Although the large number of false negatives suggests that self-report of hearing loss or tinnitus cannot be considered a good screening test for referring the patient to an audiometry, the low number of false positives suggests the need to value the patient's complaint for referral. Otherwise, this study reinforces the importance of audiological monitoring during treatment with MA, especially in those patients with self-reporting of hearing loss or tinnitus when treated with 20 mg Sb5+/kg/day via IM.
Topics: Humans; Male; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Meglumine Antimoniate; Ototoxicity; Tinnitus; Meglumine; Antiprotozoal Agents; Longitudinal Studies; Prospective Studies; Organometallic Compounds; Leishmaniasis, Cutaneous; Hearing Loss; Deafness
PubMed: 38354178
DOI: 10.1371/journal.pone.0296728 -
BioRxiv : the Preprint Server For... Jan 2024Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain...
Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain unknown, but mitochondria have emerged as potential mediators of cisplatin ototoxicity. Direct observation of changes in hair cell mitochondrial function are challenging because the mammalian inner ear is optically inaccessible. Here, we perform live imaging of hair cells within the zebrafish lateral-line organ to evaluate the role of mitochondria in cisplatin ototoxicity. Using a genetically encoded biosensor that measures cumulative mitochondrial activity in hair cells, we demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conduct time-lapse imaging of individual hair cells to understand dynamic changes in mitochondrial homeostasis. We observe spikes in mitochondrial calcium and cytosolic calcium immediately prior to hair cell death. Furthermore, we use a mitochondrially-localized probe that fluoresces in the presence of cisplatin to show that cisplatin accumulates in hair cell mitochondria. Lastly, we demonstrate that this accumulation occurs before mitochondrial dysregulation, Caspase-3 activation, and ultimately, hair cell death. Our findings provide additional evidence that suggest mitochondria are integral to cisplatin ototoxicity and cisplatin directly targets hair cell mitochondria.
PubMed: 38352581
DOI: 10.1101/2024.01.29.577846 -
Heliyon Feb 2024Pulmonary infections by gram-negative organisms are important in cystic fibrosis (CF). Aminoglycosides (AG) are often part of the treatment regimen. However, they are a...
BACKGROUND
Pulmonary infections by gram-negative organisms are important in cystic fibrosis (CF). Aminoglycosides (AG) are often part of the treatment regimen. However, they are a well-known cause of ototoxicity. Even minimal hearing impairment in children could have a future impact on functional well-being.We aimed to investigate the progression of sensorineural hearing loss (SNHL) over several years in pediatric CF patients, and to identify risk factors, such as the use of AG, including both intravenous (IV) and inhaled AG.
METHODS
Retrospective analyses of patient records from children and adolescents followed up at the CF clinic of the Antwerp University Hospital, Belgium, were performed. We collected data on age, sex, pure-tone audiometry, and the use of AG. Descriptive and binary logistic regression analyses, and if indicated generalized estimating equations (GEE) analyses were performed.
RESULTS
Forty pediatric patients were enrolled in the study taking part from 2013 to 2020. Pure-tone audiometry revealed an important rate of SNHL over several years, with a prevalence of 29 % for high-frequency SNHL (i.e. 8 kHz). Increasing age was identified as a significant risk factor for the development of SNHL at 8 kHz if 5 or more IV AG courses (p = 0.01) were reported or when IV AG were combined with inhaled AG (p = 0.002).
CONCLUSIONS
Age combined with the use of IV AG (≥5 courses or in combination with inhaled AG) are predictive for developing high-frequency SNHL (i.e. 8 kHz). We suggest routine annual hearing screening (incl. high-frequency thresholds) in CF patients, starting from childhood.
PubMed: 38333844
DOI: 10.1016/j.heliyon.2024.e25190 -
Frontiers in Pharmacology 2024The inner ear is the organ responsible for hearing and balance. Inner ear dysfunction can be the result of infection, trauma, ototoxic drugs, genetic mutation or... (Review)
Review
The inner ear is the organ responsible for hearing and balance. Inner ear dysfunction can be the result of infection, trauma, ototoxic drugs, genetic mutation or predisposition. Often, like for Ménière disease, the cause is unknown. Due to the complex access to the inner ear as a fluid-filled cavity within the temporal bone of the skull, effective diagnosis of inner ear pathologies and targeted drug delivery pose significant challenges. Samples of inner ear fluids can only be collected during surgery because the available procedures damage the tiny and fragile structures of the inner ear. Concerning drug administration, the final dose, kinetics, and targets cannot be controlled. Overcoming these limitations is crucial for successful inner ear precision medicine. Recently, notable advancements in microneedle technologies offer the potential for safe sampling of inner ear fluids and local treatment. Ultrasharp microneedles can reach the inner ear fluids with minimal damage to the organ, collect μl amounts of perilymph, and deliver therapeutic agents . This review highlights the potential of ultrasharp microneedles, combined with nano vectors and gene therapy, to effectively treat inner ear diseases of different etiology on an individual basis. Though further research is necessary to translate these innovative approaches into clinical practice, these technologies may represent a true breakthrough in the clinical approach to inner ear diseases, ushering in a new era of personalized medicine.
PubMed: 38327988
DOI: 10.3389/fphar.2024.1328460 -
Acta Pharmaceutica Sinica. B Feb 2024According to the World Health Organization's world report on hearing, nearly 2.5 billion people worldwide will suffer from hearing loss by 2050, which may contribute to... (Review)
Review
According to the World Health Organization's world report on hearing, nearly 2.5 billion people worldwide will suffer from hearing loss by 2050, which may contribute to a severe impact on individual life quality and national economies. Sensorineural hearing loss (SNHL) occurs commonly as a result of noise exposure, aging, and ototoxic drugs, and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear, which is mainly triggered by reactive oxygen species accumulation, inflammation, and mitochondrial dysfunction. Though recent advances have been made in understanding the ability of cochlear repair and regeneration, there are still no effective therapeutic drugs for SNHL. Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine. Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL, and elucidate their molecular mechanisms of action, to pave the way for further research and development of novel effective drugs in this field.
PubMed: 38322328
DOI: 10.1016/j.apsb.2023.11.001 -
Frontiers in Psychology 2023Congenital toxoplasmosis (CT) occurs mainly by primary maternal infection during pregnancy. It is estimated that the incidence of vertical transmission to the fetus is...
BACKGROUND
Congenital toxoplasmosis (CT) occurs mainly by primary maternal infection during pregnancy. It is estimated that the incidence of vertical transmission to the fetus is 20% and that infected women are more likely to have a premature birth or low birth weight neonate since there is an association between CT and the rate of premature birth and low birth weight. In addition to severe neurological and ophthalmic consequences, hearing disorders such as hearing loss are also among the clinical manifestations seen in children with CT. Given the above, the objective of this study is to verify what are the auditory disorders seen in children with CT.
METHODS
This literature review was structured according to the PRISMA statement and based on the terms of Study Target Population, Intervention, Comparison, Outcomes, and Study Types (PICOS). To obtain the studies, the following electronic databases were consulted: PubMed, Web of Science, Scopus, and Lilacs. The combined terms used for the search were: ("auditory evoked potentials" OR "hearing" OR "hearing loss") AND ("congenital toxoplasmosis"). The selection of articles was carried out independently, blindly, by two of the authors, to minimize risk of bias.
RESULTS
The search in the databases identified 172 articles, after excluding duplicate articles, 105 studies were identified. From the selection made by reading the titles and abstracts, 11 studies were selected for full-text reading. A total of 94 studies were excluded. An article was selected from the list of references. Therefore, 12 studies were included in the final analysis. It was observed that a significant percentage of studies sought to study the peripheral auditory pathway, verifying the occurrence or association between hearing loss and the presence of congenital infection. Only two studies evaluated the central auditory pathway, using the Brainstem Auditory Evoked Potential (BAEP) and the Frequency Following Response (FFR).
CONCLUSION
Toxoplasmosis affects not only the peripheral areas but central areas as well. Most studies suggest this pathology as a risk factor for both peripheral and central impairment. Research has found a greater association between CT and mild to moderate hearing loss, in addition to alterations in exams such as BAEP and FFR. These data recommend that CT be reported as a global public health problem and can help assess complications and impacts of hearing disorders as a result of CT. There is a gap about studies that retract the co-occurrence between CT and other Risk Indicators for Hearing Loss (RIHL), such as prematurity, permanence in the intensive care unit, and use of ototoxic medications, lack of longitudinal studies, that accompany the development of hearing and language of children with CT, since the consequences of this infection may be late.
PubMed: 38298366
DOI: 10.3389/fpsyg.2023.1286211