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Frontiers in Neurology 2021Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients. Development of effective biomarkers for Menière's...
Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients. Development of effective biomarkers for Menière's disease are needed. miRNAs are small RNA sequences that downregulate mRNA translation and play a significant role in a variety of disease states, ultimately making them a promising biomarker. miRNAs can be readily isolated from human inner ear perilymph and serum, and may exhibit disease-specific profiles. Perilymph sampling was performed in 10 patients undergoing surgery; 5 patients with Meniere's disease and 5 patients with otosclerosis serving as controls. miRNAs were isolated from the serum of 5 patients with bilateral Menière's disease and compared to 5 healthy age-matched controls. For evaluation of miRNAs an Agilent miRNA gene chip was used. Analysis of miRNA expression was carried out using Qlucore and Ingenuitey Pathway Analysis software. Promising miRNAs biomarkers were validated using qPCR. In the perilymph of patients with Menière's disease, we identified 16 differentially expressed miRNAs that are predicted to regulate over 220 different cochlear genes. Six miRNAs are postulated to regulate aquaporin expression and twelve miRNAs are postulated to regulate a variety of inflammatory and autoimmune pathways. When comparing perilymph with serum samples, miRNA-1299 and-1270 were differentially expressed in both the perilymph and serum of Ménière's patients compared to controls. Further analysis using qPCR confirmed miRNA-1299 is downregulated over 3-fold in Meniere's disease serum samples compared to controls. Patients with Ménière's disease exhibit distinct miRNA expression profiles within both the perilymph and serum. The altered perilymph miRNAs identified can be linked to postulated Ménière's disease pathways and may serve as biomarkers. miRNA-1299 was validated to be downregulated in both the serum and perilymph of Menière's patients.
PubMed: 34220670
DOI: 10.3389/fneur.2021.646928 -
Scientific Reports Oct 2022A mouse model with cisplatin-induced ototoxicity was used in addition to human samples from the ITMAT Biobank at the University of Pennsylvania. Mouse auditory brainstem...
A mouse model with cisplatin-induced ototoxicity was used in addition to human samples from the ITMAT Biobank at the University of Pennsylvania. Mouse auditory brainstem responses (ABR), inner ear histology, perilymph cisplatin sampling, and measurement of serum prestin via ELISA were performed. Human serum prestin level was measured via ELISA in patients with otological issues after cisplatin treatment and compared to matched controls. Serum prestin was significantly elevated before ABR threshold shifts in mice exposed to cisplatin compared to control mice. Prestin concentration also correlated with the severity of hearing threshold shifts in mice. After an extended rest post-cisplatin treatment, prestin returned to baseline levels in mice and humans. Prestin was significantly elevated in the serum before the onset of objective hearing loss and correlated with the severity of hearing damage indicating that prestin may function as an effective biomarker of cisplatin-induced ototoxicity. Human serum prestin levels responded similarly to mice > 3 weeks from ototoxic exposure with decreased levels of prestin in the serum.
Topics: Humans; Mice; Animals; Cisplatin; Ototoxicity; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Biomarkers; Antineoplastic Agents
PubMed: 36302835
DOI: 10.1038/s41598-022-23034-x -
Frontiers in Bioengineering and... 2023Cisplatin (CIS) is widely used to treat various cancers but can cause ototoxicity and sensory hair cell loss in the inner ear. Copper induces an excessive production of...
Cisplatin (CIS) is widely used to treat various cancers but can cause ototoxicity and sensory hair cell loss in the inner ear. Copper induces an excessive production of reactive oxygen species (ROS) in hair cells, leading to the development of various antioxidants. This study aimed to evaluate the potential antioxidant properties of curcumin (CUR) in the inner ear organ of corti-1 cells (OC1) and animal models (zebrafish and guinea pigs). Graphene oxide quantum dots (GOQDs) enabled CUR to penetrate the round window membrane (RWM) and maintain the concentration in the perilymph after inner ear administration. The results showed that CUR/GOQDs had favorable biocompatibility and strongly affected ROS generation induced by CIS in OC1 cells. DCFHDA Green staining demonstrated that CUR/GOQDs successfully reversed the decrease in mitochondrial membrane potential induced by CIS and rescued cells from early cuproptosis, which was confirmed by FDX1 staining. Additionally, the experiment found that CUR decreased the expression of cuproptosis proteins (FDX1, LIAS, and LIPT1) and increased the expression of the Bcl-2 protein. The results demonstrate that CUR/GOQDs is a promising therapeutic agent that can prevent CIS-induced ototoxicity by blocking the cuproptosis signal pathway.
PubMed: 37152642
DOI: 10.3389/fbioe.2023.1183197 -
Hearing Research Oct 2018Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we... (Review)
Review
Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration.
Topics: Animals; Drug Delivery Systems; Ear, Inner; Hearing; Hearing Loss; Humans; Labyrinth Diseases; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 29551306
DOI: 10.1016/j.heares.2018.03.002 -
PloS One 2022Methotrexate (MTX) has been used in treating various types of cancers but can also cause damage to normal organs and cell types. Folinic acid (FA) is a well-known MTX...
Methotrexate (MTX) has been used in treating various types of cancers but can also cause damage to normal organs and cell types. Folinic acid (FA) is a well-known MTX antidote that protects against toxicity caused by the drug and has been used for decades. Since hearing loss caused by MTX treatment is not well studied, herein we aimed to investigate the efficiency of the antioxidant Avenanthramide-C (AVN-C) on high-dose MTX (HDMTX) toxicity in the ear and provide insights into the possible mechanism involved in MTX-induced hearing loss in normal adult C57Bl/6 mice and HEI-OC1 cells. Our results show that the levels of MTX increased in the serum and perilymph 30 minutes after systemic administration. MTX increased hearing thresholds in mice, whereas AVN-C and FA preserved hearing within the normal range. MTX also caused a decrease in wave I amplitude, while AVN-C and FA maintained it at higher levels. MTX considerably damaged the cochlear synapses and neuronal integrity, and both AVN-C and FA rescued the synapses. MTX reduced the cell viability and increased the reactive oxygen species (ROS) level in HEI-OC1 cells, but AVN-C and FA reversed these changes. Apoptosis- and ROS-related genes were significantly upregulated in MTX-treated HEI-OC1 cells; however, they were downregulated by AVN-C and FA treatment. We show that MTX can cause severe hearing loss; it can cross the blood-labyrinth barrier and cause damage to the cochlear neurons and outer hair cells (OHCs). The antioxidant AVN-C exerts a strong protective effect against MTX-induced ototoxicity and preserved the inner ear structures (synapses, neurons, and OHCs) from MTX-induced damage. The mechanism of AVN-C against MTX suggests that ROS is involved in HDMTX-induced ototoxicity.
Topics: Animals; Antioxidants; Apoptosis; Cell Line; Cisplatin; Hearing Loss; Methotrexate; Mice; Ototoxicity; Reactive Oxygen Species; ortho-Aminobenzoates
PubMed: 35353852
DOI: 10.1371/journal.pone.0266108 -
Hong Kong Medical Journal = Xianggang... Aug 2012Dizziness is among the commonest of chief complaints. It often presents a significant challenge to the attending physician, because the symptoms and signs are often... (Review)
Review
Dizziness is among the commonest of chief complaints. It often presents a significant challenge to the attending physician, because the symptoms and signs are often vague and non-specific. However, a robust systematic approach can usually arrive at the diagnosis. Maintaining balance requires sensory inputs from the vestibular, visual, and somatosensory systems and the cerebellum fine-tunes inaccurate motor outputs. Causes of vertigo are most commonly otological, followed by central, somatosensory, and visual. The first question in approaching patients with dizziness is to categorise dizziness into one of the four groups: lightheadedness, pre-syncope, disequilibrium, and vertigo. Secondly, central vertigo has to be differentiated with peripheral vertigo. For peripheral vertigo, the most common cause is benign paroxysmal positional vertigo and should be specifically looked for. The tempo of the vertiginous attacks and other associated symptoms can help differentiate the other causes of peripheral vertigo, including Meniere's disease, vestibular neuronitis, labyrinthitis, and a perilymph fistula.
Topics: Humans; Labyrinthitis; Meniere Disease; Physical Examination; Vertigo; Vestibular Neuronitis
PubMed: 22865178
DOI: No ID Found -
British Medical Journal Feb 1979
Topics: Hearing Loss, Sudden; Humans; Mumps; Mumps virus; Perilymph
PubMed: 421111
DOI: 10.1136/bmj.1.6159.343-b -
Anatomical Record (Hoboken, N.J. : 2007) Nov 2012This review addresses the current status of steroid therapies for hearing and vestibular disorders and how certain misconceptions may be undermining the efficacy in... (Review)
Review
This review addresses the current status of steroid therapies for hearing and vestibular disorders and how certain misconceptions may be undermining the efficacy in restoring normal ear function, both experimentally and clinically. Specific misconceptions addressed are that steroid therapy is not effective, steroid-responsive hearing loss proves an underlying inflammatory problem in the ear, and steroids only have application to the hearing disorders listed below. Glucocorticoid therapy for hearing and balance disorders has been employed for over 60 years. It is recommended in cases of sudden hearing loss, Meniére's disease, immune-mediated hearing loss, and any vestibular dysfunction suspected of having an inflammatory etiology. The predominant steroids employed today are dexamethasone, prednisone, prednisolone, and methylprednisolone. Despite years of use, little is known of the steroid responsive mechanisms in the ear that are influenced by glucocorticoid therapy. Furthermore, meta-analyses and clinical study reviews occasionally question whether steroids offer any benefit at all. Foremost in the minds of clinicians is the immune suppression and anti-inflammatory functions of steroids because of their efficacy for autoimmune hearing loss. However, glucocorticoids have a strong binding affinity for the mineralocorticoid (aldosterone) and glucocorticoid receptors, both of which are prominent in the ear. Because the auditory and vestibular end organs require tightly regulated endolymph and perilymph fluids, this ion homeostasis role of the mineralocorticoid receptor cannot be overlooked in both normal and pathologic functions of the ear. The function of the glucocorticoid receptor is to provide anti-inflammatory and antiapoptotic signals by mediating survival factors.
Topics: Adrenal Cortex Hormones; Animals; Hearing Loss; Humans; Vertigo
PubMed: 23044978
DOI: 10.1002/ar.22576 -
Frontiers in Cell and Developmental... 2022The high complexity of the cellular architecture of the human inner ear and the inaccessibility for tissue biopsy hampers cellular and molecular analysis of inner ear...
The high complexity of the cellular architecture of the human inner ear and the inaccessibility for tissue biopsy hampers cellular and molecular analysis of inner ear disease. Sampling and analysis of perilymph may present an opportunity for improved diagnostics and understanding of human inner ear pathology. Analysis of the perilymph proteome from patients undergoing cochlear implantation was carried out revealing a multitude of proteins and patterns of protein composition that may enable characterisation of patients into subgroups. Based on existing data and databases, single proteins that are not present in the blood circulation were related to cells within the cochlea to allow prediction of which cells contribute to the individual perilymph proteome of the patients. Based on the results, we propose a human atlas of the cochlea. Finally, druggable targets within the perilymph proteome were identified. Understanding and modulating the human perilymph proteome will enable novel avenues to improve diagnosis and treatment of inner ear diseases.
PubMed: 35573665
DOI: 10.3389/fcell.2022.847157 -
Indian Journal of Otolaryngology and... Aug 2022This study has aimed to determine the anatomical site of labyrinthine fistula in patients of chronic suppurative otitis media at our centre. Labyrinthine fistulae (LF)...
This study has aimed to determine the anatomical site of labyrinthine fistula in patients of chronic suppurative otitis media at our centre. Labyrinthine fistulae (LF) are caused by abnormal communications between the inner ear and surrounding structures resulting in perilymph leakage and hearing loss. Labyrinthine fistula represents as erosive loss of the enchondral bone overlying the semicircular canals without loss of perilymph. The manifestations of fistula like vertigo, hearing loss vary in severity and complexity, commonly ranging from very mild to incapacitating. Cholesteatoma induced fistula most commonly involves lateral semicircular canal probably because of its close proximity to the middle ear, but can involve other semicircular canals and rarely cochlea. This is a retrospective analysis of 36 patients of chronic suppurative otitis media with history of vertigo undergoing tympanomastoid surgery in whom there was an evidence of labyrinthine fistula on HRCT scan of temporal bone. The incidence of patients with labyrinthine fistula presenting with vertigo, nystagmus, sensorineural hearing loss, history of vertigo were analysed. The anatomical location of the fistula was supported by Radiological evidence. Patients underwent either canal wall down mastoidectomy or cortical mastoidectomy. The anatomical site and length of the labyrinthine fistula were analysed. Amongst the 36 patients of chronic suppurative otitis media with labyrinthine fistula 22 (61.1%) patients had atticoantral disease, 4 (11.1%) patients had chronic otitis media with extensive granulation, 2 (5.5%) patients had Tubotympanic disease with polyps, 4 (11.1%) patients had Tuberculous otitis media, 1 (2.77%) patient had Tubotympanic disease with extensive tympanosclerosis eroding the dome of lateral semicircular canal, 1 (2.77%) patient had extensive cholesteatoma with cerebellar abscess, 1 (2.77%) patient had fistula in the promontory following trauma, 1 (2.77%) patient had extensive tympanosclerosis with erosion of promontory. It was noticed that, in 14 (38.88%) patients the fistula was at the centre, in 17 (47.22%) patients the fistula is towards the ampullary end of horizontal semicircular canal and in 5 (13.88%) patients the fistula was towards the non ampullary end of lateral semicircular canal. The maximum length of fistula noticed was 6 mm and the minimum length of the fistula noticed was 2 mm. Labyrinthine fistula are most commonly noticed in the ampullary end of the lateral semicircular canal. The average length of the fistula was found to be 4 mm. Careful elevation of the cholesteatoma matrix over the endosteal membrane and immediate placement of temporal fascia over the exposed fistula is important to avoid injury to the inner ear. Maximum number of fistula were seen in the atticoantral type of Chronic suppurative otitis media. Prior knowledge of anatomical location of the fistulous tract in HRCT temporal bone is important to address the fistula.
PubMed: 36032823
DOI: 10.1007/s12070-020-01857-2