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Biomedicine & Pharmacotherapy =... Jan 2023Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss. The main etiologies are stria vascularis... (Review)
Review
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.
Topics: Humans; Cisplatin; Antineoplastic Agents; Hair Cells, Auditory; Ototoxicity; Cochlea; Apoptosis
PubMed: 36455457
DOI: 10.1016/j.biopha.2022.114045 -
Environmental Research Dec 2023Meniere's disease (MD) is a severe inner ear condition known by debilitating symptoms, including spontaneous vertigo, fluctuating and progressive hearing loss, tinnitus,... (Review)
Review
Meniere's disease (MD) is a severe inner ear condition known by debilitating symptoms, including spontaneous vertigo, fluctuating and progressive hearing loss, tinnitus, and aural fullness or pressure within the affected ear. Prosper Meniere first described the origins of MD in the 1860s, but its underlying mechanisms remain largely elusive today. Nevertheless, researchers have identified a key histopathological feature called Endolymphatic Hydrops (ELH), which refers to the excessive buildup of endolymph fluid in the membranous labyrinth of the inner ear. The exact root of ELH is not fully understood. Still, it is believed to involve several biological and bioenvironmental etiological factors such as genetics, autoimmunity, infection, trauma, allergy, and new theories, such as saccular otoconia blocking the endolymphatic duct and sac. Regarding treatment, there are no reliable and definitive cures for MD. Most therapies focus on managing symptoms and improving the overall quality of patients' life. To make significant advancements in addressing MD, it is crucial to gain a fundamental understanding of the disease process, laying the groundwork for more effective therapeutic approaches. This paper provides a comprehensive review of the pathophysiology of MD with a focus on old and recent theories. Current treatment strategies and future translational approaches (with low-level evidence but promising results) related to MD are also discussed, including patents, drug delivery, and nanotechnology, that may provide future benefits to patients suffering from MD.
Topics: Humans; Meniere Disease; Endolymphatic Hydrops; Otolithic Membrane
PubMed: 37648189
DOI: 10.1016/j.envres.2023.116972 -
Proceedings of the National Academy of... Jun 2023The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional...
The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional network governing cochlear late-stage maturation and particularly the differentiation of its lateral nonsensory region. Here, we establish ZBTB20 as an essential transcription factor required for cochlear terminal differentiation and maturation and hearing. ZBTB20 is abundantly expressed in the developing and mature cochlear nonsensory epithelial cells, with transient expression in immature hair cells and spiral ganglion neurons. Otocyst-specific deletion of causes profound deafness with reduced endolymph potential in mice. The subtypes of cochlear epithelial cells are normally generated, but their postnatal development is arrested in the absence of ZBTB20, as manifested by an immature appearance of the organ of Corti, malformation of tectorial membrane (TM), a flattened spiral prominence (SP), and a lack of identifiable Boettcher cells. Furthermore, these defects are related with a failure in the terminal differentiation of the nonsensory epithelium covering the outer border Claudius cells, outer sulcus root cells, and SP epithelial cells. Transcriptome analysis shows that ZBTB20 regulates genes encoding for TM proteins in the greater epithelial ridge, and those preferentially expressed in root cells and SP epithelium. Our results point to ZBTB20 as an essential regulator for postnatal cochlear maturation and particularly for the terminal differentiation of cochlear lateral nonsensory domain.
Topics: Animals; Mice; Cochlea; Hair Cells, Auditory; Hearing; Mammals; Spiral Ganglion; Transcription Factors
PubMed: 37279265
DOI: 10.1073/pnas.2220867120 -
Clinical and Experimental... Feb 2022Meniere disease (MD) is a rare set of conditions associated with the accumulation of endolymph in the cochlear duct and the vestibular labyrinth with a decrease of... (Review)
Review
Meniere disease (MD) is a rare set of conditions associated with the accumulation of endolymph in the cochlear duct and the vestibular labyrinth with a decrease of endocochlear potential. It is considered a chronic inflammatory disorder of the inner ear with a multifactorial origin. The clinical syndrome includes several groups of patients with a core phenotype: sensorineural hearing loss, episodes of vertigo, and tinnitus with a non-predictable course. Genetic factors and the innate immune response seem to play a central role in the pathophysiology of the condition. Autoimmune MD should be diagnosed if a patient fulfills the diagnostic criteria for MD and one of the following autoimmune disorders: autoimmune thyroid disease, psoriasis, autoimmune arthritis, ankylosing spondylitis, or systemic lupus erythematosus. We summarize the evidence to support autoimmune MD as an endophenotype in bilateral MD associated with the allelic variant rs4947296 and nuclear factor-kappa B (NF-κB)-mediated inflammation, the role of cytokines (particularly interleukin-1β and tumor necrosis factor-α) in defining a subset of patients with autoinflammation, and the potential role of cytokines as biomarkers to distinguish between patients with MD and vestibular migraine. Finally, we also introduce a list of potential drugs that could regulate the immune response in MD with potential for repurposing in clinical trials.
PubMed: 35124944
DOI: 10.21053/ceo.2021.00920 -
Neurochemistry International Jun 2020Glia use multiple mechanisms to mediate potassium fluxes that support neuronal function. In addition to changes in potassium levels within synapses, these ions are... (Review)
Review
Glia use multiple mechanisms to mediate potassium fluxes that support neuronal function. In addition to changes in potassium levels within synapses, these ions are dynamically dispersed through the interstitial parenchyma, perivascular spaces, leptomeninges, cerebrospinal fluid, choroid plexus, blood, vitreous, and endolymph. Neural circuits drive diversity in the glia that buffer potassium and this is reciprocal. Glia mediate buffering of potassium locally at glial-neuronal interfaces and via widespread networked connections. Control of potassium levels in the central nervous system is mediated by mechanisms operating at various loci with complexity that is difficult to model. However, major components of networked glial buffering are known. The role that potassium buffering plays in homeostasis of the CNS underlies some pathologic phenomena. An overview of potassium fluxes in the CNS is relevant for understanding consequences of pathogenic sequence variants in genes that encode potassium buffering proteins. Potassium flows in the CNS are described as follows: K1, the coordinated potassium fluxes within the astrocytic cradle around the synapse; K2, temporary storage of potassium within astrocytic processes in proposed microdomains; K3, potassium fluxes between oligodendrocytes and astrocytes; K4, potassium fluxes between astrocytes; K5, astrocytic potassium flux mediation of neurovasular coupling; K6, CSF delivery of potassium to perivascular spaces with dispersion to interstitial fluid between astrocytic endfeet; K7, astrocytic delivery of potassium to CSF and K8, choroid plexus (modified glia) regulation of potassium at the blood-CSF barrier. Components, mainly potassium channels, transporters, connexins and modulators, and the pathogenic sequence variants of their genes with the associated diseases are described.
Topics: Animals; Astrocytes; Central Nervous System; Homeostasis; Humans; Neuroglia; Oligodendroglia; Potassium
PubMed: 32194142
DOI: 10.1016/j.neuint.2020.104727