Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(22), P. 16545 - 16545

Published: Nov. 20, 2023

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

Language: Английский

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The crucial role of diverse animal models to investigate cochlear aging and hearing loss

Hearing Research, Journal Year: 2024, Volume and Issue: 445, P. 108989 - 108989

Published: March 11, 2024

Age-related hearing loss affects a large and growing segment of the population, with profound impacts on quality life. pathology cochlea-the mammalian organ-underlies age-related loss. Because investigating changes in cochlea humans is challenging often impossible, animal models are indispensable to investigate these mechanisms as well complex consequences brain behavior. In this review, we advocate for comparative interdisciplinary approach while also addressing challenges comparing across species varying lifespans. We describe experimental advantages limitations areas future research well-established loss, including mice, rats, gerbils, chinchillas, birds. indicate need expand characterization other established models, especially guinea pigs, cats, non-human primates, which auditory function characterized but cochlear understudied. Finally, highlight potential emerging advancing our understanding deer their notably extended lifespans preserved hearing, naked mole exceptional longevity extensive vocal communications, zebrafish, offer genetic tractability suitability drug screening. Ultimately, research, combining insights from various human studies, key robust reliable outcomes that better advance treatment

Language: Английский

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LDHA-mediated glycolysis in stria vascularis endothelial cells regulates macrophages function through CX3CL1-CX3CR1 pathway in noise-induced oxidative stress

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 3, 2025

Abstract According to the World Health Organization, more than 12% of world’s population suffers from noise-induced hearing loss (NIHL). Oxidative stress-mediated damage stria vascularis (SV) is one pathogenic mechanisms NIHL. Recent studies indicate that glycolysis plays a critical role in endothelial cells (ECs)-related diseases. However, specific dysfunction SV-ECs remain largely unknown. In this study, we investigated effects on vitro and SV vivo. Our previous research identified pathway as potential mechanism underlying injuries induced by oxidative stress. We further examined expression levels glycolytic genes under H 2 O stimulation noise-exposed mice. found gene protein glycolytic-related enzyme LDHA significantly decreased at early phase after stress injury both vivo, exhibited anti-inflammatory macrophages (Mφ). Moreover, analyzed differential secretomes with without inhibition using LC-MS/MS technology, identifying CX3CL1 candidate mediator for cellular communication between Mφ. secretion was following Mφ via CX3CR1 pathway. Similarly, pro-inflammatory effect LDHA-overexpressing attenuated CX3CL1. conclusion, our study revealed glycolysis-related reduced stress-induced SV-ECs, elicited Mφ, least partially through CX3CL1-CX3CR1 These findings suggest represent novel therapeutic strategy treatment

Language: Английский

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Vascular Pathology in Age-Related Hearing Loss

Ageing & Longevity, Journal Year: 2025, Volume and Issue: 1.2025, P. 69 - 72

Published: Feb. 20, 2025

Age-related hearing loss (ARHL) is a growing global healthcare challenge. An increasing body of research suggests an association between ARHL and conditions such as dementia, hypertension, diabetes, obesity. However, the causal relationships these pathologies remain poorly understood. We propose that vascular pathology may be key pathogenetic link connecting conditions, particularly given inherent vulnerability cochlear blood supply microvasculature. One promising approach for studying in ageing cochlea involves combining optical tissue clearing, light-sheet microscopy, advanced 3D network analysis. This enables comprehensive assessment its spatial mapping onto other structures. To fully disentangle factors contributing to ARHL, this should integrated into extensive, systematic animal studies, incorporating models ageing, noise exposure, ARHL-related comorbidities combination isolation. Keywords: age-related loss; sensorineural metabolic cochlea; vasculature; pathology; stria vascularis

Language: Английский

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GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(11)

Published: March 11, 2025

Inflammation is among the known causes of cisplatin-induced hearing loss (CIHL), but its exact pathophysiological mechanisms remain unclear. Herein, we demonstrated that pyroptosis—a recently identified inflammatory type regulated cell death dependent on gasdermin D (GSDMD)—was activated in cochleae cisplatin-treated mice, causing CIHL. Meanwhile, treatment with GSDMD inhibitor necrosulfonamide alleviated CIHL these mice. To further examine role GSDMD-mediated pyroptosis CIHL, conducted experiments Gsdmd- deficient mice . Gsdmd −/− significantly lower cochlear damage than control and appeared to be invulnerable Furthermore, stria vascularis (SV), not hair cells (HCs), played a dominant In marginal (MCs) SV, cisplatin induced caspase-dependent cleavage, pore-forming N-terminal rapidly localized mitochondria, leading abnormal mitochondrial aggregation oxidative stress. The consequent dysfunction MCs might result severe progression inflammation, SV damage, HC loss. Notably, pharmacological inhibition using FDA-approved drug disulfiram effectively symptoms Collectively, findings offer broad avenue for inhibiting pyroptosis-induced ototoxicity provide valuable theoretical insights clinical management

Language: Английский

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The Stria Vascularis: Renewed Attention on a Key Player in Age-Related Hearing Loss

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5391 - 5391

Published: May 15, 2024

Age-related hearing loss (HL), or presbycusis, is a complex and heterogeneous condition, affecting significant portion of older adults involving various interacting mechanisms. Metabolic type age-related HL, characterized by the dysfunction stria vascularis, which crucial for maintaining endocochlear potential necessary hearing. Although attention on metabolic presbycusis has waned in recent years, research continues to identify strial pathology as key factor HL. This narrative review integrates past research, bridging findings from animal models human studies, examine contributions vascularis It provides brief overview structure function then examines mechanisms contributing dysfunction, including altered ion transport, changes pigmentation, inflammatory responses, vascular atrophy. Importantly, this outlines contribution highlighting areas future research. emphasizes interdependence sensorineural HL highlights importance understanding underlying The comprehensive mechanistic investigation all factors cochlear remains identifying developing personalized, protective, restorative treatments.

Language: Английский

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Molecular differences between young and mature stria vascularis from organotypic explants and transcriptomics

iScience, Journal Year: 2025, Volume and Issue: 28(2), P. 111832 - 111832

Published: Jan. 18, 2025

The stria vascularis (SV) is an essential component of the inner ear that regulates ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding SV, and consequently therapeutic availability degeneration, lacking. We developed whole-tissue explant model from neonatal mature mice create platform advancing research. validated our by demonstrating proliferative behavior in vitro mimics vivo. also provided evidence pharmacological experimentation investigating role Wnt/β-catenin signaling proliferation. Finally, we performed single-cell RNA sequencing vivo mouse surrounding tissue revealed key genes pathways may play proliferation maintenance. Together, results contribute new insights into biological solutions SV-associated loss.

Language: Английский

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Sex differences in auditory function of the desert locust

Hearing Research, Journal Year: 2025, Volume and Issue: 460, P. 109228 - 109228

Published: March 2, 2025

Language: Английский

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Metabolomic and Cellular Mechanisms of Drug‐Induced Ototoxicity and Nephrotoxicity: Therapeutic Implications of Uric Acid Modulation

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Certain medications, including cisplatin and neomycin, often cause both hearing loss renal dysfunction. This study aims to uncover the common mechanisms behind drug-induced ototoxicity nephrotoxicity aid early diagnosis treatment. Metabolomic analyses reveal simultaneous disruptions in endogenous metabolic networks kidney, inner ear, serum after administrating or neomycin. Notably, a marked elevation uric acid (UA), recognized indicator of tubular injury, is identified. Supplementing UA inhibiting its excretion worsen hair cell damage. Single-cell nucleus sequencing immunohistochemistry major changes xanthine oxidase ABCG2, crucial for metabolism, primarily cochlear stria vascularis cells rather than cells. Cisplatin triggers significant release from cells, reaching concentrations sufficient induce autophagy-dependent ferroptosis In coculture system, targeted interventions against these two proteins through either pharmacological inhibition genetic manipulation, markedly decrease elevated subsequent These findings suggest connection between ear highlighting therapeutic potential modulating mitigate ototoxicity.

Language: Английский

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Targeting inflammation to prevent and treat sensorineural hearing loss

Chinese Medical Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

To the Editor: Sensorineural hearing loss (SNHL) is most prevalent form of loss. The pathogenesis SNHL remains elusive, resulting in a lack definitive and effective treatments for types. There substantial evidence that inflammation significantly contributes to progression. Various injurious agents damage tissues cells, prompting macrophages identify these necrotic material produce inflammatory mediators. Inflammatory mediators are transported cochlea through bloodstream, where they activate resident stimulate monocyte infiltration, thereby initiating cochlear inflammation. Inflammation triggers various pathological alterations within cochlea, primarily characterized by diminished hair cells synapses, reduced spiral neuron numbers, compromised blood–labyrinth barrier (BLB) integrity [Supplementary Figure 1, https://links.lww.com/CM9/C342].[1] Thus, exploring role provides distinct insights its treatment. Pathways research: complex process regulated multiple signaling pathways cytokines Table https://links.lww.com/CM9/C342]. mitogen-activated protein kinase (MAPK) pivotal cellular gene expression, transducing extracellular stimuli into diverse intracellular responses, including apoptosis, inflammation, differentiation. classical MAPK include signal-regulated (ERK), c-Jun N-terminal (JNK), p38. Toll-like receptor 4 (TLR-4) pattern-recognition (PRR) responsible recognizing binding pathogen-associated molecular patterns, such as lipopolysaccharides (LPS) or damage-associated patterns (DAMPs), heat-shock proteins (HSPs), subsequently downstream pathways, nuclear factor-κB (NF-κB), which turn promotes production proinflammatory molecules. Aside from producing factors, TLR pathway regulates antigen-presenting function macrophages. NOD-like (NLR) also serves PRR, inflammasome assembly regulating composition. NLR family pyrin domain-containing 3 (NLRP3) processes interleukin (IL)-1 IL-18 their mature forms via caspase-1 activation, full activation Sirtuins (SIRT) group nicotinamide adenine dinucleotide (NAD) dependent enzymes deacetylases adenosine diphosphate (ADP)-ribosyl transferases. SIRT1 predominantly located nucleus, while SIRT3 mitochondria. Poly (ADP-ribose) polymerase (PARP)-1 activated response DNA damage, facilitating repair breakdown NAD+ ADP-ribose. Excessive PARP-1 heightened degradation during injury increase catabolism lower levels, leading decline SIRT activity, augmented factor kappa-light-chain-enhancer B (NF-κB) deacetylation, increased Restoring expression activity can reduce level exhibit protective effect on raising levels. NF-κB broadly refers inducible dimeric transcription factors comprising NF-κB/Rel members. It be stimuli, cytokines, LPS, viruses, both physical chemical stressors, inducing an extensive array adhesion molecules, acute-phase proteins, complements, receptors. plays antiviral responses induced interferon genes. According available literature, PARP–SIRT age-related (ARHL) noise-induced (NIHL), NLRP3 investigated patients with cryopyrin-associated periodic syndromes (CAPS, kind hereditary [HHL]). In addition, TLR-4 implicated aspects development. acts central hub, coordinating regulate immune 2, Diverse etiologies processes: Based etiology, classified age-related, noise-induced, viral, hereditary, drug-induced 3, ARHL type SNHL. Aging reduction system functionality diminishes body's capacity levels decreased anti-inflammatory cytokines. This imbalance facilitates chronic tissue aging, ultimately culminating deterioration structure emergence functional disorders.[2] NIHL after ARHL. Exposure noise initially sparks acute reaction early mediator playing critical role. Given there few clinical studies NIHL, animal models acoustic brief exposure intense noise, notable gap understanding individuals exposed prolonged has consistently been shown evident some kinds HHL, linking certain Specifically, mutations collagen (COL4) lead Alport syndrome (AS), marked progressive renal failure AS, stems thickening capillary basement membrane, especially stria vascular. markers, chemokines, chemokine receptors, were AS mice compared wild-type mice. increases absorption ototoxic drugs cochlea. causes dilation permeability BLB, enhancing drug transport across upregulates channels (e.g., transient potential vanilloid 1 [TRPV1] channel) cells. cisplatin) elicit directly stimulating cytokine release synthesis. Congenital cytomegalovirus (cCMV) infection cause among children globally. cCMV compromises promoting hematogenous dissemination virus development promoted direct CMV. Medications techniques targeting inflammation: A number have developed mitigate inhibition mechanism action current treatment multifaceted summarized follows: (1) Regulation expression: involves reducing IL-1β, IL-6, tumor necrosis factor-α (TNF-α) concurrently IL-10. (2) Inhibition pathways: These intervene block steps response. (3) enzyme activities: formation prostaglandins inhibiting cyclooxygenase-2 (COX-2). (4) Indirect achieved e.g., oxidative stress protection mitochondria heat shock detailed classification mechanisms provided Supplementary https://links.lww.com/CM9/C342. Among outlined, only glucocorticoids (GC) widely used treating recommended guidelines sudden Several currently tested trials anakinra, canakinumab, resveratrol) demonstrated improvement studies. Other remain basic research phase but promising results suppression at types Overall, significant addition themselves, delivery technologies undergone rich developments. Numerous devised implemented address issue low concentrations reaching inner ear systemic administration BLB. Intratympanic injections GC utilized contraindications those experiencing incomplete recovery following initial Conversely, round window employed therapy trial phase.[3] Nanomaterials emerged focus field delivery. nanomaterials loaded drugs, when administered tympanic cavity, enhance improve hearing. Although not yet practice, ongoing advancements technology pharmaceutical expected refine ability load more precisely, offering safer treatments. Furthermore, suggests specific acupuncture points may effectively alleviate issues ear. many discussed derived herbal extracts, this exploration valuable efficacy reinforces discovery traditional Chinese medicine remedies therapeutic approaches. Challenges future prospects: intricately structured, housing functionally distinct. Research related concentrated relatively less attention given fibroblasts, marginal ganglion neurons. other supporting even scarce. examination interactions, functions, roles cell crucial advancing our Future should encompass types, aiming comprehensively decipher viable strategies. challenge acquiring specimens historically impeded precise measurement living human consequently obstructing validation findings Recent assessing feasible measuring perilymph fluid[4] analyzing high-resolution imaging.[5] appear addressing previously mentioned challenges. Nevertheless, utility novel methods necessitates thorough investigations sensitivity specificity. Moreover, application additional innovative essential comprehensive assessment manifestations. considerable SNHL, still limited. Most date focused impact insufficient underlying mechanisms. Particularly level, scant knowledge how modulate protect pathways. Consequently, concentrate elucidating actions develop Such efforts will comprehension biological systems could unveil targets, propelling forward Despite advances ear, several challenges persist. trauma procedural manipulations, limited residence time uneven distribution, sluggish pace technological translation. introduction nanotechnology represents shift inner-ear delivery, enhanced precision localization control. enables highly targeted areas likely further refining nanotechnologies. aim achieve control over effects, frequency safety effectiveness Funding was supported grants National Natural Science Foundation China (Nos. 82071057 82101229) Key Development Program Hubei Province Project (No. 2021BCA144). Conflicts interest None.

Language: Английский

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