GPR83 protects cochlear hair cells against ibrutinib-induced hearing loss through AKT signaling pathways DOI Creative Commons

Yuhua Zhang,

Yun Xiao, Yongjun Zhu

et al.

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: April 3, 2025

Introduction Ibrutinib, widely used in leukemia treatment, has been implicated sensorineural hearing loss; however, its underlying mechanisms remain unclear. Methods This study investigated the impact of ibrutinib on using HEI-OC1 cells, cochlear explants and C57BL/6 J mice. We RNA-sequences analysis to investigate potential ibrutinib-induced ototoxicity. Mice received auditory thresholds were assessed via brainstem response testing; assess protective effects, we co-administered caspase inhibitor Z-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK) monitored hearing. Results Z-VAD-FMK mitigated loss by inhibiting apoptosis cells. Ibrutinib exposure resulted hair cell (HC) damage subsequent protein kinase B G protein-coupled receptor 83 (GPR83) pathways. RNA sequencing suggested that GPR83 protects HCs modulating autophagy. application overexpression attenuated HC decline. Conclusion These findings confirm ibrutinib’s ototoxicity highlight role loss, supporting future clinical investigations into as interventions for or other chemotherapeutic drug-induced

Language: Английский

4‐octyl itaconate alleviates cisplatin‐induced ferroptosis possibly via activating the NRF2/HO‐1 signalling pathway DOI Creative Commons
Li Zhang,

Wenao Song,

Hua Li

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(7)

Published: March 20, 2024

Abstract Ferroptosis, characterized by iron‐dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin‐induced ototoxicity. Existing research has suggested that cisplatin‐mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4‐Octyl itaconate (4‐OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti‐inflammatory as well antioxidant effects several disease models. Our study aimed investigate the effect of 4‐OI on underlying molecular mechanisms. The survival rates HEI‐OC1 mice cochlea hair were measured CCK8 immunofluorescence, respectively. brainstem response (ABR) audiometry was used detect changes thresholds before after treatment. Levels ROS evaluated DCFH‐DA. Real‐time PCR quantified inflammatory cytokines TNF‐α, IL‐6 IL‐1β. Network Pharmacology RNA sequencing (RNA‐seq) analysis potential mechanism resistance ferroptosis. expressions ferroptosis‐related factors (GPX4, SLC7A11 PTGS2) important (NRF2, HO‐1, GCLC NQO1) tested real‐time PCR, Western blot immunofluorescence. Results demonstrated significant factor release, reduced NRF2 expression, hindered nuclear translocation activated Pretreatment with exhibited effects, along ferroptosis, ultimately mitigating loss. In present study, we show inhibits possibly through activation NRF2/HO‐1 signalling pathway, thereby exerting protective against cells, providing new therapeutic strategy for

Language: Английский

Citations

10
Metabolomic and Cellular Mechanisms of Drug‐Induced Ototoxicity and Nephrotoxicity: Therapeutic Implications of Uric Acid Modulation DOI Creative Commons

Suhan Guo,

Cheng Cheng, Yunhao Wu

et al.

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

Citations

1
Combining Copper and Zinc into a Biosensor for Anti-Chemoresistance and Achieving Osteosarcoma Therapeutic Efficacy DOI Creative Commons
Yan Yik Lim,

Ahmad Mujahid Ahmad Zaidi,

Azizi Miskon

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(7), P. 2920 - 2920

Published: March 24, 2023

Due to its built-up chemoresistance after prolonged usage, the demand for replacing platinum in metal-based drugs (MBD) is rising. The first MBD approved by FDA cancer therapy was cisplatin 1978. Even nearly four and a half decades of trials, there has been no significant improvement osteosarcoma (OS) therapy. In fact, many have developed, but problem raised remains unresolved. This motivates us elucidate possibilities copper zinc (CuZn) combination replace MBD. Thus, anti-chemoresistance properties CuZn their physiological functions OS are highlighted. Herein, we summarise chelators, main organic solvents, ligand structures that involved properties. Through this review, it rational discuss ligands' roles as biosensors drug delivery systems. Hereafter, an in-depth understanding redox photoactive function relationships provided. disadvantage other cannot be elaborated on here. As result, review being which expected intensify with higher cure rates. Nonetheless, advancement intends solve major obstacle towards clinical efficacy.

Language: Английский

Citations

18
Apelin-13 protects against cisplatin-induced ototoxicity by inhibiting apoptosis and regulating STAT1 and STAT3 DOI
Haiyan Yin,

Yinuo Sun,

Bailiu Ya

et al.

Archives of Toxicology, Journal Year: 2023, Volume and Issue: 97(9), P. 2477 - 2493

Published: July 3, 2023

Language: Английский

Citations

14
Dual stimuli-responsive and sustained drug delivery NanoSensoGel formulation for prevention of cisplatin-induced ototoxicity DOI
Neeraj S. Thakur, Iulia Rus,

Ethan Sparks

et al.

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 368, P. 66 - 83

Published: Feb. 21, 2024

Language: Английский

Citations

6
KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss DOI Creative Commons
Matthew A. Ingersoll,

Richard D. Lutze,

Regina G. Kelmann

et al.

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: unknown, P. e2174232024 - e2174232024

Published: March 28, 2024

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit large portion of the world population. Here we found that mice devoid protein kinase suppressor RAS 1 (KSR1) their tissues (germline KO mice) exhibit resistance both cisplatin- noise-induced permanent compared wild-type KSR1 littermates. scaffold brings proximity mitogen-activated (MAPK) proteins BRAF, MEK1/2 ERK1/2 assists activation through phosphorylation cascade induced by cisplatin noise insults cochlear cells. KSR1, MEK1/2, are all ubiquitously expressed cochlea. Deleting tempered down MAPK cells following conferred protection up 30 dB SPL three tested frequencies male female mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, protected from loss. Dabrafenib treatment did not enhance mice, providing evidence dabrafenib works primarily pathway. Thus, either elimination gene expression or drug inhibition cellular pathway resulted profound noise-induce Inhibition pathway, responds damage cells, can prove valuable strategy treat Significance Statement Ten percent population suffers but this impairment may be preventable. We show (KO) littermates harbor protein. Removing tempers BRAF-MEK-ERK cochlea insults. and, importantly, confer additional Hence, has unique role responding removing results protection.

Language: Английский

Citations

6
Protection from cisplatin-induced hearing loss with lentiviral vector-mediated ectopic expression of the anti-apoptotic protein BCL-XL DOI Creative Commons
Larissa Nassauer, Hinrich Staecker, Peixin Huang

et al.

Molecular Therapy — Nucleic Acids, Journal Year: 2024, Volume and Issue: 35(1), P. 102157 - 102157

Published: Feb. 19, 2024

Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity closely related to the accumulation of reactive oxygen species (ROS) and subsequent death hair cells (HCs) spiral ganglion neurons (SGNs). Despite various strategies combat ototoxicity, only one therapeutic agent has thus far been clinically approved. Therefore, we have developed gene therapy concept protect cochlear from cisplatin-induced toxicity. Self-inactivating lentiviral (LV) vectors were used ectopically express antioxidant enzymes or anti-apoptotic proteins enhance cellular ROS scavenging prevent apoptosis affected cell types. In direct comparison, mediated stronger reduction cytotoxicity than enzymes. Importantly, overexpression most promising candidate, Bcl-xl, achieved an up 2.5-fold HEI-OC1 cells, phoenix auditory neurons, primary SGN cultures. BCL-XL protected against cisplatin-mediated tissue destruction explants. Strikingly, vivo application LV vector improved increased HC survival cisplatin-treated mice. conclusion, established preclinical approach mice that potential be translated clinical use cancer

Language: Английский

Citations

5
Activating transcription factor 6 contributes to cisplatin‑induced ototoxicity via regulating the unfolded proteins response DOI Creative Commons
Yuchen Liu,

Xue Bai,

Bing Liao

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 177, P. 117025 - 117025

Published: June 28, 2024

Language: Английский

Citations

5
Magnetic/Acoustic Dual‐Controlled Microrobot Overcoming Oto‐Biological Barrier for On‐Demand Multidrug Delivery against Hearing Loss DOI
Xinyang Yi,

Lifang Guo,

Qi Zeng

et al.

Small, Journal Year: 2024, Volume and Issue: 20(44)

Published: July 17, 2024

Multidrug combination therapy in the inner ear faces diverse challenges due to distinct physicochemical properties of drugs and difficulties overcoming oto-biologic barrier. Although nanomedicine platforms offer potential solutions multidrug delivery, access remains limited. Micro/nanomachines, capable delivering cargo actively, are promising tools for bio-barriers. Herein, a novel microrobot-based strategy penetrate round window membrane (RWM) is presented on-demand manner delivered. The tube-type microrobot (TTMR) constructed using template-assisted layer-by-layer (LbL) assembly chitosan/ferroferric oxide/silicon dioxide (CS/Fe

Language: Английский

Citations

5
Mangiferin alleviates cisplatin-induced ototoxicity in sensorineural hearing loss DOI Open Access
Xiaochan Lu, Na Yin, Chen Chen

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 178, P. 117174 - 117174

Published: Aug. 3, 2024

Mangiferin(MGF) exhibits crucial biological roles, including antioxidant and anti-inflammatory functions. However, how to clearly elucidate the functioning mechanism of MGF for inhibiting cisplatin-induced hearing loss requires in-depth investigation. In this work, we aimed at gaining insight into functions as protective agent against cisplatin-triggered ototoxicity using various assays. The variation reactive oxygen species (ROS) concentrations was determined with MitoSOX-Red 2',7'-Dichlorodihydrofluorescein diacetate staining (DCFH-DA). function corresponding in hair cell survival House Ear Institute-Organ Corti (HEI-OC1) line were assessed RNA sequencing (RNA-Seq). Our findings demonstrated that significantly alleviated injury cells vitro, encompassing lines cochlear explants, well vivo models, C57BL/6 J mice zebrafish larvae. Mechanistic studies revealed reversed increased accumulation ROS inhibited apoptosis through mitochondrial-mediated intrinsic pathway. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) western blotting data indicated protected cisplatin-mediated via mitogen-activated protein kinase pathway (MAPK). These has significant potential promise combating ototoxicity, offering a foundation expanded investigation therapeutic approaches auditory protection.

Language: Английский

Citations

5