The miRNA cargos and roles of small extracellular vesicles from cochlear explants in a model of cisplatin-induced ototoxicity
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PROVIDER: PRJNA1108761 | ENA |
REPOSITORIES: ENA
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Project description:Small extracellular vesicles (sEVs) play an important role in intercellular communication as well as pathological development. Here, to explore the roles of sEVs in the progression of cisplatin-induced ototoxicity, we isolated sEVs from the conditioned culture medium of cisplatin-induced cochlear explants (Cis-sEVs) and the control group (Ctrl-sEVs) and profiled their cargos using label-free LC-MS/MS. Numerous proteins involved in the regulation of the damage response were enriched in the Cis-sEVs. Cltc, Cct2, and Hspa8, which are potentially involved in protein homeostasis and autophagy, are up-regulated in Cis-sEVs compared to Ctrl-sEVs but not in cisplatin-damaged cochlear tissue or in HEI-OC1 cell lysates.
2025-09-01 | PXD052123 | Pride
Project description:Small extracellular vesicles (sEVs) play an important role in intercellular communication as well as pathological development. To explore the roles of sEVs in the progression of cisplatin-induced ototoxicity, we isolated sEVs from the conditioned culture medium of cisplatin-induced cochlear explants (Cis-sEVs) and the control group (Ctrl-sEVs) and profiled their miRNA cargos using small RNA sequencing
2025-09-03 | GSE266947 | GEO
Project description:Background Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk. Results We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGSHL) and a biologically informed PGS for CIO (PGSCIO). The PGSCIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGSCIO demonstrated superior performance (P = 5.54 × 10− 5) relative to PGSHL (P = 2.93 × 10− 3). PGSCIO was also associated with CIO in our test cohort (P = 0.04), while the PGSHL did not show a significant association with CIO (P = 0.52). Conclusion This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.
2024-11-14 | GSE281324 | GEO
Project description:As one of the widely-used broad-spectrum anti-cancer drug, ototoxicity occurrence limited the usage of Cisplatin in clinical practice. At the same time, Eleutheroside E are found with kindny and never protection. However, the mechanism of the protection is remained unclear. In this study, 27 C57BL/6J mice were used and divided into Ctrl group with normal Saline injected, Cis and Cis + EE group with injection of Cis and Cis + EE peritoneally for Cisplatin-reduced ototoxicity modelling and intervention, then cochlears were dissected for proteomics. Network pharmacology to predict the target and biological mechanism of Eleutheroside E against cisplatin ototoxicity and Eleutheroside E might play an antagonistic role through the regulation of MAPK and pyrogenic signaling pathway. Compare with Cis group, Cis+EE group mice have a lower threshold value in ABR result and the group shows less cell pyroptosis than Cis group. Morphology results also indicated that Cis+EE group reduced space of spiral ganglion and the vascular structure was relatively clear than the Cis group. In addition, compared with Cis group, mRNA expression of NLRP3, GSDMD, ASC, Caspase-1, IL-1β and IL-18 genes in Cis+EE group decreased. The expression of p-JNK, p-ERK, P-P38, NF-κB P65, Cleaved Caspase-1, GSDMD was decreased, and the expression of IκB was increased. This study demonstrated that Eleutheroside E exerts an antagonistic effect on Cisplatin ototoxicity by down-regulating the activity of MAPK/NF-κB/NLRP3 signaling pathway, reducing the expression level of pyroptosis related proteins and inflammatory factors after cisplatin administration, and then inhibiting pyroptosis.
2023-11-16 | PXD047048 |
Project description:Aging, noise exposure, and ototoxic drugs represent the three main causes of SNHL, leading to substantial similarities in pathophysiological characteristics of cochlear degeneration. Although the common molecular mechanisms are widely assumed to underlie these similarities, its validity lacks systematic examination. To address this question, we generated three SNHL mouse models from aging, noise exposure, and cisplatin ototoxicity and constructed gene coexpression networks for the cochlear transcriptome data across different hearing-damaged stages.
2022-02-16 | GSE196870 | GEO
Project description:Strategies to overcome irreversible cochlear hair cell (HC) damage and loss are of vital importance to develop a treatment for hearing loss. HC regeneration in adult cochlea relies on a two-phase process: 1) Reprogramming mature cochlear (SCs) to regain the properties of their younger selves; 2) Activating Atoh1, a gene responsible for HC fate-determining, in the reprogrammed adult SCs for HC regeneration. We have shown that, by transient co-activation of Myc and NICD (Notch1 intracellular domain), the adult mouse cochlea can be successfully reprogrammed to a relatively younger stage and regain progenitor capacity, with the regeneration of HCs following Atoh1 overexpression in vitro and in vivo. To identify molecules to reprogram mature cochlear SCs and HC regeneration, we utilized single-cell RNA sequencing and uncovered the pathways and their target genes underlying MYC/NICD-mediated reprogramming. We used an in-house adult cochlea explant culture system and carried out single-cell RNA sequencing to examine the gene expression profiles of cochlear explants from a transgenic mouse model, rtTa/tet-Myc/-tet-NICD, in response to Dox-induced MYC/NICD co-activation. We compared gene expression profiles between Atoh1 activation vs. MYC/NICD/Atoh1 co-activation.
2023-06-01 | GSE218325 | GEO
Project description:Strategies to overcome irreversible cochlear hair cell (HC) damage and loss are of vital importance to develop a treatment for hearing loss. HC regeneration in adult cochlea relies on a two-phase process: 1) Reprogramming mature cochlear (SCs) to regain the properties of their younger selves; 2) Activating Atoh1, a gene responsible for HC fate-determining, in the reprogrammed adult SCs for HC regeneration. We have shown that, by transient co-activation of Myc and NICD (Notch1 intracellular domain), the adult mouse cochlea can be successfully reprogrammed to a relatively younger stage and regain progenitor capacity, with the regeneration of HCs following Atoh1 overexpression in vitro and in vivo. We identified a combination (the cocktail) of drug-like molecules composing of small molecules and siRNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. To identify molecules to reprogram mature cochlear SCs and HC regeneration, we utilized single-cell RNA sequencing and uncovered the pathways and their target genes underlying chemical-mediated reprogramming. We used an in-house adult cochlea explant culture system and carried out single-cell RNA sequencing to examine the gene expression profiles of cochlear explants, in response to chemical-induced reprogramming. We compared gene expression profiles between Vehicle/ad.Atoh1 activation vs. Cocktail (chemical reprogramming)/ad.Atoh1 activation.
2023-06-01 | GSE218324 | GEO
Project description:Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases.
| S-EPMC6715625 | biostudies-literature
Project description:Cisplatin is a chemotherapy drug used to treat different solid tumors, including ovarian, bladder, lung, and head and neck cancers. One of its significant side effects is ototoxicity, especially when high doses are required. Cisplatin-induced ototoxicity is associated with increased cochlear cell death resulting from DNA damage, caspase activation, oxidative stress, inflammation, and glutamate excitotoxicity. The regulator of G protein signaling 17 (RGS17), a member of the RGS-RZ subfamily, hastens the hydrolysis of GTP to GDP on the Gα subunit. In the current study, we demonstrate the role of RGS17 in cisplatin-induced cochlear inflammation and ototoxicity. C57BL/6J mice treated with two cycles of cisplatin (3.5 mg/kg) showed a significant elevation in ABR thresholds, along with loss of outer hair cells and inner hair cells synapse. Furthermore, immunohistochemical analysis revealed that cisplatin administration upregulates CXCL1, accompanied by an increase in the number of CD45 and CD68-positive immune cells. On the other hand, RGS17 knockout in hair cells protects against cisplatin-induced elevation of ABR thresholds, outer hair cell loss, cochlear inflammation, and inner hair cell synaptopathy. Moreover, RGS17 knockout downregulates CXCL1 immunolabeling and decreases the number of CD45 and CD68-positive immune cells induced by cisplatin. These results suggest that RGS17 is implicated in cisplatin ototoxicity, potentially by initiating the immune cascade, and indicate RGS17 as a relevant target for treating cisplatin ototoxicity.
| S-EPMC11885124 | biostudies-literature
Project description:Cisplatin is a very effective chemotherapeutic, but severe and permanent hearing loss remains a prevalent side effect. The processes underpinning cisplatin-induced ototoxicity are not well understood. Gap junction channels composed of connexin (Cx) subunits allow for the passage of small molecules and ions between contacting neighboring cells. These specialized channels have been postulated to enhance cisplatin-induced cell death by spreading "death signals" throughout the supporting cells of the organ of Corti. This study sought to investigate the role of Cx43 in cisplatin-induced ototoxicity using organotypic cochlear cultures from control and two Cx43-mutant mouse strains harboring either a moderate (Cx43I130T/+) or severe (Cx43G60S/+) reduction of Cx43 function. Cochlear cultures from Cx43-mutant mice with a severe reduction in Cx43-based gap junctional intercellular communication (GJIC) had an enhanced number of hair cells that were positive for cleaved caspase 3, a marker of active apoptosis, after cisplatin treatment. In cisplatin-treated organotypic cochlear cultures, there was a decrease in the co-localization of Cx26 and Cx30 compared with untreated cultures, suggesting that cisplatin causes reorganization of connexin composition in supporting cells. Both Cx26 and Cx30 protein expression as well as GJIC were decreased in organotypic cochlear cultures treated with the gap-junction blocker carbenoxolone. When cisplatin and carbenoxolone were co-administered, there were no differences in hair cell loss compared with cisplatin treatment alone. Using cisplatin-treated control and Cx43-ablated organ of Corti derived HEI-OC1 mouse cells, we found that greatly reducing GJIC led to preferential induction of an ER stress pathway. Taken together, this study strongly suggests that inhibition of GJIC in organ of Corti cells does not lead to differential susceptibility to cisplatin-induced ototoxicity. Although cisplatin causes the same degree of cell death in gap junction competent and incompetent cochlear cells, the engagement of the mitochondrial dysregulation and ER stress differs.
| S-EPMC7214471 | biostudies-literature