Pioglitazone ameliorates gentamicin ototoxicity by affecting the TLR and STAT pathways in the early postnatal organ of Corti
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ABSTRACT:
PROVIDER: PRJNA665218 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12697716.fastq.gz | Fastqsanger.gz | |||
| SRR12697717.fastq.gz | Fastqsanger.gz | |||
| SRR12697718.fastq.gz | Fastqsanger.gz | |||
| SRR12697719.fastq.gz | Fastqsanger.gz | |||
| SRR12697720.fastq.gz | Fastqsanger.gz |
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Project description:We evaluated the effects of pioglitazone in mouse organ of Corti (OC) explants to characterize its influence on signaling pathways involved in auditory hair cell damage. Organ of Corti explants were cultured with pioglitazone, gentamicin, or a combination of both agents. Pioglitazone treatment resulted in a significant repression of interferon (IFN)-alpha and -gamma pathways and downstream cytokines, as assessed by RNA sequencing and quantitative PCR gene expression assays. More detailed investigation at the single gene and protein level showed that pioglitazone mediated its anti-inflammatory effects through alterations of the Toll-like receptor (TLR) and STAT pathways. Together, these results indicate that pioglitazone significantly represses IFN and TLR in the cochlea, dampening the activity of gentamicin-induced pathways. These data support our previous results demonstrating significant protection of auditory hair cells in organ of Corti explants exposed to pioglitazone and other PPAR-targeted agents.
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Project description:Noise trauma, infection, and ototoxic drugs are frequent external causes of hearing loss. With no pharmacological treatments currently available, understanding the mechanisms and pathways leading to auditory hair cell (HC) damage and repair is crucial for identifying potential pharmacological targets. Prior research has implicated increased reactive oxygen species (ROS) and inflammation as general mechanisms of hearing loss common to diverse causes. Novel targets of these two key mechanisms of auditory damage may provide new paths toward the prevention and treatment of hearing loss. Pioglitazone, an oral antidiabetic drug from the class of thiazolidinediones, acts as an agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) and is involved in the regulation of lipid and glucose metabolism. PPAR-γ is an important player in repressing the expression of inflammatory cytokines and signaling molecules. We evaluated the effects of pioglitazone in the mouse Organ of Corti (OC) explants to characterize its influence on signaling pathways involved in auditory HC damage. The OC explants was cultured with pioglitazone, gentamicin, or a combination of both agents. Pioglitazone treatment resulted in significant repression of interferon (IFN)-α and -gamma pathways and downstream cytokines, as assessed by RNA sequencing and quantitative PCR gene expression assays. More detailed investigation at the single gene and protein level showed that pioglitazone mediated its anti-inflammatory effects through alterations of the Toll-like receptor (TLR) and STAT pathways. Together, these results indicate that pioglitazone significantly represses IFN and TLR in the cochlea, dampening the activity of gentamicin-induced pathways. These data support our previous results demonstrating significant protection of auditory HCs in the OC explants exposed to pioglitazone and other PPAR-targeted agents.
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Project description:Gentamicin is a highly efficacious antibiotic against gram-negative bacteria. However, its usefulness in treating infection is compromised by its poorly understood renal toxicity. This toxic effect is seen in a variety of organisms. While the yeast Saccharomyces cerevisiae is relatively insensitive to gentamicin, mutations in any one of 20 or so genes causes a dramatic increase in sensitivity. Many of these genes encode proteins important for translation termination or specific protein trafficking complexes. Here, we demonstrate by microarray analysis that gentamicin treatment leads to dramatic decreases in genes under the control of the MADS box protein Mcm1, including genes encoding products involved in mating, nitrogen utilization, and ribosome biogenesis. Furthermore, microarray analysis also demonstrates an increase in a Rlm1-dependent set of genes involved in maintaining the structure of the cell wall that are also induced by the antifungal agents caspofungin and calcofluor white. Subsequent inspection of the physical and genetic interactions of the remaining gentamicin sensitive mutants revealed a network centered around chitin synthase and the Arf Pathway. Furthermore, conditional arf1 mutants are hypersensitive to gentamicin even under permissive conditions. These results suggest that gentamicin may act as a cell wall stress, possibly by disrupting Arf-dependent trafficking of proteins involved in forming the cell wall. Keywords: disease state analysis, comparative genomic analysis +/- gentamicin treatment
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Project description:Gentamicin is a highly efficacious antibiotic against gram-negative bacteria. However, its usefulness in treating infection is compromised by its poorly understood renal toxicity. This toxic effect is seen in a variety of organisms. While the yeast Saccharomyces cerevisiae is relatively insensitive to gentamicin, mutations in any one of 20 or so genes causes a dramatic increase in sensitivity. Many of these genes encode proteins important for translation termination or specific protein trafficking complexes. Here, we demonstrate by microarray analysis that gentamicin treatment leads to dramatic decreases in genes under the control of the MADS box protein Mcm1, including genes encoding products involved in mating, nitrogen utilization, and ribosome biogenesis. Furthermore, microarray analysis also demonstrates an increase in a Rlm1-dependent set of genes involved in maintaining the structure of the cell wall that are also induced by the antifungal agents caspofungin and calcofluor white. Subsequent inspection of the physical and genetic interactions of the remaining gentamicin sensitive mutants revealed a network centered around chitin synthase and the Arf Pathway. Furthermore, conditional arf1 mutants are hypersensitive to gentamicin even under permissive conditions. These results suggest that gentamicin may act as a cell wall stress, possibly by disrupting Arf-dependent trafficking of proteins involved in forming the cell wall. Experiment Overall Design: The yeast strain 4073 was grown to mid-log with and without gentamicin (500 mg/ml) (n=4 for each condition). Yeast cells were pelleted and snap frozen. Total RNA was isolated using the Epicentre Masterpure Yeast RNA Purification kit. RNA samples were brought to the Indiana University Center for Medical Genomics who performed the microarray analysis using Affymetrix GeneChip Scanner 3000 and the Affymetrix Yeast arrays.
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