Role of Endoplasmic Reticulum Stress in Otitis Media

Zhao, Hongchun; Wang, Yanfei; Li, Bo; Zheng, Tianyu; Liu, Xiuzhen; Hu, Bo; Juan, Che; Zhao, Tong; Hatzoglou, Maria; Zhang, Xiaolin; Fan, Zhaomin; Zheng, Qingyin

doi:10.3389/fgene.2020.00495

Cited by 5 publications

(4 citation statements)

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“…Major cellular pathways in our network analysis relate to endoplasmic reticulum (ER) function, including intracellular protein transport, protein transport, and vesicle-mediated transport. When otitis media is induced, a rise in ER stress function is observed with an associated increase in proinflammatory gene expression ( Zhao et al, 2020 ). ER dysfunction is known to cause various inflammatory diseases ( Cao et al, 2013 ; Zhang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Novel candidate genes for cholesteatoma in chronic otitis media

et al. 2023

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Cholesteatoma is a rare and benign disease, but its propensity to cause erosive damage through uninhibited growth can be detrimental to hearing and health. Prior reports indicated a genetic component to pathogenesis in at least a subset of patients. In this study, we aimed to identify rare DNA variants in affected patients. The salivary DNA of six patients whose middle ear tissues were obtained during tympanoplasty/mastoidectomy surgeries were submitted for exome sequencing. Tissue samples from the same patients were previously submitted for mRNA sequencing and analyzed for differentially expressed genes (DEGs). From the generated exome sequence data, rare predicted-to-be-damaging variants were selected within previously identified DEGs, and the candidate genes within which these rare variants lie were used for network analysis. Exome sequencing of six DNA samples yielded 5,078 rare variants with minor allele frequency <.001. A total of 510 variants were predicted to be deleterious and 52 were found to lie within previously identified DEGs. After selecting variants based on quality control measures, 12 variants were identified all from one pediatric patient. Network analysis identified ten significant cellular pathways, including protein transport, viral process, regulation of catalytic activity and cell cycle, and apoptotic and rhythmic processes. We hypothesize that the candidate genes identified in this study may be part of key signaling pathways during the mucosal response to middle ear infection. The occurrence of multiple rare variants may play a role in earlier onset of cholesteatoma formation in chronic otitis media.

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Section: Discussionmentioning

confidence: 99%

Novel candidate genes for cholesteatoma in chronic otitis media

et al. 2023

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“…Despite these observations, little is currently known about the exact molecular mechanism underlying these phenomena. In general, inhibition of ER stress and stabilization of the UPR pathways have been considered important mechanisms underlying the biological functions of TUDCA (35)(36)(37). Notably, TUDCA has been used as an inhibitor of ER stress in previous studies (38,39).…”

Section: Discussionmentioning

confidence: 99%

TUDCA protects against tunicamycin‑induced apoptosis of dorsal root ganglion neurons by suppressing activation of ER stress

Chen

et al. 2022

Exp Ther Med

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The existence of endoplasmic reticulum (ER) stress in neurodegenerative diseases has been well established. Tauroursodeoxycholic acid (TUDCA) is a bile acid taurine conjugate derived from ursodeoxycholic acid, which has been reported to exert cytoprotective effects on several types of cells by inhibiting ER stress. The present study explored the effects of TUDCA on primary cultured rat dorsal root ganglion (DRG) neurons. Cell viability and apoptosis of DRG neurons treated with TUDCA and tunicamycin were detected by CellTiter-Blue assay and TUNEL staining, respectively. The protein levels and phosphorylation of apoptosis and ERS-related signaling pathway molecules were detected by western blot, and the mRNA levels of related genes were assessed by reverse transcription-quantitative PCR. Notably, TUDCA had no significant cytotoxic effect on DRG neurons at concentrations ≤250 µM. In addition, the apoptosis induced by tunicamycin exposure was markedly suppressed by TUDCA, as indicated by the percentage of TUNEL-positive cells, the activities of caspases and the changes in expression levels of critical apoptosis factors. Furthermore, the cytotoxicity of tunicamycin in DRG neurons was accompanied by an increase in malondialdehyde (MDA) content, reactive oxygen species (ROS) and lactate dehydrogenase (LDH) production, and a decrease in glutathione (GSH) levels. The changes in oxidative stress-related factors (ROS, LDH, MDA and GSH) were reversed by TUDCA. Furthermore, as determined by western blotting, the increase in C/EBP homologous protein, glucose-regulated protein 78 and cleaved caspase-12 expression following tunicamycin treatment suggested the activation of ER stress. Downregulation of ER stress components and unfolded protein response sensors by TUDCA confirmed the implication of ER stress in the effects of TUDCA on DRG neurons. In conclusion, the present study indicated that TUDCA may protect against tunicamycin-induced DRG apoptosis by suppressing the activation of ER stress. The protective effect and the therapeutic value of TUDCA in nervous system injury require further study in animal models.

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“…Animals were randomly distributed over the different experimental conditions and blinding was applied during data acquisition and analysis when possible. OM was induced by PGPS as previously reported, the dose of PGPS was 5.5 mg/ml [ 51 ]. They were treated for normal saline, PGPS (BD Bioscience, San Jose, USA), and PGPS + DFO (MCE, USA).…”

Section: Methodsmentioning

confidence: 99%

Ferroptosis is involved in PGPS-induced otitis media in C57BL/6 mice

Yan

Xie

et al. 2022

Cell Death Discov.

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Otitis media (OM) is a common disease that can cause hearing loss in children. Currently, the main clinical treatment for OM is antibiotics, but the overuse of antibiotics might lead to bacterial resistance, which is a worldwide public health challenge. Studying the pathogenesis of OM will help us develop new effective treatments. Ferroptosis is one type of programmed cell death characterized by the occurrence of lipid peroxidation driven by iron ions. Many studies have shown that ferroptosis is associated with infectious diseases. It is presently unclear whether ferroptosis is involved in the pathogenesis of OM. In this study, we explored the relationship between ferroptosis and OM by PGPS-induced OM in C57BL/6 mice and treating the induced OM with ferroptosis inhibitors deferoxamine (DFO), Ferrostatin-1 (Fer-1), and Liperoxstatin-1 (Lip-1). We examined the expression of ferroptosis-related proteins acyl-CoA synthetase long chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2 (Cox2), glutathione peroxidase 4 (GPX4) protein as well as lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). The results showed that in PGPS-induced OM model mice, several ferroptosis-related proteins including ACSL4 and Cox2 were up-regulated compared to mice treated with saline. Meanwhile, a ferroptosis-related protein GPX4 was down-regulated upon PGPS treatment. The DFO treatment in PGPS-inoculated mice effectively inhibited the development of OM. The inhibitors treatment caused a significant decrease in the expression of ACSL4, Cox2, 4 HNE, MDA, reduction in free iron. Meanwhile, the ferroptosis inhibitors treatment caused increase in the expression of inflammation-related factors tumor necrosis factor-α (TNF-α) and antioxidant protein GPX4. Our results suggest that there is a crosstalk between ferroptosis signaling pathway and the pathogenesis of OM. Ferroptosis inhibition can alleviate PGPS-induced OM.

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Role of Endoplasmic Reticulum Stress in Otitis Media

Cited by 5 publications

References 50 publications

Novel candidate genes for cholesteatoma in chronic otitis media

Novel candidate genes for cholesteatoma in chronic otitis media

TUDCA protects against tunicamycin‑induced apoptosis of dorsal root ganglion neurons by suppressing activation of ER stress

Ferroptosis is involved in PGPS-induced otitis media in C57BL/6 mice

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