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International Journal of Molecular... Nov 2021Telmisartan (TM) has been proposed to relieve inflammatory responses by modulating peroxisome proliferator activator receptor-γ (PPARγ) signaling. This study aimed to...
Telmisartan (TM) has been proposed to relieve inflammatory responses by modulating peroxisome proliferator activator receptor-γ (PPARγ) signaling. This study aimed to investigate the protective effects of TM on kanamycin(KM)-induced ototoxicity in rats. Forty-eight, 8-week-old female Sprague Dawley rats were divided into four groups: (1) control group, (2) TM group, (3) KM group, and (4) TM + KM group. Auditory brainstem response was measured. The histology of the cochlea was examined. The protein expression levels of angiotensin-converting enzyme 2 (ACE2), HO1, and PPARγ were measured by Western blotting. The auditory threshold shifts at 4, 8, 16, and 32 kHz were lower in the TM + KM group than in the KM group (all < 0.05). The loss of cochlear outer hair cells and spiral ganglial cells was lower in the TM + KM group than in the KM group. The protein expression levels of ACE2, PPARγ, and HO1 were higher in the KM group than in the control group (all < 0.05). The TM + KM group showed lower expression levels of PPARγ and HO1 than the KM group.TM protected the cochlea from KM-induced injuries in rats. TM preserved hearing levels and attenuated the increase in PPARγ and HO1 expression levels in KM-exposed rat cochleae.
Topics: Angiotensin-Converting Enzyme 2; Animals; Anti-Bacterial Agents; Antihypertensive Agents; Auditory Threshold; Cochlea; Evoked Potentials, Auditory, Brain Stem; Female; Heme Oxygenase (Decyclizing); Kanamycin; Ototoxicity; PPAR gamma; Rats; Rats, Sprague-Dawley; Telmisartan
PubMed: 34884516
DOI: 10.3390/ijms222312716 -
Journal of Neurophysiology Apr 2021Cisplatin is an antitumor drug that is widely used for the treatment of various solid tumors. Unfortunately, patients are often troubled by serious side effects,...
Cisplatin is an antitumor drug that is widely used for the treatment of various solid tumors. Unfortunately, patients are often troubled by serious side effects, especially hearing loss. Up to now, there have been no clear and effective measures to prevent cisplatin-induced ototoxicity in clinical use. We explored the role of autophagy and the efficacy of metformin in cisplatin-induced ototoxicity in cells, zebrafish, and mice. Furthermore, the underlying molecular mechanism of how metformin affects cisplatin-induced ototoxicity was examined. In in vitro experiments, autophagy levels in HEI-OC1 cells were assessed using fluorescence and Western blot analyses. In in vivo experiments, whether metformin had a protective effect against cisplatin ototoxicity was validated in zebrafish and C57BL/6 mice. The results showed that cisplatin induced autophagy activation in HEI-OC1 cells. Metformin exerted antagonistic effects against cisplatin ototoxicity in HEI-OC1 cells, zebrafish, and mice. Notably, metformin activated autophagy and increased the expression levels of the adenosine monophosphate-activated protein kinase (AMPK) and the transcription factor Forkhead box protein O3 (FOXO3a), whereas cells with AMPK silencing displayed otherwise. Our findings indicate that metformin alleviates cisplatin-induced ototoxicity possibly through AMPK/FOXO3a-mediated autophagy machinery. This study underpins further researches on the prevention and treatment of cisplatin ototoxicity. Cisplatin is an antitumor drug that is widely used for the treatment of various solid tumors. Up to now, there have been no clear and effective measures to prevent cisplatin-induced ototoxicity in clinical use. We investigated the protective effect of metformin on cisplatin ototoxicity in vitro and in vivo. Our findings indicate that metformin alleviates cisplatin-induced ototoxicity possibly through AMPK/FOXO3a-mediated autophagy machinery. This study underpins further researches on the prevention and treatment of cisplatin ototoxicity.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Antineoplastic Agents; Autophagy; Cells, Cultured; Cisplatin; Disease Models, Animal; Forkhead Box Protein O3; Hair Cells, Auditory; Male; Metformin; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Ototoxicity; Protein Kinases; Zebrafish
PubMed: 33625942
DOI: 10.1152/jn.00417.2020 -
Alternative Therapies in Health and... Feb 2022Presbycusis is age-related, progressive, and symmetrical hearing loss in both ears. Acupuncture can play a vital role in the diagnosis and treatment of deafness, but its...
CONTEXT
Presbycusis is age-related, progressive, and symmetrical hearing loss in both ears. Acupuncture can play a vital role in the diagnosis and treatment of deafness, but its functional mechanism is still not entirely clear.
OBJECTIVE
The study intended to explore acupuncture's protective effects and mechanism of treatment in addressing ototoxicity induced by gentamicin (GM) in aged mice.
DESIGN
The research team designed an animal study, and a mouse model of ototoxicity induced by GM was established.
SETTING
The study took place in Nanchong Central Hospital, Sichuan, China.
ANIMALS
The animals were 48 male, Kunming mice, with sixteen being three months old and 32 being 18 month old.
INTERVENTION
The three-month-old mice were randomly assigned to a control group (n = 8) and a GM group (n = 8). The 18-month-old mice were randomly divided into four groups with eight mice each: a positive control group; a negative control group, the GM group; and two intervention groups, the acupuncture + GM group and the drug + GM group. The GM groups were intraperitoneally injected with 100 mg/kg daily of GM for 10 consecutive days. The acupuncture + GM group received acupuncture, and the drug + GM group was injected intraperitoneally with Genadol.
OUTCOME MEASURES
The effects of GM induction and treatment with acupuncture or a drug on the numbers of auditory cochlear hair cells were evaluated via an auditory test and cell staining. A real-time polymerase chain reaction (PCR) was performed for gene detection. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) were measured.
RESULTS
The aged mice were susceptible to GM ototoxicity. After acupuncture, the threshold of the auditory brainstem response and the number of cochlear hair cells increased significantly. Acupuncture inhibited oxidative stress via the nuclear factor erythroid-derived factor 2-related factor 2 (NRF2) signaling pathway in the mice.
CONCLUSIONS
The data demonstrated that acupuncture can alleviate GM ototoxicity via the NRF2 signaling pathway, providing important support for acupuncture in treatment of GM ototoxicity.
Topics: Acupuncture Therapy; Animals; Cochlea; Gentamicins; Hair Cells, Auditory; Male; Mice; Ototoxicity
PubMed: 34847071
DOI: No ID Found -
Scientific Reports Oct 2022A mouse model with cisplatin-induced ototoxicity was used in addition to human samples from the ITMAT Biobank at the University of Pennsylvania. Mouse auditory brainstem...
A mouse model with cisplatin-induced ototoxicity was used in addition to human samples from the ITMAT Biobank at the University of Pennsylvania. Mouse auditory brainstem responses (ABR), inner ear histology, perilymph cisplatin sampling, and measurement of serum prestin via ELISA were performed. Human serum prestin level was measured via ELISA in patients with otological issues after cisplatin treatment and compared to matched controls. Serum prestin was significantly elevated before ABR threshold shifts in mice exposed to cisplatin compared to control mice. Prestin concentration also correlated with the severity of hearing threshold shifts in mice. After an extended rest post-cisplatin treatment, prestin returned to baseline levels in mice and humans. Prestin was significantly elevated in the serum before the onset of objective hearing loss and correlated with the severity of hearing damage indicating that prestin may function as an effective biomarker of cisplatin-induced ototoxicity. Human serum prestin levels responded similarly to mice > 3 weeks from ototoxic exposure with decreased levels of prestin in the serum.
Topics: Humans; Mice; Animals; Cisplatin; Ototoxicity; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Biomarkers; Antineoplastic Agents
PubMed: 36302835
DOI: 10.1038/s41598-022-23034-x -
Experimental and Clinical... Feb 2020Early trials of tacrolimus in renal transplant recipients have not revealed hearing loss as an adverse effect. Here, we present a case report and a review of the... (Review)
Review
Early trials of tacrolimus in renal transplant recipients have not revealed hearing loss as an adverse effect. Here, we present a case report and a review of the literature of deafness after tacrolimus use. The review of the literature and our experience suggested that the possible reason for hearing loss could be due to an initiation of a sudden spike in the tacrolimus serum level, which was later worsened by its cumulative toxic effect.
Topics: Calcineurin Inhibitors; Hearing; Hearing Loss, Sensorineural; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Ototoxicity; Tacrolimus; Treatment Outcome
PubMed: 29969081
DOI: 10.6002/ect.2017.0114 -
Frontiers in Neuroscience 2022Cisplatin is a known ototoxic chemotherapy drug, causing irreversible hearing loss. Evidence has shown that cisplatin causes inner ear damage as a result of adduct... (Review)
Review
Cisplatin is a known ototoxic chemotherapy drug, causing irreversible hearing loss. Evidence has shown that cisplatin causes inner ear damage as a result of adduct formation, a proinflammatory environment and the generation of reactive oxygen species within the inner ear. The main cochlear targets for cisplatin are commonly known to be the outer hair cells, the stria vascularis and the spiral ganglion neurons. Further evidence has shown that certain transporters can mediate cisplatin influx into the inner ear cells including organic cation transporter 2 (OCT2) and the copper transporter Ctr1. However, the expression profiles for these transporters within inner ear cells are not consistent in the literature, and expression of OCT2 and Ctr1 has also been observed in supporting cells. Organ of Corti supporting cells are essential for hair cell activity and survival. Special interest has been devoted to gap junction expression by these cells as certain mutations have been linked to hearing loss. Interestingly, cisplatin appears to affect connexin expression in the inner ear. While investigations regarding cisplatin-induced hearing loss have been focused mainly on the known targets previously mentioned, the role of supporting cells for cisplatin-induced ototoxicity has been overlooked. In this mini review, we discuss the implications of supporting cells expressing OCT2 and Ctr1 as well as the potential role of gap junctions in cisplatin-induced cytotoxicity.
PubMed: 35573297
DOI: 10.3389/fnins.2022.867034 -
Archives of Biochemistry and Biophysics Oct 2023FAM134B, the initial endoplasmic reticulum (ER)-phagy receptor identified, facilitates ER-phagy during ER stress. The malfunction of FAM134B has been demonstrated to...
AIMS
FAM134B, the initial endoplasmic reticulum (ER)-phagy receptor identified, facilitates ER-phagy during ER stress. The malfunction of FAM134B has been demonstrated to have a crucial role in the pathological mechanisms of diverse human ailments. However, the role of FAM134B-mediated ER-phagy in ototoxicity, particularly in cisplatin-induced ototoxicity, remains unclear. The present study endeavors to investigate whether FAM134B is expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) and C57BL/6 murine cochlear hair cells (HCs), and to explore its potential function in cisplatin-mediated ototoxicity, with the aim of discovering new insights that can mitigate or forestall the irreversible adverse effect of cisplatin.
METHODS
Immunofluorescence (IF) staining was used to test the expression pattern of FAM134B, levels of C/EBP-homologous protein (CHOP), autophagy, and co-localization ratio of lysosomes and ER. Western blotting was employed to measure changes in expression levels of FAM134B, LC3B, ER stress-related proteins, LAMP1 and apoptotic mediators. Cell apoptosis was examined using transferase dUTP nick end labeling (TUNEL) assay and flow cytometry.
RESULTS
In the present investigation, it was observed that FAM134B exhibited a diffuse expression pattern in the cytoplasm and nuclei of control HEI-OC1 cells. Following cisplatin administration, FAM134B was found to accumulate and form distinct dots around the nuclei, concomitant with increased levels of ER-phagy, ER stress, unfolded protein response (UPR), and cell apoptosis. Additionally, knockdown of FAM134B resulted in reduced ER-phagy, mitigated ER stress and UPR, and decreased apoptotic activity in HEI-OC1 cells following cisplatin exposure.
CONCLUSIONS
Collectively, the findings of this study demonstrate that FAM134B-mediated ER-phagy enhances the susceptibility of HCs to ER stress and apoptosis in response to cisplatin-induced stress. This suggests a sequential progression of ER-phagy, ER stress and apoptosis following cisplatin stimulus, and implies the potential therapeutic benefit of inhibiting of FAM134B-mediated ER-phagy in the prevention of cisplatin-related ototoxicity.
Topics: Mice; Humans; Animals; Cisplatin; Ototoxicity; Endoplasmic Reticulum Stress; Hair Cells, Auditory; Autophagy; Endoplasmic Reticulum; Apoptosis
PubMed: 37813237
DOI: 10.1016/j.abb.2023.109766 -
Audiology & Neuro-otology 2020Inner ear structures may be included in the radiation fields when irradiation is used to treat patients with head and neck cancers. These patients may also have...
BACKGROUND
Inner ear structures may be included in the radiation fields when irradiation is used to treat patients with head and neck cancers. These patients may also have concurrent infections that require gentamicin treatment. Radiation and gentamicin are both potentially ototoxic, and their combined use has been shown to result in synergistic ototoxicity in animals.
OBJECTIVE
We aimed to confirm the synergistic ototoxicity of combined gentamicin and low-dose irradiation treatment and identify the underlying molecular mechanisms using an in vitro model.
METHOD
We compared the ototoxic effects of gentamicin, low-dose irradiation, and their combination in the OC-k3 mouse cochlear cell line using cell viability assay, live/dead stain, apoptosis detection assay, oxidative stress detection, and studied the molecular mechanisms involved using immunoblot analysis.
RESULTS
Combined treatment led to prolonged oxidative stress, reduced cell viability, and synergistic apoptosis. Gentamicin induced the concurrent accumulation of LC3b-II and SQSTM1/p62, suggesting an impairment of autophagic flux. Low-dose irradiation induced transient p53 phosphorylation and persistent Akt phosphorylation in response to DNA damage. In combined treatment, gentamicin attenuated irradiation-induced Akt activation.
CONCLUSIONS
Besides increased oxidative stress, synergistic apoptosis observed in combined treatment could be attributed to gentamicin-induced perturbation of autophagic flux and attenuation of Akt phosphorylation, which led to an impairment of radiation-induced DNA repair response.
Topics: Animals; Apoptosis; Cell Line; Cochlea; Gentamicins; Mice; Ototoxicity; Phosphorylation; Radiotherapy
PubMed: 31838466
DOI: 10.1159/000503133 -
Molecules (Basel, Switzerland) Oct 2019In this study, we investigated whether the curcuminoids, CLEFMA and EF24, improved cisplatin efficacy and reduced cisplatin ototoxicity. We used the lung cancer cell...
In this study, we investigated whether the curcuminoids, CLEFMA and EF24, improved cisplatin efficacy and reduced cisplatin ototoxicity. We used the lung cancer cell line, A549, to determine the effects of the curcuminoids and cisplatin on cell viability and several apoptotic signaling mechanisms. Cellular viability was measured using the MTT assay. A scratch assay was used to measure cell migration and fluorescent spectrophotometry to measure reactive oxygen species (ROS) production. Western blots and luminescence assays were used to measure the expression and activity of apoptosis-inducing factor (AIF), caspases-3/7, -8, -9, and -12, c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK), and proto-oncogene tyrosine-protein kinase (Src). A zebrafish model was used to evaluate auditory effects. Cisplatin, the curcuminoids, and their combinations had similar effects on cell viability (IC values: 2-16 μM) and AIF, caspase-12, JNK, MAPK, and Src expression, while caspase-3/7, -8, and -9 activity was unchanged or decreased. Cisplatin increased ROS yield (1.2-fold), and curcuminoid and combination treatments reduced ROS (0.75-0.85-fold). Combination treatments reduced A549 migration (0.51-0.53-fold). Both curcuminoids reduced auditory threshold shifts induced by cisplatin. In summary, cisplatin and the curcuminoids might cause cell death through AIF and caspase-12. The curcuminoids may potentiate cisplatin's effect against A549 migration, but may counteract cisplatin's effect to increase ROS production. The curcuminoids might also prevent cisplatin ototoxicity.
Topics: A549 Cells; Animals; Antineoplastic Agents; Benzylidene Compounds; Caspases; Cell Death; Cisplatin; Diarylheptanoids; Evoked Potentials, Auditory; Humans; Inhibitory Concentration 50; Ototoxicity; Piperidones; Proto-Oncogene Mas; Zebrafish
PubMed: 31671767
DOI: 10.3390/molecules24213889 -
Journal of Cell Science Jul 2023Cisplatin is an effective platinum-based chemotherapeutic with several side effects, including ototoxicity. Cochlear cells have low rates of proliferation yet are highly...
Cisplatin is an effective platinum-based chemotherapeutic with several side effects, including ototoxicity. Cochlear cells have low rates of proliferation yet are highly susceptible to cisplatin. We hypothesised that cisplatin ototoxicity might be caused by cisplatin-protein interactions rather than cisplatin-DNA interactions. Two known cisplatin-binding proteins are involved in the stress granule (SG) response. SGs are a pro-survival mechanism involving formation of transient ribonucleoprotein complexes during stress. We examined the effects of cisplatin on SG dynamics and composition in cell lines derived from the cochlea and retinal pigment epithelium. Cisplatin-induced SGs are significantly diminished in size and quantity compared to arsenite-induced SGs and are persistent after 24 h recovery. Additionally, cisplatin pre-treated cells were unable to form a typical SG response to subsequent arsenite stress. Cisplatin-induced SGs had significant reductions in the sequestration of eIF4G and the proteins RACK1 and DDX3X. Live-cell imaging of Texas Red-conjugated cisplatin revealed its localisation to SGs and retention for at least 24 h. We show cisplatin-induced SGs have impaired assembly, altered composition and are persistent, providing evidence of an alternate mechanism for cisplatin-induced ototoxicity via an impaired SG response.
Topics: Humans; Cisplatin; Arsenites; Ototoxicity; Stress Granules; Cytoplasmic Granules
PubMed: 37334742
DOI: 10.1242/jcs.260590