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BACKGROUND: The Ca2+/calmodulin-dependent protein kinase kinases (CaMKKs) are serine/threonine-directed protein kinases that are activated following increases in intracellular calcium, playing a critical role in neuronal signaling. Inner-ear-trauma-induced calcium overload in sensory hair cells has been well documented in the pathogenesis of traumatic noise-induced hair cell death and hearing loss, but there are no established pharmaceutical therapies available due to a lack of specific therapeutic targets. In this study, we investigated the activation of CaMKKß in the inner ear after traumatic noise exposure and assessed the prevention of noise-induced hearing loss (NIHL) with RNA silencing. RESULTS: Treatment with short hairpin RNA of CaMKKß (shCaMKKß) via adeno-associated virus transduction significantly knocked down CaMKKß expression in the inner ear. Knockdown of CaMKKß significantly attenuated noise-induced hair cell loss and hearing loss (NIHL). Additionally, pretreatment with naked CaMKKß small interfering RNA (siCaMKKß) attenuated noise-induced losses of inner hair cell synapses and OHCs and NIHL. Furthermore, traumatic noise exposure activates CaMKKß in OHCs as demonstrated by immunolabeling for p-CaMKI. CaMKKß mRNA assessed by fluorescence in-situ hybridization and immunolabeling for CaMKKß in OHCs also increased after the exposure. Finally, pretreatment with siCaMKKß diminished noise-induced activation of AMPKα in OHCs. CONCLUSIONS: These findings demonstrate that traumatic-noise-induced OHC loss and hearing loss occur primarily via activation of CaMKKß. Targeting CaMKKß is a key strategy for prevention of noise-induced hearing loss. Furthermore, our data suggest that noise-induced activation of AMPKα in OHCs occurs via the CaMKKß pathway.
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Surdez , Perda Auditiva Provocada por Ruído , Proteínas Quinases Ativadas por AMP/metabolismo , Cálcio/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Morte Celular , Surdez/metabolismo , Cabelo/metabolismo , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/patologia , Perda Auditiva Provocada por Ruído/etiologia , Perda Auditiva Provocada por Ruído/patologia , Perda Auditiva Provocada por Ruído/prevenção & controle , Humanos , Proteínas Serina-Treonina Quinases , RNA Interferente Pequeno/metabolismoRESUMO
Regulating proteasome activity is a potent therapeutic aspect of age-related hearing loss, which has been proven to protect neurons from age-related damaging. PSMD11, subunit of the 19S proteasome regulatory particle, is known to mainly up-regulate proteasome activity and prolong aging. However, the mechanism of PSMD11 in age-related hearing loss has not been deeply explored. In the present study, we explore the function and mechanism of PSMD11 protecting neurons in d-Galactose (D-Gal) mimetic aging models. Age-related pathologies were detected by Taq-PCR, ABR, Transmission electron microscopy, toluidine blue and ß-galactosidase staining. The relative expressions of the proteins were explored by Western blotting, oxyblot, immunoprecipitation and immunofluorescence. Flow cytometry was used to manifest the oxidative state. We discovered that proteasome activity was impaired with aging, and that ROS and toxic protein accumulated in D-Gal induced aging models. PSMD11 changed with aging, and was associated with the metabolism of proteasome activity in the D-Gal treated models. Moreover, the knockdown or overexpression of PSMD11 was sufficient to change the oxidative state caused by D-Gal. Our results also demonstrated that PSMD11 could bond to AMPKα1/2 in the auditory cortex and PC12 cells, and AMPKα2 but not AMPKα1 was efficient to regulate the function of PSMD11. Deeper insights into the mechanisms of regulating PSMD11 for the anti-aging process are needed, and may offer novel therapeutic methods for central presbycusis.
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Envelhecimento/metabolismo , Galactose/metabolismo , Galactose/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Córtex Auditivo/metabolismo , Córtex Auditivo/patologia , Citoplasma/metabolismo , DNA Mitocondrial/metabolismo , Masculino , Estresse Oxidativo/fisiologia , Presbiacusia/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Ratos WistarRESUMO
Presbycusis is a sensorineural hearing loss caused by hearing system aging and degeneration. The clinical manifestations are progressive bilateral symmetrical hearing loss, and the hearing curve is mostly slope-shaped with high-frequency reduction, sometimes flat. The results of the second national sample survey of disabled persons (2006) showed that the total number of hearing and speech disability in China was 27.8 million, accounting for 34% of the total number of disabled people in China. Among them are people over 60 years old. There are 20.4541 million people with hearing disabilities. There are 9.49 million senile deaf patients, accounting for 34.1% of the total number of hearing disabilities. As society gradually becomes aging, the incidence of presbycusis is getting higher and higher. The study of its pathogenesis is of great significance for the diagnosis, treatment, and prevention of presbycusis. The rapid progress of molecular biology experimental technology has provided us with a new opportunity to fully understand and reveal the presbycusis. In the near future, early diagnosis of presbycusis-related genes and early prevention or delay of the occurrence and development of presbycusis will become a reality.
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Perda Auditiva Neurossensorial/prevenção & controle , Presbiacusia/prevenção & controle , China , HumanosRESUMO
We have synthesized hollow mesoporous silica (HMS) at a zeolitic imidazolate framework (ZIF) capsule that can be used as a drug delivery system for gentamicin (GM). The GM is first loaded into HMS. Then, the outer surface of the GM/HMS is coated with uniformed ZIF nanoparticles (denoted as GM/HMS@ZIF). The GM/HMS@ZIF has been successfully prepared and acts as a capsule for GM. The GM/HMS@ZIF shows a good biocompatibility and a good cellular uptake in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. The GM is released slowly within 10 h under acidic conditions, which is used to simulate the pH of the endosome and lysosome compartments. The in vivo assay shows that the signal from fluorescein isothiocyanate (FITC) can be observed after 15 days, when the mice were injected with FITC/HMS@ZIF. This opens new opportunities to construct a delivery system for GM via one controlled low dose and sustained release for the therapy of Ménière's disease.
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Antibacterianos/síntese química , Sistemas de Liberação de Medicamentos/métodos , Gentamicinas/síntese química , Imidazóis/síntese química , Dióxido de Silício/síntese química , Zeolitas/síntese química , Animais , Antibacterianos/administração & dosagem , Cápsulas , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Gentamicinas/administração & dosagem , Humanos , Imidazóis/administração & dosagem , Células MCF-7 , Camundongos , Dióxido de Silício/administração & dosagem , Zeolitas/administração & dosagemRESUMO
Stem cells offer new therapeutic avenues for the repair and replacement of damaged tissues and organs owing to their self-renewal and multipotent differentiation capabilities. In this paper, we conduct a systematic review of the characteristics of various types of stem cells and offer insights into their potential applications in both cellular and cell-free therapies. In addition, we provide a comprehensive summary of the technical routes of stem cell therapy and discuss in detail current challenges, including safety issues and differentiation control. Although some issues remain, stem cell therapy demonstrates excellent potential in the field of regenerative medicine and provides novel tactics and methodologies for managing a wider spectrum of illnesses and traumas.
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OBJECTIVE: This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the causal links between psychiatric disorders and sensorineural hearing loss (SNHL). METHODS: Instrumental variables were chosen from genome-wide association studies of schizophrenia (SCH, N = 127,906), bipolar disorder (BD, N = 51,710), major depressive disorder (MDD, N = 500,199), and SNHL (N = 212,544). In the univariable MR analysis, the inverse-variance weighted method (IVW) was conducted as the primary analysis, complemented by various sensitivity analyses to ensure result robustness. RESULTS: SCH exhibited a decreased the risk of SNHL (OR = 0.949, P = 0.005), whereas BD showed an increased incidence of SNHL (OR = 1.145, P = 0.005). No causal association was found for MDD on SNHL (OR = 1.088, P = 0.246). Multivariable MR validated these results. In the reverse direction, genetically predicted SNHL was linked to a decreased risk of SCH with suggestive significance (OR = 0.912, P = 0.023). No reverse causal relationships were observed for SNHL influencing BD or MDD. These findings remained consistent across various MR methods and sensitivity analyses. CONCLUSION: This study demonstrated that the causal relationships between diverse psychiatric disorders with SNHL were heterogeneous. Specifically, SCH was inversely associated with SNHL susceptibility, and similarly, a reduced risk of SNHL was observed in schizophrenia patients. In contrast, BD exhibited an increased incidence of SNHL, although SNHL did not influence the prevalence of BD. No causal association between MDD and SNHL was found.
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Transtorno Depressivo Maior , Perda Auditiva Neurossensorial , Transtornos Mentais , Humanos , Análise da Randomização Mendeliana , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/genéticaRESUMO
Cisplatin is widely used in clinical tumor chemotherapy but has severe ototoxic side effects, including tinnitus and hearing damage. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. In this study, we used CBA/CaJ mice to establish an ototoxicity model of cisplatin-induced hair cell loss, and our results showed that cisplatin treatment could reduce FOXG1 expression and autophagy levels. Additionally, H3K9me2 levels increased in cochlear hair cells after cisplatin administration. Reduced FOXG1 expression caused decreased microRNA (miRNA) expression and autophagy levels, leading to reactive oxygen species (ROS) accumulation and cochlear hair cell death. Inhibiting miRNA expression decreased the autophagy levels of OC-1 cells and significantly increased cellular ROS levels and the apoptosis ratio in vitro. In vitro, overexpression of FOXG1 and its target miRNAs could rescue the cisplatin-induced decrease in autophagy, thereby reducing apoptosis. BIX01294 is an inhibitor of G9a, the enzyme in charge of H3K9me2, and can reduce hair cell damage and rescue the hearing loss caused by cisplatin in vivo. This study demonstrates that FOXG1-related epigenetics plays a role in cisplatin-induced ototoxicity through the autophagy pathway, providing new ideas and intervention targets for treating ototoxicity.
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Hearing loss has become a common sensory defect in humans. Because of the limited regenerative ability of mammalian cochlear hair cells (HCs), HC damage (caused by ototoxic drugs, aging, and noise) is the main risk factor of hearing loss. However, how HCs can be protected from these risk factors remains to be investigated. Autophagy is a process by which damaged cytoplasmic components are sequestered into lysosomes for degradation. Ferroptosis is a novel form of non-apoptotic regulated cell death involving intracellular iron overloading and iron-dependent lipid peroxide accumulation. Recent studies have confirmed that autophagy is associated with ferroptosis, and their crosstalk may be the potential therapeutic target for hearing loss. In this review, we provide an overview of the mechanisms of ferroptosis and autophagy as well as their relationship with HC damage, which may provide insights for a new future in the protection of HCs.
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Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise-induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin- and neomycin-induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer-1 on tert-butyl hydroperoxide (TBHP)-induced hair cell damage in vitro in cochlear explants and HEI-OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis-inducing factor mitochondria-associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer-1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer-1 significantly alleviated noise-induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer-1 significantly reduced noise- and TBHP-induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer-1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer-1 exerted its protective effects by scavenging of ROS and inhibition of TfR1-mediated ferroptosis and P53-AIFM2 signaling pathway-mediated apoptosis. Our findings suggest that Fer-1 is a promising drug for treating NIHL because of its ability to inhibit noise-induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.
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Ferroptose , Perda Auditiva Provocada por Ruído , Camundongos , Animais , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Perda Auditiva Provocada por Ruído/etiologia , Perda Auditiva Provocada por Ruído/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53 , Camundongos Endogâmicos CBA , ApoptoseRESUMO
In recent years, neural stem cell transplantation has received widespread attention as a new treatment method for supplementing specific cells damaged by disease, such as neurodegenerative diseases. A number of studies have proved that the transplantation of neural stem cells in multiple organs has an important therapeutic effect on activation and regeneration of cells, and restore damaged neurons. This article describes the methods for inducing the differentiation of endogenous and exogenous stem cells, the implantation operation and regulation of exogenous stem cells after implanted into the inner ear, and it elaborates the relevant signal pathways of stem cells in the inner ear, as well as the clinical application of various new materials. At present, stem cell therapy still has limitations, but the role of this technology in the treatment of hearing diseases has been widely recognized. With the development of related research, stem cell therapy will play a greater role in the treatment of diseases related to the inner ear.
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Attenuation of noise-induced hair cell loss and noise-induced hearing loss (NIHL) by treatment with FK506 (tacrolimus), a calcineurin (CaN/PP2B) inhibitor used clinically as an immunosuppressant, has been previously reported, but the downstream mechanisms of FK506-attenuated NIHL remain unknown. Here we showed that CaN immunolabeling in outer hair cells (OHCs) and nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) in OHC nuclei are significantly increased after moderate noise exposure in adult CBA/J mice. Consequently, treatment with FK506 significantly reduces moderate-noise-induced loss of OHCs and NIHL. Furthermore, induction of reactive oxygen species (ROS) by moderate noise was significantly diminished by treatment with FK506. In agreement with our previous finding that autophagy marker microtubule-associated protein light chain 3B (LC3B) does not change in OHCs under conditions of moderate-noise-induced permanent threshold shifts, treatment with FK506 increases LC3B immunolabeling in OHCs after exposure to moderate noise. Additionally, prevention of NIHL by treatment with FK506 was partially abolished by pretreatment with LC3B small interfering RNA. Taken together, these results indicate that attenuation of moderate-noise-induced OHC loss and hearing loss by FK506 treatment occurs not only via inhibition of CaN activity but also through inhibition of ROS and activation of autophagy.
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The abnormality of RNA-binding proteins (RBPs) is closely related to the tumorigenesis and development of esophageal squamous cell carcinoma (ESCC), and has been an area of interest for research recently. In this study, 162 tumors and 11 normal samples are obtained from The Cancer Genome Atlas database, among which 218 differentially expressed RBPs are screened. Finally, a prognostic model including seven RBPs (CLK1, DDX39A, EEF2, ELAC1, NKRF, POP7, and SMN1) is established. Further analysis reveals that the overall survival (OS) rate of the high-risk group is lower than that of the low-risk group. The area under the receiver operating characteristic (ROC) curve (AUC) of the training group and testing group is significant (AUCs of 3 years are 0.815 and 0.694, respectively, AUCs of 5 years are 0.737 and 0.725, respectively). In addition, a comprehensive analysis of seven identified RBPs shows that most RBPs are related to OS in patients with ESCC, among which EEF2 and ELCA1 are differentially expressed at the protein level of ESCC and control tissues. CLK1 and POP7 expressions in esophageal cancer tumor samples are undertaken using the tissue microarray, and show that CLK1 mRNA levels are relatively lower, and POP7 mRNA levels are higher compared with non-cancerous esophageal tissues. Survival analysis reveals that a higher expression of CLK1 predicts a significant worse prognosis, and a lower expression of POP7 predicts a worse prognosis in esophageal cancer. These results suggest that CLK1 may promote tumor progression, and POP7 may hinder the development of esophageal cancer. In addition, gene set enrichment analysis reveals that abnormal biological processes related to ribosomes and abnormalities in classic tumor signaling pathways such as TGF-ß are important driving forces for the occurrence and development of ESCC. Our results provide new insights into the pathogenesis of ESCC, and seven RBPs have potential application value in the clinical prognosis prediction of ESCC.
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Hearing loss is one of the most common disabilities affecting both children and adults worldwide. However, traditional treatment of hearing loss has some limitations, particularly in terms of drug delivery system as well as diagnosis of ear imaging. The blood-labyrinth barrier (BLB), the barrier between the vasculature and fluids of the inner ear, restricts entry of most blood-borne compounds into inner ear tissues. Nanoparticles (NPs) have been demonstrated to have high biocompatibility, good degradation, and simple synthesis in the process of diagnosis and treatment, which are promising for medical applications in hearing loss. Although previous studies have shown that NPs have promising applications in the field of inner ear diseases, there is still a gap between biological research and clinical application. In this paper, we aim to summarize developments and challenges of NPs in diagnostics and treatment of hearing loss in recent years. This review may be useful to raise otology researchers' awareness of effect of NPs on hearing diagnosis and treatment.
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Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.Abbreviations: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.
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Autofagia , Presbiacusia , Envelhecimento/metabolismo , Apoptose/genética , Autofagia/genética , Sobrevivência Celular , Fatores de Transcrição Forkhead/metabolismo , Células Ciliadas Auditivas , Humanos , Proteínas do Tecido Nervoso/metabolismo , Presbiacusia/genética , Presbiacusia/metabolismoRESUMO
Deafness is one of the major global health problems that seriously affects the quality of human life. At present, there are no successful treatments for deafness caused by cochlear hair cell (HC) damage. The irreversibility of mammalian hearing impairment is that the inner ear's sensory epithelium cannot repair lost hair cells and neurons through spontaneous regeneration. The goal of stem cell therapy for sensorineural hearing loss is to reconstruct the damaged inner ear structure and achieve functional repair. microRNA (miRNA), as a class of highly conserved endogenous non-coding small RNAs, plays an important role in the development of cochlea and HCs. miRNA also participates in the regulation of stem cell proliferation and differentiation, and plays an important role in the process of regeneration of inner ear HCs, miRNA has a broad application prospect of clinical treatment of hearing loss, which is conducive to solving the medical problem of inner ear HC regeneration.
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Sensorineural deafness is mainly caused by damage to the tissues of the inner ear, and hearing impairment has become an increasingly serious global health problem. When the inner ear is abnormally developed or is damaged by inflammation, ototoxic drugs, or blood supply disorders, auditory signal transmission is inhibited resulting in hearing loss. Forkhead box G1 (FoxG1) is an important nuclear transcriptional regulator, which is related to the differentiation, proliferation, development, and survival of cells in the brain, telencephalon, inner ear, and other tissues. Previous studies have shown that when FoxG1 is abnormally expressed, the development and function of inner ear hair cells is impaired. This review discusses the role and regulatory mechanism of FoxG1 in inner ear tissue from various aspects - such as the effect on inner ear development, the maintenance of inner ear structure and function, and its role in the inner ear when subjected to various stimulations or injuries - in order to explain the potential significance of FoxG1 as a new target for the treatment of hearing loss.
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BACKGROUND: Aberrant methylation of DNA plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC). In the current study, we aimed to integrate three cohorts profile datasets to identify abnormally methylated-differentially expressed genes and pathways associated with NPC. METHODS: Data of gene expression microarrays (GSE53819, GSE412452) and gene methylation microarrays (GSE52068) obtained from the GEO database. Aberrantly methylated differentially expressed genes (DEGs) were obtained by GEO2R. The David database was utilized to perform enrichment and functional analysis regarding selected genes. To create a protein-protein interaction (PPI), STRING and Cytoscape software were utilized. The MCODE was used for module analysis of the PPI network. RESULTS: In total, 181 hypomethylation-high expression genes were identified, which were enriched in the biological mechanisms involved in the differentiation of endodermal cell, mitotic nuclear division, mitotic cell cycle process, chromosome segregation and cell cycle phase transition, etc. Pathway enrichment showed ECM-receptor interaction, PI3K-Akt signaling pathway, Focal adhesion, Protein digestion and absorption and Amoebiasis, etc. The top 3 hub genes of PPI network were FANCI, POSTN, and IFIH1. Additionally, 210 hypermethylation-low expression genes were identified, and our data revealed enrichment in biological processes including axoneme assembly, micro tubular formation, assembly of axonemal dynein complex, cilium movement and cilium organization, etc. Pathway analysis indicated enrichment in B cell receptor signaling pathway, Hematopoietic cell lineage, Leukocyte transendothelial migration, Complement and coagulation cascades and Fc gamma R-mediated phagocytosis, etc. The ZMYND10, PACRG and POU2AF1 were identified as the top three hub genes of PPI network. After validation in TCGA and GEPIA database, most hub genes remained significant. Patients with high expression of POSTN found to have shorter overall survival, while in patients with high expression of ZMYND10 and POU2AF1 longer overall survival was identified. CONCLUSIONS: The data revealed novel aberrantly methylated-differentially expressed genes and pathways in NPC by bioinformatics analysis, potentially providing novel insights for the molecular mechanisms governing NPC progression. Hub genes including FANCI, POSTN, IFIH1, ZMYND10, PACRG and POU2AF1 might serve as novel biomarkers for precision diagnosis and providing medical treatment for patient with NPC.
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Biomarcadores Tumorais/genética , Metilação de DNA/genética , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Biomarcadores Tumorais/análise , Estudos de Casos e Controles , Progressão da Doença , Epigênese Genética/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Marcadores Genéticos/genética , Humanos , Análise em Microsséries/métodos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética , TranscriptomaRESUMO
Agerelated hearing loss, also termed central presbycusis, is a progressive neurodegenerative disease; it is a devastating disorder that severely affects the quality of life of elderly individuals. Substantial evidence has indicated that oxidative stress and associated protein folding dysfunction have a marked influence on neurodegenerative diseases. In this study, we aimed to cells to investigate whether metformin protects against agerelated pathologies and to elucidate the underlying mechanisms; specifically, we focused on the role of unfolded protein response (UPR) via the AMPK/ERK1/2 signaling pathways. For this purpose, the biguanide compound, metformin, a medication widely used in the treatment of type 2 diabetes, was administered to rats in a model of mimetic aging. In addition, senescent PC12 were treated with metformin. Although it has been well established that UPR signaling is activated in response to cellular stress and is associated with the pathogenesis of neuronal deterioration, the detailed functions of the UPR in the auditory cortex remain unclear. We found that metformin treatment markedly affected the UPR and the AMPK/ERK1/2 signaling pathway, and maintained the auditory brainstem response (ABR) threshold during the aging process. The results indicated that the regulation of the UPR and AMPK/ERK1/2 signaling pathway by metformin significantly attenuated hearing loss, cell apoptosis and agerelated neurodegeneration. Reversing these harmful effects through the use of metformin suggests its involvement in restoring the antioxidant status and protein homeostasis related to the underlying pathology of presbycusis. The findings of this study may provide a better approach for the treatment of agerelated neurodegeneration diseases.
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Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metformina/farmacologia , Resposta a Proteínas não Dobradas/fisiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/análise , Apoptose/efeitos dos fármacos , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/metabolismo , Modelos Animais de Doenças , Galactose/efeitos adversos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Presbiacusia , Ratos , Ratos Sprague-DawleyRESUMO
Noise-induced hearing loss (NIHL) is associated with both acute and chronic noise exposure. The application of steroid hormones is the first-line treatment for NIHL. However, a high dose of steroid hormone in the body is necessary to maintain its efficacy and causes side effects, such as headache and osteoporosis. In this work, we prepared a zeolitic imidazolate framework (ZIF)-based system for steroid hormone delivery in the inner ear. Methylprednisolone (MP), a typical steroid hormone, was encapsulated into ZIF-90 nanoparticles (NPs) using one-pot synthesis method. The obtained MP@ZIF-90 NPs are negatively charged and 120 nm in size and showed good biocompatibility and stability at a pH value of 7.4. After intraperitoneal injection, ZIF-90 could efficiently protect drugs during peripheral blood circulation, enter the inner ear via the blood labyrinthine barrier (BLB) and slowly release the drugs. Auditory brainstem response (ABR) tests indicated that MP@ZIF-90 exhibits better protection of mice from noise than those using the free MP and ZIF-8 with encapsulated MP (MP@ZIF-8). More importantly, MP@ZIF-90 showed no defects to the inner ear after being treated for noise and low nephrotoxicity during therapy, which demonstrates the biocompatibility of this material. We believe the ZIF-90 based delivery system is an efficient strategy for inner ear therapy of NIHL.
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Orelha Interna , Perda Auditiva Provocada por Ruído , Estruturas Metalorgânicas , Nanopartículas , Zeolitas , Animais , CamundongosRESUMO
Inflammation is a self-defense response to protect individuals from infection and tissue damage, but excessive or persistent inflammation can have adverse effects on cell survival. Many individuals become especially susceptible to chronic-inflammation-induced sensorineural hearing loss as they age, but the intrinsic molecular mechanism behind aging individuals' increased risk of hearing loss remains unclear. FoxG1 (forkhead box transcription factor G1) is a key transcription factor that plays important roles in hair cell survival through the regulation of mitochondrial function, but how the function of FoxG1 changes during aging and under inflammatory conditions is unknown. In this study, we first found that FoxG1 expression and autophagy both increased gradually in the low concentration lipopolysaccharide (LPS)-induced inflammation model, while after high concentration of LPS treatment both FoxG1 expression and autophagy levels decreased as the concentration of LPS increased. We then used siRNA to downregulate Foxg1 expression in hair cell-like OC-1â¯cells and found that cell death and apoptosis were significantly increased after LPS injury. Furthermore, we used d-galactose (D-gal) to create an aging model with hair cell-like OC-1â¯cells and cochlear explant cultures in vitro and found that the expression of Foxg1 and the level of autophagy were both decreased after D-gal and LPS co-treatment. Lastly, we knocked down the expression of Foxg1 under aged inflammation conditions and found increased numbers of dead and apoptotic cells. Together these results suggest that FoxG1 affects the sensitivity of mimetic aging hair cells to inflammation by regulating autophagy pathways.