A novel sensitive fluorescent probe with double channels for highly effective recognition of biothiols.

Biothiols play a crucial role in maintaining redox balance in organisms, and anomalous levels of biothiols in human organs can lead to various sicknesses and biological disorders. This work developed a novel sensitive fluorescent probe TZ-NBD with double channels for highly efficient recognition of biothiols. TZ-NBD adopts 4-Chloro-7-nitrobenzofurazan (NBD-Cl) as the recognition moiety with simultaneous fluorescence output. By incorporating NBD-Cl with the other fluorophore, benzothiazole dihydrocyclopentachromene derivative (TZ-OH), the dual-channel sensitive fluorescence probe TZ-NBD was built. The existence of Cys/ Hcy could significantly trigger both the green and red fluorescent emissions, which were derived from fluorophores amine-substituted NBD and TZ-OH, respectively. While exposing to GSH, only the red-channel fluorescence signal could be detected, indicating the release of TZ-OH. The phenomena was mainly attributed to the fact that sulfur-substituted NBD has nearly no fluorescence, while amine-substituted NBD shows obvious green fluorescence. In our study, TZ-NBD exhibited dual-channel sensitivity, fast response, and excellent selectivity to biothiols in vitro. Moreover, TZ-NBD was favorably utilized for recognition of biothiols in vivo. We believe that the sensitive fluorescence probe with double channels can afford an alternate approach for monitoring biothiols in organisms and would be useful for studying diseases associated with biothiols.

Paclitaxel-loaded ROS-responsive nanoparticles for head and neck cancer therapy.

High intracellular reactive oxygen species (ROS) level is characteristic of cancer cells and could act as a target for the efficient targeted drug delivery for cancer treatment. Consequently, biomaterials that react to excessive levels of ROS are essential for biomedical applications. In this study, a novel ROS-responsive polymer based on D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly (ß-thioester) (TPGS-PBTE) was synthesized for targeted delivery of the first-line antineoplastic drug, paclitaxel (PTX). The resultant TPGS-PBTE NPs showed good ROS-responsive capability in size change and drug release. Compared to PTX, PTX-loaded nanoparticles (PTX@TPGS-PBTE NPs) showed enhanced cytotoxicity and higher level of apoptosis toward squamous cell carcinoma (SCC-7) cells. Tumor-targeted delivery of the NPs was also observed, especially after being modified with a tumor-targeting peptide, cRGD. Enhanced tumor growth inhibition was also observed in head and neck cancer SCC-7 murine models. In summary, PTX@TPGS-PBTE NPs can achieve good therapeutic effects of PTX against head and neck cancer both in vitro and in vivo, especially when modified by cRGD for active targeting, which enriched the application of ROS responsive system utilized in the delivery of anticancer drugs.

Enhanced photodynamic therapy/photothermo therapy for nasopharyngeal carcinoma via a tumour microenvironment-responsive self-oxygenated drug delivery system.

The hypoxic nature of tumours limits the efficiency of oxygen-dependent photodynamic therapy (PDT). Hence, in this study, indocyanine green (ICG)-loaded lipid-coated zinc peroxide (ZnO2) nanoparticles (ZnO2@Lip-ICG) was constructed to realize tumour microenvironment (TME)-responsive self-oxygen supply. Near infrared light irradiation (808 nm), the lipid outer layer of ICG acquires sufficient energy to produce heat, thereby elevating the localised temperature, which results in accelerated ZnO2 release and apoptosis of tumour cells. The ZnO2 rapidly generates O2 in the TME (pH 6.5), which alleviates tumour hypoxia and then enhances the PDT effect of ICG. These results demonstrate that ZnO2@Lip-ICG NPs display good oxygen self-supported properties and outstanding PDT/PTT characteristics, and thus, achieve good tumour proliferation suppression.

Association of plasma lead, cadmium and selenium levels with hearing loss in adults: National Health and Nutrition Examination Survey (NHANES) 2011-2012.

To determine the association between hearing loss and environmental Pb, Cd and Se exposure, a total of 1503 American adults from National Health and Nutrition Examination Survey (NHANES) (2011-2012) were assessed. The average of four audiometric frequencies (0·5, 1, 2 and 4 kHz) was used to identify speech-frequency hearing loss (SFHL), while the average of 3 audiometric frequencies (3, 4 and 6 kHz) was used to identify high-frequency hearing loss (HFHL). HFHL adjusted OR determined by comparing the highest and lowest blood Pb and Cd quartiles were 1·98 (95 % CI: 1·27, 3·10) and 1·81 (95 % CI: 1·13, 2·90), respectively. SFHL was significantly associated with blood Cd with the OR = 2·42 for the highest quartile. When further stratified by age, this association appeared to be limited to adults aged 35-52 years. After stratified by gender, except for Pb and Cd, we observed that blood Se showed a dose-dependent association with SFHL in men. In women, only Cd showed a dose-dependent association with speech and high-frequency hearing loss. Hearing loss was positively associated with blood levels of Pb and Cd. Additionally, our study provided novel evidence suggesting that excessive Se supplement would increase SFHL risk in men.

Systematic Analysis of Survival-Associated Alternative Splicing Signatures in Thyroid Carcinoma.

Alternative splicing (AS) is a key mechanism involved in regulating gene expression and is closely related to tumorigenesis. The incidence of thyroid cancer (THCA) has increased during the past decade, and the role of AS in THCA is still unclear. Here, we used TCGA and to generate AS maps in patients with THCA. Univariate analysis revealed 825 AS events related to the survival of THCA. Five prognostic models of AA, AD, AT, ES, and ME events were obtained through lasso and multivariate analyses, and the final prediction model was established by integrating all the AS events in the five prediction models. Kaplan-Meier survival analysis revealed that the overall survival rate of patients in the high-risk group was significantly shorter than that of patients in the low-risk group. The ROC results revealed that the prognostic capabilities of each model at 3, 5, and 8 years were all greater than 0.7, and the final prognostic capabilities of the models were all greater than 0.9. By reviewing other databases and utilizing qPCR, we verified the established THCA gene model. In addition, gene set enrichment analysis showed that abnormal AS events might play key roles in tumor development and progression of THCA by participating in changes in molecular structure, homeostasis of the cell environment and in cell energy. Finally, a splicing correlation network was established to reveal the potential regulatory patterns between the predicted splicing factors and AS event candidates. In summary, AS should be considered an important prognostic indicator of THCA. Our results will help to elucidate the underlying mechanism of AS in the process of THCA tumorigenesis and broaden the prognostic and clinical application of molecular targeted therapy for THCA.

The expression profiles and prognostic values of HSPs family members in Head and neck cancer.

BACKGROUND: Head and neck squamous cell carcinoma (HNSC) ranks as the sixth most common malignancy. The identification of highly specific and sensitive prognostic markers and potential drug targets can contribute to enhanced patient prognosis and individualized treatments. Heat shock proteins (HSPs) act as molecular chaperones and play a crucial role in maintaining cell homeostasis. Recently, research has indicated that HSPs also act as "evil chaperones" in cancer development. METHODS: In this study, we assessed the expression of HSPs in HNSC patients using the ONCOMINE, GEPIA, and UALCAN databases. Mutations of HSP genes were also analysed using the cBioPortal database. Additionally, the expression levels of HSPs were verified using the Human Protein Altas (THPA) database. RESULTS: We found that the expression levels of HSPH1, HSPD1, SERPINH1, HSPA4, and HSP90AA1 were significantly higher in tissues from HNSC patients compared with normal tissues. Moreover, HSPH1, HSPD1, SERPINH1, HSPA4 and HSP90AA1 expressions were linked to disease progression. Survival analysis with the GEPIA and OncoLnc databases indicated that upregulation of HSPH1, HSPD1, SERPINH1, HSPA4 and HSP90AA1 was related to poor overall survival (OS). CONCLUSION: This study suggests that the HSPH1, HSPD1, SERPINH1, HSPA4 and HSP90AA1 genes are potential clinical targets and prognostic biomarkers for patients with HNSC.

A Novel Surgery Classification for Endoscopic Approaches to Middle Ear Cholesteatoma.

This study aimed to develop a novel surgery classification for an endoscopic approach to middle ear cholesteatoma. We retrospectively analyzed the surgical approaches and outcomes of patients with middle ear cholesteatoma. Middle ear cholesteatoma surgeries were divided into four types and two special types as follows: type I, attic retraction pocket, which only requires tympanostomy tube placement or retraction pocket resection and cartilage reconstruction; type II, cholesteatoma which is limited to the attic or in which endoscopy can confirm complete removal of mastoid cholesteatoma lesions, including type II a, requiring only use of a curette, and type II b, requiring use of an electric drill or chisel; type III, cholesteatoma not limited to the attic, in which endoscopy cannot confirm complete removal of mastoid cholesteatoma lesions, requiring the combined use of endoscope and microscope to perform endoscopic tympanoplasty and "Canal Wall Up" mastoidectomy; type IV, extensive involvement of mastoid cavity cholesteatoma lesions and/or cases with a potential risk of complications, removal of which can only be performed under a microscope for "Canal Wall Down" mastoidectomy. In addition, there were two special types: "difficult external auditory canal" and congenital cholesteatoma in children. In our system, type I and type II middle ear cholesteatoma surgery was completely performed under an endoscope alone. However, estimating the extent of the lesions, determining the choice of mastoid opening and reestablishing ventilation are the key points for an endoscopic approach to middle ear cholesteatoma. The classification of endoscopic middle ear cholesteatoma surgery may benefit the selection of surgical indications.

Association between the expression of secreted phosphoprotein - related genes and prognosis of human cancer.

BACKGROUND: While many studies have assessed the predictive value of secreted phosphoprotein (SPP) genes in cancer, the findings have been inconsistent. To resolve these inconsistencies, we systematically analyzed the available data to determine whether SPP1 and SPP2 are prognostic markers in the context of human cancer. METHODS: The expression of SPP1 and SPP2 was assessed by Oncomine analysis. The PrognoScan database was used to assess the prognostic value of SPP1 and SPP2, with cBioPortal used to assess copy number variations. The STRING database was used to generate a Protein - Protein Interaction (PPI) network for SPP genes. RESULTS: SPP1 was more likely to be over-expressed in breast, bladder, colorectal, head, neck, liver, lung, and esophageal cancers. SPP2 was expressed at lower levels in colorectal cancer, leukemia, liver cancer and pancreatic cancer. In addition, SPP1 and SPP2 mutations mainly occurred in cutaneous melanoma and endometrial cancer. CONCLUSIONS: Our results suggest that SPP1 and SPP2 may be effective therapeutic or diagnostic targets in certain cancers. Further research is required to confirm these results and verify the value of SPP1 and SPP2 as clinical markers of cancer prognosis.

Endoplasmic reticulum stress is involved in spiral ganglion neuron apoptosis following chronic kanamycin-induced deafness.

Aminoglycoside antibiotics-induced hearing loss is a common sensorineural impairment. Spiral ganglion neurons (SGNs) are first-order neurons of the auditory pathway and are critical for the maintenance of normal hearing. In the present study, we investigated the time-course of morphological changes and the degeneration process of spiral ganglion cells (SGCs) following chronic kanamycin-induced deafness and determined whether the endoplasmic reticulum (ER) stress was involved in the degeneration of SGNs. We detected density changes in SGCs and the expressions of Bip, inositol requirement 1 (IRE1)α, activating transcription factor-6α, p-PERK, p-eIF2α, CHOP, and caspase-12 at each time point after kanamycin treatment. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was also performed. The number of SGC deletions reached ∼50% at the 70th day after kanamycin administration and the ER of most SGCs were dilated. The expression of p-PERK, p-eIF2α, p-IRE1α, Bip, caspase-12, and Chop was significantly unregulated after kanamycin treatment. The number of SGCs that were positive for both TUNEL and caspase-12 increased from day 7 to 28. Taken together, these data demonstrate that ER stress was involved in kanamycin-induced apoptosis of SGNs. Kanamycin-induced SGN apoptosis is mediated, at least in part, by ER stress-induced upregulation of CHOP and caspase-12.

DNA methylation biomarkers for hepatocellular carcinoma.

BACKGROUND: Aberrant methylation of DNA is a key driver of hepatocellular carcinoma (HCC). In this study, we sought to integrate four cohorts profile datasets to identify such abnormally methylated genes and pathways associated with HCC. METHODS: To this end, we downloaded microarray datasets examining gene expression (GSE84402, GSE46408) and gene methylation (GSE73003, GSE57956) from the GEO database. Abnormally methylated differentially expressed genes (DEGs) were sorted and pathways were analyzed. The String database was then used to perform enrichment and functional analysis of identified pathways and genes. Cytoscape software was used to create a protein-protein interaction network, and MCODE was used for module analysis. Finally, overall survival analysis of hub genes was performed by the OncoLnc online tool. RESULTS: In total, we identified 19 hypomethylated highly expressed genes and 14 hypermethylated lowly expressed genes at the screening step, and finally found six mostly changed hub genes including MAD2L1, CDC20, CCNB1, CCND1, AR and ESR1. Pathway analysis showed that aberrantly methylated-DEGs mainly associated with the cell cycle process, p53 signaling, and MAPK signaling in HCC. After validation in TCGA database, the methylation and expression status of hub genes was significantly altered and same with our results. Patients with high expression of MAD2L1, CDC20 and CCNB1 and low expression of CCND1, AR, and ESR1 was associated with shorter overall survival. CONCLUSIONS: Taken together, we have identified novel aberrantly methylated genes and pathways linked to HCC, potentially offering novel insights into the molecular mechanisms governing HCC progression and serving as novel biomarkers for precision diagnosis and disease treatment.

Identification of candidate aberrantly methylated and differentially expressed genes in thyroid cancer.

Aberrant methylation of DNA sequences plays a criticle role in finding novel aberrantly methylated genes and pathways in thyroid cancer (THCA). This study aimed to integrate three cohorts profile datasets to find novel aberrantly methylated genes and pathways in THCA. Data of gene expression profiling microarrays (GSE33630 and GSE65144) and gene methylation profiling microarrays (GSE51090) were downloaded from the Gene Expression Omnibus database. Aberrantly methylated and differentially expressed genes were sorted and pathways were analyzed. Functional and enrichment analyses of selected genes were performed using the String database. A protein-protein interaction network was constructed using the Cytoscape software, and module analysis was performed using Molecular Complex detection. In total, we identified 12 hypomethylation/high-expression genes and 30 hypermethylation/low-expression genes at the screening step and, finally, found 6 mostly changed hub genes including PPARGC1A, CREBBP, EP300, CD44, SPP1, and MMP9. Pathway analysis showed that aberrantly methylated differentially expressed genes were mainly associated with the thyroid hormone signaling pathway, AMP-activated protein kinase (AMPK) signaling pathway, and cell cycle process in THCA. After validation in the Cancer Genome Atlas database, the methylation and expression status of hub genes was significantly altered and the same with our results. Taken together, we identified novel aberrantly methylated genes and pathways in THCA, which could improve our understanding of the cause and underlying molecular events, and these candidate genes could serve as aberrant methylation-based biomarkers for precise diagnosis and treatment of THCA.

Association of TNF-α promoter polymorphism and Graves' disease: an updated systematic review and meta-analysis.

Graves' disease (GD) is a common autoimmune disorder with a genetic predisposition. Owing to the biological effect of tumor necrosis factor-α (TNF-α) on the thyroid gland and its gene location, TNF-α should be able to influence an individual's susceptibility to GD. In the present study, we conduct a meta-analysis of rs1800629 and rs361525 in TNF-α gene from all eligible case-control studies to assess the associations amongst reported TNF-α gene with GD. A total of ten case-control studies involving 2790 GD patients and 3472 healthy controls were included. The results showed that a significant association was characterized between the rs1800629 polymorphism and GD in the homozygous model (AA compared with GG: odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.27-3.06, P=0.002) and recessive model (AA compared with GA + GG: OR = 1.62, 95% CI = 1.04-2.50, P=0.03). GD susceptibility was significantly detected in European population in all genetic models after ethnicity stratification. In sharp contrast, no significant association could be detected in Asian population. Next, we conducted a meta-analysis for another promoter SNP rs361525. However, SNP rs361525 did not show a significant association with GD in any genetic model before and after ethnicity stratification. Together, our data support that only the promoter single-nucleotide polymorphism (SNP) rs1800629 within the TNF-α gene is associated with increased risk for developing GD, especially in European population. Future large-scale studies are required to validate the associations between TNF-α gene and GD.

Association between polymorphism within interleukin related genes and Graves' disease: a meta-analysis of 22 case-control studies.

Graves' disease (GD) is a common autoimmune disorder with a genetic predisposition. There is strong evidence to suggest that both Th1 and Th2 circulating cytokines are involved in the development of GD. In this study, we conducted a meta-analysis to assess the impact of seven variations of five IL-related genes on the susceptibility to GD. A total of 22 case-control studies involving 5338 GD patients and 6446 healthy controls were included. The results showed that only one SNP rs1800795 in IL-6 was significantly associated with GD in homozygous model (CC vs. GG: OR = 2.714, 95% CI = 1.047-7.039, p = 0.04), heterozygous model (CG vs. GG: OR = 1.295, 95% CI = 1.013-1.655, p = 0.039), dominant model (CC+CG vs. GG: OR = 1.418, 95% CI = 1.122-1.793, p = 0.003) and additive model (C vs. G: OR = 1.432, 95% CI = 1.087-1.886, p = 0.011).To explain the heterogeneity, we performed the subgroup analysis by ethnicity. The ethnicity stratification revealed that the association between rs1800795 and GD tended to be much stronger for Asian than European population in homozygous, dominant, recessive, and additive models. The remaining 6 SNPs in 4 genes did not show any significant association with GD in any genetic models. Together, our data support that rs1800795 within the IL-6 gene confers genetic susceptibility for GD. Future large-scale studies are required to validate the associations between IL-6 and others IL-related genes and GD.

Association between rs3087243 and rs231775 polymorphism within the cytotoxic T-lymphocyte antigen 4 gene and Graves' disease: a case/control study combined with meta-analyses.

We conducted a case/control study to assess the impact of SNP rs3087243 and rs231775 within the CTLA4 gene, on the susceptibility to Graves' disease (GD) in a Chinese Han dataset (271 cases and 298 controls). The frequency of G allele for rs3087243 and rs231775 was observed to be significantly higher in subjects with GD than in control subjects (p = 0.005 and p = 0.000, respectively). After logistic regression analysis, a significant association was detected between SNP rs3087243 and GD in the additive and recessive models. Similarly, association for the SNP rs231775 could also be detected in the additive model, dominant model and recessive model. A meta-analysis, including 27 published datasets along with the current dataset, was performed to further confirm the association. Consistent with our case/control results, rs3087243 and rs231775 showed a significant association with GD in all genetic models. Of note, ethnic stratification revealed that these two SNPs were associated with susceptibility to GD in populations of both Asian and European descent. In conclusion, our data support that the rs3087243 and rs231775 polymorphisms within the CTLA4 gene confer genetic susceptibility to GD.

Invasive Laryngeal Squamous Cell Carcinoma in a Boy.

Laryngeal squamous cell carcinoma (SCC) is rare in children. Usually, laryngeal SCC in children has a poor prognosis. A 9-year-old boy is reported who was diagnosed as having poorly differentiated laryngeal squamous cell carcinoma with neck metastasis. This report aims to highlight the importance of a comprehensive knowledge of differential diagnosis, putting great attention to the onset of symptoms, early application of flexible laryngoscopy, and intensive studies on similar cases.

Assessment of type 2 diabetes risk conferred by SNPs rs2241766 and rs1501299 in the ADIPOQ gene, a case/control study combined with meta-analyses.

We conducted a case/control study to assess the impact of two SNPs, rs2241766 and rs1501299 within the ADIPOQ gene, on type 2 diabetes (T2D) susceptibility in a Chinese Han dataset (741 cases and 902 controls). SNP rs2241766 was found significantly associated with T2D risk in the additive model, dominant model and recessive model. A marginal association was detected for SNP rs1501299 in the additive model and recessive model after Bonferroni correction, and haplotype analysis provided additional evidence supporting the association between these two SNPs and T2D risk. A meta-analysis including 29 published datasets along with current dataset was next carried out to further confirm the association. In consistent with our case/control results, rs2241766 showed a significant association with T2D in the dominant model and additive model, and the association between rs1501299 and T2D was also characterized in the homozygote model, dominant model, recessive model, and additive model. Of note, the association became much stronger in East Asians after exclusion of ethnic stratification. Together, our data support that the rs2241766 and rs1501299 polymorphisms within the ADIPOQ gene confer genetic susceptibility for type 2 diabetes, especially in the Chinese Han population.

Protective effects of membrane-anchored and secreted DNA vaccines encoding fatty acid-binding protein and glutathione S-transferase against Schistosoma japonicum.

In order to explore the high performance bivalent DNA-based vaccine against schistosomes, SjFABP and Sj26GST were selected and used to construct a vaccine. Two strategies were used to construct the bivalent DNA vaccine. In the first strategy, a plasmid encoding antigen in the secreted form was used, while in the other, a plasmid encoding a truncated form of SjFABP and Sj26GST targeted to the cell surface was used. Various parameters, including antibody and cytokine response, proliferation, histopathological examination, and characterization of T cell subsets were used to evaluate the type of immune response and the level of protection against challenge infection. Injection with secreted pIRES-sjFABP-sj26GST significantly increased the levels of antibody, splenocyte proliferation, and production of IFN-γ, compared with membrane-anchored groups. Analysis of splenic T cell subsets showed that the secreted vaccine significantly increased the percentage of CD3(+)CD4(+) and CD3(+)CD8(+) T cells. Liver immunopathology (size of liver granulomas) was significantly reduced in the secreted group compared with the membrane-anchored groups. Moreover, challenge experiments showed that the worm and egg burdens were significantly reduced in animals immunized with recombinant vaccines. Most importantly, secreted Sj26GST-SjFABP markedly enhanced protection, by reducing worm and egg burdens by 31.8% and 24.78%, respectively, while the membrane-anchored group decreased worm and egg burdens by 24.80% and 18.80%, respectively. Taken together, these findings suggest that the secretory vaccine is more promising than the membrane-anchored vaccine, and provides support for the development and application of this vaccine.

[The MRI and clinical features of acinic cell carcinoma of the parotid gland].

OBJECTIVE: To analyze the MR imaging findins of acinic cell carcinoma(ACC) in parotid gland and develop the diagnosis of this disease. METHOD: The MR imaging fearures of 11 patients with pathologically proved ACC were retrospectively analyzed. MR imagings were analyzed in relation to the follow:amount, location, size, shape, margin, pseudocapsule, MR signal intensity and enhanced pattern and the cervical lymphadenopathy. The clinical analysis on patients included age, sex, and follow-up. RESULT: There were 11 patients, 7 lesions was located in the right parotid gland and 4 lesions was located in the left parotid gland; the average maximum diameter was (2.66±0.99)cm; 7 lesions showed lobulated,and 4 lesions showed round; 8 lesions had no pseudocapsules and 3 lesions had incomplete pseudocapsule. All lesions showed homogeneous or heterogeneous isointense and slight hyperintense on T1 WI and T2WI. On post contrast images, the tumor parenchyma ingredients showed remarkable enhancement in all lesions. CONCLUSION: The MR imaging of ACC in the parotid gland don't have specific features, but when the tumor of the parotid gland showed no pseudocapsule (or showed incomplete pseudocapsule), lobulate, small cysitc and remarkable enhancement, it may indicate ACC, and the correct diagnosis depends on clinical pathology.

Reversible neurotoxicity of kanamycin on dorsal cochlear nucleus.

The time course of aminoglycoside neurotoxic effect on cochlear nucleus is still obscure. We examined dynamic pathological changes of dorsal cochlear nucleus (DCN) and investigated whether apoptosis or autophagy was upregulated in the neurotoxic course of kanamycin on DCN after kanamycin treatment. Rats were treated with kanamycin sulfate/kg/day at a dose of 500mg by subcutaneous injection for 10 days. Dynamic pathological changes, neuron density and neuron apoptosis of the DCN were examined at 1, 7, 14, 28, 56, 70 and 140 days after kanamycin treatment. The expressions of JNK1, DAPK2, Bcl-2, p-Bcl-2, Caspase-3, LC3B and Beclin-1 were also detected. Under transmission electron microscopy, the mitochondrial swelling and focal vacuoles as well as endoplasmic reticulum dilation were progressively aggravated from 1 day to 14 days, and gradually recovered from 28 days to 140 days. Meanwhile, both autophagosomes and autolysosomes were increased from 1 day to 56 days. Only few neurons were positive to the TUNEL staining. Moreover, neither the expressions of caspase-3 and DAPK2 nor neurons density of DCN changed significantly. LC3-II was drastically increased at 7 days. Beclin-1 was upgraded at 1 and 7 days. P-Bcl-2 increased at 1, 7, 14 and 28 days. JNK1 increased at 7 days, and Bcl-2 was downgraded at 140 days. LC3-B positive neurons were increased at 1, 7 and 14 days. These data demonstrated that the neurons damage of the DCN caused by kanamycin was reversible and autophagy was upregulated in the neurotoxic course of kanamycin on DCN through JNK1-mediated phosphorylation of Bcl-2 pathway.

Mitochondrial transcription factor A overexpression and base excision repair deficiency in the inner ear of rats with D-galactose-induced aging.

Oxidative damage to mtDNA is associated with excessive reactive oxygen species production. The mitochondrial common deletion (mtDNA 4977-bp and 4834-bp deletion in humans and rats, respectively) is the most typical and frequent form of mtDNA damage associated with aging and degenerative diseases. The accumulation of the mitochondrial common deletion has been proposed to play a crucial role in age-related hearing loss (presbycusis). However, the mechanisms underlying the formation and accumulation of mtDNA deletions are still obscure. In the present study, a rat mimetic aging model induced by D-Gal was used to explore the origin of deletion mutations and how mtDNA repair systems modulate this process in the inner ear during aging. We found that the mitochondrial common deletion was greatly increased and mitochondrial base excision repair capacity was significantly reduced in the inner ear in D-Gal-treated rats as compared with controls. The overexpression of mitochondrial transcription factor A induced by D-Gal significantly stimulated mtDNA replication, resulting in an increase in mtDNA copy number. In addition, an age-related loss of auditory sensory cells in the inner ear was observed in D-Gal-treated rats. Taken together, our data suggest that mitochondrial base excision repair capacity deficiency and an increase in mtDNA replication resulting from mitochondrial transcription factor A overexpression may contribute to the accumulation of mtDNA deletions in the inner ear during aging. This study also provides new insights into the development of presbycusis.