Activation of Nrf2 inhibits ferroptosis and protects against oxaliplatin-induced ototoxicity.

Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.

CCDC86 promotes the aggressive behavior of nasopharyngeal carcinoma by positively regulating EGFR and activating the PI3K/Akt signaling.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck. A number of studies have confirmed that coiled-coil domain-containing protein 86 (CCDC86) plays an important role in the pathogenesis of lymphoma but the role of CCDC86 in NPC has not yet been reported. Here, in vivo and in vitro experiments were conducted to explore whether CCDC86 plays a role in the pathogenesis of NPC and to identify the specific mechanism. We found that CCDC86 was highly expressed in NPC tissues and cells, and the expression level of CCDC86 was correlated with the prognosis of patients with advanced NPC. CCDC86 promoted the proliferation, invasion, and migration of NPC cells in vivo and in vitro by promoting the EMT process and upregulating the expression of MMPs. Then, we confirmed that EGFR is a downstream target gene of CCDC86 and that CCDC86 can promote the proliferation, invasion, and migration of NPC cells by upregulating the expression of EGFR and activating downstream PI3K/Akt. Furthermore, we confirmed that CCDC86 did not directly bind to EGFR but positively regulated EGFR by binding to NPM1. CCDC86 is expected to be used as a novel biomarker and therapeutic target for predicting the prognosis of NPC.

GRß Regulates Glucocorticoid Resistance in Sudden Sensorineural Hearing Loss.

BACKGROUND: In recent years, the incidence of sudden deafness has gradually increased, with a very limited understanding of its etiology and pathogenesis. Glucocorticoids are the first choice of the treatment, but some hormone-resistant patients are not sensitive to glucocorticoid therapy. The pathogenesis is not yet known. In this study, we aim to construct the HEI-OC1 cell line stably overexpressing Glucocorticoid Receptor Beta (GRß), and identify its exact role in the cases of glucocorticoidresistant sudden deafness. METHODS: We used the endotoxin lipopolysaccharide-stimulated cochlear hair cells (HEI-OC1) to investigate the relationship of inflammation factor IL-2, TNF alpha, and SRp30c with the high expression GRß. We built a stable GRß high expression HEI-OC1 cell line and clarified its effects on the therapeutic effect of dexamethasone. MTT assay, colony formation assay, CCK-8 assay, Western blot, and RT-qPCR were utilized for characterizations. RESULTS: Dexamethasone reduced the LPS-induced inflammatory response from HEI-OC1 cells (p<0.05), detected by MTT assay. Dexamethasone could protect HEI-OC1 cells, but its protective effect was weakened due to the transfection of SRp30c over-expression plasmid (p<0.05). The transfection of SRp30c over-expression plasmid in HEI-OC1 cells could elevate the expressions of GRß (p<0.05). CONCLUSION: We clarified the mechanisms of high expression of GRß in glucocorticoid-resistant sudden sensorineural hearing loss, and proved that the inhibition of SRp30c may act as a new treatment way of glucocorticoid-resistant sudden sensorineural hearing loss.

Metformin attenuates the D­galactose­induced aging process via the UPR through the AMPK/ERK1/2 signaling pathways.

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.

Autophagy regulates the degeneration of the auditory cortex through the AMPK-mTOR-ULK1 signaling pathway.

Presbycusis is the most common sensory impairment associated with aging; however, the underlying molecular mechanism remains unclear. Autophagy has been demonstrated to serve a key role in diverse diseases; however, no studies have examined its function in central presbycusis. The aim of the present study was to investigate the changes of autophagy in the physiological processes of the auditory cortex and its role in the degeneration of the auditory cortex, as well as the related mechanisms using naturally aging rats and a D­galactose (D­gal)­induced mimetic rat model of aging. The present study demonstrated that autophagy increased from 3 months to 15 months in the normal saline (NS) control group, while it decreased in the D­gal group. Compared with the age­matched NS group, the D­gal group demonstrated significantly increased levels of the autophagy­related proteins, LC3 and Beclin 1 (BECN1) and the anti­apoptotic proteins B­cell lymphoma (BCL)2 and BCL­extra large (BCL­xL) at 3 months, with no obvious changes in cell apoptosis level and neuron ultrastructural morphology. However, LC3, BECN1, BCL2 and BCL­xL were decreased at 15 months in the D-gal group, with cell apoptosis significantly increased and substantial neuron degeneration. Additionally, 5' AMP­activated protein kinase (AMPK) activity was enhanced, and mechanistic target of rapamycin (mTOR) and ULK1 phosphorylation (Ser 757) activities were inhibited at 3 months compared with those of the NS group, while the opposite was observed at 9 and 15 months. The present results suggested that autophagy increases from young to adult and decreases at old age in the physiological processes of the auditory cortex, and has anti­apoptotic as well as anti­aging functions in the degeneration of the auditory cortex. Additionally, autophagy was regulated through AMPK activation and mTOR suppression, and impairment of autophagy may serve a key role in the degeneration of the auditory cortex, even in the pathogenesis of central presbycusis.

The role of sodium hydrosulfide in attenuating the aging process via PI3K/AKT and CaMKKß/AMPK pathways.

Age-related dysfunction of the central auditory system, known as central presbycusis, is characterized by defects in speech perception and sound localization. It is important to determine the pathogenesis of central presbycusis in order to explore a feasible and effective intervention method. Recent work has provided fascinating insight into the beneficial function of H2S on oxidative stress and stress-related disease. In this study, we investigated the pathogenesis of central presbycusis and tried to explore the mechanism of H2S action on different aspects of aging by utilizing a mimetic aging rat and senescent cellular model. Our results indicate that NaHS decreased oxidative stress and apoptosis levels in an aging model via CaMKKß and PI3K/AKT signaling pathways. Moreover, we found that NaHS restored the decreased activity of antioxidants such as GSH, SOD and CAT in the aging model in vivo and in vitro by regulating CaMKKß and PI3K/AKT. Mitochondria function was preserved by NaHS, as indicated by the following: DNA POLG and OGG-1, the base excision repair enzymes in mitochondrial, were upregulated; OXPHOS activity was downregulated; mitochondrial membrane potential was restored; ATP production was increased; and mtDNA damage, indicated by the common deletion (CD), declined. These effects were also achieved by activating CaMKKß/AMPK and PI3K/AKT signaling pathways. Lastly, protein homeostasis, indicated by HSP90 alpha, was strengthened by NaHS via CaMKKß and PI3K/AKT. Our findings demonstrate that the ability to resist oxidative stress and mitochondria function are both decreased as aging developed; however, NaHS, a novel free radical scavenger and mitochondrial protective agent, precludes the process of oxidative damage by activating CaMKKß and PI3K/AKT. This study might provide a therapeutic target for aging and age-related disease.

MiR-608 rs4919510 is associated with prognosis of hepatocellular carcinoma.

Single nucleotide polymorphisms (SNPs) within microRNAs (miRNAs) are considered potential markers for risk and prognosis of various cancers. In the current study, we aimed to determine whether miR-608 rs4919510 affected hepatocellular carcinoma (HCC) prognosis. We genotyped rs4919510 using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. Associations between rs4919510 and overall survival (OS) and demographic characteristics and clinical features were estimated using the Cox proportional hazards model. Results showed that HCC patients who carried the rs4919510 CC genotype had a significantly longer OS compared to those who carried the GG genotype (P = 0.013, hazard ratio [HR] = 0.600, 95 % confidence interval [CI] 0.402-0.897) and the CG + GG genotype (P = 0.033, HR = 0.681, 95 % CI 0.479-0.970) in univariate analysis. Similar results were obtained in multivariate analysis. Further stratification analysis indicated that rs4919510 was significantly associated with OS in patients who were satisfied with one of the following criteria: male gender, HbsAg-positive, α-fetoprotein (AFP)-positive, tumor size >5 cm, cirrhosis, solitary tumor, I + II pTNM stage, or no tumor capsule. Finally, a significantly higher frequency of rs4919510 CC genotype was observed in patients with cirrhosis (22.9 %, 55/240) than those without cirrhosis (14.0 %, 17/121) (P = 0.047). In conclusion, our results illustrated the potential role of miR-608 rs4919510 as a prognostic marker for HCC patients undergoing surgical resection of the tumor.

miR-492G>C polymorphism (rs2289030) is associated with overall survival of hepatocellular carcinoma patients.

Single-nucleotide polymorphisms (SNPs) of microRNAs (miRNAs) are considered potential markers of cancer risk and prognosis in various cancers. In the current study, the primary aim is to determine whether the miR-492G>C polymorphism (rs2289030) altered hepatocellular carcinoma (HCC) prognosis. The SNP rs2289030 of miR-492 was genotyped using DNA from blood samples of 362 HCC patients that had undergone surgical resection of a HCC tumor. The associations between overall survival and demographic characteristics, clinical features, and the SNP rs2289030 were estimated using the Cox proportional hazards model. Results showed that patients who carried the CG genotype (P = 0.015, hazard ratio [HR] = 0.704, 95 % confidence interval [CI] 0.530-0.934) and CG+GG genotype (P = 0.011, HR = 0.703, 95 % CI 0.536-0.924) had significantly decreased risk of death compared to those with the CC genotype. Similar results were found in the multivariate analysis adjusted by tumor size and venous invasion. Further stratification analysis indicated that the effect of rs2289030 had more prominence in patients ≤50 years old and that reported ever using alcohol, male gender, a family history of HCC, being HbsAg or alpha fetoprotein (AFP) positive, differentiation I + II, presence of venous invasion or cirrhosis, multiple tumors, and pTNM stage I + II. Results from this study illustrate the potential use of miR-492 rs2289030 as a prognostic marker for HCC patients that have undergone a surgical resection of the tumor.