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1.
Int J Mol Med ; 45(3): 715-730, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922237

RESUMO

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.

2.
Int J Mol Med ; 41(4): 2086-2098, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29344647

RESUMO

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.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento , Córtex Auditivo/fisiologia , Autofagia , Transdução de Sinais , Animais , Apoptose , Córtex Auditivo/citologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Masculino , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo
3.
Sci Rep ; 7(1): 13248, 2017 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-29038536

RESUMO

Studies have reported attenuation of insulin resistance (IR) by improving phosphorylation of the insulin signalling pathway. However, the upstream molecular signalling pathway is still elusive. In this study, Western blot was used to evaluate the phosphorylation level of the insulin signalling pathway and the AMPK pathway. 2-NBDG was used to evaluate glucose uptake. Ca2+ imaging was used to assess change of intracellular Ca2+ concentration. We found that NaHS enhanced the intracellular Ca2+ concentration and glucose uptake and activated the insulin signalling cascade in a palmitic acid (PA)-induced IR model in C2C12 cells. Furthermore, activation of the IRS1/PI3K/AKT pathway and glucose uptake were decreased when AMPK or CaMKKß was inhibited. Our study also showed that the mitochondrial electron transport chain, ATP production, and intramitochondrial cAMP declined in the IR model but that this effect was reversed by NaHS, an effect that may be mediated by the Ca2+/CaMKK2/AMPK and PI3K/AKT pathways. Our data indicate that H2S improves activation of the insulin signalling cascade and glucose uptake via activation of the Ca2+/CaMKK2/AMPK pathway and mitochondrial metabolism in C2C12 cells. Furthermore, NaHS protects mitochondrial function and maintains normal ATP production by activating the cAMP system and the Ca2+/CaMKK2/AMPK and PI3K/ATK pathways.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Sulfeto de Hidrogênio/farmacologia , Animais , Linhagem Celular , Resistência à Insulina , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácido Palmítico/farmacologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos
4.
Redox Biol ; 12: 987-1003, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28499253

RESUMO

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.


Assuntos
Envelhecimento/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Presbiacusia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sulfetos/administração & dosagem , Adenilato Quinase/metabolismo , Envelhecimento/metabolismo , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Galactose/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Animais , Fosfatidilinositol 3-Quinases/metabolismo , Presbiacusia/induzido quimicamente , Presbiacusia/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Sulfetos/farmacologia
5.
Tumour Biol ; 37(7): 9931-42, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26815502

RESUMO

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.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Seguimentos , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
6.
Tumour Biol ; 37(7): 8961-72, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26753964

RESUMO

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.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Predisposição Genética para Doença/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Feminino , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto Jovem
7.
FEBS J ; 282(14): 2758-74, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25996168

RESUMO

Age-associated degeneration in the central auditory system, which is defined as central presbycusis, can impair sound localization and speech perception. Research has shown that oxidative stress plays a central role in the pathological process of central presbycusis. Thioredoxin 2 (Trx2), one member of thioredoxin family, plays a key role in regulating the homeostasis of cellular reactive oxygen species and anti-apoptosis. The purpose of this study was to explore the association between Trx2 and the phenotype of central presbycusis using a mimetic aging animal model induced by long-term exposure to d-galactose (d-Gal). We also explored changes in thioredoxin-interacting protein (TXNIP), apoptosis signal regulating kinase 1 (ASK1) and phosphorylated ASK1 (p-ASK1) expression, as well as the Trx2-TXNIP/Trx2-ASK1 binding complex in the auditory cortex of mimetic aging rats. Our results demonstrate that, compared with control groups, the levels of Trx2 and Trx2-ASK1 binding complex were significantly reduced, whereas TXNIP, ASK1 p-ASK1 expression, and Trx2-TXNIP binding complex were significantly increased in the auditory cortex of the mimetic aging groups. Our results indicated that changes in Trx2 and the TXNIP-Trx2-ASK1 signal pathway may participate in the pathogenesis of central presbycusis.


Assuntos
Córtex Auditivo/metabolismo , Proteínas de Transporte/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Tiorredoxinas/metabolismo , Envelhecimento , Animais , Antioxidantes/metabolismo , Apoptose/genética , Córtex Auditivo/citologia , Córtex Auditivo/fisiologia , Córtex Auditivo/ultraestrutura , Proteínas de Transporte/genética , Proteínas de Ciclo Celular , Regulação da Expressão Gênica , MAP Quinase Quinase Quinase 5/genética , Malondialdeído/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Tiorredoxinas/genética
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