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1.
BMC Bioinformatics ; 20(1): 599, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747877

RESUMO

BACKGROUND: Cellular aging is best studied in the budding yeast Saccharomyces cerevisiae. As an example of a pleiotropic trait, yeast lifespan is influenced by hundreds of interconnected genes. However, no quantitative methods are currently available to infer system-level changes in gene networks during cellular aging. RESULTS: We propose a parsimonious mathematical model of cellular aging based on stochastic gene interaction networks. This network model is made of only non-aging components: the strength of gene interactions declines with a constant mortality rate. Death of a cell occurs in the model when an essential node loses all of its interactions with other nodes, and is equivalent to the deletion of an essential gene. Stochasticity of gene interactions is modeled using a binomial distribution. We show that the exponential increase of mortality rate over time can emerge from this gene network model during the early stages of aging.We developed a maximal likelihood approach to estimate three lifespan-influencing network parameters from experimental lifespans: t0, the initial virtual age of the network system; n, the average lifespan-influencing interactions per essential node; and R, the initial mortality rate. We applied this model to yeast mutants with known effects on replicative lifespans. We found that deletion of SIR2, FOB1, and HXK2 considerably altered the initial virtual age but not the average lifespan-influencing interactions per essential node, suggesting that these mutations mainly influence the reliability of gene interactions but not the overall configurations of gene networks.We applied this model to investigate replicative lifespans of yeast natural isolates. We estimated that the average number of lifespan-influencing interactions per essential node is 7.0 (6.1-8) and the average estimated initial virtual age is 45.4 (30.6-74) cell divisions in these isolates. We also found that t0 could potentially mediate the observed Strehler-Mildvan correlation in yeast natural isolates. CONCLUSIONS: Our theoretical model provides a parsimonious interpretation of experimental lifespan data from the perspective of gene networks. We hope that our work will stimulate more interest in developing network models to study aging as a pleiotropic trait.


Assuntos
Senescência Celular/genética , Redes Reguladoras de Genes , Modelos Genéticos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Funções Verossimilhança , Mutação/genética , Fenótipo , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/isolamento & purificação , Proteínas de Saccharomyces cerevisiae/metabolismo , Processos Estocásticos
2.
Adv Exp Med Biol ; 1192: 521-544, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31705512

RESUMO

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder, and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis, or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time, this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.


Assuntos
Senescência Celular/genética , Leucócitos/metabolismo , Transtornos Mentais/genética , Telomerase , Telômero/metabolismo , Idoso , Humanos , Transtornos Mentais/diagnóstico , Homeostase do Telômero , Encurtamento do Telômero
3.
Cancer Immunol Immunother ; 68(12): 2041-2054, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31720814

RESUMO

Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is usually considered an inflammation-related cancer associated with chronic inflammation triggered by exposure to HBV and tumor antigens. T-cell exhaustion is implicated in immunosuppression of chronic infections and tumors. Although immunotherapies that enhance immune responses by targeting programmed cell death-1(PD-1)/PD-L1 are being applied to malignancies, these treatments have shown limited response rates, suggesting that additional inhibitory receptors are also involved in T-cell exhaustion and tumor outcome. Here, we analyzed peripheral blood samples and found that coexpression of PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) was significantly upregulated on CD4+ and CD8+ T cells from patients with HBV-HCC compared with those from patients with chronic HBV or HBV-liver cirrhosis. Additionally, PD-1+ TIGIT+ CD8+ T-cell populations were elevated in patients with advanced stage and progressed HBV-HCC. Importantly, PD-1+ TIGIT+ CD8+ T-cell populations were negatively correlated with overall survival rate and progression-free survival rates. Moreover, we showed that PD-1+ TIGIT+ CD8+ T cells exhibit features of exhausted T cells, as manifested by excessive activation, high expression of other inhibitory receptors, high susceptibility to apoptosis, decreased capacity for cytokine secretion, and patterns of transcription factor expression consistent with exhaustion. In conclusion, PD-1+ TIGIT+ CD8+ T-cell populations are associated with accelerated disease progression and poor outcomes in HBV-HCC, which might not only have important clinical implications for prognosis but also provide a rationale for new targets in immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B/imunologia , Neoplasias Hepáticas/imunologia , Adulto , Carcinogênese , Carcinoma Hepatocelular/mortalidade , Senescência Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B/mortalidade , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Receptores Imunológicos/metabolismo , Análise de Sobrevida
4.
Nat Commun ; 10(1): 3589, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399573

RESUMO

Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 - RELB - C/EBPß axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPß. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.


Assuntos
Neoplasias da Mama/patologia , Fator de Transcrição RelB/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Mama/citologia , Mama/patologia , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Senescência Celular/genética , Células Epiteliais , Feminino , Técnicas de Silenciamento de Genes , Humanos , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Cultura Primária de Células , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Ativadas por p21/genética
5.
Clin Interv Aging ; 14: 1277-1283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371933

RESUMO

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly. Considering the relatively limited effect of therapy on early AMD, it is important to focus on the pathogenesis of AMD, especially early AMD. Ageing is one of the strongest risk factors for AMD, and analysis of the impact of ageing on AMD development is valuable. Among all the ageing hallmarks, increased DNA damage accumulation is regarded as the beginning of cellular senescence and is related to abnormal expression of inflammatory cytokines, which is called the senescence-associated secretory phenotype (SASP). The exact pathway for DNA damage that triggers senescence-associated hallmarks is poorly understood. Recently, mounting evidence has shown that the cGAS/STING pathway is an important DNA sensor related to proinflammatory factor secretion and is associated with another hallmark of ageing, SASP. Thus, we hypothesized that the cGAS/STING pathway is a vital signalling pathway for early AMD development and that inhibition of STING might be a potential therapeutic strategy for AMD cases.


Assuntos
Dano ao DNA/fisiologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Degeneração Macular/metabolismo , Degeneração Macular/fisiopatologia , Idoso , Senescência Celular/genética , Humanos , Degeneração Macular/patologia , Nucleotidiltransferases/metabolismo , Transdução de Sinais
6.
Ecotoxicol Environ Saf ; 183: 109465, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31376806

RESUMO

Our group found that long-term low-dose exposure to hexavalent chromium [Cr(VI)] in L-02 hepatocytes resulted in premature senescence, which accompanied by the increased expression of Clusterin (CLU), but the functional role of CLU in premature senescence has never been explored. In the present study, the CLU overexpressed or silenced L-02 hepatocytes were established by lentiviral vector transfection. Cell viability assay, cell cycle analysis, western blotting, plate clone formation assay, and confocal microcopy were performed. The results indicated that Cr(VI)-induced premature senescence was associated with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway inhibition, and high expression of CLU in the senescent cells exerted its functional role of promoting cell proliferation. CLU could complex with eukaryotic translation initiation factor 3 subunit I (EIF3I) and prevent its degradation, leading to the increase of AKT activity in Cr(VI)-exposed senescent hepatocytes. Blockage of the PI3K/AKT pathway with its inhibitor LY294002 eliminated the inhibitory effect of CLU on Cr(VI)-induced premature senescence. We concluded that high expression of CLU suppressed Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway, which will provide the experimental basis for the study of Cr(VI)-induced liver cancer, especially for the elucidation of the mechanism of liver cancer cells escaping from senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Cromo/toxicidade , Clusterina/genética , Hepatócitos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Senescência Celular/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
7.
Int J Mol Sci ; 20(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31330953

RESUMO

A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aß42) is the protein that is most associated with Alzheimer's disease, this study has focused on how simvastatin influences the turnover of native Aß42 and Aß42 fused with green fluorescent protein (GFP), in the simplest eukaryotic model organism, Saccharomyces cerevisiae. Previous studies have established that yeast constitutively producing Aß42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aß42. Young cells clear the GFP fusion protein and do not have green fluorescence while the older population of cells retains the fusion protein and exhibits green fluorescence, offering a fast and convenient means of studying factors that affect Aß42 turnover. In this study the proportion of cells having GFP fused to Aß after exposure to simvastatin, atorvastatin and lovastatin was analyzed by flow cytometry. Simvastatin effectively reduced levels of the cellular Aß42 protein in a dose-dependent manner. Simvastatin promoted the greatest reduction as compared to the other two statins. A comparison with fluconazole, which targets that same pathway of ergosterol synthesis, suggests that effects on ergosterol synthesis do not account for the reduced amounts of Aß42 fused to GFP. The levels of native Aß42 following treated with simvastatin were also examined using a more laborious approach, quantitative MALDI TOF mass spectrometry. Simvastatin efficiently reduced levels of native Aß42 from the population. This work indicates a novel action of simvastatin in reducing levels of Aß42 providing new insights into how simvastatin exerts its neuroprotective role. We hypothesize that this reduction may be due to protein clearance.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Leveduras/efeitos dos fármacos , Leveduras/metabolismo , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Senescência Celular/genética , Ergosterol/biossíntese , Expressão Gênica , Ordem dos Genes , Genes Reporter , Humanos , Plasmídeos/genética , Proteólise , Proteínas Recombinantes de Fusão , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Leveduras/genética
8.
Ecotoxicol Environ Saf ; 182: 109384, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31272023

RESUMO

Exposure to polycyclic aromatic hydrocarbons (PAHs) and phthalates link to oxidative stress and inflammatory response, which exert cellular aging. However, modification effect of seasonal factor on the association of PAHs or phthalates exposure with relative telomere length (RTL) or mitochondrial DNA copy number (mtDNA-CN) has remained unclear. In this pilot study, 106 subjects were from an urban population (n = 1240) who lived in the two districts in Wuhan city, China. Participants completed physical examinations and provided 191 blood samples for RTL and mtDNA-CN analysis and 627 urine samples for monohydroxylated-PAHs (OH-PAHs) and phthalate metabolites measurements in the winter and summer seasons. We assessed the associations of urinary OH-PAHs or phthalates metabolites with RTL or mtDNA-CN by linear regression analysis and linear mixed-effect models. We found that urinary OH-PAHs were positively associated with mtDNA-CN at lag 2 day and 3-day moving average, but negatively related to RTL at lag 0, lag 1 and lag 2 day and 3-day moving average (p < 0.05). Urinary phthalate metabolites were negatively associated with mtDNA lag 0, lag 1 and lag 2 day and 3-day moving average, but positively related to RTL at lag 0 day (p < 0.05). Seasonal factor modified the association of urinary OH-PAHs with mtDNA-CN as well as urinary phthalate metabolites with RTL. In vitro experiment showed that under certain conditions, benzo[a]pyrene increased mtDNA-CN at 48 h and di (2-ethylhexyl) phthalate did RTL at 24 h in HepG2 cells. Seasonal variations in the metabolisms of PAHs or phthalates in human body may affect the relation of PAHs or phthalates exposure with cellular aging.


Assuntos
Senescência Celular/efeitos dos fármacos , Variações do Número de Cópias de DNA/efeitos dos fármacos , DNA Mitocondrial/sangue , Ácidos Ftálicos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Telômero/efeitos dos fármacos , Adulto , Senescência Celular/genética , China , Células Hep G2 , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ácidos Ftálicos/urina , Projetos Piloto , Hidrocarbonetos Policíclicos Aromáticos/urina , Estações do Ano , Adulto Jovem
9.
Nucleic Acids Res ; 47(16): 8548-8562, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31276581

RESUMO

Cockayne syndrome is an accelerated aging disorder, caused by mutations in the CSA or CSB genes. In CSB-deficient cells, poly (ADP ribose) polymerase (PARP) is persistently activated by unrepaired DNA damage and consumes and depletes cellular nicotinamide adenine dinucleotide, which leads to mitochondrial dysfunction. Here, the distribution of poly (ADP ribose) (PAR) was determined in CSB-deficient cells using ADPr-ChAP (ADP ribose-chromatin affinity purification), and the results show striking enrichment of PAR at transcription start sites, depletion of heterochromatin and downregulation of H3K9me3-specific methyltransferases SUV39H1 and SETDB1. Induced-expression of SETDB1 in CSB-deficient cells downregulated PAR and normalized mitochondrial function. The results suggest that defects in CSB are strongly associated with loss of heterochromatin, downregulation of SETDB1, increased PAR in highly-transcribed regions, and mitochondrial dysfunction.


Assuntos
Senescência Celular/genética , Síndrome de Cockayne/genética , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Histonas/genética , Mitocôndrias/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Metiltransferases de Proteína/genética , Fatores de Transcrição/genética , Linhagem Celular Transformada , Cromatina/química , Cromatina/metabolismo , Síndrome de Cockayne/metabolismo , Síndrome de Cockayne/patologia , DNA/genética , DNA/metabolismo , Dano ao DNA , DNA Helicases/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Metiltransferases/genética , Metiltransferases/metabolismo , Mitocôndrias/patologia , Mutação , NAD/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Metiltransferases de Proteína/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição , Transcrição Genética
10.
Int Heart J ; 60(4): 944-957, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257341

RESUMO

Cardiac fibrosis plays an important role in cardiac remodeling after myocardial infarction (MI). The molecular mechanisms that promote cardiac fibrosis after MI are well studied; however, the mechanisms by which the progression of cardiac fibrosis becomes attenuated after MI remain poorly understood. Recent reports show the role of cellular senescence in limiting tissue fibrosis. In the present study, we tested whether cellular senescence of cardiac fibroblasts (CFs) plays a role in attenuating the progression of cardiac fibrosis after MI. We found that the number of γH2AX-positive CFs increased up to day 7, whereas the number of proliferating CFs peaked at day 4 after MI. Senescent CFs were also observed at day 7, suggesting that attenuation of CF proliferation occurred simultaneously with the activation of the DNA damage response (DDR) system and the appearance of senescent CFs. We next cultured senescent CFs with non-senescent CFs and showed that senescent CFs suppressed proliferation of the surrounding non-senescent CFs in a juxtacrine manner. We also found that the blockade of DDR by Atm gene deletion sustained the proliferation of CFs and exacerbated the cardiac fibrosis at the early stage after MI. Our results indicate the role of DDR activation and cellular senescence in limiting cardiac fibrosis after MI. Regulation of cellular senescence in CFs may become one of the therapeutic strategies for preventing cardiac remodeling after MI.


Assuntos
Senescência Celular/genética , Dano ao DNA/genética , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Remodelação Ventricular/genética , Animais , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Citometria de Fluxo , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/patologia
11.
Sci Total Environ ; 689: 1201-1211, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31358486

RESUMO

Senescence is an irreversible process that is a characteristic of age-associated disease like Type 2 diabetes (T2D). Bisphenol-A (BPA), one of the most common endocrine disruptor chemicals, received special attention in the development of insulin resistance and T2D. To understand the role played by BPA in cellular senescence under metabolic stress, zebrafish embryos were exposed to BPA in the absence and presence of hyperglycaemia. Transcriptional levels of the senescence markers p15, p53, Rb1 and ß-galactosidase were increased when BPA was combined with metabolic stress. In addition, zebrafish embryos that were exposed to combination of hyperglycaemia and BPA exhibited increased levels of apoptosis. However, cellular senescence remained induced by a combination of hyperglycaemia and BPA exposure even in the absence of a translated p53 protein suggesting that senescence is primarily independent of it but dependent on the p15-Rb1 pathway under our experimental conditions. To confirm that our results hold true in adult mammalian tissues, we validated our embryonic experiments in an adult mammalian metabolic model of skeletal muscle cells. Our work reveals a novel and unique converging role of senescence and apoptosis axis contributing to glucose dyshomeostasis. Thus, we conclude that BPA exposure can exacerbate existing metabolic stress to increase cellular senescence that leads to aggravation of disease phenotype in age-associated diseases like type 2 diabetes.


Assuntos
Compostos Benzidrílicos/toxicidade , Senescência Celular/genética , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Proteína Supressora de Tumor p53/genética , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Animais , Embrião não Mamífero/fisiologia , Estresse Fisiológico , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
12.
J Ovarian Res ; 12(1): 53, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176373

RESUMO

OBJECT: To explore the mechanisms of ovarian aging, we performed overall analysis on the age-related alterations of gene expression profiles in mouse germinal vesicle (GV) stage oocytes by means of single-cell RNA-sequencing method (scRNA-seq). METHODS: Two age groups (5-week-old and 32-week-old) female KM mice were used as young and old models. Subsequently, GV oocytes were collected for scRNA-seq. The bioinformatics was performed to analyze and compare the differences of gene expression profile between GV oocytes of young and old mice. RESULTS: The analysis of scRNA-seq data showed that there were 624 differential expressed genes (DEGs) between two age groups of mouse GV stage oocytes. Four hundred forty-nine DEGs were up-regulated while 175 DEGs were down-regulated in the GV oocytes of the old group. KEGG pathway analysis revealed that the genes involved in mitochondrial function including oxidative phosphorylation and ATP production pathway were significantly down-regulated in GV oocytes of 32-week-old mice, especially the mitochondrial encoded NADH dehydrogenase (mt-Nd), including mt-Nd2, mt-Nd3, mt-Nd4, mt-Nd4L and mt-Nd5. Analysis of DEGs revealed that endoplasmic reticulum stress-related genes including AdipoR2, IRAK-1, RCAN1 and MsrB1 were significantly down-regulated in GV oocytes of 32-week-old mice. Also, analysis of DEGs demonstrated that anti-oxidation-related genes including Erbb3、Rcan1、Gsto2 and Msrb1 were significantly down-regulated in GV oocytes of old group. CONCLUSION: The disorder of mitochondrial function, endoplasmic reticulum stress and the reduced antioxidant capability might be involved in the progression of oocyte aging. Especially, the down regulation of mitochondrial encoded subunits of respiratory chain complexes might play critical roles in the relevant mechanisms.


Assuntos
Senescência Celular/genética , Estresse do Retículo Endoplasmático/genética , Mitocôndrias/genética , Oócitos/metabolismo , Envelhecimento , Animais , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Oócitos/citologia , Oócitos/crescimento & desenvolvimento , Estresse Oxidativo/genética , Análise de Célula Única
13.
Nucleic Acids Res ; 47(15): 8239-8254, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31216022

RESUMO

XAB2 is a multi-functional protein participating processes including transcription, splicing, DNA repair and mRNA export. Here, we report POLR2A, the largest catalytic subunit of RNA polymerase II, as a major target gene down-regulated after XAB2 depletion. XAB2 depletion led to severe splicing defects of POLR2A with significant intron retention. Such defects resulted in substantial loss of POLR2A at RNA and protein levels, which further impaired global transcription. Treatment of splicing inhibitor madrasin induced similar reduction of POLR2A. Screen using TMT-based quantitative proteomics identified several proteins involved in mRNA surveillance including Dom34 with elevated expression. Inhibition of translation or depletion of Dom34 rescued the expression of POLR2A by stabilizing its mRNA. Immuno-precipitation further confirmed that XAB2 associated with spliceosome components important to POLR2A expression. Domain mapping revealed that TPR motifs 2-4 and 11 of XAB2 were critical for POLR2A expression by interacting with SNW1. Finally, we showed POLR2A mediated cell senescence caused by XAB2 deficiency. Depletion of XAB2 or POLR2A induced cell senescence by up-regulation of p53 and p21, re-expression of POLR2A after XAB2 depletion alleviated cellular senescence. These data together support that XAB2 serves as a guardian of POLR2A expression to ensure global gene expression and antagonize cell senescence.


Assuntos
Senescência Celular/genética , RNA Polimerases Dirigidas por DNA/genética , Íntrons/genética , Fatores de Transcrição/genética , Transcrição Genética , Linhagem Celular , Linhagem Celular Tumoral , RNA Polimerases Dirigidas por DNA/metabolismo , Células HEK293 , Células HeLa , Humanos , Interferência de RNA , Processamento de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
14.
Psychopharmacology (Berl) ; 236(11): 3245-3255, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31161452

RESUMO

RATIONALE: Human telomeres consist of tandem repeats at chromosome ends which protect chromosomal DNA from degradation. Telomere shortening occurs as part of natural aging; however, life stressors, smoking, drug use, BMI, and psychiatric disorders could disrupt cell aging and affect telomere length (TL). In this context, studies have evaluated the effects of alcohol consumption on TL; however, results have been inconsistent, which may reflect diverse drinking cut-offs and categorizations. OBJECTIVES: To help clarify this, the present study addresses the association of TL with alcohol use disorder (AUD), drinking behaviors, lifetime stress, and chronological age. METHODS: TL was quantified as the telomere to albumin ratio (T/S ratio) obtained from peripheral blood DNA using the quantitative PCR assay, from 260 participants with AUD and 449 non-dependent healthy controls (HC) from an existing National Institute on Alcohol Abuse and Alcoholism (NIAAA) database. RESULTS: AUD participants showed shorter TL compared to HC with both, age, and AUD, as independent predictors as well as a significant AUD with age interaction effect on TL. TL was also associated with impulsiveness in AUD participants. We did not observe an association between TL and chronicity of alcohol use, alcohol doses ingested, or childhood trauma exposures in either AUD or HC, although very few HC reported a history of childhood trauma. CONCLUSION: Our results support previous findings of telomere shortening with chronic alcohol exposures and show both an effect of AUD on TL that is independent of age as well as a significant AUD by age interaction on TL. These findings are consistent with accelerated cellular aging in AUD.


Assuntos
Envelhecimento/genética , Alcoolismo/genética , Senescência Celular/genética , Encurtamento do Telômero/genética , Adulto , Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Envelhecimento/patologia , Envelhecimento/psicologia , Alcoolismo/diagnóstico , Alcoolismo/psicologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Telômero/genética , Telômero/patologia
15.
J Exp Clin Cancer Res ; 38(1): 244, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174563

RESUMO

BACKGROUND: Gallbladder cancer (GBC) is the most malignant cancer occurring in the biliary tract cancer featured with undesirable prognosis, in which most patients die within a year of cholecystectomy. Long noncoding RNAs (lncRNAs) function as critical regulators of multiple stages of cancers. Herein, the mechanism of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in GBC is investigated. METHODS: Microarray-based analysis initially provided data suggesting that the expression of MALAT1 was up-regulated while that of the ABI family member 3 binding protein (ABI3BP) was down-regulated in GBC tissues and cell lines. Kaplan-Meier method was then adopted to analyze the relationship between the MALAT1 expression and overall survival and disease-free survival of patients with GBC. A set of in vitro and in vivo experiments were conducted by transducing ABI3BP-vector or sh-MALAT1 into GBC cells. RESULTS: The results confirmed that the cancer prevention effects triggered by restored ABI3BP and depleted MALAT1 as evidenced by suppressed cell growth and enhanced cell senescence. MALAT1 was observed to down-regulate ABI3BP expression through recruitment of the enhancer of zeste homolog 2 (EZH2) to the ABI3BP promoter region while the silencing of MALAT1 or suppression of H3K27 methylation was observed to promote the expression of ABI3BP. Furthermore, GBC patients with high expression of MALAT1 indicated poor prognosis. CONCLUSION: The current study clarifies that MALAT1 silencing and ABI3BP elevation impede the GBC development through the H3K27 methylation suppression induced by EZH2, highlighting a promising competitive paradigm for therapeutic approaches of GBC.


Assuntos
Proteínas de Transporte/genética , Senescência Celular/genética , Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Interferência de RNA , RNA Longo não Codificante/genética , Adulto , Animais , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Feminino , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Xenoenxertos , Histonas/metabolismo , Humanos , Masculino , Metilação , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Prognóstico , Adulto Jovem
16.
Radiat Res ; 192(2): 200-207, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31237817

RESUMO

p53BP1 forms discrete foci within minutes of radiation exposure, at sites of DNA double-strand breaks, which ordinarily decay to background levels within 24 h of induction. Longer lived, persisting 53BP1 foci are thought to mark unrepaired or misrepaired damage and potentially, to be associated with genomic instability. It is known that repair of DNA damage is impaired in senescent (permanently arrested) and aged cells. We examined this further by measuring the induction and persistence of 53BP1 foci in proliferating and non-proliferating mid-passage (non-aged) and late-passage (in vitro aged) normal human bronchial epithelial cells. Our results showed background levels of 53BP1 foci to be elevated in in vitro aged cultures as expected and induction of 53BP1 foci after radiation exposure to be independent of culture age or proliferative status. In terms of 53BP1 decay, more cells with persisting foci were seen in in vitro aged cultures compared to non-aged populations; furthermore, this was observed in both non-cycling (nominally senescent) cells, as well as in actively proliferating cells. In conclusion, perturbation in radiation-induced damage processing is a function of increasing chronological cellular age per se and should be considered when extrapolating experimental data for radiation risk modeling.


Assuntos
Senescência Celular/genética , Senescência Celular/efeitos da radiação , Dano ao DNA , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Humanos , Antígeno Ki-67/metabolismo , beta-Galactosidase/metabolismo
17.
Int J Mol Sci ; 20(12)2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31238513

RESUMO

Cardiovascular diseases (CVDs) are the most serious health problem in the world, displaying high rates of morbidity and mortality. One of the main risk factors for CVDs is age. Indeed, several mechanisms are at play during aging, determining the functional decline of the cardiovascular system. Aging cells and tissues are characterized by diminished autophagy, causing the accumulation of damaged proteins and mitochondria, as well as by increased levels of oxidative stress, apoptosis, senescence and inflammation. These processes can induce a rapid deterioration of cellular quality-control systems. However, the molecular mechanisms of age-associated CVDs are only partially known, hampering the development of novel therapeutic strategies. Evidence has emerged indicating that noncoding RNAs (ncRNAs), such as long ncRNAs (lncRNAs) and micro RNAs (miRNAs), are implicated in most patho-physiological mechanisms. Specifically, lncRNAs can bind miRNAs and act as competing endogenous-RNAs (ceRNAs), therefore modulating the levels of the mRNAs targeted by the sponged miRNA. These complex lncRNA/miRNA/mRNA networks, by regulating autophagy, apoptosis, necrosis, senescence and inflammation, play a crucial role in the development of age-dependent CVDs. In this review, the emerging knowledge on lncRNA/miRNA/mRNA networks will be summarized and the way in which they influence age-related CVDs development will be discussed.


Assuntos
Envelhecimento/genética , Doenças Cardiovasculares/etiologia , Redes Reguladoras de Genes , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Doenças Cardiovasculares/diagnóstico , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Senescência Celular/genética , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos
18.
Nat Commun ; 10(1): 2568, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189923

RESUMO

Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. Here, we report that the zinc-finger transcription factor Slug is highly expressed in quiescent SCs of mice and functions as a direct transcriptional repressor of p16Ink4a. Loss of Slug promotes derepression of p16Ink4a in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16Ink4a depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16Ink4a accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16Ink4a transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at advanced age. As p16Ink4a dysregulation is the chief cause for regenerative defects of human geriatric SCs, these findings highlight Slug as a potential therapeutic target for aging-associated degenerative muscle disease.


Assuntos
Autorrenovação Celular/genética , Senescência Celular/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Células Satélites de Músculo Esquelético/fisiologia , Fatores de Transcrição da Família Snail/metabolismo , Envelhecimento/fisiologia , Animais , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Fatores de Transcrição da Família Snail/genética
19.
Nucleic Acids Res ; 47(14): 7294-7305, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31251810

RESUMO

Cellular senescence, an integral component of aging and cancer, arises in response to diverse triggers, including telomere attrition, macromolecular damage and signaling from activated oncogenes. At present, senescent cells are identified by the combined presence of multiple traits, such as senescence-associated protein expression and secretion, DNA damage and ß-galactosidase activity; unfortunately, these traits are neither exclusively nor universally present in senescent cells. To identify robust shared markers of senescence, we have performed RNA-sequencing analysis across eight diverse models of senescence triggered in human diploid fibroblasts (WI-38, IMR-90) and endothelial cells (HUVEC, HAEC) by replicative exhaustion, exposure to ionizing radiation or doxorubicin, and expression of the oncogene HRASG12V. The intersection of the altered transcriptomes revealed 50 RNAs consistently elevated and 18 RNAs consistently reduced across all senescence models, including many protein-coding mRNAs and some non-coding RNAs. We propose that these shared transcriptome profiles will enable the identification of senescent cells in vivo, the investigation of their roles in aging and malignancy and the development of strategies to target senescent cells therapeutically.


Assuntos
Senescência Celular/genética , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Transcriptoma , Envelhecimento/genética , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular , Células Cultivadas , Doxorrubicina/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/efeitos da radiação , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Humanos , Neoplasias/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Radiação Ionizante , Análise de Sequência de RNA/métodos
20.
Nat Rev Cancer ; 19(8): 439-453, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235879

RESUMO

Cellular senescence plays a critical role in tumorigenesis. Once thought of as a tissue culture artefact by some researchers, senescence is now a major field of study. Although there are common molecular mechanisms that enforce the growth arrest that characterizes the phenotype, the impact of senescence is varied and can, in some instances, have opposite effects on tumorigenesis. It has become clearer that the cell of origin and the tissue in question dictate the impact of senescence on tumorigenesis. In this Review, we unravel this complexity by focusing on how senescence impacts tumorigenesis when it arises within incipient tumour cells versus stromal cells, and how these roles can change in different stages of disease progression. In addition, we highlight the diversity of the senescent phenotype and its functional output beyond growth arrest: the senescence-associated secretory phenotype (SASP). Fortunately, a number of new genetic and pharmacologic tools have been developed that are now allowing the senescence phenotype to be parsed further.


Assuntos
Transformação Celular Neoplásica , Senescência Celular/genética , Neoplasias/patologia , Antineoplásicos/farmacologia , Apoptose , Dano ao DNA , Progressão da Doença , Fibroblastos/metabolismo , Humanos , Sistema Imunitário , Neoplasias/genética , Fenótipo , Regiões Promotoras Genéticas
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