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1.
Toxicol Appl Pharmacol ; 401: 115079, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32497534

RESUMO

Thioredoxin 1 (Trx1) and telomerase play key roles in the development and progression process of most tumors, and they both are promising drug therapy targets. We have, for the first time, discovered that Trx1 and telomerase had a dual-target synergistic effect. Based on that results, we designed a series of 6-dithio-2'-deoxyguanosine analogs (named as YLS00X) and verified whether they can inhibit Trx1 and telomerase simultaneously. TrxR1/Trx1 system activity and telomerase expression were significantly inhibited by 6-dithio-2'-deoxyguanosine analogs, especially YLS004. YLS004 can also cause ROS accumulation, and induce tumor cell apoptosis. The vitro antitumor activity of 6-dithio-2'-deoxyguanosine analogs using MTT assay on 11 different human cancer cells and found that human colon cancer cells(HCT116) and melanoma cells (A375) were the most sensitive cells to 6-dithio-2'-deoxyguanosine analogs treatment and vivo xenografts models also confirmed that. The serum biochemical parameters and multiple organs HE staining results of subacute experiments indicated that YLS004 might be mildly toxic to immune organs, including the thymus, spleen, and hematopoietic system. Besides, YLS004 was rapidly metabolized in the rats' blood. Our study revealed that YLS004, a Trx1 and telomerase inhibitor, has strong anti-tumor effects to colon cancer and melanoma cells and is a promising new candidate drug.


Assuntos
Desoxiguanosina/análogos & derivados , Desoxiguanosina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Espécies Reativas de Oxigênio/agonistas , Telomerase/antagonistas & inibidores , Tiorredoxinas/antagonistas & inibidores , Células A549 , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Espécies Reativas de Oxigênio/metabolismo , Telomerase/metabolismo , Tiorredoxinas/metabolismo
2.
Chemosphere ; 251: 126352, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32443248

RESUMO

Limited data are available on seasonal associations of polycyclic aromatic hydrocarbons (PAHs) exposure with oxidative DNA damage. We conducted a pilot study with 20 postgraduates, and measured urinary levels of mono-hydroxyl PAHs (OH-PAHs) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) for 7 consecutive days in the four seasons. We assessed the relationships of urinary OH-PAHs with urinary 8-OHdG in the whole year as well as cold- and warm-seasons. Summed OH-PAHs (∑OH-PAHs) were higher in cold season than in warm season. Each ln-unit (ln-transformed unit) increase in ∑OH-PAHs in the whole year corresponded to a 34%, 16% or 23% increase in urinary 8-OHdG levels at lag0, lag1 or lag2 day as well as a 26% increase in urinary 8-OHdG levels at lag0-2 days (cumulative effects). Each ln-unit increase in ∑OH-PAHs corresponded to a 36%, 26% or 46% increase in urinary 8-OHdG levels in cold season at lag0 day, lag1 day or lag2 day as well as a 36% increase in urinary 8-OHdG in warm season at lag0 day. Distributed non-linear cumulative lag models (DLNMs) indicated that each ln-unit increase in ∑OH-PAHs within the range of 5.7-8.1 nmol/mmol Cr had a stronger effect (coefficient ß: 1.11-2.97 nmol/mmol Cr) on urinary 8-OHdG rather than non-cumulative DLNMs (coefficient ß: 1.08-1.43 nmol/mmol Cr) as well as the non-linear dose-response relationships of ∑OH-PAHs with urinary 8-OHdG. PAHs exposure exhibited the lagged and cumulative effects on urinary 8-OHdG levels.


Assuntos
8-Hidroxi-2'-Desoxiguanosina/urina , Exposição Ambiental/estatística & dados numéricos , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Grupo com Ancestrais do Continente Asiático , Biomarcadores/urina , Dano ao DNA , Desoxiguanosina/análogos & derivados , Exposição Ambiental/análise , Feminino , Humanos , Masculino , Projetos Piloto , Hidrocarbonetos Policíclicos Aromáticos/análise , Estações do Ano , Estudantes
3.
Cancer Res ; 80(5): 929-936, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31948943

RESUMO

Cell membrane transporters facilitate the passage of nucleobases and nucleosides for nucleotide synthesis and metabolism, and are important for the delivery of nucleoside analogues used in anticancer drug therapy. Here, we investigated if cell membrane transporters are involved in the cellular uptake of the nucleoside analogue DNA damage mediator 6-thio-2'-deoxyguanosine (6-thio-dG). A large panel of non-small cell lung cancer (NSCLC) cell lines (73 of 77) were sensitive to 6-thio-dG; only four NSCLC lines were resistant to 6-thio-dG. When analyzed by microarray and RNA sequencing, the resistant NSCLC cell lines clustered together, providing a molecular signature for patients that may not respond to 6-thio-dG. Significant downregulation of solute carrier family 43 A3 (SLC43A3), an equilibrative nucleobase transporter, was identified as a candidate in this molecular resistance signature. High levels of SLC43A3 mRNA predicted sensitivity to 6-thio-dG and therefore SLC43A3 could serve as a promising biomarker for 6-thio-dG sensitivity in patients with NSCLC. SIGNIFICANCE: These findings identify a biomarker of resistance to the telomeric DNA damage mediator 6-thio-2'-deoxyguanosine.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Sistemas de Transporte de Aminoácidos/metabolismo , Biomarcadores Tumorais/metabolismo , Desoxiguanosina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Tionucleosídeos/farmacologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Sistemas de Transporte de Aminoácidos/genética , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/farmacologia , Desoxiguanosina/uso terapêutico , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , RNA Interferente Pequeno/metabolismo , Telômero/efeitos dos fármacos , Tionucleosídeos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Medicine (Baltimore) ; 98(39): e17373, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574886

RESUMO

Ionizing radiation can induce deoxyribonucleic acid (DNA) methylation pattern change, and ionizing radiation-induced oxidative damage may also affect DNA methylation status. However, the influence of low-dose ionizing radiation, such as occupational radiation exposure, on DNA methylation is still controversial.By investigating the relationship between occupational radiation exposure and DNA methylation changes, we evaluated whether radiation-induced oxidative damage was related to DNA methylation alterations and then determined the relationship among occupational radiation level, DNA methylation status, and oxidative damage in interventional physicians.The study population included 117 interventional physicians and 117 controls. We measured global methylation levels of peripheral blood leukocyte DNA and expression level of DNA methyltransferase (Dnmts) and homocysteine (Hcy) in serum to assess the DNA methylation status of the body. We measured 8-hydroxy-2'-deoxyguanosine (8-OHDG) and 4-hydroxynonenal (4-HNE) levels as indices of oxidative damage. Relevance analysis between multiple indices can reflect the relationship among occupational radiation exposure, DNA methylation changes, and oxidative damage in interventional physicians.The expression levels of Dnmts, 4-HNE, and 8-OHDG in interventional physicians were higher than those in controls, while there was no statistical difference in total DNA methylation rate and expression of Hcy between interventional physicians and controls. Total cumulative personal dose equivalent in interventional physicians was positively correlated with the expression levels of Dnmts, 8-OHDG, and 4-HNE. The expression levels of 8-OHDG in interventional physicians were negatively correlated with global DNA methylation levels and positively correlated with the expression levels of Hcy.Occupational radiation exposure of interventional physicians has a certain effect on the expression of related enzymes in the process of DNA methylation, while ionizing radiation-induced oxidative damage also has a certain effect on DNA methylation. However, there was no evidence that dose burden of occupational exposure was associated to changes of DNA methylation status of interventional physicians, since it is rather unclear which differences are observed among the effects produced by radiation exposure and oxidative damage.


Assuntos
Dano ao DNA/efeitos da radiação , Metilação de DNA/efeitos da radiação , Exposição Ocupacional/análise , Estresse Oxidativo/efeitos da radiação , Exposição à Radiação/análise , Radiologia Intervencionista/estatística & dados numéricos , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Aldeídos/sangue , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Feminino , Homocisteína/sangue , Humanos , Leucócitos/metabolismo , Masculino , Metiltransferases/sangue , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Médicos/estatística & dados numéricos , Exposição à Radiação/efeitos adversos
5.
Chem Pharm Bull (Tokyo) ; 67(10): 1123-1130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582632

RESUMO

The adenosine triphosphate derivatives of 2-oxo-1,3-diazaphenoxazine (dAdapTP) showed a significant discrimination ability for the template strand including that between 8-oxo-2'-deoxyguanosine (8-oxodG) and 2'-deoxyguanosine (dG) by the single nucleotide primer extension reaction using the Klenow Fragment. In this study, we synthesized new dAdapTP derivatives, i.e., 2-amino-dAdapTP, 2-chloro-dAdapTP and 2-iodo-dAdapTP, to investigate the effect on the selectivity and efficiency of incorporation for the primer extension reaction using a variety of DNA polymerases. In contrast to the previously tested dAdapTP, the selectivity and efficiency of the 2-halo-dAdapTP incorporation were dramatically decreased using the Klenow Fragment. Moreover, the efficiency of the 2-amino-dAdapTP incorporation into the T-containing template was almost the same with that of dAdapTP. In the case of the Bsu DNA polymerase, the efficiency of all the dAdapTP derivatives decreased compared to that using the Klenow Fragment. However, the incorporation selectivity of dAdapTP had improved against the oxodG-containing template for all the template sequences including the T-containing template. Moreover, 2-amino-dAdapTP showed a better efficiency than dAdapTP using the Bsu DNA polymerase. The 2-amino group of the adenosine unit may interact with syn-oxodG at the active site of the Bsu DNA polymerase during the single primer extension reaction.


Assuntos
Adenosina/metabolismo , Compostos Aza/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Oxazinas/metabolismo , Polifosfatos/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Adenosina/química , Compostos Aza/química , DNA Polimerase Dirigida por DNA/química , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Desoxiguanosina/metabolismo , Estrutura Molecular , Oxazinas/química , Polifosfatos/química
6.
Medicine (Baltimore) ; 98(32): e16518, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393354

RESUMO

BACKGROUND: The main objective was to evaluate and compare the local genotoxicity of sevoflurane and desflurane in bronchoalveolar cells, while the secondary outcome was to detect systemic oxidative DNA damage. To our knowledge, our study is the first one to evaluate the local effects of inhalation anesthetics in human bronchoalveolar cells in patients. METHODS: American Society of Anesthesiologists group I-II patients scheduled for lumbar discectomy surgery were enrolled in this randomized prospective study. Patients were randomized to sevoflurane or desflurane for anesthesia maintenance. Bronchoalveolar lavage samples and peripheral blood samples were taken at 2-time points: the first point (baseline, T1); and the second point (postexposure, T2). Final number of 48 samples were the sevoflurane (n = 22) and desflurane (n = 26) groups. Comet assay was applied to examine genotoxic properties. Oxidative DNA damage in plasma was measured with 8-hydroxy-2'-deoxyguanosine (8-OHdG). RESULTS: T2 values were higher than baseline values in both the desflurane group (tail-length: 66 ±â€Š24, %DNA in tail: 72 ±â€Š60, tail moment: 47.52 ±â€Š14.4; P = .001, P = .005, P = .001, respectively) and the sevoflurane group (tail-length: 58 ±â€Š33, %DNA in tail: 88 ±â€Š80, tail moment: 51.04 ±â€Š26.4; P = .001, P = .012, P = .001, respectively). T2 plasma 8-OHdG levels were also higher than baseline levels in the desflurane group (3.91 ±â€Š0.19 ng/ml vs 1.32 ±â€Š0.20 ng/ml, P = .001) and sevoflurane group (3.98 ±â€Š0.18 ng/ml vs 1.31 ±â€Š0.11 ng/ml, P = .001). There were no differences between the 2 groups in comet parameters and 8-OHdG levels. CONCLUSION: Our results indicate that both inhalation agents cause DNA damage in the bronchoalveolar cells. Also, we detected increases in plasma 8-OHdG concentrations. Local genotoxicity and systemic oxidized DNA damage were similar in both groups.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Anestésicos Inalatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Dano ao DNA/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Idoso , Ensaio Cometa , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Desflurano/efeitos adversos , Desflurano/farmacologia , Discotomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Estudos Prospectivos , Sevoflurano/administração & dosagem , Sevoflurano/farmacologia
7.
Environ Pollut ; 254(Pt A): 112921, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31394349

RESUMO

The associations between bisphenol analogues (BPs) exposure and oxidative damage was explored in this 3-year longitudinal study of 275 school children in East China. Nine BPs in first morning urine samples were measured to assess BPs exposure, and 8-hydroxydeoxyguanosine (8-OHdG) and 8-oxo-7,8-dihydroguanosine (8-OHG) were measured as biomarkers of oxidative DNA and RNA damage. Linear mixed model (LMM) was used for repeated measures analysis. School children were mainly exposed to BPA, BPS, BPF, and BPAF (detection frequencies: 97.9%, 42.2%, 13.3%, and 12.8%) with median concentrations of 1.55, 0.355, 0.236 and 0.238 µg g-1Cre, respectively. An interquartile range (IQR) increase in urinary BPA was significantly associated with 12.9% (95% CI: 6.1%, 19.6%) increase in 8-OHdG and 19.4% (95% CI: 11.7%, 27.1%) increase in 8-OHG, and for total of BPs (the sum of BPA, BPS, BPF, and BPAF), they were 17.4% (95% CI: 8.9%, 26.0%) for 8-OHdG and 25.9% (95% CI: 16.1%, 35.7%) for 8-OHG, respectively. BPS was positively associated with 8-OHG, but not with 8-OHdG. The study found positive associations of urinary levels of BPA and total BPs with 8-OHdG and 8-OHG and indicated that BPs exposure might cause oxidative RNA damage.


Assuntos
Compostos Benzidrílicos/urina , Dano ao DNA , Desoxiguanosina/análogos & derivados , Exposição Ambiental/análise , Poluentes Ambientais/urina , Fenóis/urina , 8-Hidroxi-2'-Desoxiguanosina , Compostos Benzidrílicos/toxicidade , Biomarcadores/urina , Criança , China , DNA , Desoxiguanosina/urina , Poluentes Ambientais/toxicidade , Humanos , Estudos Longitudinais , Oxirredução , Estresse Oxidativo , Fenóis/toxicidade , RNA , Projetos de Pesquisa
8.
ACS Chem Biol ; 14(8): 1708-1716, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31347832

RESUMO

Endogenous metabolites and exogenous chemicals can induce covalent modifications on DNA, producing DNA lesions. The N2 of guanine was shown to be a common alkylation site in DNA; however, not much is known about the influence of the size of the alkyl group in N2-alkyldG lesions on cellular DNA replication or how translesion synthesis (TLS) polymerases modulate DNA replication past these lesions in human cells. To answer these questions, we employ a robust shuttle vector method to investigate the impact of four N2-alkyldG lesions (i.e., with the alkyl group being a methyl, ethyl, n-propyl, or n-butyl group) on DNA replication in human cells. We find that replication through the N2-alkyldG lesions was highly efficient and accurate in HEK293T cells or isogenic CRISPR-engineered cells with deficiency in polymerase (Pol) ζ or Pol η. Genetic ablation of Pol ι, Pol κ, or Rev1, however, results in decreased bypass efficiencies and elicits substantial frequencies of G → A transition and G → T transversion mutations for these lesions. Moreover, further depletion of Pol ζ in Pol κ- or Pol ι-deficient cells gives rise to elevated rates of G → A and G → T mutations and substantially decreased bypass efficiencies. Cumulatively, we demonstrate that the error-free replication past the N2-alkyldG lesions is facilitated by a specific subset of TLS polymerases, and we find that longer alkyl chains in these lesions induce diminished bypass efficiency and fidelity in DNA replication.


Assuntos
Replicação do DNA/efeitos dos fármacos , DNA/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Alquilação , DNA/genética , Dano ao DNA , Reparo do DNA , DNA Polimerase Dirigida por DNA/fisiologia , Desoxiguanosina/toxicidade , Células HEK293 , Humanos , Estrutura Molecular , Mutação , Conformação de Ácido Nucleico
9.
Int J Occup Environ Med ; 10(3): 124-136, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31325295

RESUMO

BACKGROUND: Coke oven workers are exposed to polycyclic aromatic hydrocarbons (PAHs) with possible genotoxicity and carcinogenicity. Metabolizing enzymes genes and DNA repair genes are suspected to be correlated with the level of DNA damage. They may contribute to variable individual sensitivity to DNA damage induced by PAHs exposure at workplace. OBJECTIVE: To investigate the relationship between biomarkers of PAHs: 1-hydroxypyrene (1-OHP), DNA adducts, and 8-hydroxy-2-deoxyguanosine (8-OHdG) in coke oven workers, and to assess the role of cytochrome P2E1 (CYP2E1) gene expression and DNA repairing gene (XRCC1) polymorphism in detecting workers at risk. METHODS: 85 exposed workers and 85 unexposed controls were enrolled into this study. Urinary 1-OHP, 8-OHdG, and BPDE-DNA adduct were measured. CYP2E1 gene expression and genotyping of XRCC1 399 Arg/Gln were evaluated by real-time PCR. RESULTS: The median urinary 1-OHP levels (6.3 µmol/mol creatinine), urinary 8-OHdG (7.9 ng/mg creatinine), DNA adducts (6.7 ng/µg DNA) in the exposed group were significantly higher than those in the unexposed group. Carriers of the variant allele (Gln) of XRCC1 had the highest levels of 1-OHP, DNA adducts and 8-OHdG, and the lowest level of CYP2E1 gene expression. In exposed workers, significant positive correlations were found between 1-OHP level and each of the work duration, 8-OHdG, and DNA adducts levels. There was a significant negative correlation between 1-OHP level and CYP2E1 gene expression. Work duration and CYP2E1 gene expression were predictors of DNA adducts level; 1-OHP level and work duration were predictors of urinary 8-OHdG level. CONCLUSION: Workers with higher exposure to PAH were more prone to oxidative DNA damage and cancer development. DNA adducts level reflects the balance between their production by CYP2E1 and elimination by XRCC1 gene.


Assuntos
Citocromo P-450 CYP2E1/genética , Adutos de DNA/genética , Desoxiguanosina/análogos & derivados , Monitoramento Ambiental/métodos , Exposição Ocupacional/análise , Pirenos/urina , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Biomarcadores/urina , Coque , Citocromo P-450 CYP2E1/biossíntese , Adutos de DNA/urina , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/genética , Desoxiguanosina/urina , Egito , Humanos , Masculino , Pessoa de Meia-Idade , Hidrocarbonetos Policíclicos Aromáticos/urina , Polimorfismo Genético , Medição de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/biossíntese , Adulto Jovem
10.
Chem Pharm Bull (Tokyo) ; 67(7): 707-712, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257326

RESUMO

Hypobromous acid (HOBr) is generated not only by eosinophils but also by neutrophils in the presence of Br- at the plasma concentration. Reactivity of HOBr is greatly modulated by coexistent compounds such as amines and amides. In this study, we investigated effects of urea in the reaction of nucleosides with HOBr. When nucleosides were incubated with HOBr without urea in potassium phosphate buffer at pH 7.4 and 37°C, the reactions almost completed within 10 min, with consumptions in the order of 2'-deoxyguanosine > 2'-deoxycytidine > 2'-deoxythymidine > 2'-deoxyadenosine, generating 8-bromo-2'-deoxyguanosine and 5-bromo-2'-deoxycytidine. In the presence of urea, the reaction of nucleosides with HOBr was relatively slow, continuing over several hours. When HOBr was preincubated without urea in potassium phosphate buffer at pH 7.4 and 37°C for 48 h, the preincubated HOBr solution did not react with nucleosides. However, a similar preincubated solution of HOBr with urea reacted with nucleosides to generate 8-bromo-2'-deoxyguanosine and 5-bromo-2'-deoxycytidine. These results imply that a reactive bromine compound with a long life, probably bromourea, is generated by HOBr in neutral urea solution and reacts with nucleosides, resulting in brominated nucleosides.


Assuntos
Bromatos/química , Nucleosídeos/química , Ureia/química , Cromatografia Líquida de Alta Pressão , Desoxicitidina/química , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análise , Desoxiguanosina/química , Halogenação , Fosfatos/química , Compostos de Potássio/química , Espectrometria de Massas por Ionização por Electrospray , Timidina/química
11.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 193-198, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31257797

RESUMO

OBJECTIVE: To investigate the vascular damage effects and possible mechanism of acute exposure to ozone (O3) in male Wistar rats. METHODS: One hundred and twenty male Wistar rats were randomly divided into six groups, 20 in each group. The experimental animals were placed in a gas poisoning cabinet, the control group was exposed to filtered air, and the treatment group was exposed to ozone at concentrations of 0.12 ppm, 0.5 ppm, 1.0 ppm, 2.0 ppm, and 4.0 ppm, respectively, for 4 hours. Arterial blood pressure data were obtained by PC-lab medical physiological signal acquisition system. Blood rheology indicators and blood biochemical indicators were detected by Tianjin Dean Diagnostic Laboratory. Serum endothelin-1 (ET-1), homocysteine (HCY), von Willebrand factor (vWF), 8-hydroxydeoxyguanosine (8-OhdG), interleukin (IL-6) and tumor necrosis factor alpha (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA) microplate assay. Oxidative stress indicators superoxide dismutase (SOD) activity and malondialdehyde (MDA) were determined by xanthine oxidase method, thiobarbituric acid (TBA) method, reduced glutathione (GSH) and nitric oxide (NO) were tested by using microplate colorimetry. Paraffin sections were prepared from thoracic aorta tissue, and vascular structure was observed by HE staining. RESULTS: Acute exposure to 0.12 ppm ozone could cause a significant increase in arterial systolic blood pressure (SBP). Exposure to different concentrations of ozone could cause a significant increase in plasma viscosity, and the K value of the ESR equation was significantly increased in the 1.0 ppm ozone exposure group. Both the relative and reduced viscosities were significantly reduced at ozone concentrations of 0.5 ppm and 4.0 ppm, while the red blood cell deformation index was increased significantly at ozone concentrations of 0.12 ppm, 0.5 ppm, 1.0 ppm, and 2.0 ppm. Acute ozone exposure resulted in the decrease of total cholesterol content. The content of high-density lipoprotein cholesterol (HDL-C) was significantly reduced in the 0.12 ppm ozone exposure group. When the ozone concentration was higher than 1.0 ppm, the body may also had an inflammatory reaction (increased TNF-α) and oxidative stress (increased MDA, decreased GSH). Acute exposure to ozone could lead to elevated levels of ET-1 in the blood, with significant differences in the 4.0 ppm concentration group, while HCY levels were decreased firstly and then increased, reaching the highest in the 1.0 ppm concentration group. No obvious pathological changes were observed in the thoracic aorta. CONCLUSION: Acute ozone exposure can affect arterial blood pressure, blood rheology and cholesterol metabolism in rats. The possible mechanism is that ozone exposure leads to inflammatory reaction and oxidative stress reaction, causing vascular endothelial function damage, and vascular endothelial cells increase with ozone exposure concentration.


Assuntos
Vasos Sanguíneos/lesões , Estresse Oxidativo , Ozônio/toxicidade , 8-Hidroxi-2'-Desoxiguanosina , Animais , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Endotelina-1/sangue , Homocisteína/sangue , Interleucina-6/sangue , Masculino , Malondialdeído/análise , Ratos , Ratos Wistar , Superóxido Dismutase/análise , Fator de Necrose Tumoral alfa/sangue , Fator de von Willebrand/análise
12.
Food Chem Toxicol ; 132: 110600, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31228599

RESUMO

Diisononyl phthalate (DIDP) is commonly used as a plasticizer in industrial and consumer products, however, its toxicity remains unclear. This study investigated the possible involvement of oxidative stress in DIDP-induced liver and kidney toxicity. Liver function and kidney function, tissue lesions, oxidative stress biomarkers, inflammatory mediators and apoptosis factors were investigated in this study. The results showed that oral exposure to DIDP induced a marked increase in lever of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urinary nitrogen (UREA) and creatinine (CREA), decrease in albumin (ALB) level, as well as causing hepatic and renal histopathological change. Investigation of the role of oxidative stress pathways showed that DBP exposure could lead to a significant increase in levels of reactive oxygen species (ROS), malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB), while a decrease in glutathione (GSH) levels were observed. Administration of vitamin E to DIDP-treated mice restored these biochemical parameters to within normal levels, and resulted in less damage to livers and kidneys. Overall, these results suggest that the oxidative stress pathway is involved in DIDP-induced toxicity.


Assuntos
Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , 8-Hidroxi-2'-Desoxiguanosina , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Glutationa/metabolismo , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Rim/patologia , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ácidos Ftálicos/administração & dosagem , Plastificantes/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31172968

RESUMO

The etiopathogenesis of potentially malignant oral disorders (PMOD) has not been fully understood yet. Recent results suggest that oxidative stress may be involved in the etiology of PMOD. Production of oxidants seems to be the major biological effect responsible for tissue injury and inflammatory response to air pollution. The aim of this study was to compare the oxidative stress markers and antioxidant potential in saliva of PMOD subjects and healthy controls in periods of high and low air pollution. Among enrolled 40 participants, there were 20 PMOD patients and 20 healthy volunteers. The exposure to air pollution was assessed by exhaled CO (eCO). Four oxidative status parameters: 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), reduced glutathione (GSH) and total antioxidant capacity (TAC) were measured in saliva. Measurements were carried out in June (low air pollution) and November (increased air pollution). In both groups, significantly higher concentrations of 8-OHdG (P < 0.001 for PMOD patients and P = 0.001 for healthy controls), MDA (P = 0.002 and P = 0.012 respectively) and eCO (P < 0.001 and P < 0.001 respectively) were observed in periods of high air pollution. The concentration of TAC did not change between visits. The concentration of salivary GSH (P < 0.001 and P < 0.001 for both groups) decreased when compared between consecutive visits. We conclude that exhaled carbon monoxide (reflecting exposure to air pollution) correlated with the oxidative stress markers in patients with PMOD and healthy controls.


Assuntos
Poluição do Ar , Monóxido de Carbono/metabolismo , Exposição Ambiental , Doenças da Boca/metabolismo , Estresse Oxidativo , Saliva/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Idoso , Biomarcadores/metabolismo , Testes Respiratórios , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Expiração , Feminino , Glutationa/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Polônia
14.
Environ Sci Pollut Res Int ; 26(22): 22562-22574, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165450

RESUMO

Zingerone (ZO), one of the active components of ginger (Zingiber officinale), is a phenolic alkanone with antioxidant, antiapoptotic, and anti-inflammatory properties. Cisplatin (CP) is a widely used chemotherapeutic drug for solid tumors, but its therapeutic use is limited due to dose-dependent nephrotoxicity. In the present study, we investigated the ameliorative effect of ZO against CP-induced nephrotoxicity. Intraperitoneal administration of single-dose CP (7 mg/kg body weight) on the first day enhanced kidney lipid peroxidation and reduced antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH). CP increased serum urea and creatinine levels and disrupted histological integrity while causing a decrease aquaporin 1 (AQP1) level in the kidney tissues. CP induced inflammatory responses by elevating the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-33 (IL-33) and nuclear factor kappa B (NF-κB), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, it also caused oxidative DNA damage and activation of apoptotic pathway by increasing of 8-hydroxy-2'-deoxyguanosine (8-OHdG), p53, cysteine aspartate-specific protease-3 (caspase-3), and Bcl-2-associated x protein (bax) while decreasing B cell lymphoma-2 (Bcl-2). However, treatment with ZO at a dose of 25 and 50 mg/kg b.wt. for 7 days significantly decreased oxidative stress, apoptosis, inflammation, and histopathological alterations while increased AQP1 levels in the kidney tissue. The results of the current study suggested that ZO as an effective natural product attenuates CP-induced nephrotoxicity.


Assuntos
Antioxidantes/metabolismo , Cisplatino/toxicidade , Guaiacol/análogos & derivados , Rim/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Animais , Apoptose/efeitos dos fármacos , Autofagia , Nitrogênio da Ureia Sanguínea , Catalase/metabolismo , Dano ao DNA , Desoxiguanosina/análogos & derivados , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Guaiacol/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Peroxidação de Lipídeos , Masculino , NF-kappa B/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo , Testes de Toxicidade , Fator de Necrose Tumoral alfa/metabolismo
15.
Anticancer Res ; 39(6): 3241-3248, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177174

RESUMO

BACKGROUND/AIM: The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC. MATERIALS AND METHODS: The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC. RESULTS: Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis. CONCLUSION: Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression.


Assuntos
Neoplasias dos Ductos Biliares/enzimologia , Biomarcadores Tumorais/análise , Colangiocarcinoma/enzimologia , DNA Glicosilases/análise , Reparo do DNA , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Dano ao DNA , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análise , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Tempo
16.
J Trace Elem Med Biol ; 54: 103-109, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109599

RESUMO

Arsenic is a well-known toxic heavy metal that is naturally dispersed in groundwater. Whereas arsenic is widely accepted to be involved in oxidative stress damage, little is known about arsenic-induced oxidative damage in relationship to contaminated drinking water as a source. The aim of this study was to determine the association between arsenic exposure through drinking water and oxidative stress status by measuring levels of urinary 8-hydroxydeoxyguanosine (8-OHdG) as a biomarker of oxidative stress damage in a Myanmar population. A questionnaire-based survey and drinking water and urine sampling (n = 198) were performed to assess the association between arsenic exposure and urinary 8-OHdG concentration in the Ayeyarwady Region, Myanmar. Urinary arsenic concentrations were significantly correlated with drinking water arsenic concentrations (Spearman's rho = 0.32, p < 0.001). Multivariate linear regression analysis showed that higher urinary arsenic concentrations were significantly associated with higher 8-OHdG concentrations (coefficient = 0.09, 95% confidence interval, 0.03 - 0.15; p = 0.002). The present study identified that exposure to arsenic through drinking water could induce an increase in the urinary 8-OHdG concentration, reflecting increased oxidative DNA damage. These findings provide evidence that may explain the role of arsenic-induced oxidative stress in the pathophysiology of arsenic-induced diseases including cancers.


Assuntos
Arsênico/urina , Água Potável/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Estudos Transversais , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Masculino , Metais Pesados/urina , Pessoa de Meia-Idade , Análise Multivariada , Mianmar , Estresse Oxidativo/efeitos dos fármacos , Inquéritos e Questionários , Poluentes Químicos da Água
17.
Int J Oral Maxillofac Surg ; 48(12): 1558-1563, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31109746

RESUMO

The actual role of splint therapy in preventing excessive loading of the temporomandibular joint (TMJ) is still debated. Lower intra-articular pressure levels have been measured in patients wearing occlusal splints, which may also reduce oxidative stress in the articular spaces. The aim of this study was to determine whether splint therapy reduces oxidative stress and inflammation in TMJ internal derangement patients by measuring interleukin 6 (IL-6), malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) levels in the synovial fluid (SF). Twenty-four patients with a temporomandibular disorder (TMD) were included in the study. TMJ SF samples were obtained prior to arthrocentesis. Twelve patients used a 2-mm hard acrylic, maxillary stabilization-type splint for 3 months after arthrocentesis. Twelve patients had no treatment after the SF aspiration. Second SF samples were obtained from all patients at 3 months post arthrocentesis. IL-6, MDA, and 8-OHdG levels in the samples were evaluated. All patients showed a significant symptomatic improvement after treatment (P < 0.005). No statistical correlation was found between the two groups concerning pre-treatment and 3-month SF levels of MDA, 8-OHdG, and IL-6. Although splint therapy was found to be successful in eliminating clinical symptoms of TMD, the results showed no beneficial effect on inflammation and oxidative stress markers in the synovial fluid.


Assuntos
Placas Oclusais , Transtornos da Articulação Temporomandibular , 8-Hidroxi-2'-Desoxiguanosina , Desoxiguanosina/análogos & derivados , Humanos , Interleucina-6 , Malondialdeído , Líquido Sinovial , Resultado do Tratamento
18.
Chemistry ; 25(44): 10408-10419, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31062885

RESUMO

Nucleoside configuration (α-d vs. ß-d), nucleobase substituents, and the helical DNA environment of silver-mediated 5-aza-7-deazaguanine-cytosine base pairs have a strong impact on DNA stability. This has been demonstrated by investigations on oligonucleotide duplexes with silver-mediated base pairs of α-d and ß-d anomeric 5-aza-7-deaza-2'-deoxyguanosines and anomeric 2'-deoxycytidines incorporated in 12-mer duplexes. To this end, a new synthetic protocol has been developed to access the pure anomers of 5-aza-7-deaza-2'-deoxyguanosine by glycosylation of either the protected nucleobase or its salt followed by separation of the glycosylation products by crystallization and chromatography. Thermal stability measurements were performed on duplexes with α-d/α-d and ß-d/ß-d homo base pairs or α-d/ß-d and ß-d/α-d hybrid pairs within two sequence environments, positions 6 or 7, of oligonucleotide duplexes. The respective Tm stability increases observed after silver ion addition differ significantly. Homo base pairs with ß-d/ß-d or α-d/α-d nucleoside combinations are more stable than α-d/ß-d hybrid base pairs. The positional switch of silver-ion-mediated base pairs has a significant impact on stability. Nucleobase substituents introduced at the 5-position of the dC site of silver-mediated base pairs affect base pair stability to a minor extent. Our investigation might lead to applications in the construction of bioinspired nanodevices, in DNA diagnostics, or metal-DNA hybrid materials.


Assuntos
DNA/química , Desoxiguanosina/análogos & derivados , Prata/química , Pareamento Incorreto de Bases , Pareamento de Bases , Cátions Monovalentes , Citosina/química , Desoxicitidina/química , Desoxiguanosina/química , Glicosilação , Guanina/análogos & derivados , Guanina/química , Modelos Moleculares , Conformação de Ácido Nucleico , Oligonucleotídeos/síntese química , Oligonucleotídeos/química , Relação Estrutura-Atividade , Termodinâmica
19.
Chem Commun (Camb) ; 55(48): 6850-6853, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31123731

RESUMO

PAGE and UV melting analysis revealed that longer LNA-based splice-switching oligonucleotides (SSOs) formed secondary structures by themselves, reducing their effective concentration. To avoid such secondary structure formation, we introduced 7-deaza-2'-deoxyguanosine or 2'-deoxyinosine into the SSOs. These modified SSOs, with fewer secondary structures, showed higher exon skipping activities.


Assuntos
Éxons , Oligonucleotídeos/química , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Inosina/análogos & derivados , Inosina/química , Conformação de Ácido Nucleico , Oxirredução
20.
Talanta ; 201: 271-279, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122423

RESUMO

In this work, an innovative aptamer-based magnetic adsorbent (Fe3O4@PDA-aptamer MNPs) was prepared by hydrothermal synthesis method followed by the surface functionalization of nanoparticles. After fixing in a steel stainless tube as sorbent of magnetic solid phase extraction (MSPE), an online magnetic solid phase extraction-high performance liquid chromatography-mass spectrometry (online-MSPE-HPLC-MS) method was developed and applied for the determination of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) simultaneously in urine. The synthesized sorbent presented outstanding features, including large specific surface area, high enrichment capacity and excellent stability. High throughput analysis can be achieved by affinity-specific adsorption of 8-OHdG and non-specific adsorption of OH-PAHs at the same time. In addition, online MSPE can greatly simplify the analysis process, reduce human errors and enhance the sensitivity. When compared with offline MSPE, a sensitivity enhancement of 30-400 times was obtained for the online method. Some experimental parameters such as the amount of the sorbent, sampling flow rate and sample volume, were optimized systematically. Under the optimal conditions, the limits of detection (LOD) were in the range of 0.028-0.114 ng mL-1, and the correlation coefficients (R2) were higher than 0.9962. The relative standard deviations (RSDs) were less than 16.1% (n = 5) and the recoveries ranged from 71% to 116%. The above results show that the rapid, sensitive and automated online-MSPE-HPLC-MS method has potential application in the simultaneous determination of 8-OHdG and PAHs in complex sample matrix to assess the environmental exposure level.


Assuntos
Aptâmeros de Nucleotídeos/química , Desoxiguanosina/análogos & derivados , Hidrocarbonetos Policíclicos Aromáticos/urina , Extração em Fase Sólida/métodos , 8-Hidroxi-2'-Desoxiguanosina , Adolescente , Adsorção , Adulto , Sequência de Bases , Cromatografia Líquida de Alta Pressão , Desoxiguanosina/urina , Humanos , Limite de Detecção , Nanopartículas de Magnetita/química , Espectrometria de Massas , Adulto Jovem
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