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1.
Einstein (Sao Paulo) ; 17(4): eAO4742, 2019 Sep 09.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31508660

RESUMO

OBJECTIVE: To evaluate the induction of DNA damage in peripheral blood mononuclear cells of patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea. METHODS: The study subjects were divided into two groups: one group of 22 patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea, and a Control Group composed of 24 patients with sickle cell disease who were not treated with hydroxyurea. Peripheral blood samples were submitted to peripheral blood mononuclear cell isolation to assess genotoxicity by the cytokinesis-block micronucleus cytome assay, in which DNA damage biomarkers - micronuclei, nucleoplasmic bridges and nuclear buds - were counted. RESULTS: Patients with sickle cell disease treated with hydroxyurea had a mean age of 25.4 years, whereas patients with sickle cell disease not treated with hydroxyurea had a mean age of 17.6 years. The mean dose of hydroxyurea used by the patients was 12.8mg/kg/day, for a mean period of 44 months. The mean micronucleus frequency per 1,000 cells of 8.591±1.568 was observed in the Hydroxyurea Group and 10.040±1.003 in the Control Group. The mean frequency of nucleoplasmic bridges per 1,000 cells and nuclear buds per 1,000 cells for the hydroxyurea and Control Groups were 0.4545±0.1707 versus 0.5833±0.2078, and 0.8182±0.2430 versus 0.9583±0.1853, respectively. There was no statistically significant difference between groups. CONCLUSION: In the study population, patients with sickle cell disease treated with the standard dose of hydroxyurea treatment did not show evidence of DNA damage induction.


Assuntos
Anemia Falciforme/genética , Dano ao DNA/efeitos dos fármacos , Hidroxiureia/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Criança , Pré-Escolar , Citocinese , Dano ao DNA/genética , Feminino , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Testes de Mutagenicidade , Mutação/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/efeitos adversos , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Adulto Jovem
2.
Anticancer Res ; 39(8): 4011-4017, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366482

RESUMO

BACKGROUND/AIM: Genotoxicity is the capacity of an agent to induce damage to DNA. Given the close relationship between genotoxicity and carcinogenesis, several assays have been developed for detecting genetic damage. Among them, the single-cell gel (comet) assay plays an important role for evaluating DNA damage in mammalian cells, including those of the oral cavity. The purpose of this article was to provide a critical review of the application of single-cell gel comet assay to buccal cells. MATERIAL AND METHODS: A search of the scientific literature was conducted of published studies available on single-cell gel comet assay and oral cells. RESULTS: The results showed that the majority of studies were conducted on humans, whereas few were designed for use in rodents and in vitro. CONCLUSION: Further studies within the field are relevant for better understanding the underlying mechanisms of genotoxicity in oral cells, especially since the use of humans is quite complicated due to issues of ethics.


Assuntos
Carcinogênese/genética , Dano ao DNA/genética , Boca/efeitos dos fármacos , Análise de Célula Única/métodos , Ensaio Cometa/métodos , DNA/genética , Humanos , Boca/patologia , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Mutagênicos
3.
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
4.
Environ Pollut ; 251: 879-884, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31234253

RESUMO

Genotoxic analyses are commonly used in ecotoxicological studies as early biomarkers to investigate the potential effects of environmental contaminants on biological models. Several pollutants can induce DNA damage and, therefore, counting micronuclei and other nuclear abnormalities are efficient tools to evaluate genotoxicity. Some pollutants such as 4-nonylphenol (NP), a detergent used mainly in industries, and Cyproterone Acetate (CPA), an antiandrogenic medicine, have already shown genotoxic effects on some vertebrates. However, although amphibians are considered bioindicators of environmental quality and their populations are declining worldwide, the effects of these compounds on anurans are not yet known and, therefore, we believe that it is important to investigate such effects on anurans. Since water contamination is one of the ultimate causes of amphibian decline, ecotoxicological studies are important to discuss the appropriate solutions to avoid species extinction. Thus, this study investigates the genotoxic effects on Rana catesbeiana tadpoles and juveniles after being exposed to 1, 10 and 100 µg/L NP and 0.025, 0.25 and 2.5 ng/L CPA, by counting the nuclear abnormalities after exposure. The laboratory experiments lasted 28 days. The experimental conditions were the same except for the water volume since tadpoles and juveniles exhibit different habits at different developmental stages. Compared to juveniles, tadpoles were more susceptible to both compounds as indicated by the increased nuclear abnormalities observed in the highest NP concentration and all tested CPA concentrations. The juveniles, on the other hand, responded only to the two highest CPA concentrations. We concluded that CPA, even at very low concentrations, is extremely harmful to both anuran developmental stages and, particularly, to tadpoles. The significant effects observed on tadpoles is an important outcome of this study since 100 µg/L or higher NP concentrations are frequently detected in the environment.


Assuntos
Anuros/embriologia , Acetato de Ciproterona/toxicidade , Larva/efeitos dos fármacos , Fenóis/toxicidade , Rana catesbeiana/embriologia , Poluentes Químicos da Água/toxicidade , Animais , Anuros/genética , Núcleo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Poluição Ambiental , Larva/crescimento & desenvolvimento , Rana catesbeiana/genética
5.
Nat Commun ; 10(1): 2588, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197172

RESUMO

The brain is a genomic mosaic shaped by cellular responses to genome damage. Here, we manipulate somatic genome stability by conditional Knl1 deletion from embryonic mouse brain. KNL1 mutations cause microcephaly and KNL1 mediates the spindle assembly checkpoint, a safeguard against chromosome missegregation and aneuploidy. We find that following Knl1 deletion, segregation errors in mitotic neural progenitor cells give rise to DNA damage on the missegregated chromosomes. This triggers rapid p53 activation and robust apoptotic and microglial phagocytic responses that extensively eliminate cells with somatic genome damage, thus causing microcephaly. By leaving only karyotypically normal progenitors to continue dividing, these mechanisms provide a second safeguard against brain somatic aneuploidy. Without Knl1 or p53-dependent safeguards, genome-damaged cells are not cleared, alleviating microcephaly, but paradoxically leading to total pre-weaning lethality. Thus, mitotic genome damage activates robust responses to eliminate somatic mutant cells, which if left unpurged, can impact brain and organismal fitness.


Assuntos
Aneuploidia , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/genética , Segregação de Cromossomos/genética , Dano ao DNA/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Instabilidade Genômica , Humanos , Cinetocoros/metabolismo , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Cultura Primária de Células , Deleção de Sequência , Fuso Acromático/metabolismo
6.
Nat Chem ; 11(7): 629-637, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209299

RESUMO

In DNA, the loss of a nucleobase by hydrolysis generates an abasic site. Formed as a result of DNA damage, as well as a key intermediate during the base excision repair pathway, abasic sites are frequent DNA lesions that can lead to mutations and strand breaks. Here we present snAP-seq, a chemical approach that selectively exploits the reactive aldehyde moiety at abasic sites to reveal their location within DNA at single-nucleotide resolution. Importantly, the approach resolves abasic sites from other aldehyde functionalities known to exist in genomic DNA. snAP-seq was validated on synthetic DNA and then applied to two separate genomes. We studied the distribution of thymine modifications in the Leishmania major genome by enzymatically converting these modifications into abasic sites followed by abasic site mapping. We also applied snAP-seq directly to HeLa DNA to provide a map of endogenous abasic sites in the human genome.


Assuntos
DNA/genética , Genoma/genética , Análise de Sequência de DNA/métodos , Aldeídos/química , Sequência de Bases , DNA/química , Dano ao DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Leishmania major/genética , Sondas Moleculares/síntese química , Sondas Moleculares/química , Timina/química , Uracila-DNA Glicosidase/química
7.
Biochim Biophys Acta Rev Cancer ; 1872(1): 60-65, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152819

RESUMO

Hepatocellular carcinoma (HCC), the most common form of liver cancer, represents a health problem in hepatic viruses-eradicating era because obesity, type 2 diabetes, and nonalcoholic steatohepatitis (NASH) are considered emerging pathogenic factors. Metabolic disorders underpin mitotic errors that lead to numerical and structural chromosome aberrations in a significant proportion of cell divisions. Here, we review that genomically unstable HCCs show evidence for a paradoxically DNA damage response (DDR) which leads to ongoing chromosome segregation errors. The understanding of DDR induced by defective mitoses is crucial to our ability to develop or improve liver cancer therapeutic strategies.


Assuntos
Carcinoma Hepatocelular/genética , Genoma Humano/genética , Instabilidade Genômica/genética , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Instabilidade Cromossômica/genética , Segregação de Cromossomos/genética , Dano ao DNA/genética , Humanos , Neoplasias Hepáticas/patologia , Mitose/genética
8.
Biochim Biophys Acta Rev Cancer ; 1872(1): 37-48, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152823

RESUMO

Esophageal adenocarcinoma (EAC) has one of the fastest rising incidence rates in the U.S. and many other Western countries. One of the unique risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duodenal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, progression to EAC is underlined by continuous DNA damage caused by reflux and chronic inflammatory factors that increase the mutation rate and promote genomic instability. Despite recent successes in cancer diagnostics and treatment, EAC remains a poorly treatable disease. Recent research has shed new light on molecular alterations underlying progression to EAC and revealed novel treatment options. This review focuses on the genetic and molecular studies of EAC. The molecular changes that occur during the transformation of normal Barrett's esophagus to esophageal adenocarcinoma are also discussed.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Refluxo Gastroesofágico/genética , Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Dano ao DNA/genética , Neoplasias Esofágicas/patologia , Refluxo Gastroesofágico/patologia , Humanos , Fatores de Risco , Transdução de Sinais/genética
9.
Anticancer Res ; 39(5): 2307-2315, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092422

RESUMO

BACKGROUND: Several studies have highlighted hyperthermia's ability to enhance the effectiveness of radiation and chemotherapy in various in vitro and in vivo cancer models. MATERIALS AND METHODS: In vivo murine models of malignant melanoma and colon carcinoma were utilized for demonstrating hyperthermia's therapeutic effectiveness by examining levels of caspase 3, COX-2 and phospho-H2A.X (Ser139) as endpoints of apoptosis, proliferation and DNA damage respectively. RESULTS: Hyperthermia induced in vitro cytotoxicity in malignant melanoma (B16-F10) and colon carcinoma (CT26) cell lines. In addition, it reduced post-in vitro proliferation and suppression of tumor growth by inducing the expression of caspase-3 and phospho-H2A.X (Ser139) while reducing the expression of COX-2 in both murine cancer models. CONCLUSION: Hyperthermia can exert therapeutic effectiveness against melanoma and colon carcinoma by inhibiting a number of critical cellular cascades including apoptosis, proliferation and DNA damage.


Assuntos
Neoplasias do Colo/terapia , Hipertermia Induzida , Melanoma Experimental/terapia , Melanoma/terapia , Animais , Apoptose/efeitos da radiação , Carcinoma/patologia , Carcinoma/terapia , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Dano ao DNA/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Histonas/genética , Humanos , Melanoma/patologia , Melanoma Experimental/genética , Camundongos
10.
Nat Protoc ; 14(5): 1489-1508, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962605

RESUMO

Non-coding RNA (ncRNA) molecules have been shown to play a variety of cellular roles; however, the contributions of different types of RNA to specific phenomena are often hard to dissect. To study the role of RNA in the assembly of DNA damage response (DDR) foci, we developed the RNase A treatment and reconstitution (RATaR) method, in which cells are mildly permeabilized, incubated with recombinant RNase A and subsequently reconstituted with different RNA species, under conditions of RNase A inactivation and inhibition of endogenous transcription. The block of transcription right after RNase A removal represents a key innovation of RATaR, preventing potential contributions of endogenously neo-synthesized transcripts to the phenotypes studied. A critical aspect of this technique is the balance between sufficient permeabilization of membranes to allow enzyme/RNA access into the cell nucleus and cell viability. Here, we present our protocol for RNA-dependent DDR foci disassembly and reassembly using fluorescent DDR RNAs (DDRNAs) in NIH2/4 cells, an engineered NIH3T3-derived cell line. The use of sequence-specific, fluorescent RNA molecules permits the concomitant determination of their subcellular localization and biological functions. We also outline adaptations of RATaR when implemented in different cell lines exposed to various genotoxic treatments, such as γ-radiation, restriction enzymes and telomere deprotection. In all these cases, the entire procedure can be completed within 2 h without the need for special equipment or uncommon skills. We believe this technique will prove useful for investigating the contribution of RNA to a variety of relevant cellular processes.


Assuntos
Dano ao DNA , Reparo do DNA , RNA não Traduzido , Ribonuclease Pancreático/metabolismo , Animais , Dano ao DNA/genética , Dano ao DNA/fisiologia , Reparo do DNA/genética , Reparo do DNA/fisiologia , Técnicas Genéticas , Células HeLa , Humanos , Camundongos , Células NIH 3T3 , RNA/análise , RNA/genética , RNA/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/fisiologia
11.
Oncol Rep ; 41(6): 3305-3312, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942468

RESUMO

Histone H2B monoubiquitination has been shown to play critical roles in diverse cellular processes including DNA damage response. Although recent data indicate that H2B monoubiquitination is strongly connected with tumor progression and regulation, the implications of this modification in lung adenocarcinoma are relatively unknown. In the present study, we demonstrated the clinical implication of H2B monoubiquitination and the potential role of tumor necrosis factor receptor­associated factor­interacting protein (TRAIP) in regulating its modification in lung adenocarcinoma. Immunohistochemical analysis showed that H2B monoubiquitination was significantly downregulated in 68 human lung adenocarcinoma patient samples compared to their normal adjacent tissues. Depletion of TRAIP by specific siRNA treatment markedly decreased ionizing radiation (IR)­induced H2B monoubiquitination. In addition, deletion mutants without RING domain or C­terminus of TRAIP diminished the ability to induce H2B monoubiquitination at lysine 120. Notably, the nuclear expression of TRAIP was positively related with H2B monoubiquitination levels in patients with lung adenocarcinoma. Furthermore, statistical analysis indicated that low levels of both TRAIP and H2B monoubiquitination, not each alone, in patients with lung adenocarcinoma were strongly correlated with poor survival. Taken together, these results suggest that TRAIP is a novel regulator of H2B monoubiquitination in DNA damage response and cancer development in lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/genética , Histonas/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/radioterapia , Dano ao DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Lisina/genética , Masculino , Domínios Proteicos/efeitos da radiação , RNA Interferente Pequeno/genética , Radiação Ionizante , Deleção de Sequência/genética
12.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010235

RESUMO

Currently we are faced with an ever-growing use of Δ9-tetrahydrocannabinol (THC) preparations, often used as supportive therapies for various malignancies and neurological disorders. As some of illegally distributed forms of such preparations, like cannabis oils and butane hash oil, might contain over 80% of THC, their consumers can become intoxicated or experience various detrimental effects. This fact motivated us for the assessments of THC toxicity in vivo on a Wistar rat model, at a daily oral dose of 7 mg/kg which is comparable to those found in illicit preparations. The main objective of the present study was to establish the magnitude and dynamics of DNA breakage associated with THC exposure in white blood and brain cells of treated rats using the alkaline comet assay. The extent of oxidative stress after acute 24 h exposure to THC was also determined as well as changes in activities of plasma and brain cholinesterases (ChE) in THC-treated and control rats. The DNA of brain cells was more prone to breakage after THC treatment compared to DNA in white blood cells. Even though DNA damage quantified by the alkaline comet assay is subject to repair, its elevated level detected in the brain cells of THC-treated rats was reason for concern. Since neurons do not proliferate, increased levels of DNA damage present threats to these cells in terms of both viability and genome stability, while inefficient DNA repair might lead to their progressive loss. The present study contributes to existing knowledge with evidence that acute exposure to a high THC dose led to low-level DNA damage in white blood cells and brain cells of rats and induced oxidative stress in brain, but did not disturb ChE activities.


Assuntos
Encéfalo/metabolismo , Colinesterases/metabolismo , Dano ao DNA/efeitos dos fármacos , Dronabinol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Catalase/metabolismo , Dano ao DNA/genética , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/genética , Ratos , Ratos Wistar
13.
Chemosphere ; 227: 323-328, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30999172

RESUMO

In the present study, we investigated the association between methylation of DNA damage response-related genes such as cyclin-dependent kinase inhibitor (CDKN)2A, Ras association (RalGDS/AF-6) domain family member (RASSF)1A, O6-methylguanine DNA methyltransferase (MGMT), Kirsten rat sarcoma viral oncogene homolog (KRAS), and spleen-associated tyrosine kinase (SYK) and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride (VC). Sixty-four healthy rats were randomly divided into three VC exposure groups (5, 25, and 125 mg/kg) and an untreated negative control group (n = 16 each). VC was administered by intraperitoneal injection every other day for a total of three times a week. Eight randomly selected rats from each group were sacrificed at the end of 6 and 12 weeks, and liver tissue was harvested for the comet assay and for assessment of DNA methylation level and mRNA expression of related genes by PCR. Overall methylation levels in the genome of hepatocytes in VC-exposed rats were higher than those in the control group at 6 and 12 weeks (P < 0.05), although no differences were observed with regarding to dose (P > 0.05). After 12 weeks of exposure, differences in the methylation of RASSF1A and MGMT promoter regions were observed between the high-dose group and other groups (P < 0.05), whereas no differences were observed for the KRAS, SYK, and CDKN2A promoters (P > 0.05). These results suggest that DNA damage and increased genome-wide methylation are biomarkers for VC exposure and that RASSF1A and MGMT promoter methylation is related to the carcinogenic mechanism of VC.


Assuntos
Dano ao DNA/genética , Metilação de DNA , Hepatócitos/efeitos dos fármacos , Cloreto de Vinil/toxicidade , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Ratos , Proteínas Supressoras de Tumor/genética
14.
Radiol Med ; 124(8): 736-744, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30949891

RESUMO

The frequency of imaging examinations requiring radiation exposure in children (especially CT) is rapidly increasing. This paper reviews the current evidence in radiation protection in pediatric imaging, focusing on the recent knowledge of the biological risk related to low doses exposure. Even if there are no strictly defined limits for patient radiation exposure, it is recommended to try to keep doses as low as reasonably achievable (the ALARA principle). To achieve ALARA, several techniques to reduce the radiation dose in radiation-sensitive patients groups are reviewed. The most recent recommendations that provide guidance regarding imaging of pregnant women are also summarized, and the risk depending on dose and phase of pregnancy is reported. Finally, the risk-benefit analysis of each examination, and careful communication of this risk to the patient, is emphasized.


Assuntos
Doses de Radiação , Exposição à Radiação/prevenção & controle , Proteção Radiológica/métodos , Tolerância a Radiação , Radiação Ionizante , Criança , Pré-Escolar , Dano ao DNA/genética , Feminino , Feto/efeitos da radiação , Fluoroscopia/métodos , Gônadas/efeitos da radiação , Humanos , Neoplasias Induzidas por Radiação/prevenção & controle , Gravidez , Exposição à Radiação/legislação & jurisprudência , Lesões por Radiação/complicações , Lesões por Radiação/prevenção & controle , Proteção Radiológica/legislação & jurisprudência , Radiografia/efeitos adversos , Valores de Referência , Risco , Medição de Risco , Tomografia Computadorizada por Raios X/métodos , Tomografia Computadorizada por Raios X/normas
15.
Cancer Invest ; 37(2): 113-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836777

RESUMO

The 8-hydroxy-2'-deoxyguanosine (8-OHdG) damages are base damages induced by reactive oxygen species. We aimed to investigate the role of Androgen Receptor and NKX3.1 in 8-OHdG formation and repair activation by quantitating the DNA damage using Aklides.NUK system. The data demonstrated that the loss of NKX3.1 resulted in increased oxidative DNA damage and its overexpression contributes to the removal of menadione-induced 8-OHdG damage even under oxidative stress conditions. Moreover, 8-oxoguanine DNA glycosylase-1 (OGG1) expression level positively correlates to NKX3.1 expression. Also in this study, first time a reliable cell-based quantitation method for 8-OHdG damages is reported and used for data collection.


Assuntos
Dano ao DNA/genética , Proteínas de Homeodomínio/genética , Estresse Oxidativo/genética , Neoplasias da Próstata/genética , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Desoxiguanosina/genética , Genômica/métodos , Humanos , Masculino , Células PC-3 , Receptores Androgênicos/genética
16.
Artigo em Inglês | MEDLINE | ID: mdl-30857729

RESUMO

Periodontitis is a bacterial infection characterized by the presence of a dense inflammatory infiltrate, which may result in increased DNA damage and other nuclear/cellular abnormalities. Therefore, it is important to evaluate the periodontal diseases influence on DNA damage and other nuclear/cellular abnomalies formation as cancer risk markers. Thus, the aim of this study was to evaluate the periodontal diseases effect, according to its severity, on the occurrence of DNA damage and other nuclear/cellular abnormalities. This is a cross-sectional study with 77 subjects from the dentistry clinic of the University of Santa Cruz do Sul, Brazil, divided in control group (26 subjects), moderate periodontal disease group (26 subjects) and severe periodontal disease group (25 subjects). All subjects answered self-referenced questionnaires, underwent periodontal clinical examinations and allowed the collection of oral mucosa cells for the BMCyt. In relation to DNA damage biomarkers (micronuclei (MN) and/or nuclear buds (NBUD)), our results indicated no increase in MN frequencies (p > 0.05), however it indicated significant difference in NBUD frequencies between groups (p < 0.024). This result suggests that the periodontal disease status may influence DNA damage. Regarding the other nuclear/cellular abnormalities, was observed a significant difference in the binucleated (BN) frequencies between groups (p < 0.05). Moreover, the periodontitis severity was associated to an increase in the combined (summed) frequency of cells with different levels of DNA damage (MN and/or NBUD), cytokinetic defects (BN cells) and/or cell death (karyorrhexis, pyknotic and karyolytic cells) (r = 0.235; p = 0.040). Periodontal disease depending on its severity, induces nuclear anomalies in buccal cells.


Assuntos
Dano ao DNA/genética , Instabilidade Genômica/genética , Mucosa Bucal/citologia , Periodontite/genética , Adulto , Idoso , Brasil , Estudos Transversais , Feminino , Humanos , Masculino , Micronúcleos com Defeito Cromossômico , Testes para Micronúcleos , Pessoa de Meia-Idade , Periodontite/microbiologia , Periodontite/patologia , Espécies Reativas de Oxigênio/metabolismo , Inquéritos e Questionários
17.
Environ Sci Pollut Res Int ; 26(13): 13366-13380, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30903470

RESUMO

Eight nuclear abnormalities of genotoxicity and cytotoxicity were studied in peripheral blood erythrocytes of herring (Clupea harengus membras), flounder (Platichthys flesus), and Atlantic cod (Gadus morhua) sampled (2010-2017) from the Polish and the Lithuanian Exclusive Economic Zones (EEZ) in the Baltic Sea. At all study stations, total genotoxicity (∑Gentox) was found to be higher than total cytotoxicity (∑Cytox). A significant time-related decrease in genotoxicity was detected in the Lithuanian EEZ (2015-2017), while in the Polish EEZ (2014-2016), the opposite tendency was revealed. The highest ∑Gentox and ∑Cytox values recorded in fish sampled at the study stations located relatively close to each other clearly indicate an increased environmental genotoxicity and cytotoxicity pressure for fish in these areas. Exceptionally high and high-level genotoxicity risks to herring followed by those to flounder and cod were determined at a higher percentage of the stations studied.


Assuntos
Núcleo Celular/química , Dano ao DNA/genética , Peixes/sangue , Animais , Países Bálticos , Dano ao DNA/fisiologia , Linguado , Gadus morhua , Oceanos e Mares , Polônia
18.
Phytother Res ; 33(4): 1084-1094, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30834631

RESUMO

In this study, the antitumor activity of two furanoflavanoid derivatives, Pongapin and Karanjin, was evaluated in comparison with Plumbagin, a plant-derived polyphenol with proven antitumor activity. The compounds differentially inhibit the growth of different cancer cell lines (most effective on HeLa cells), with very low inhibitory effect on the growth of normal mouse embryonic fibroblast cell line. Pongapin like Plumbagin could significantly increase the intracellular reactive oxygen species (ROS) in the HeLa cells by stabilization of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-κB) expression and reduction of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression. In contrast, Karanjin could decrease ROS level by inhibition of I-κB degradation resulting restriction of NF-κB nuclear translocation. Pongapin and Plumbagin significantly increased DNA damage-induced p53 expression and p21 nuclear expression. However, Karanjin treatment showed low DNA damage with increased p53 expression. The compounds induced G2/M arrest and increase in SubG1 population, indicating induction of apoptosis. Apoptosis was further validated by acridine orange/ethidium bromide dual staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay in HeLa cells after treatment with the compounds. The compounds induced caspase-dependent apoptosis through induction of Bax/Bcl-2 ratio either through increased expression of Bax by Pongapin and Plumbagin or low expression of Bcl-2 by Karanjin. Thus, Pongapin and Karanjin may be potential natural anticancer agents in the future, like Plumbagin.


Assuntos
Apoptose/efeitos dos fármacos , Linfócitos B/metabolismo , Benzopiranos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA/genética , Flavonas/uso terapêutico , Millettia/química , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Benzopiranos/farmacologia , Feminino , Flavonas/farmacologia , Células HeLa , Humanos , Transdução de Sinais , Neoplasias do Colo do Útero/patologia
19.
J Biosci ; 44(1)2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30837373

RESUMO

Cancer is a physiological condition that has both the endogenous and exogenous influences on its progression. It originates from unusual cell growth, where the cells undergo massive genetic alterations, bypass the signaling machinery and compromise its genetic cohesion. Literature has well narrated the DNA damage studies including driver mutations that interfere with the treatment strategies. However, with evolving medical excellence, recent day studies are trying to unveil the contribution of RNAs in the progression of tumor malignancies. A number of non-coding RNAs have been identified as an active component in cancer genomics. This article aims to review the role of long non-coding RNAs in the spectra of cancers and its prognostic value as the biomarkers in molecular targeting with clinical utility and therapeutic beneficence.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Dano ao DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias/patologia , Transdução de Sinais/genética
20.
PLoS Genet ; 15(3): e1008001, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30822309

RESUMO

We have used two different live-cell fluorescent protein markers to monitor the formation and localization of double-strand breaks (DSBs) in budding yeast. Using GFP derivatives of the Rad51 recombination protein or the Ddc2 checkpoint protein, we find that cells with three site-specific DSBs, on different chromosomes, usually display 2 or 3 foci that may coalesce and dissociate. This motion is independent of Rad52 and microtubules. Rad51-GFP, by itself, is unable to repair DSBs by homologous recombination in mitotic cells, but is able to form foci and allow repair when heterozygous with a wild type Rad51 protein. The kinetics of formation and disappearance of a Rad51-GFP focus parallels the completion of site-specific DSB repair. However, Rad51-GFP is proficient during meiosis when homozygous, similar to rad51 "site II" mutants that can bind single-stranded DNA but not complete strand exchange. Rad52-RFP and Rad51-GFP co-localize to the same DSB, but a significant minority of foci have Rad51-GFP without visible Rad52-RFP. We conclude that co-localization of foci in cells with 3 DSBs does not represent formation of a homologous recombination "repair center," as the same distribution of Ddc2-GFP foci was found in the absence of the Rad52 protein.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/genética , Quebras de DNA de Cadeia Dupla , Rad51 Recombinase/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Proteínas de Saccharomyces cerevisiae/genética , Dano ao DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Fluorescência Verde/genética , Recombinação Homóloga/genética , Cinética , Meiose/genética , Saccharomyces cerevisiae/genética
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