Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.895
Filtrar
1.
Toxicol Lett ; 329: 80-84, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360788

RESUMO

A large number of computer-based prediction methods to determine the potential of chemicals to induce mutations at the gene level has been developed over the last decades. Conversely, only few such methods are currently available to predict potential structural and numerical chromosome aberrations. Even fewer of these are based on the preferred testing method for this endpoint, i.e. the micronucleus test. For the present work, in vivo micronucleus test results of 718 structurally diverse compounds were collected and applied for the construction of new models by means of the freely available SARpy in silico model building software. Multiple QSAR models were created using parameter variation and manual verification of (non-) alerting structures. To this extent, the original set of 718 compounds was split into a training (80 %) and a test (20 %) set. SARpy was applied on the training set to automatically extract sets of rules by generating and selecting substructures based on their prediction performance whereas the test set was used to evaluate model performance. Five different splits were made randomly, each of which had a similar balance between positive and negative substances compared to the full dataset. All generated models were characterised by an overall better performance than existing free and commercial models for the same endpoint, while demonstrating high coverage.


Assuntos
Cromossomos/efeitos dos fármacos , Simulação por Computador , Bases de Dados de Ácidos Nucleicos , Testes para Micronúcleos , Modelos Biológicos , Relação Quantitativa Estrutura-Atividade , Animais , Sensibilidade e Especificidade , Software
2.
Mycotoxin Res ; 36(1): 73-81, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31441013

RESUMO

Recently, it was reported that ochratoxin A (OTA) mycotoxin, produced by a number of Aspergillus and Penicillium fungal species, may cause neuropsychological impairment or mental and emotional disorders but the mechanism of neurotoxicity remains unknown. Adverse effects of OTA in human (SHSY5Y) and mouse (HT22) neuronal cell lines were studied in vitro. OTA was found to be non-cytotoxic in both cell lines at concentrations 2.5-30 µmol/l, which are above the levels reported for human and animal plasma. OTA led to slightly elevated chromosomal instability in HT22 cells at concentrations of 15-30 µmol/l after 48 h, while in SHSY5Y cells, no evidence for genotoxic effects was observed at concentrations of 2.5-30 µmol/l. OTA treatment at 10 µmol/l resulted in elevated levels of unmethylated cytosines in CpG dinucleotides (up to 1.4-fold), elevated levels of intracellular reactive oxygen species (up to 1.6-fold), and in elevated levels of oxidized DNA purines (up to 2.2-fold) in both cell lines. Detected global DNA hypomethylation and oxidative stress were found to be reversible in 96 h and 24-72 h, respectively. In general, the observed pattern of OTA-induced effects in both cell lines was similar, but HT22 cells exhibited higher sensitivity, as well as better repair capacity in response to OTA toxicity. In conclusion, the results suggest that oxidative stress and epigenetic changes are directly involved in OTA-induced neurotoxicity, while cytotoxicity and genotoxicity cannot be considered as primary cause of toxicity in neuronal cells in vitro.


Assuntos
Metilação de DNA/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ocratoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular , Cromossomos/efeitos dos fármacos , Humanos , Camundongos , Micotoxinas/toxicidade , Neurônios/patologia , Síndromes Neurotóxicas
3.
Mutat Res ; 847: 403025, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31699346

RESUMO

An aneuploidy workgroup was established as part of the 7th International Workshops on Genotoxicity Testing. The workgroup conducted a review of the scientific literature on the biological mechanisms of aneuploidy in mammalian cells and methods used to detect chemical aneugens. In addition, the current regulatory framework was discussed, with the objective to arrive at consensus statements on the ramifications of exposure to chemical aneugens for human health risk assessment. As part of these efforts, the workgroup explored the use of adverse outcome pathways (AOPs) to document mechanisms of chemically induced aneuploidy in mammalian somatic cells. The group worked on two molecular initiating events (MIEs), tubulin binding and binding to the catalytic domain of aurora kinase B, which result in several adverse outcomes, including aneuploidy. The workgroup agreed that the AOP framework provides a useful approach to link evidence for MIEs with aneuploidy on a cellular level. The evidence linking chemically induced aneuploidy with carcinogenicity and hereditary disease was also reviewed and is presented in two companion papers. In addition, the group came to the consensus that the current regulatory test batteries, while not ideal, are sufficient for the identification of aneugens and human risk assessment. While it is obvious that there are many different MIEs that could lead to the induction of aneuploidy, the most commonly observed mechanisms involving chemical aneugens are related to tubulin binding and, to a lesser extent, inhibition of mitotic kinases. The comprehensive review presented here should help with the identification and risk management of aneugenic agents.


Assuntos
Rotas de Resultados Adversos , Aneuploidia , Doenças Genéticas Inatas/induzido quimicamente , Mitose/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Neoplasias/induzido quimicamente , Animais , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/fisiologia , Carcinógenos/toxicidade , Aberrações Cromossômicas/induzido quimicamente , Segregação de Cromossomos/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Genes Reporter , Doenças Genéticas Inatas/genética , Células Germinativas/efeitos dos fármacos , Células Germinativas/ultraestrutura , Humanos , Camundongos , Testes para Micronúcleos , Microtúbulos/efeitos dos fármacos , Mitose/fisiologia , Testes de Mutagenicidade/normas , Mutagênicos/análise , Neoplasias/genética , Não Disjunção Genética/efeitos dos fármacos , Gestão de Riscos/legislação & jurisprudência , Moduladores de Tubulina/toxicidade
4.
Mutat Res ; 847: 403032, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31699349

RESUMO

Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process. Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence. The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.


Assuntos
Aneuploidia , Carcinogênese/genética , Carcinógenos/toxicidade , Instabilidade Cromossômica , Testes de Mutagenicidade/métodos , Neoplasias/induzido quimicamente , Animais , Centrossomo , Transtornos Cromossômicos/genética , Cromossomos/efeitos dos fármacos , Síndrome de Down/complicações , Síndrome de Down/genética , Predisposição Genética para Doença , Humanos , Camundongos , Modelos Animais , Testes de Mutagenicidade/normas , Mutagênicos/toxicidade , Neoplasias/genética , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Fuso Acromático/efeitos dos fármacos , Moduladores de Tubulina/toxicidade
5.
Cytogenet Genome Res ; 157(3): 158-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974432

RESUMO

Amongst 15 bird species, representative of 7 orders, recurrent breakages evocating the presence of fragile sites were detected in the chromosomes of the 5 species belonging to Passeriformes. These breaks appeared when 5-bromodeoxyuridine (BrdU) was added to the cell culture medium at a dose inefficient for inducing chromosome structure alterations in other birds and mammals. They involved, similarly in male and female, 3 loci on the Z chromosome of 3 Turdus species (Turdidae). Labeling by BrdU antibody confirmed the correlation between BrdU incorporation into DNA and breakage, especially around and in the sites of breakage. Thus, 3 BrdU-sensitive fragile sites were present in the Z chromosomes of these birds. Three fragile sites were also detected at different locations in the Z chromosomes of the European robin (Erithacus rubecula, Muscicapidae), suggesting that a structural rearrangement occurred during the evolution of Turdidae and Muscicapidae. Chromosome banding confirmed this interpretation. Finally, in the more distantly related species Parus major (Paridae), the almost acrocentric Z chromosome displayed a single BrdU-sensitive fragile site in its short arm, and the W appeared to be pulverized by BrdU incorporation. Although it cannot be excluded that the BrdU-sensitive fragile sites may be involved in rearrangements, their conservation in many species, and possibly all Passeriformes, provides evidence that they do not constitute a pejorative character during evolution.


Assuntos
Bromodesoxiuridina/farmacologia , Cromossomos/efeitos dos fármacos , Passeriformes/genética , Animais , Composição de Bases , Bandeamento Cromossômico , Sítios Frágeis do Cromossomo , Cromossomos/genética , Evolução Molecular , Feminino , Masculino , Passeriformes/classificação
6.
Biochem Biophys Res Commun ; 513(2): 313-318, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30955862

RESUMO

Topo II inhibitors, e.g. etoposide, doxorubicin and mitoxantrone, etc., which exert their functions by trapping the covalent 'topo II-DNA cleavable complex' via intercalation into DNA base pairs, leading to DNA damage and degradation of topo II, and inducing decline of cell sensitivity and corresponding multidrug resistance (MDR). E17 is a recently identified topo II inhibitor in our lab which has validated to possess a strong topo II inhibitory activity on cell viability, colony formation, and cell migration. Especially, E17 can trigger G2/M cell cycle arrest through inhibiting chromosome condensation without causing obvious DNA damage in colorectal cancer (CRC) HCT116 cell. E17 can also induce the accumulation of topo II-DNA complex without leading to degradation of topo II, which was different from topo II inhibitors VP16 or ICRF-187, suggesting E17 might be a potential lead for further development by serving as a strong topo II inhibitor.


Assuntos
Antineoplásicos/farmacologia , Cromossomos/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromossomos/metabolismo , Cromossomos/ultraestrutura , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Descoberta de Drogas , Células HCT116 , Células HeLa , Humanos , Inibidores da Topoisomerase II/química
7.
Artigo em Inglês | MEDLINE | ID: mdl-30771494

RESUMO

The progressive growth of aquaculture implicates a dependence on large water amounts, which are submitted to disinfection processes, namely ozonation. Considering the importance of genomic integrity, it is critical to improve the knowledge on ozone-related genotoxic hazard to organisms reared in recirculating aquaculture systems (RAS) applying ozonation. Therefore, genetic damage induced by ozone exposure in the Senegalese sole (Solea senegalensis) was assessed, combining the comet and the erythrocytic nuclear abnormalities (ENA) assays, reflecting different damage levels, i.e. DNA and chromosomal damage, respectively. Fish were subjected to a daily 6-h ozone (0.15 mg L-1) exposure, repeated for 3 consecutive days, simulating a short-term event of overozonation. To assess the temporal impact of the previous event, the progression of damage was evaluated 7 days later, following transference to ozone-free water or to 0.07 mg L-1 ozone, a routinely adopted level in RAS. Both endpoints pointed to the ozone genotoxic potential, displaying DNA oxidation as a possible mechanism of damage. Overall, the present findings pointed out the genotoxic hazard of ozone to fish, highlighting the importance of these types of studies and contributing to improve aquaculture practices, namely in RAS systems. These early genotoxic signals may be a prelude to negative repercussions on fish health, which may affect the aquaculture productivity. The present findings recommend precautions in relation to accidental or intentional overozonation in fish-farming, even when short-term events are considered. The strategies to mitigate the impact of ozonation in S. senegalensis may include a dietary extra supplementation of antioxidants (regularly, or punctually in cases of overozonation).


Assuntos
Aberrações Cromossômicas/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Linguados/genética , Ozônio/toxicidade , Purificação da Água/métodos , Animais , Aquicultura/métodos , Dano ao DNA , Estresse Oxidativo
8.
Biomolecules ; 9(2)2019 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-30691136

RESUMO

It has recently emerged that human chromosomes vary between one another in terms of features that impact their behaviour during impaired chromosome segregation, leading to non-random aneuploidy in the daughter cell population. During the process of chromosome congression to the metaphase plate, chromosome movement is guided by kinesin-like proteins, among which centromere-associated protein E (CENP-E) is important to transport chromosomes along the microtubules of the mitotic spindle. It is known that the inhibition of CENP-E notably impairs alignment for a subset of chromosomes, particularly those positioned close to the centrosome at nuclear envelope breakdown ('polar chromosomes'); it is, however, not clear whether chromosome identity could influence this process. Since a popular strategy to model aneuploidy is to induce congression defects (for example combining CENP-E inhibitors with mitotic checkpoint abrogation), variance in congression efficiency between chromosomes might influence the landscape of aneuploidy and subsequent cell fates. By combining immunofluorescence, live cell imaging and fluorescence in situ hybridisation, we investigated the behaviour of polar chromosomes and their dependency upon CENP-E-mediated congression in human cells. We observed a bias in congression efficiency related to chromosome size, with larger chromosomes more sensitive to CENP-E inhibition. This bias is likely due to two contributing factors; an initial propensity of larger chromosomes to be peripheral and thus rely more upon CENP-E function to migrate to the metaphase plate, and additionally a bias between specific chromosomes' ability to congress from a polar state. These findings may help to explain the persistence of a subset of chromosomes at the centrosome following CENP-E disruption, and also have implications for the spectrum of aneuploidy generated following treatments to manipulate CENP-E function.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cromossomos/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células Cultivadas , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Aberrações Cromossômicas/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Humanos , Sarcosina/análogos & derivados , Sarcosina/farmacologia
9.
J Cell Physiol ; 234(5): 7492-7497, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30478952

RESUMO

Intersectins (ITSNs) have been shown to act as adaptor proteins that govern multiple cellular events via regulating Cdc42 activity. However, it remains to be determined whether the ITSN-Cdc42 pathway is functional in porcine oocytes. To address this question, we used a small molecule, ZCL278, to selectively disrupt the ITSN2-Cdc42 interaction. In the present study, we find that porcine oocytes exposed to ZCL278 are unable to completely progress through meiosis. Meanwhile, the spindle defects and chromosomal congression failure are frequently detected in these oocytes. In support of this, we observed the accumulated distribution of vesicle-like ITSN2 signals around the chromosome/spindle region during porcine oocyte maturation. In addition, our results also showed that inhibition of the ITSN-Cdc42 interaction impairs the actin polymerization in porcine oocytes. In summary, the findings support a model where ITSNs, through the interaction with Cdc42, modulates the assembly of meiotic apparatus and actin polymerization, consequently ensuring the orderly meiotic progression during porcine oocyte maturation.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Meiose/fisiologia , Oócitos/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Actinas/metabolismo , Animais , Benzamidas/farmacologia , Segregação de Cromossomos/efeitos dos fármacos , Segregação de Cromossomos/fisiologia , Cromossomos/efeitos dos fármacos , Cromossomos/metabolismo , Feminino , Meiose/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/metabolismo , Fuso Acromático/fisiologia , Suínos , Tioureia/análogos & derivados , Tioureia/farmacologia
10.
Biol Trace Elem Res ; 190(2): 318-326, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30443707

RESUMO

Iron deficiency is the most prevalent nutritional deficiency and the main cause of anemia worldwide. Since children aged 6-24 months are among the most vulnerable groups at risk, daily supplementation with ferrous sulfate is recommended by the Argentine Society of Pediatrics as preventive treatment of anemia. However, a single weekly dose would have fewer adverse side effects and has been therefore proposed as an alternative treatment. Ferrous sulfate is known by its pro-oxidative properties, which may lead to increased oxidative stress as well as lipid, protein, and DNA damage. We analyzed the effect of daily and weekly preventive treatment of iron deficiency anemia (IDA) on cell viability, oxidative stress, chromosome, and cytomolecular damage in peripheral blood cultured in vitro. The study protocol included the following: untreated negative control; bleomycin, hydrogen peroxide, or ethanol-treated positive control; daily 0.14 mg ferrous sulfate-supplemented group; and weekly 0.55 mg ferrous sulfate-supplemented group. We assessed cell viability (methyl-thiazolyl-tetrazolium and neutral red assays), lipid peroxidation (thiobarbituric acid reactive substances assay), antioxidant response (superoxide dismutase and catalase enzyme analysis), chromosome damage (cytokinesis-blocked micronucleus cytome assay), and cytomolecular damage (comet assay). Lipid peroxidation, antioxidant response, and chromosome and cytomolecular damage decreased after weekly ferrous sulfate supplementation (p < 0.05), suggesting less oxygen free radical production and decreased oxidative stress and genomic damage. Such a decrease in oxidative stress and genomic damage in vitro positions weekly supplementation as a better alternative for IDA treatment. Further studies in vivo would be necessary to corroborate whether weekly supplementation could improve IDA preventive treatment compliance in children.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Cromossomos/efeitos dos fármacos , Dano ao DNA , Compostos Ferrosos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adulto , Anemia Ferropriva/sangue , Anemia Ferropriva/prevenção & controle , Sobrevivência Celular/efeitos dos fármacos , Cromossomos/genética , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Compostos Ferrosos/administração & dosagem , Humanos , Relação Estrutura-Atividade , Adulto Jovem
11.
Environ Mol Mutagen ; 60(2): 154-167, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30387535

RESUMO

Infant acute leukemias are aggressive and characterized by rapid onset after birth. The majority harbor translocations involving the MLL gene with AF9 as one of its most common fusion partners. MLL and AF9 loci contain breakpoint cluster regions (bcrs) with sequences hypothesized to be targets of topoisomerase II inhibitors that promote translocation formation. Overlap of MLL bcr sequences associated with both infant acute leukemia and therapy-related leukemia following exposure to the topoisomerase II inhibitor etoposide led to the hypothesis that exposure during pregnancy to biochemically similar compounds may promote infant acute leukemia. We established a reporter system to systematically quantitate and stratify the potential for such compounds to promote chromosomal translocations between the MLL and AF9 bcrs analogous to those in infant leukemia. We show bioflavonoids genistein and quercetin most biochemically similar to etoposide have a strong association with MLL-AF9 bcr translocations, while kaempferol, fisetin, flavone, and myricetin have a weak but consistent association, and other compounds have a minimal association in both embryonic stem (ES) and hematopoietic stem cell (HSC) populations. The frequency of translocations induced by bioflavonoids at later stages of myelopoiesis is significantly reduced by more than one log. The MLL and AF9 bcrs are sensitive to these agents and recombinogenic independent of their native context suggesting bcr sequences themselves are drivers of illegitimate DNA repair reactions and translocations, not generation of functional oncogenic fusions. This system provides for rapid systematic screening of relative risk, dose dependence, and combinatorial impact of multitudes of dietary and environmental exposures on MLL-AF9 translocations. Environ. Mol. Mutagen. 60: 154-167, 2019. © 2018 Wiley Periodicals, Inc.


Assuntos
Flavonoides/toxicidade , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética/efeitos dos fármacos , Quebra Cromossômica/efeitos dos fármacos , Pontos de Quebra do Cromossomo/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Cromossomos/genética , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Lactente , Leucemia/induzido quimicamente , Leucemia/patologia , Gravidez , Medição de Risco
12.
Mutagenesis ; 34(1): 91-100, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30085209

RESUMO

Two major endpoints for genotoxicity tests are gene mutation and chromosome damage (CD), which includes clastogenicity and aneugenicity detected by chromosomal aberration (CA) test or micronucleus (MN) test. Many in silico prediction systems for bacterial mutagenicity (i.e. Ames test results) have been developed and marketed. They show good performance for prediction of Ames mutagenicity. On the other hand, it seems that in silico prediction of CD does not progress as much as Ames prediction. Reasons for this include different mechanisms and detection methods, many false positives and conflicting test results. However, some (quantitative) structure-activity relationship ((Q)SAR) models (e.g. Derek Nexus [Derek], ADMEWorks [AWorks] and CASE Ultra [MCase]) can predict CA test results. Therefore, performances of the three (Q)SAR models were compared using the expanded Carcinogenicity Genotoxicity eXperience (CGX) dataset for understanding current situations and future development. The constructed dataset contained 440 chemicals (325 carcinogens and 115 non-carcinogens). Sensitivity, specificity, accuracy or applicability of each model were 56.0, 86.9, 68.6 or 89.1% in Derek, 67.7, 61.5, 65.2 or 99.3% in AWorks, and 91.0, 64.9, 80.5 or 97.7% in MCase, respectively. The performances (sensitivity and accuracy) of MCase were higher than those of Derek or AWorks. Analysis of predictivity of (Q)SAR models of certain chemical classes revealed no remarkable differences among the models. The tendency of positive prediction by (Q)SAR models was observed in alkylating agents, aromatic amines or amides, aromatic nitro compounds, epoxides, halides and N-nitro or N-nitroso compounds. In an additional investigation, high sensitivity but low specificity was noted in in vivo MN prediction by MCase. Refinement of test data to be used for in silico system (e.g. consideration of cytotoxicity or re-evaluation of conflicting test results) will be needed to improve performance of CD prediction.


Assuntos
Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Mutagênicos/química , Relação Quantitativa Estrutura-Atividade , Carcinógenos/toxicidade , Aberrações Cromossômicas/efeitos dos fármacos , Simulação por Computador , Testes de Mutagenicidade , Mutagênicos/toxicidade
13.
Wei Sheng Yan Jiu ; 47(6): 966-970, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30593330

RESUMO

OBJECTIVE: To explore the effect of cadmium on nerve function and whether the phosphatase and tensin homolog deleted on chromosome ten(PTEN)was involved in its toxicity. METHODS: The healthy adult ICR mice were randomly divided into4 groups which included CdCl_20, 0. 5, 1. 0 and 2. 0 mg/kg, all the mice were intraperitoneally injected administration every day for 14 days. 15-point disease score scale were used to assess neurological function, after the elevation, all the brain were removed and harvested, the level of MDA, CAT, GSH and T-SOD were elevated. qRT-PCR and western blotting were used to detected the expression of PTEN. SPSS 20. 0 was used to analyze the data. RESULTS: The body weight in CdCl_22. 0 mg/kg group was(-0. 6±0. 9)g, was significant lower than the others(F=9. 211, P<0. 05);the level of MDA in2. 0 mg/kg was increased[(19. 3±3. 7)nmol/mg pro](F=4. 123, P<0. 05)and GSH[(81. 1±8. 2)mg/g pro]decreased compared with the blank(F=7. 644, P<0. 05);the level of CAT in 1. 0 mg/kg[(56. 0±8. 5)U/mg pro]was decreased compared with the blank and 0. 5 mg/kg(F=3. 542, P<0. 05);the level of p-PTEN(Ser380)was significantly improved in western blotting(F=389. 2, P<0. 05). CONCLUSION: Cadmium cause the damage to the nervous system at least partially by activating the lipid phosphatase activity of PTEN.


Assuntos
Cádmio , Sistema Nervoso , PTEN Fosfo-Hidrolase , Tensinas , Animais , Encéfalo , Cádmio/toxicidade , Cromossomos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Sistema Nervoso/efeitos dos fármacos , PTEN Fosfo-Hidrolase/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Tensinas/genética
14.
Future Microbiol ; 13: 1637-1646, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30480459

RESUMO

AIM: Geraniol and linalool are major constituents of the essential oils of medicinal plants. MATERIALS & METHODS: Antifungal activity of geraniol and linalool were evaluated against five Candida species. The genotoxicity of these compounds was evaluated by the cytokinesis-block micronucleus test, and the embryotoxic assays use zebrafish model. RESULTS: Geraniol and linalool inhibited Candida growth, but geraniol was more effective. The geraniol at concentration of 800 µg/ml and the linalool at concentration of 125 µg/ml significantly increased chromosome damage. Geraniol was more toxic to zebrafish embryo than linalool: LC50 values were 31.3 and 193.3 µg/ml, respectively. CONCLUSION: Geraniol and linalool have anticandidal activity, but they also exert genotoxic and embryotoxic effects at the highest tested concentrations.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Monoterpenos/farmacologia , Terpenos/farmacologia , Peixe-Zebra , Monoterpenos Acíclicos , Animais , Candida/crescimento & desenvolvimento , Linhagem Celular/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Testes de Mutagenicidade , Óleos Voláteis/farmacologia , Plantas Medicinais/química , Análise de Sobrevida , Teratogênios
15.
Biometals ; 31(6): 1101-1114, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30284644

RESUMO

The rise of antibiotic resistance in pathogenic bacteria is endangering the efficacy of antibiotics, which consequently results in greater use of silver as a biocide. Chromosomal mapping of the Cus system or plasmid encoded Sil system and their relationship with silver resistance was studied for several gram-negative bacteria. However, only few reports investigated silver detoxification mediated by the Sil system integrated in Escherichia coli chromosome. Accordingly, this work aimed to study the Sil system in E. coli ATCC 8739 and to produce evidence for its role in silver resistance development. Silver resistance was induced in E. coli ATCC 8739 by stepwise passage in culture media containing increasing concentrations of AgNO3. The published genome of E. coli ATCC 8739 contains a region showing strong homology to the Sil system genes. The role of this region in E. coli ATCC 8739 was assessed by monitoring the expression of silC upon silver stress, which resulted in a 350-fold increased expression. De novo sequencing of the whole genome of a silver resistant strain derived from E. coli ATCC 8739 revealed mutations in ORFs putative for SilR and CusR. The silver resistant strain (E. coli AgNO3R) showed constitutive expression of silC which posed a cost of fitness resulting in retarded growth. Furthermore, E. coli AgNO3R exhibited cross-resistance to ciprofloxacin and a slightly increased tolerance to ampicillin. This study demonstrates that E. coli is able to develop resistance to silver, which may pose a threat towards an effective use of silver compounds as antiseptics.


Assuntos
Antibacterianos/farmacologia , Cromossomos/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Nanopartículas Metálicas/química , Prata/farmacologia , Mapeamento Cromossômico , Testes de Sensibilidade Microbiana
16.
Toxicol Appl Pharmacol ; 361: 62-67, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30030095

RESUMO

In vitro studies using target and effecter cells of mineral-induced cancers have been critical in determining the mechanisms of pathogenesis as well as the properties of elongated mineral particles (EMPs) important in eliciting these responses. Historically, in vitro models of 'mutagenesis' and immortalized cell lines were first used to test the theory that EMPs were mutagenic to cells, and 'genotoxicity', as defined as damage to DNA often culminating in cell death, was observed in a dose-dependent fashion as responses of many cell types to a number of EMPs. As two-stage and multi-step models of cancer development emerged in the 1970s and 1980s, differentiated 3D organ cultures and monolayers of lung epithelial and mesothelial cells were used to probe the mechanisms of cancer development. These studies demonstrated a spectrum of pre-neoplastic changes, including hyperplasia and squamous metaplasia, in response to long (>5 µm in length) needlelike EMPs whereas long, curly chrysotile fibers caused acute cytotoxicity. Shorter fibers of many types were taken up by cells and encompassed in phagolysosomes. Comparative studies using chemical carcinogens showed that chemical agents interacted directly with DNA whereas long EMPs appeared to be promoters of cancers via a number of mechanisms such as inflammation, generation of oxidants, and instigation of cell division. The multitude of these signaling cascades and epigenetic mechanisms of both lung cancers and mesotheliomas have been most recently studied in normal or telomerase immortalized human cells. Importantly, many of these pathways are elicited by long, straight amphibole asbestos fibers or carbon nanotubes in rodents and not by short (<5 µm) EMPs, fragments, or nonfibrous particles. However, the chemistry and surface properties of long fibers are also critical in cell responses to minerals.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Carcinógenos/toxicidade , Minerais/toxicidade , Animais , Asbestos/toxicidade , Carcinogênese , Transformação Celular Neoplásica/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , DNA/efeitos dos fármacos , Humanos
17.
Mater Sci Eng C Mater Biol Appl ; 89: 205-212, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29752090

RESUMO

Here, a facile method for the preparation of polymeric particles from a sugar molecule, maltitol (ML) in single step was reported via microemulsion polymerization/crosslinking technique with a high yield, 89 ±â€¯6%. Furthermore, poly(Maltitol) (p(ML)) particles were chemically modified to induce different physicochemical characteristic using different anionic and cationic modifying agents such as taurine (TA) and diethylenetriamine (DETA) to prepare m-p(ML)/TA and m-p(ML)/DETA. The blood compatibility of the p(ML) particles and their modified forms were tested with fresh blood, and found that p(ML) and m-(ML)/DETA particles are blood compatible with about 5% hemolysis, and above 80% blood clotting indices. Moreover, the cytotoxicity results against L929 fibroblast cell line revealed that p(ML) based particle are biocompatible up to 100 µg/mL with 85% cell viability regardless of their nature, and at 200 µg/mL dosage of p(ML), m-p(ML)/TA and m-p(ML)/DETA particles, the cell viabilities were determined as 83.33, 64.03 and 73.89% on for L929 fibroblast cells implying the slightly less biocompatibility nature of m-p(ML)/TA in accord with the blood compatibility results. Additionally, the apoptotic and necrotic indices were determination for p(ML) based particles on L929 fibroblast cells, and the results revealed that these particles do not induce any and stress on the cells. Also, it does not have genotoxic effect as determined against CHO cells.


Assuntos
Materiais Biocompatíveis/química , Maltose/análogos & derivados , Polímeros/química , Álcoois Açúcares/química , Açúcares/química , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Cromossomos/metabolismo , Ciprofloxacino/química , Ciprofloxacino/metabolismo , Cricetinae , Cricetulus , Portadores de Fármacos/química , Hemólise/efeitos dos fármacos , Humanos , Maltose/síntese química , Maltose/química , Maltose/farmacologia , Tamanho da Partícula , Poliaminas/química , Álcoois Açúcares/síntese química , Álcoois Açúcares/farmacologia , Taurina/química
18.
Int J Radiat Biol ; 94(6): 558-568, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29671693

RESUMO

PURPOSE: Exposure to ionizing radiation causes damage to the genomic integrity and stability of the cell. Though a large number of molecules have been studied for their radioprotective capability, no single agent is available today that meets all the requirements of a good radiprotector. In this study, we have investigated a combination of Resveratrol (RSV) and 3,3'-Diindolyl methane (DIM) for its efficacy for radioprotection. It is our hypothesis that this combination that possesses less toxicity than synthetic compounds, free radical scavenging potential, and the capacity to interfere with the several of the signaling cascades that trigger damage to cell by ionizing radiation may possess good radioprotective capability. MATERIALS AND METHODS: Mice were pre-treated with a combination of RSV and DIM and the 30-day mortality assay, endogenous antioxidant levels in intestinal mucosa, metaphase chromosomal aberrations, and micronuclei formation were assessed after exposed to ionizing radiation. RESULTS: The dose modifying factor (DRF) obtained for RSV, DIM, and the combination is 1.15, 1.17, and 1.3, respectively. Pre-treatment of mice with the combination results in significant (***p = .001) protection of the endogenous antioxidant levels, chromosomal aberrations, micronuclei formation, after exposure to ionizing radiation. CONCLUSIONS: Our findings suggest that pre-treatment with the combination of RSV and DIM protects effectively from the ionizing radiation-induced damage at the molecular, cellular, and tissue levels by counteracting both the direct and indirect effects.


Assuntos
Indóis/farmacologia , Protetores contra Radiação/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos da radiação , Cromossomos/efeitos dos fármacos , Cromossomos/efeitos da radiação , Interações Medicamentosas , Hematopoese/efeitos dos fármacos , Hematopoese/efeitos da radiação , Masculino , Camundongos
19.
Comb Chem High Throughput Screen ; 21(4): 262-270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29600754

RESUMO

BACKGROUND: More than 2,000 chemicals have been used in the tannery industry. Although some tannery chemicals have been reported to have harmful effects on both human health and the environment, only a few have been subjected to genotoxicity and cytotoxicity evaluations. OBJECTIVE: This study focused on cytotoxicity and genotoxicity of ten tannery chemicals widely used in China. MATERIALS AND METHODS: DNA-damaging effects were measured using the SOS/umu test with Salmonella typhimurium TA1535/pSK1002. Chromosome-damaging and cytotoxic effects were determined with the high-content in vitro Micronucleus test (MN test) using the human-derived cell lines MGC-803 and A549. CONCLUSION: The cytotoxicity of the ten tannery chemicals differed somewhat between the two cell assays, with A549 cells being more sensitive than MGC-803 cells. None of the chemicals induced DNA damage before metabolism, but one was found to have DNA-damaging effects on metabolism. Four of the chemicals, DY64, SB1, DB71 and RR120, were found to have chromosome-damaging effects. A Quantitative Structure-Activity Relationship (QSAR) analysis indicated that one structural feature favouring chemical genotoxicity, Hacceptor-path3-Hacceptor, may contribute to the chromosome-damaging effects of the four MN-test-positive chemicals.


Assuntos
Substâncias Perigosas/farmacologia , Testes para Micronúcleos , Curtume/métodos , Animais , Linhagem Celular , China , Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Humanos , Mutagênicos , Relação Quantitativa Estrutura-Atividade , Salmonella typhimurium/efeitos dos fármacos
20.
Sci Rep ; 8(1): 3371, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29463873

RESUMO

For mutagenicity testing, primary lymphocytes or mammalian cell lines are employed. However, the true target for carcinogenic action of mutagenic chemicals may be stem cells. Since hematopoietic cancers induced by chemical agents originate at the hematopoietic stem cell (HSC) stage and since one of the side effects of chemotherapeutic cancer treatment is the induction of secondary tumors, often leukemias, HSC may be a suitable cell system. We compared the sensitivity of HSC with the genotoxicity testing cell line TK6 for chromosomal mutations. HSC were less sensitive than TK6 cells for the genotoxic effects of the model genotoxins and chemotherapeutic agents doxorubicin, vinblastine, methyl methanesulfonate (MMS) and equally sensitive for mitomycin C (MMC). However, loss of viability after mitomycin C treatment was higher in HSC than in TK6 cells. Among the factors that may influence sensitivity for genomic damage, the generation or response to reactive oxygen species (ROS) and the effectiveness of DNA damage response can be discussed. Here we show that HSC can be used in a standard micronucleus test protocol for chromosomal mutations and that their sensitivity was not higher than that of a classical testing cell line.


Assuntos
Núcleo Celular/efeitos dos fármacos , Citostáticos/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Mutagênicos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Humanos , Mutação , Sensibilidade e Especificidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA