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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(9): 4805-4810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519582

RESUMO

BACKGROUND/AIM: Ro 90-7501 has been reported as an inhibitor of the amyloid ß42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. MATERIALS AND METHODS: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. RESULTS: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. CONCLUSION: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.


Assuntos
Aminas/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzimidazóis/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo
3.
Anticancer Res ; 39(9): 4845-4851, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519587

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) constitutes 15-20% of all breast carcinomas, affecting younger women more often and has a worse prognosis than other types of breast cancer, due to the combination of more aggressive clinical behavior and lack of molecular targets for therapy. This study assessed the effects of non-genotoxic concentrations of tributyltin isothiocyanate (TBT-ITC) and triphenyltin isothiocyanate (TPT-ITC) on MDA-MB-231 cells. MATERIALS AND METHODS: MTT assay, comet assay, kinetic imaging and flow cytometry were used for analysis of MDA-MB-231 cells. RESULTS: The results showed that 100 nM concentration of TBT-ITC and TPT-ITC, that did not affect viability or DNA integrity, slowed-down migration by CD44 down-regulation. Moreover, both compounds demonstrated immunomodulatory properties, attenuating PD-L1 expression in MDA-MB-231 cells. CONCLUSION: TPT-ITC was more effective in down-regulating CD44 expression and reducing migration than TBT-ITC, while TBT-ITC was more potent in lowering PD-L1 expression in comparison with TPT-ITC.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais , Movimento Celular/efeitos dos fármacos , Isotiocianatos/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Imunofenotipagem , Isotiocianatos/química , Compostos Orgânicos de Estanho/química
4.
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 , 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
5.
J Agric Food Chem ; 67(31): 8668-8676, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31271028

RESUMO

This study investigated the effect of Chlorella vulgaris (C. vulgaris) on genotoxicity, cytotoxicity, and apoptosis in Caco-2 and HT-29 cells. C. vulgaris significantly induced DNA damage in both cell lines at a concentration of 200 µg dry matter/mL (comet tail intensity CTI: 24.6 ± 4.7% for Caco-2, 16.6 ± 0.9% for HT-29). The application of processing (sonication, ball-milling) did not affect the genotoxicity negatively and lowered the lipid peroxidation in C. vulgaris preparations. C. vulgaris-induced intracellular formation of reactive oxygen species in human cell lines and might be responsible for the genotoxic effect. A solid fraction mainly triggered the observed DNA damage (CTI: 41.5 ± 1.9%), whereas a hydrophilic (CTI: 7.9 ± 1.7%) and lipophilic (CTI: 10.2 ± 2.1%) fraction revealed a significantly lower tail intensity. C. vulgaris significantly induced DNA damage in both cell lines possibly through intracellular formation of reactive oxygen species; however, it was repaired after a 2 h recovery time or was even avoided at lower concentrations. In addition, none of the preparations indicated an adverse effect on cell proliferation or revealed apoptotic activity.


Assuntos
Chlorella vulgaris/química , Dano ao DNA/efeitos dos fármacos , Células Epiteliais/citologia , Mutagênicos/toxicidade , Extratos Vegetais/toxicidade , Apoptose/efeitos dos fármacos , Processos Autotróficos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chlorella vulgaris/crescimento & desenvolvimento , Chlorella vulgaris/efeitos da radiação , Ensaio Cometa , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Luz , Peroxidação de Lipídeos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
6.
Chem Biol Interact ; 309: 108713, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31226288

RESUMO

Liver cancer is one of the most frequently occurring types of cancer with high mortality rate. Hepatocellular carcinoma (HCC) frequently metastasizes to lung, portal vein, and portal lymph nodes and most HCCs show strong resistance to conventional anticancer drugs. Cancer stem cells (CSCs) are considered to be responsible for resistance to therapies. Hence, recent advancements in the use of liver cancer stem cells (LCSCs) are rapidly gaining recognition as an efficient and organized means for developing antitumor agents. We aimed to use a non-target-based high-throughput screening (HTS) approach to specifically target α-fetoprotein (AFP)+/cluster of differentiation (CD)133+ HCC present in mixed populations of HCC cells and hepatocytes. Herein, we identified actinomycin D (ActD) as a potential antitumor agent that significantly inhibits activity of LCSCs without affecting the co-cultured hepatocytes. To determine the mechanism of ActD-induced tumor-specificity in LCSC, we applied various cell-based assay models in vitro. In fact, ActD significantly increased reactive oxygen species (ROS) accumulation and DNA damage in Huh7 HCC cells, but not in Fa2N-4 cells, immortalized hepatocytes. Treatment of spheroid-forming LCSCs with ActD effectively decreased spheroid formation and the CD133+ HCC cell population. Importantly, these ActD-mediated effects are a result of inhibition of cystine/glutamate transporter xCT expression, via attenuation of CD133 synthesis. These results indicate that ActD suppresses stemness and malignant properties in HCC cells through destabilization of xCT, by inhibition of CD133 expression in LCSCs. The effects of ActD on LCSCs provide novel therapeutic strategies for targeting cancer stem-like cells in liver cancer.


Assuntos
Antígeno AC133/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Dactinomicina/farmacologia , Expressão Gênica/efeitos dos fármacos , Antígeno AC133/antagonistas & inibidores , Antígeno AC133/genética , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares/efeitos dos fármacos
7.
Eur J Med Chem ; 178: 81-92, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176097

RESUMO

DNA topoisomerase IB (TOP1) regulates DNA topological structure in many cellular metabolic processes and is a validated target for development of antitumor agents. Our previous study revealed that the benzophenanthridone scaffold is a novel chemotype for the discovery of TOP1 inhibitors. In this work, a series of novel 5-aminoethyl substituted benzophenanthridone derivatives have been synthesized and evaluated for TOP1 inhibition and cytotoxicity. Compound 12 exhibits the most potent TOP1 inhibition (+++) and cytotoxicity in human cancer cell lines with GI50 values at nanomolar concentration range. 12 induces the cellular TOP1cc formation and DNA damage, resulting in HCT116 cell apoptosis. The pharmacokinetics, acute toxicity and antitumor efficiency in vivo of 12 were also studied.


Assuntos
Antineoplásicos/farmacocinética , Benzofenantridinas/farmacocinética , Inibidores da Topoisomerase I/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzofenantridinas/síntese química , Benzofenantridinas/metabolismo , Benzofenantridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nat Commun ; 10(1): 2820, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249297

RESUMO

Bats are unusual mammals, with the ability to fly, and long lifespans. In addition, bats have a low incidence of cancer, but the mechanisms underlying this phenomenon remain elusive. Here we discovered that bat cells are more resistant than human and mouse cells to DNA damage induced by genotoxic drugs. We found that bat cells accumulate less chemical than human and mouse cells, and efficient drug efflux mediated by the ABC transporter ABCB1 underlies this improved response to genotoxic reagents. Inhibition of ABCB1 triggers an accumulation of doxorubicin, DNA damage, and cell death. ABCB1 is expressed at higher levels in several cell lines and tissues derived from bats compared to humans. Furthermore, increased drug efflux and high expression of ABCB1 are conserved across multiple bat species. Our findings suggest that enhanced efflux protects bat cells from DNA damage induced by genotoxic compounds, which may contribute to their low cancer incidence.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Quirópteros/genética , Quirópteros/metabolismo , Dano ao DNA/efeitos dos fármacos , Mutagênicos/toxicidade , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Doxorrubicina/toxicidade , Humanos , Camundongos
9.
Food Chem ; 293: 491-498, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151640

RESUMO

Synthetic food preservatives like sodium acetate (SA), sodium benzoate (SB), potassium sorbate (PS) and Butyl paraben (BP) have been widely used in food and pharmacy industries. One of the toxicological aspects of food additives is evaluation of their interaction with serum proteins such as albumin. These additives interaction with human serum albumin (HSA) can exert considerable effect on the absorption, distribution, metabolism and toxicity of chemical compounds. It should be noticed that the aforementioned food preservatives intake increase mainly in the presence of glucose may lead to complex formation of SA, SB, PS and BP with HSA and accelerate the development of variety disease such as cancer, diabetes, multiple sclerosis, brain damage, nausea and cardiac disease. Therefore, to understand the mechanisms of aforementioned food additives interaction and conformational changes of proteins, we aim to review various studies that investigated albumin interaction with these additives using several procedures.


Assuntos
Conservantes de Alimentos/química , Albumina Sérica/química , Citocinas/genética , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Conservantes de Alimentos/toxicidade , Humanos , Estresse Oxidativo/efeitos dos fármacos , Parabenos/química , Parabenos/toxicidade , Acetato de Sódio/química , Acetato de Sódio/toxicidade , Benzoato de Sódio/química , Benzoato de Sódio/toxicidade , Ácido Sórbico/química , Ácido Sórbico/toxicidade
10.
Int J Nanomedicine ; 14: 3911-3928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213808

RESUMO

Background: Several in vitro studies have revealed that zinc oxide nanoparticles (ZnO-NPs) were able to target cancerous cells selectively with minimal damage to healthy cells. Purpose: In the current study, we aimed to evaluate the antitumor activity of ZnO-NPs in Ehrlich solid carcinoma (ESC) bearing mice by measuring their effect on the expression levels of P53, Bax and Bcl2 genes as indicators of apoptotic induction in tumor tissues. Also, we assessed the potential ameliorative or potentiation effect of 100 mg/kg N-acetyl cysteine (NAC) in combination with ZnO-NPs. Materials and methods: ESC bearing mice were gavaged with three different doses of ZnO-NPs (50, 300 and 500 mg/kg body weight) alone or in combination with NAC for seven consecutive days. In addition to measuring the tumor size, pathological changes, zinc content, oxidative stress biomarkers and DNA damage in ESC, normal muscle, liver and kidney tissues were assessed. Results: Data revealed a significant reduction in tumor size with a significant increase in p53 and Bax and decrease in Bcl2 expression levels in the tissues of ZnO-NPs treated ESC bearing mice. Moreover, a significant elevation of MDA accompanied with a significant reduction of CAT and GST. Also, a marked increase in all comet assay parameters was detected in ZnO-NPs treated groups. On the other hand, the combined treatment with ZnO-NPs and NAC significantly reduced reactive oxygen species production and DNA damage in liver and kidney tissues in all ZnO-NPs treated groups. Conclusion: ZnO-NPs exhibited a promising anticancer efficacy in ESC, this could serve as a foundation for developing new cancer therapeutics. Meanwhile, the combined treatment with ZnO-NPs and NAC could act as a protective method for the healthy normal tissue against ZnO-NPs toxicity, without affecting its antitumor activity.


Assuntos
Acetilcisteína/farmacologia , Apoptose , Nanopartículas/toxicidade , Neoplasias/patologia , Estresse Oxidativo , Óxido de Zinco/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspase 3/metabolismo , Dano ao DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , Especificidade de Órgãos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
11.
DNA Cell Biol ; 38(8): 763-772, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170002

RESUMO

Nepenthes plants are a folk medicine in many Southeast Asia countries for curing diseases but its anticancer effect is rarely investigated. The objectives of this study were to investigate the antioral cancer ability of ethyl acetate extract of Nepenthes ventricosa x maxima (EANV). The preferential killing ability of EANV was determined by MTS-based cell viability assays. The bioactive effects were further screened by flow cytometry for apoptosis, oxidative stress, and DNA damage. At 24 h treatment, EANV dose dependently decreased six types of oral cancer cells, but the normal oral cells (HGF-1) kept a 90% viability. EANV also showed chronic antiproliferative effects and inhibited 3D sphere formation ability of oral cancer cells. Ca9-22 and CAL 27 oral cancer cells with high response to EANV increased subG1 populations and enhanced Annexin V- and pancaspase-detected apoptosis in these cells. EANV also induced the generation of reactive oxygen species (ROS) and mitochondrial superoxide and the dysfunction of mitochondrial membrane potential. Moreover, the oxidative DNA damage level such as 8-oxo-2'deoxyguanosine was increased in EANV-treated oral cancer cells. Taken together, EANV has a preferential killing effect against oral cancer cells associated with oxidative stress, apoptosis, and DNA damage, suggesting EANV as a potential antioral cancer agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Caryophyllales/química , Neoplasias Bucais/tratamento farmacológico , Extratos Vegetais/farmacologia , Acetatos/química , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Bucais/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas por Ionização por Electrospray
12.
Chem Biol Interact ; 309: 108689, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31173751

RESUMO

Diabetes mellitus is an independent risk factor for renal impairment in patients exposed to contrast media. It doubles the risk and decreases survival rate of contrast induced nephropathy (CIN). Sulforaphane has antioxidant properties via Nrf2 activation. The interaction of diabetes and/or sulforaphane with contrast media on Nrf2 regulation is not yet understood. Herein, diabetes was induced by a single intra-peritoneal injection of streptozotocin. Animals were then divided into five groups; control non-diabetic group; diabetic group; diabetic/sulforaphane group; diabetic/CIN group; diabetic/CIN/sulforaphane group. Animals were assessed 24 h after CIN induction. Sulforaphane improved the impaired nephrotoxicity parameters, histopathological features, and oxidative stress markers induced by contrast media (meglumine diatrizoate) in diabetic rats. Immunofluorescence detection revealed increased Nrf2 expression in kidney sections after sulforaphane pretreatment. Moreover, gene expression of Nrf2 and HO-1 were up-regulated, while IL-6 and caspase3 were down-regulated in kidney tissues of animals pretreated with sulforaphane. In NRK-52E cells, sulforaphane pretreatment significantly ameliorated the cytotoxicity of meglumine diatrizoate. However, silencing Nrf2 using small interfering RNA (siRNA) abolished the cytoprotective effects of sulforaphane. Collectively, the results of this study suggest that Nrf2/HO-1 pathway has a protective role against CIN and support the clinical implication of Nrf2 activators, such as sulforaphane, in CIN particularly in diabetic patients.


Assuntos
Apoptose/efeitos dos fármacos , Meios de Contraste/toxicidade , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diatrizoato de Meglumina/toxicidade , Isotiocianatos/química , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antioxidantes/química , Linhagem Celular , Meios de Contraste/química , Diabetes Mellitus Experimental/induzido quimicamente , Diatrizoato de Meglumina/química , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Nefrite/induzido quimicamente , Nefrite/metabolismo , Nefrite/patologia , Interferência de RNA , RNA Interferente Pequeno , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
13.
Chemistry ; 25(47): 11085-11097, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31219221

RESUMO

Naphthalene diimide (NDI) dyads exhibiting a different substitution pattern and linker length have been synthesised and evaluated as G-quadruplex (G4) ligands, by investigating their cytotoxicity in selected cell lines. The dyads with the long C7 linker exhibit extremely low IC50 values, below 10 nm, on different cancer cell lines. Contrary, the dyads with the shorter C4 linker were much less effective, with IC values increasing up to 1 µm. Among the three dyads with the longest linker, small differences in the IC50 values emerge, suggesting that the linker length plays a more important role than the substitution pattern. We have further shown that the dyads are able to induce cellular DNA damage response, which is not limited to the telomeric regions and is likely the origin of their cytotoxicity. Both absorption titration and dynamic light scattering of the most cytotoxic dyads in the presence of hTel22 highlight their ability to induce effective G4 aggregation, acting as non-covalent cross-linking agents.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Quadruplex G , Imidas/farmacologia , Naftalenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidas/síntese química , Imidas/química , Ligantes , Metáfase/efeitos dos fármacos , Microscopia de Fluorescência , Naftalenos/síntese química , Naftalenos/química , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Telômero/efeitos dos fármacos , Telômero/metabolismo
14.
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
15.
J Photochem Photobiol B ; 196: 111514, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31154277

RESUMO

Retinal disorders account for a large proportion of ocular disorders that can lead to visual impairment or blindness, and yet our limited knowledge in the pathogenesis and choice of appropriate animal models for new treatment modalities may contribute to ineffective therapies. Although genetic in vivo models are favored, the variable expressivity and penetrance of these heterogeneous disorders can cause difficulties in assessing potential treatments against retinal degeneration. Hence, an attractive alternative is to develop a chemically-induced model that is both cost-friendly and standardizable. Sodium iodate is an oxidative chemical that is used to simulate late stage retinitis pigmentosa and age-related macular degeneration. In this study, retinal degeneration was induced through systemic administration of sodium iodate (NaIO3) at varying doses up to 80 mg/kg in Sprague-Dawley rats. An analysis on the visual response of the rats by electroretinography (ERG) showed a decrease in photoreceptor function with NaIO3 administration at a dose of 40 mg/kg or greater. The results correlated with the TUNEL assay, which revealed signs of DNA damage throughout the retina. Histomorphological analysis also revealed extensive structural lesions throughout the outer retina and parts of the inner retina. Our results provided a detailed view of NaIO3-induced retinal degeneration, and showed that the administration of 40 mg/kg NaIO3 was sufficient to generate disturbances in retinal function. The pathological findings in this model reveal a degenerating retina, and can be further utilized to develop effective therapies for RPE, photoreceptor, and bipolar cell regeneration.


Assuntos
Iodatos/toxicidade , Retina/efeitos dos fármacos , Degeneração Retiniana/patologia , Animais , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Eletrorretinografia , Ratos , Ratos Sprague-Dawley , Retina/patologia , Retina/fisiologia
17.
Nat Commun ; 10(1): 2538, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182708

RESUMO

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Senescência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desoxiadenosinas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Lesões Experimentais por Radiação/prevenção & controle , Úlcera/prevenção & controle , Animais , Apoptose , Linhagem Celular , Senescência Celular/efeitos da radiação , Dano ao DNA/efeitos da radiação , Desoxiadenosinas/toxicidade , Fibroblastos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/patologia , Ratos Sprague-Dawley , Úlcera/tratamento farmacológico , Úlcera/patologia , Raios X/efeitos adversos
18.
Phytother Res ; 33(6): 1627-1638, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069872

RESUMO

Milk thistle (Silybum marianum) is a medicinal plant from the Asteraceae family. Silymarin is the major constituent of milk thistle extract and is a mixture of some flavonolignans such as silybin, which is the most active component of silymarin. It is most commonly known for its hepatoprotective effect. Also, studies have shown other therapeutic effects such as anticancer, anti-Alzheimer, anti-Parkinson, and anti-diabetic, so its safety is very important. It has no major toxicity in animals. Silymarin was mutagen in Salmonella typhimurium strains in the presence of metabolic enzymes. Silybin, silydianin, and silychristin were not cytotoxic and genotoxic at concentration of 100 µM. Silymarin is safe in humans at therapeutic doses and is well tolerated even at a high dose of 700 mg three times a day for 24 weeks. Some gastrointestinal discomforts occurred like nausea and diarrhea. One clinical trial showed silymarin is safe in pregnancy, and there were no anomalies. Consequently, caution should be exercised during pregnancy, and more studies are needed especially in humans. Silymarin has low-drug interactions, and it does not have major effects on cytochromes P-450. Some studies demonstrated that the use of silymarin must be with caution when co-administered with narrow therapeutic window drugs.


Assuntos
Cardo Mariano/química , Extratos Vegetais/uso terapêutico , Silimarina/uso terapêutico , Animais , Antioxidantes/efeitos adversos , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Antioxidantes/toxicidade , Asteraceae/química , Asteraceae/classificação , Sistema Enzimático do Citocromo P-450/metabolismo , Citoproteção/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Interações de Medicamentos , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Cardo Mariano/efeitos adversos , Degeneração Neural/prevenção & controle , Extratos Vegetais/efeitos adversos , Gravidez , Silimarina/efeitos adversos
19.
Ecotoxicol Environ Saf ; 180: 168-178, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31082581

RESUMO

Fluorene-9-bisphenol (BHPF), a substitute for bisphenol A, is a chemical component of plastics for industrial production. There is evidence that BHPF exerts an antioestrogenic effect on mice, induces endometrial atrophy and leads to adverse pregnancy outcomes. However, the effects of BHPF on oocyte maturation and ovary development as well as its possible mechanisms remain unclear. The objective of this study was to investigate the toxicity and mechanism of BHPF exposure in mouse oocytes in vitro and in vivo. Our results showed that BHPF could inhibit the maturation of oocytes in vitro by reducing the protein level of p-MAPK and destroying the meiotic spindle. We found that in vitro, BHPF-treated oocytes showed increased ROS levels, DNA damage, mitochondrial dysfunction, and expression of apoptosis- and autophagy-related genes, such as Bax, cleaved-caspase 3, LC 3 and Atg 12. In addition, in vivo experiments showed that BHPF exposure could induce the expression of oxidative stress genes (Cat, Gpx 3 and Sod 2) and apoptosis genes (Bax, Bcl-2 and Cleaved-caspase 3) and increase the number of atresia follicles in the ovaries. Our data showed that BHPF exposure affected the first polar body extrusion of oocytes, increased oxidative stress, destroyed spindle assembly, caused DNA damage, altered mitochondrial membrane potentials, induced apoptosis and autophagy, and affected ovarian development.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fluorenos/toxicidade , Oócitos/patologia , Ovário/patologia , Fenóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Oogênese/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Estresse Oxidativo/efeitos dos fármacos
20.
Environ Sci Pollut Res Int ; 26(20): 20981-20988, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115805

RESUMO

The impact evaluation of pesticide exposure is conducted using combined data from biomonitoring and environmental monitoring. Damage to the human genome is, probably, the leading cause of chronic-degenerative disorders, reproductive toxicology, and developmental problems. Although the general population is exposed to pesticides, workers in the agrochemical industry and farmers represent a high-risk group due to the occupational and environmental exposure. The aim of this study is to determine whether occupational exposure to agrochemicals in Córdoba (Argentina) constitute a factor of genotoxic damage. The study was conducted in 30 pesticide applicators from the province of Córdoba. Chromosomal aberrations (CAs), micronuclei (MN), and comet assays (CO) were performed. The current study shows that occupational exposure to pesticides increases values of CAs, MN, and DNA fragmentation biomarkers, all indicators of damage to the genetic material. Evidence suggests that chronic exposure to pesticides is a potential risk to workers health.


Assuntos
Doenças dos Trabalhadores Agrícolas/epidemiologia , Dano ao DNA/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Praguicidas/toxicidade , Adulto , Argentina/epidemiologia , Biomarcadores/sangue , Colinesterases/sangue , Colinesterases/toxicidade , Aberrações Cromossômicas/induzido quimicamente , Aberrações Cromossômicas/estatística & dados numéricos , Monitoramento Ambiental/estatística & dados numéricos , Humanos , Masculino , Exposição Ocupacional/estatística & dados numéricos , Praguicidas/sangue
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