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1.
Pathol Oncol Res ; 22(4): 747-54, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27091758

RESUMO

Bladder cancer has been shown to resist programmed cell death with altered expression of both pro-apoptotic and anti-apoptotic proteins. To study is to investigate the apoptotic properties of Diindolylmethane (DIM) and Lupeol on N-Butyl-N-(4-hydroxybutyl) Nitrosamine (BBN) initiated and Dimethylarsinic Acid (DMA) promoted urinary bladder cancer. Sixty male Wistar rats were divided into 6 groups. Group I: Control. Group II: Rats were experimentally developed bladder carcinogenesis with BBN and DMA. Group III and IV: DIM and lupeol were administered after BBN treatment for 28 weeks. Group V and VI: DIM and lupeol alone treatment for 36 weeks. All the experimental rats were maintained and euthanized after 36 weeks protocol. Urinary bladder tissues were collected and processed for further investigations. Apoptotis and cell proliferative marker such as Bax, Bcl-2, caspase-3, caspase-9 and PCNA were quantified using immunohistochemical analysis. The Immunohistochemical expression of Bax, Bcl-2, caspase-3, caspase-9 and PCNA were aberrant in BBN + DMA treated tumor group. Administration of DIM and lupeol inhibited the progression of bladder cancer, induced the expression of apoptotic Bax, caspase-3, caspase-9 and inhibited the expression of anti-apoptotic Bcl-2, PCNA in the urinary bladder of rats. Administration of diindolylmethane and lupeol treatment induces apoptosis and cellular proliferation by its anti-carcinogenic properties. From our results DIM and lupeol would be the agent or adjunct for the treatment of bladder carcinogenesis.


Assuntos
Apoptose/efeitos dos fármacos , Butilidroxibutilnitrosamina/efeitos adversos , Ácido Cacodílico/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Indóis/farmacologia , Triterpenos Pentacíclicos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Carcinogênese , Carcinógenos/administração & dosagem , Caspase 3/metabolismo , Caspase 9/metabolismo , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/metabolismo , Proteína X Associada a bcl-2/metabolismo
2.
J Pharmacokinet Pharmacodyn ; 42(6): 591-609, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26194069

RESUMO

Any statistical model should be identifiable in order for estimates and tests using it to be meaningful. We consider statistical analysis of physiologically-based pharmacokinetic (PBPK) models in which parameters cannot be estimated precisely from available data, and discuss different types of identifiability that occur in PBPK models and give reasons why they occur. We particularly focus on how the mathematical structure of a PBPK model and lack of appropriate data can lead to statistical models in which it is impossible to estimate at least some parameters precisely. Methods are reviewed which can determine whether a purely linear PBPK model is globally identifiable. We propose a theorem which determines when identifiability at a set of finite and specific values of the mathematical PBPK model (global discete identifiability) implies identifiability of the statistical model. However, we are unable to establish conditions that imply global discrete identifiability, and conclude that the only safe approach to analysis of PBPK models involves Bayesian analysis with truncated priors. Finally, computational issues regarding posterior simulations of PBPK models are discussed. The methodology is very general and can be applied to numerous PBPK models which can be expressed as linear time-invariant systems. A real data set of a PBPK model for exposure to dimethyl arsinic acid (DMA(V)) is presented to illustrate the proposed methodology.


Assuntos
Ácido Cacodílico/farmacocinética , Exposição Ambiental , Poluentes Ambientais/farmacocinética , Modelos Biológicos , Modelos Estatísticos , Animais , Teorema de Bayes , Biotransformação , Ácido Cacodílico/efeitos adversos , Ácido Cacodílico/urina , Simulação por Computador , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Poluentes Ambientais/urina , Humanos , Modelos Lineares , Metilaminas/farmacocinética , Camundongos , Medição de Risco
3.
J Hazard Mater ; 181(1-3): 161-9, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20546995

RESUMO

Tens of millions of people worldwide ingest excessive amounts of arsenic (As) through drinking water and food. The dietary intake of seafood is the major As exposure route in humans and can cause As-related adverse health effects including cancers. The aim of this study was to quantify potential cancer risks of As exposure for children and adults through seafood consumption. By coupling the age-specific physiologically based pharmacokinetic (PBPK) model and a Weibull-based dose-response function, a more accurate estimate of urinary arsenic metabolites could be achieved to better characterize potential cancer risks. The simulation results show that the proportion of inorganic As, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in human urine are estimated to total 6.7, 26.9, and 66.4% for children, and 6.2, 27.4, and 66.4% for adults, respectively. The estimated median cumulative cancer incidence ratios were respectively 2.67x10(-6) and 3.83x10(-6) for children and adults, indicating a low cancer risk for local residents exposed to As through the consumption of seafood. However, it is necessary to incorporate other exposure routes into the model to make it more realistic. The methodology proposed here can not only be applied to calculate the concentrations of As metabolites in urine, but also to provide a direct estimation of adverse health effects caused by the calculated internal concentrations.


Assuntos
Arsênio/metabolismo , Arsênio/urina , Exposição Ambiental/efeitos adversos , Contaminação de Alimentos , Substâncias Perigosas/efeitos adversos , Neoplasias/induzido quimicamente , Alimentos Marinhos/efeitos adversos , Fatores Etários , Arsênio/toxicidade , Arsenicais/efeitos adversos , Arsenicais/urina , Ácido Cacodílico/efeitos adversos , Ácido Cacodílico/urina , Humanos , Neoplasias/etiologia , Farmacocinética , Risco
4.
Chem Res Toxicol ; 21(2): 550-3, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18179179

RESUMO

To obtain a rational understanding of the extraordinary interaction of pentavalent thioarsenicals with biorelevant thiol compounds, we carried out ab initio calculations on related arsenic compounds and discussed the correlation between the distribution of observed arsenic species in actual reaction systems and the corresponding calculated reaction enthalpies. Previously, it was considered that pentavalent arsenicals do not form thiol conjugates. However, the dimethylmonothioarsinic acid-glutathione conjugate (DMMTAV-GSH) was recently reported as the first stable conjugate of a pentavalent arsenical with a thiol compound. We carried out detailed analysis of the DMMTAV-GSH formation reaction and demonstrated that this conjugate could be formed nonenzymatically under weakly acidic conditions. On the basis of the ab initio calculations, this conjugation was an exothermic reaction (delta H = -4.85 kcal/mol) and gave the minimum energy point during the reaction sequence of DMMTAV with a thiol compound. However, in the case of dimethylarsinic acid (DMAV), a corresponding oxo acid to DMMTAV, conjugation with a thiol compound is an endothermic reaction (delta H = +0.06 kcal/mol). The minimum energy point of the reaction sequence of DMAV with a thiol compound was the formation of a trivalent dimethylarsinous acid (DMAIII)-GSH conjugate. Because the formation of arsenic-sulfur bonds is one of the major mechanisms for arsenic toxicity, these energetic results could account for the extraordinary behaviors and toxicities of thioarsenicals in vivo and in vitro in comparison with those of the corresponding oxo acids.


Assuntos
Intoxicação por Arsênico , Ácido Cacodílico/análogos & derivados , Poluentes Ambientais/química , Glutationa/química , Modelos Químicos , Ácido Cacodílico/efeitos adversos , Ácido Cacodílico/química , Cromatografia Líquida de Alta Pressão , Poluentes Ambientais/efeitos adversos , Espectrometria de Massas por Ionização por Electrospray , Termodinâmica
5.
Environ Mol Mutagen ; 40(3): 200-6, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12355554

RESUMO

Many aneugenic compounds are known to affect one or more components of the mitotic apparatus leading to an erroneous migration of chromosomes. Malsegregation occurs when a chromosome (or a chromatid) fails to migrate and remains at the metaphase plate. Nondisjunction implies the lack of dissociation between sister chromatids and the migration of both together to the same pole. The aim of the present study was to provide evidence that the aneugenic effect of some metal salts is the consequence of malsegregation at anaphase and that it is not caused by nondisjunction mechanisms. The frequencies of lagging chromosomes at anaphase-telophase of mitosis, hypoploid metaphases, and kinetochore-positive micronuclei induced by cadmium chloride, potassium dichromate, and cacodilic acid (dimethylarsinic acid) in MRC-5 human cells were compared. The data indicate that all the tested compounds are able to induce aneuploidy in MRC-5 human cells. Positive, statistically significant correlations were found when kinetochore-positive micronuclei, hypoploidy, and lagging chromosome frequencies were compared. The results suggest that malsegregation is the main mechanism involved in the induction of aneuploidy by metal salts in MRC-5 cells.


Assuntos
Aneuploidia , Ácido Cacodílico/efeitos adversos , Cloreto de Cádmio/efeitos adversos , Metais/efeitos adversos , Dicromato de Potássio/efeitos adversos , Sais/efeitos adversos , Anáfase/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Cromossomos/ultraestrutura , Corantes/efeitos adversos , Relação Dose-Resposta a Droga , Fibroblastos/citologia , Herbicidas/efeitos adversos , Humanos , Masculino , Testes para Micronúcleos , Não Disjunção Genética , Troca de Cromátide Irmã , Telófase/efeitos dos fármacos , Fatores de Tempo
7.
Cancer Lett ; 134(1): 29-36, 1998 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-10381127

RESUMO

Dimethylarsinic acid (DMAA) is a major metabolite of inorganic arsenicals in mammals. In the present study, we investigated its promoting effects on urinary bladder carcinogenesis in NCI-Black-Reiter (NBR) rats, which lack alpha2u-globulin synthesizing ability. Male 9-14-week-old NBR rats were treated sequentially with 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) for 4 weeks and then given 100 ppm DMAA in their drinking water (group 1) for 32 weeks. Induction of preneoplastic lesions (papillary or nodular hyperplasia) in this DMAA-treated group was significantly increased as compared to the carcinogen alone control group (P < 0.01). The development of carcinomas was also enhanced and a significant increase in the 5-bromo-2'-deoxyuridine (BrdU) labeling index of the urinary bladder epithelial cells was observed for the DMAA treatment group. These results indicate that DMAA has promoting effects on urinary bladder carcinogenesis even in NBR rats, so its effects are not dependent on the presence of alpha2u-globulin.


Assuntos
Ácido Cacodílico/efeitos adversos , Herbicidas/efeitos adversos , Neoplasias da Bexiga Urinária/induzido quimicamente , alfa-Globulinas/análise , Animais , Butilidroxibutilnitrosamina , Ácido Cacodílico/urina , Testes de Carcinogenicidade , DNA de Neoplasias/biossíntese , DNA de Neoplasias/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Imuno-Histoquímica , Rim/química , Rim/citologia , Masculino , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia
8.
J Microsc ; 109(2): 249-51, 1977 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-875010

RESUMO

Circumstantial evidence suggests that sodium cacodylate may be a far greater health hazard than has been generally assumed. Until further information is available, electron microscopists should see that extreme care is exercised during the preparation of cacodylate buffers by their staff.


Assuntos
Arsenicais/efeitos adversos , Ácido Cacodílico/efeitos adversos , Humanos , Microscopia Eletrônica , Doenças Profissionais/induzido quimicamente , Sódio/efeitos adversos
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