Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 85
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Shokuhin Eiseigaku Zasshi ; 61(1): 34-40, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32336717

RESUMO

Some illegal dietary supplements contain phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, for exerting "therapeutic" effects in erectile dysfunction. This is apparently dangerous, and thus, should be appropriately regulated. Identification of descarbonsildenafil was first reported in Singapore in a coffee sample labeled to exert male sexual performance enhancement effects. However, it is unclear whether the compound possesses PDE5 inhibitory activity. We encountered during our survey of dietary supplements, a sexual enhancement product commercially available in Tokyo, in which a peak presumed to be of descarbonsildenafil was detected by LC-UV and electrospray ionization-tandem MS (ESI-MS/MS). The compound was isolated and identified as descarbonsildenafil with liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS), NMR, and X-ray crystal structural analysis. In addition, descarbonsildenafil showed PDE5 inhibitory activity in PDE5 inhibition assay, and its IC50 value for PDE5A1 was found to be 30 nmol/L. The results of INADEQUATE NMR and X-ray crystal structural analysis in this study provide information for the identification of descarbonsildenafil. Since this study indicates that this compound is a PDE5 inhibitor having adequate activity, it is regulated as a drug component in Japan.

2.
J Toxicol Pathol ; 32(2): 119-126, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31092979

RESUMO

The Standard for Exchange of Nonclinical Data (SEND), adopted by the US Food and Drug Administration (FDA), is a set of regulations for digitalization and standardization of nonclinical study data; thus, related organizations have begun implementing processes in support of SEND. The Global Editorial and Steering Committee (GESC), which provides oversight of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND), has prepared the SEND Controlled Terminology (CT) for toxicologic pathology. SEND provides electronic data standards created by the Clinical Data Interchange Standards Consortium (CDISC), and CDISC also collaborates in the implementation of SEND. Furthermore, the Pharmaceutical Users Software Exchange (PhUSE), which includes members of the US FDA, has conducted various activities to promote realistic and effective methods to implement SEND. As we reported in 2015, there is a significant variation in the efficiency and quality of SEND data implementation across pharmaceutical companies and contractors (CROs) globally. To address this problem, the Global SEND Alliance (G-SEND) was established in August 2018 to facilitate the coordination and standardization of SEND datasets across CROs in Asia. This paper reports the first method for organizationally and jointly creating consistent SEND datasets between CROs using G-SEND.

3.
J Toxicol Pathol ; 31(4): 283-291, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30393432

RESUMO

Metabolic diseases including nonalcoholic steatohepatitis develop due to various environmental factors. In particular, the westernization of food is closely related to the development of these diseases. In this study, we investigated pathophysiological changes in the livers of Zucker fatty (ZF) rats induced by feeding Western diets. Male ZF rats were fed a sucrose/fat/cholesterol-enriched diet (Western diet, WD) or standard diet (SD) for 18 weeks, from 7 to 25 weeks of age. Body weight, food intake, and biochemical parameters were periodically measured, histopathological analyses were performed at 25 weeks, and mRNA expression in the liver was determined. ZF rats fed the WD (ZF-WD rats) developed obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and their alanine aminotransferase and aspartate aminotransferase levels increased compared with those of ZF rats fed the SD (ZF-SD rats). Hepatic lesions including fibrosis and necrosis were observed in the ZF-WD rats at 25 weeks; however, fibrosis and necrosis were not observed in the ZF-SD rats. Oxidative stress markers also increased in the livers of ZF-WD rats. Hepatic mRNA expression related to inflammation and fibrosis increased in the ZF-WD rats; however, mRNA expression related to lipid synthesis decreased. Microsomal triglyceride transfer protein mRNA levels in the ZF-WD rats also decreased. In Zucker lean rats fed the WD, similar changes were observed in the liver; however, the hepatic changes were not serious compared with ZF-WD rats. In conclusion, hepatic lesions, such as inflammation, fibrosis, and necrosis, were observed in the ZF-WD rats. The sucrose/fat/cholesterol-enriched diet induced significant lipotoxicity in the livers of animals in this insulin-resistant model.

4.
J Toxicol Sci ; 43(10): 587-600, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30298847

RESUMO

The present study comparatively examined carcinogenicity of 7 different multi-wall carbon nanotubes (MWCNTs) with different physicochemical characteristics. Physicochemical characteristics of MWCNTs (referred to as M-, N-, WL-, SD1-, WS-, SD2- and T-CNTs in the present study) were determined using scanning electron and light microscopes and a collision type inductively coupled plasma mass spectrometer. Male Fischer 344 rats (10 weeks old, 15 animals per group) were administered MWCNTs at a single intraperitoneal dose of 1 mg/kg body weight, and sacrificed up to 52 weeks after the commencement. Fibers of M-, N-, WL- and SD1-CNTs were straight and acicular in shape, and contained few agglomerates. They were relatively long (38-59% of fibers were longer than 5 µm) and thick (33% to more than 70% of fibers were thicker than 60 nm). All of these 4 MWCNTs induced mesotheliomas at absolute incidences of 100%. Fibers of WS-, SD2- and T-CNTs were curled and tightly tangled to form frequent agglomerates. They were relatively short and thin (more than 90% of measured fibers were thinner than 50 nm). WS- CNT did not induce mesothelioma, and only one of 15 rat given SD2- or T-CNT developed tumor. Any correlations existed between the metal content and neither the size or form of fibers, nor the carcinogenicity. It is thus indicated that the physicochemical characteristics of MWCNTs are critical for their carcinogenicity. The straight and acicular shape without frequent agglomerates, and the relatively long and thick size, but not the iron content, may be critical factors. The present data can contribute to the risk management, practical use and social acceptance of MWCNTs.


Assuntos
Mesotelioma/induzido quimicamente , Nanotubos de Carbono/efeitos adversos , Nanotubos de Carbono/toxicidade , Animais , Fenômenos Químicos , Injeções Intraperitoneais , Masculino , Microscopia Eletrônica de Varredura , Nanotubos de Carbono/química , Nanotubos de Carbono/ultraestrutura , Tamanho da Partícula , Ratos Endogâmicos F344 , Gestão de Riscos , Relação Estrutura-Atividade , Fatores de Tempo
5.
J Toxicol Sci ; 43(7): 435-442, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29973475

RESUMO

Teriparatide, a drug used in the treatment of osteoporosis, was administered to rats subcutaneously for the duration of 3 months, at a frequency of either once weekly or once daily to demonstrate the varying levels of anabolic action the drug can have on bone depending on the dosing frequency. The levels of biomarkers in the blood were compared and found to vary in osteocalcin (OC), a biomarker of bone formation, and cross-linked N-telopeptide of type 1 collagen (NTx), a biomarker of bone resorption, according to the dosing frequency. In the once-weekly regimen, teriparatide did not affect NTx levels at any of the doses studied, while OC levels increased with dose, peaking at 72 hr, then returning to normal before the next injection (after 1 week). Bone mineral density (BMD) levels increased moderately with no difference between doses. This was thought to result from the steady state achieved following increases in bone formation and bone absorption. In the once-daily dosing regimen, meanwhile, NTx levels increased with dose, and OC levels were markedly higher when compared to those with the once-weekly dosing. BMD levels were higher than those with the once-weekly dosing, but with no difference between doses. This was considered a result of unlimited, excessive increases in bone formation due to daily administration of the drug. These results suggest that teriparatide promotes normal bone metabolism ("stationary mini-modeling") when administered once weekly, and has an anabolic action with high metabolic turnover ("high-turnover remodeling") when administered once daily.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacologia , Osso e Ossos/metabolismo , Colágeno Tipo I/sangue , Osteocalcina/sangue , Osteogênese/efeitos dos fármacos , Osteoporose/prevenção & controle , Peptídeos/sangue , Teriparatida/administração & dosagem , Teriparatida/farmacologia , Animais , Biomarcadores/sangue , Densidade Óssea , Reabsorção Óssea/sangue , Reabsorção Óssea/diagnóstico , Relação Dose-Resposta a Droga , Esquema de Medicação , Injeções Subcutâneas , Masculino , Osteoporose/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo
6.
Cancer Sci ; 109(4): 1024-1031, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29444368

RESUMO

Engineered nanomaterials (ENM) are now used in a wide variety of fields, and, thus, their safety should urgently be assessed and secured. It has been suggested that inflammatory responses via the phagocytosis of ENM by macrophages is a key mechanism for their genotoxicity. The present study was conducted to establish a mechanism-based assay to evaluate the genotoxicity of ENM under conditions simulating an in vivo situation, featuring a co-culture system of murine lung resident cells (GDL1) and immune cells (RAW264.7). GDL1 were cultured with or without RAW264.7, exposed to a multi-walled carbon nanotube (MWCNT), and then analyzed for mutagenicity and underlying mechanisms. Mutation frequencies induced in GDL1 by the MWCNT were significantly greater with the co-existence of RAW264.7 than in its absence. Mutation spectra observed in GDL1 co-cultured with RAW264.7 were different from those seen in GDL1 cultured alone, but similar to those observed in the lungs of mice exposed to the MWCNT in vivo. Inflammatory cytokines, such as IL-1ß and TNF-α, were produced from RAW264.7 cells treated with the MWCNT. The generation of reactive oxygen species and the formation of 8-oxodeoxyguanosine in GDL1 exposed to the MWCNT were greater in the co-culture conditions than in the single culture conditions. Based on these findings, it is indicated that inflammatory responses are involved in the genotoxicity of MWCNT, and that the presently established, novel in vitro assay featuring a co-culture system of tissue resident cells with immune cells is suitable to evaluate the genotoxicity of ENM.


Assuntos
Nanotubos de Carbono/toxicidade , Animais , Linhagem Celular , Técnicas de Cocultura/métodos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Testes de Mutagenicidade/métodos , Mutação/efeitos dos fármacos , Nanoestruturas/toxicidade , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Biosci Biotechnol Biochem ; 81(11): 2209-2211, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28934910

RESUMO

Rice powder extract (RPE) from black and brown rice (Oryza sativa L. indica) improves hepatic lipid accumulation in obese and diabetic model mice via peroxisomal fatty acid oxidation. RPE showed PPARα agonistic activity which did not differ between black and brown RPE despite a higher anthocyanin content in black RPE.


Assuntos
Diabetes Mellitus/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/metabolismo , Oryza/química , PPAR alfa/metabolismo , Extratos Vegetais/farmacologia , Animais , Diabetes Mellitus/tratamento farmacológico , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fígado/metabolismo , Camundongos , Obesidade/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pós
8.
J Toxicol Pathol ; 30(3): 201-207, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28798527

RESUMO

The Standard for Exchange of Nonclinical Data (SEND), introduced by the US Food and Drug Administration (FDA), is a scheme for the computerization, electronic application, and screening of preclinical data. Since its establishment, related organizations have been working together to implement SEND. However, it is difficult for individual pharmaceutical companies that often outsource to achieve complete compliance with SEND; hence, the cooperation of contract research organizations (CROs) and SEND Registered Solution Providers (RSPs) is indispensable. In SEND, most data, including those on pathology findings, are converted into controlled terminology (CT), but it is not a simple process to convert findings or levels of severity in the field of pathology, which is a descriptive science. The authors have successfully completed an FDA trial submission for a toxicology test conducted at a CRO and in doing so acquired important knowledge. This article presents a clear picture of such important knowledge from a pathologist's viewpoint.

9.
Genes Environ ; 39: 4, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28074111

RESUMO

INTRODUCTION: It is known that fibrous particles of micrometer length, such as carbon nanotubes, which have same dimensions as asbestos, are carcinogenic. Carcinogenicity of nanomaterials is strongly related to inflammatory reactions; however, the genotoxicity mechanism(s) is unclear. Indeed, inconsistent results on genotoxicity of multi-walled carbon nanotubes (MWCNTs) have been shown in several reports. Therefore, we analyzed the in vivo genotoxicity induced by an intratracheal instillation of straight MWCNTs in rats using a different test system-the Pig-a gene mutation assay-that can reflect the genotoxicity occurring in the bone marrow. Since lungs were directly exposed to MWCNTs upon intratracheal instillation, we also performed the gpt assay using the lungs. FINDINGS: We detected no significant differences in Pig-a mutant frequencies (MFs) between the MWCNT-treated and control rats. Additionally, we detected no significant differences in gpt MFs in the lung between the MWCNT-treated and control rats. CONCLUSIONS: Our findings indicated that a single intratracheal instillation of MWCNTs was non-mutagenic to both the bone marrow and lung of rats.

10.
Yakugaku Zasshi ; 136(10): 1433-1438, 2016.
Artigo em Japonês | MEDLINE | ID: mdl-27725392

RESUMO

The present study examined the effects of formic acid and acetic acid on human adenocarcinoma-derived alveolar basal epithelial A549 cells. The organic acids were administered either individually or in combination, into either the culture medium (aqueous phase) or the gaseous phase of an air-liquid interface. When either of the acids was administered into the aqueous phase, cell proliferation was inhibited at doses of 1-10 mg/mL. In contrast, when the acids were administered either individually or in combination, into the gaseous phase of the air-liquid interface, cell proliferation was not altered. Under the gaseous phase administration, acetic acid and mixed acids caused a slight increase, decrease and increase on the interleukin-8 production, the mRNA expression of the heme oxygenase-1 (HO-1) gene and the HO-1 production, respectively, at one or more time points. The results therefore indicated that organic acids might be less reactive in the gaseous phase than in the aqueous phase. However, acetic acid in the gaseous phase either individually or in combination with formic acid exerts some effects on A549 cells.


Assuntos
Ácido Acético/efeitos adversos , Adenocarcinoma Bronquioloalveolar/patologia , Proliferação de Células/efeitos dos fármacos , Formiatos/efeitos adversos , Neoplasias Pulmonares/patologia , Células A549 , Ácido Acético/administração & dosagem , Adenocarcinoma Bronquioloalveolar/metabolismo , Relação Dose-Resposta a Droga , Formiatos/administração & dosagem , Gases , Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Interleucina-8/biossíntese , Neoplasias Pulmonares/metabolismo , RNA Mensageiro/metabolismo , Emissões de Veículos/análise , Emissões de Veículos/prevenção & controle
11.
PLoS One ; 11(6): e0157580, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27333187

RESUMO

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.


Assuntos
Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Colesterol/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Inflamação/complicações , Inflamação/patologia , Metabolismo dos Lipídeos , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Cancer Sci ; 106(9): 1240-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26080617

RESUMO

MAS1 is a receptor for angiotensin 1-7 (A1-7), which is derived from angiotensin II (A-II) by the action of angiotensin converting enzyme (ACE) 2. MAS1 induces anti-A-II phenotypes, such as vessel dilation and depression of blood pressure. Using immunohistochemistry, we examined the role of MAS1 in 132 cases of invasive ductal carcinoma (IDC) of the breast. While benign mammary tissues expressed MAS1 at high levels, MAS1 expression was attenuated in all IDC, especially in scirrhous IDC. The decrease in MAS1 expression was associated with tumor growth, lymph node metastasis, and grade. MAS1 expression was inversely associated with the proliferation index and epidermal growth factor receptor and human epidermal growth factor receptor-2 expression. Of the 132 cases, 12 (9.1%) were triple-negative breast cancer (TNBC) cases. All TNBC cases (the 12 cases and the additional 36 cases using a tissue array) expressed MAS1. Using the TNBC cell lines 4T1 and MDA-MB-468, which expresses MAS1, we found that cell growth, anti-apoptotic survival and invasion were suppressed by MAS1 activation with A1-7 treatment and enhanced by MAS1 knockdown. In contrast, synergic effect was found between tamoxifen and A1-7 in a luminal A breast cancer cell line, MCF-7. Combination treatment with cisplatin, an ACE2 activator, and an A-II type 1 receptor blocker showed synergic effects on tumor growth inhibition of 4T1 tumors in a syngeneic mouse model. These findings suggest that MAS1 might act as an inhibitory regulator of breast cancer and may be a possible molecular target for this malignancy.


Assuntos
Carcinoma Ductal de Mama/genética , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas-G/genética , Neoplasias de Mama Triplo Negativas/genética , Animais , Apoptose/genética , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Cisplatino/farmacologia , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica/métodos , Metástase Linfática/genética , Metástase Linfática/patologia , Células MCF-7 , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
13.
J Toxicol Pathol ; 28(2): 57-64, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26028814

RESUMO

The Standard for the Exchange of Nonclinical Data (SEND), adopted by the US FDA, is part of a set of regulations and guidances requiring the submission of standardized electronic study data for nonclinical and clinical data submissions. SEND is the nonclinical implementation of SDTM (Study Data Tabulation Model), the standard electronic format for clinical regulatory submissions to FDA. SEND, SDTM, and the associated Controlled Terminology have been developed by CDISC (Clinical Data Interchange Standards Consortium). In order to successfully implement SEND, interdisciplinary contributions between sponsors and CROs, need a model for task allocation. This is being undertaken by the Pharmaceutical Users Software Exchange (PhUSE). Because SEND is currently the preferred submission format of the US FDA only and will become required by it starting in December 2016, only American academic societies and companies are actively involved. An exception to this is the INHAND initiative, which leads the way in standardizing terminology for toxicological pathology. On the other hand, international globalization of other clinical and nonclinical practices is not feasible because there are substantial differences between the US and non-US countries in CRO involvement in drug development. Thus, non-US countries must consider and develop approaches to SEND that meet their needs. This paper summarizes the activities of the major organizations involved in SEND development and implementation, discusses the effective use of SEND, and details a compliance scheme (research material of the Showa University School of Medicine) illustrating how pharmaceutical companies can complete a large amount of work up to an FDA application with the effective utilization of CROs and solution providers.

14.
Cancer Sci ; 106(7): 825-32, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25940505

RESUMO

Exposure to asbestos results in serious risk of developing lung and mesothelial diseases. Currently, there are no biomarkers that can be used to diagnose asbestos exposure. The purpose of the present study was to determine whether the levels or detection rate of chemokine (C-C motif) ligand 3 (CCL3) in the serum are elevated in persons exposed to asbestos. The primary study group consisted of 76 healthy subjects not exposed to asbestos and 172 healthy subjects possibly exposed to asbestos. The secondary study group consisted of 535 subjects possibly exposed to asbestos and diagnosed with pleural plaque (412), benign hydrothorax (10), asbestosis (86), lung cancer (17), and malignant mesothelioma (10). All study subjects who were possibly exposed to asbestos had a certificate of asbestos exposure issued by the Japanese Ministry of Health, Labour and Welfare. For the primary study group, levels of serum CCL3 did not differ between the two groups. However, the detection rate of CCL3 in the serum of healthy subjects possibly exposed to asbestos (30.2%) was significantly higher (P < 0.001) than for the control group (6.6%). The pleural plaque, benign hydrothorax, asbestosis, and lung cancer groups had serum CCL3 levels and detection rates similar to that of healthy subjects possibly exposed to asbestos. The CCL3 chemokine was detected in the serum of 9 of the 10 patients diagnosed with malignant mesothelioma. Three of the patients with malignant mesothelioma had exceptionally high CCL3 levels. Malignant mesothelioma cells from four biopsy cases and an autopsy case were positive for CCL3, possibly identifying the source of the CCL3 in the three malignant mesothelioma patients with exceptionally high serum CCL3 levels. In conclusion, a significantly higher percentage of healthy persons possibly exposed to asbestos had detectable levels of serum CCL3 compared to healthy unexposed control subjects.


Assuntos
Asbestos/toxicidade , Biomarcadores Tumorais/sangue , Carcinógenos/toxicidade , Quimiocina CCL3/sangue , Exposição Ambiental , Neoplasias Pulmonares/sangue , Mesotelioma/sangue , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Pulmonares/induzido quimicamente , Masculino , Mesotelioma/induzido quimicamente , Pessoa de Meia-Idade
15.
Exp Toxicol Pathol ; 67(7-8): 383-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25983017

RESUMO

The present study examined the effects induced in vitro in human adenocarcinoma-derived alveolar basal epithelial A549 cells by diesel particulate matter (DPM) administered into the culture medium or by diesel exhaust administered at an air-liquid interface. When A549 cells were exposed to DPM in the culture medium, cell proliferation was inhibited at doses of 10-100 µg/mL; generation of interleukin (IL)-8 and the antioxidant enzyme, heme oxygenase-1 (HO-1), were inhibited at a dose of 100 µg/mL, and hydroxyl radicals were produced, but could be inhibited by catalase or superoxide dismutase. In contrast, when A549 cells were exposed to diesel exhaust, cell proliferation was inhibited in the absence, but not in the presence, of a diesel particulate filter (DPF); in the absence of a DPF IL-8 was produced in the same amount as in the control cells but was suppressed in the presence of a DPF; HO-1 mRNA was transiently over-expressed in the presence of a DPF, and it was also increased slightly produced in the absence of a DPF but statistically not significant in the presence of a DPF, and it was also increased slightly produced in the absence of a DPF but statistically not significant; HO-1 was transiently produced independent of the absence or the presence of a DPF; and hydroxyl radicals were weakly produced, even in the presence of a DPF but could be inhibited by catalase or superoxide dismutase. It is thus suggested that oxidative stress may be induced by exposure to DPM or diesel exhaust and thereby exerts cytotoxic effect. The introduction of a DPF is effective to protect cells from the toxicity of diesel exhaust presumably by suppression of an oxidative stress.


Assuntos
Proliferação de Células/efeitos dos fármacos , Emissões de Veículos/toxicidade , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia
16.
J Appl Toxicol ; 35(12): 1465-72, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25809591

RESUMO

DNA damage and cytotoxicity induced by a hydroxylated fullerene [C60 (OH)24 ], which is a spherical nanomaterial and/or a water-soluble fullerene derivative, and their protection by sulfhydryl compounds were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60 (OH)24 at a concentration of 50 µM caused time (0 to 3 h)-dependent cell death accompanied by the formation of cell surface blebs, the loss of cellular levels of ATP and reduced glutathione, accumulation of glutathione disulfide, and induction of DNA fragmentation assayed using alkali single-cell agarose-gel electrophoresis. C60 (OH)24 -induced cytotoxicity was effectively prevented by pretreatment with sulfhydryl compounds. N-acetyl-L-cysteine (NAC), L-cysteine and L-methionine, at a concentration of 2.5 mM, ameliorated cell death, accompanied by a decrease in cellular ATP levels, formation of cell surface blebs, induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential caused by C60 (OH)24 . In addition, DNA fragmentation caused by C60 (OH)24 was also inhibited by NAC, whereas an antioxidant ascorbic acid did not affect C60 (OH)24 -induced cell death and DNA damage in rat hepatocytes. Taken collectively, these results indicate that incubation of rat hepatocytes with C60 (OH)24 elicits DNA damage, suggesting that nuclei as well as mitochondria are target sites of the hydroxylated fullerene; and induction of DNA damage and oxidative stress is ameliorated by an increase in cellular GSH levels, suggesting that the onset of toxic effects may be partially attributable to a thiol redox-state imbalance caused by C60 (OH)24 .


Assuntos
Dano ao DNA/efeitos dos fármacos , Fulerenos/toxicidade , Hepatócitos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Organelas/efeitos dos fármacos , Compostos de Sulfidrila/farmacologia , Acetilcisteína/farmacologia , Animais , Ácido Ascórbico/farmacologia , Técnicas de Cultura de Células , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cisteína/farmacologia , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Masculino , Metionina/farmacologia , Organelas/metabolismo , Organelas/ultraestrutura , Ratos Endogâmicos F344 , Espécies Reativas de Oxigênio/metabolismo
17.
Toxicol Rep ; 2: 1404-1408, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-28962481

RESUMO

The fetal toxicities of multi-wall carbon nanotubes (MWCNTs) with various sizes were compared in CD1(ICR) mice. MWCNTs were suspended in 2% sodium carboxymethyl cellulose solution in phosphate-buffered saline. On day 9 of gestation, dams were administered a single intraperitoneal dose of MWCNTs (4 mg/kg body weight), while dams in the control group were administered vehicle (10 mL/kg body weight). The rectal temperatures of the dams were monitored 2 h after administaration to asses statuses of the dams. The dams and fetuses were examined on day 18 of gestation. The number of live fetus per dam decreased in some MWCNTs-administered groups. The mean percentages of live fetuses in total implantations in the MWCNTs-administered groups markedly varied from 0% to 95%, and the highest mean percentage of live fetuses in the MWCNTs-administered group was equivalent to that of the control group. The decrease in live fetuses depended on an increased number of early dead fetuses. In the groups with markedly lowered rectal temperature after administration, the fetal loss were evident. The blood levels of interleukin-6 and/or monocyte chemoattractant protein-1 in dam 2 h after administration of MWCNTs markedlyr increased, especially in the goups with significant decrease in live fetuses. These results indicated a relationship between inflammation in the dam, which probabely depended on the particular length of the MWCNTs, and the fetal toxicioty of MWCNTs in mice.

18.
J Toxicol Pathol ; 27(2): 147-51, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25352717

RESUMO

There are no reported spontaneous cases of pancreatic ductal adenocarcinoma (PDAC), and there are few reports about chemically-induced PDAC in rats. We encountered a PDAC in a Wistar Hannover GALAS rat that had been subjected to a medium-term multiorgan carcinogenicity bioassay. This article describes the histological and histochemical findings of the tumor. The tumor was located in the pancreatic tissue and had not invaded the liver parenchyma or the mucosal layer of the alimentary tract. The tumor cells were atypical and were mainly arranged in small tubules. In addition, abundant stroma and mucus production were observed in the tumor. In an immunohistochemical examination, the tumor cells were positive for cytokeratin, Sox9 and pancreas duodenum homeobox 1 and negative for amylase 2A and insulin. Therefore, the tumor was diagnosed as a PDAC based on its histological and histochemical findings. We considered that the tumor was caused by the carcinogens administered during the abovementioned bioassay.

19.
Birth Defects Res B Dev Reprod Toxicol ; 101(5): 393-401, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25283888

RESUMO

Male and female mice were housed in cages, containing different types of bedding materials (wood flakes or pulp chips), from 4 weeks of age in the F0 generation to 11 weeks of age in the F1 generation; selected reproductive and neurobehavioral parameters were measured in the F1 generation. There were no adverse effects of bedding materials on litter size, litter weight, or sex ratios at the time of birth. With regard to behavioral development parameters, bedding materials did not influence any variables (p > 0.05) in both sexes. Regarding exploratory behavior in the F1 generation, number of defecations significantly varied (p = 0.0203) with bedding materials in males at 3 weeks of age. The number of horizontal activities also significantly varied (p = 0.0342) with bedding materials in males at 8 weeks of age. Multiple-T water maze performance data indicated that the time required was significantly shortened across trials in pulp chips group than wood flakes group in males (p = 0.0211). Moreover, all spontaneous behavior variables in males significantly varied with bedding materials, particularly the average time of movement was significantly different (p = 0.0037) in distance between parallel lines of types of bedding materials in the F1 generation. The present study shows that bedding materials influence the neurobehavioral development in mice.


Assuntos
Criação de Animais Domésticos/métodos , Comportamento Animal/fisiologia , Comportamento Exploratório/fisiologia , Comportamento Sexual Animal/fisiologia , Animais , Feminino , Tamanho da Ninhada de Vivíparos/fisiologia , Masculino , Camundongos , Madeira
20.
Environ Toxicol Chem ; 33(12): 2671-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25234664

RESUMO

The present study reports on the occurrence and chiral behavior of the anti-inflammatory drug (S)-naproxen (NAP)-(S)-2-(6-methoxynaphthalen-2-yl)propionic acid-in an aquatic environment under both field and laboratory conditions. In influents and effluents of sewage treatment plants (STPs) in the Tama River basin (Tokyo), (S)-NAP was detected at concentrations of 0.03 µg L(-1) to 0.43 µg L(-1) and 0.01 µg L(-1) to 0.11 µg L(-1), respectively. The concentrations of a major metabolite, 6-O-desmethyl NAP (DM-NAP) were up to 0.47 µg L(-1) and 0.56 µg L(-1) in influents and effluents, respectively. (R)-naproxen was not detected in STP influents, although it was present in effluents, and the enantiomeric faction (= S/[S + R]) of NAP ranged from 0.88 to 0.91. Under laboratory conditions with activated sludge from STPs, rapid degradation of (S)-NAP to DM-NAP and chiral inversion of (S)-NAP to (R)-NAP were observed. During river die-away experiments, degradation and chiral inversion of NAP were extremely slow. In addition, chiral inversion of (S)-NAP to (R)-NAP was not observed during photodegradation experiments. In the river receiving STP discharge, NAP and DM-NAP concentrations reached 0.08 µg L(-1) and 0.16 µg L(-1) , respectively. The enantiomeric faction of NAP in the river ranged from 0.84 to 0.98 and remained almost unchanged with the increasing contribution of rainfall to the river water. These results suggest that the absence and decrease of (R)-NAP in river waters could indicate the inflow of untreated sewage. E


Assuntos
Anti-Inflamatórios/análise , Naproxeno/análise , Espectrometria de Massas em Tandem , Poluentes Químicos da Água/análise , Anti-Inflamatórios/metabolismo , Cromatografia Líquida de Alta Pressão , Monitoramento Ambiental , Naproxeno/metabolismo , Fotólise , Rios/química , Esgotos/química , Estereoisomerismo , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA