RESUMO
A potent xanthine oxidoreductase inhibitor (LS087) was recently proved to exhibit a similar hypouricemic potency to febuxostat. A hyperuricemia model induced by potassium oxonate and hypoxanthine was proposed in specific pathogen-free male Kunming mice, and the serum urea nitrogen, creatinine and uric acid levels were measured after oral administration of LS087. Furthermore, renal histopathology was conducted by staining with hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome stains, respectively. The results showed that the levels of serum urea nitrogen and uric acid significantly decreased compared with the model group, but the level of creatinine showed no significant changes. The pathological abnormalities in kidney tubules were improved after LS087 administration. Ten metabolites (M1-M10) of LS087 were identified after a single oral dosing of 10 mg/kg in rats. M6 was the primary LS087 metabolite in vivo with a pathway of methylation. The toxicity and potential risks of LS087 and its metabolites were predicted using the ProTox-II software. LS087 and the major metabolites (M2, M3, M5, M6, M7 and M8) were predicted to have no potential hepatotoxicity, but some metabolites with a total rate of <1% (M1, M4, M9, and M10) showed potential hepatotoxicity. M1 and M8 showed potential carcinogenicity. The LS087 biotransformation pathway in rat was well characterized.
Assuntos
Inibidores Enzimáticos , Hiperuricemia/metabolismo , Xantina Desidrogenase/antagonistas & inibidores , Animais , Biotransformação , Creatinina/sangue , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To establish a rat model of 1,2-dichloroethane (DCE)-induced subacute toxic encephalopathy. METHODS: Sixty Sprague-Dawley rats were randomly divided into five groups: negative control, positive control, low-dose DCE (1 472 mg/m(3)), middle-dose DCE (2 550 mg/m(3)), and high-dose DCE (4 418 mg/m(3)). The three DCE groups received static inhalation of DCE 6 hours a day for 6 consecutive days. The positive control group received intraperitoneal injection of lipopolysaccharide (5 mg/kg) and were sacrificed 8 hours after injection. Blood and brain tissue were collected, followed by determination of brain water content and HE staining for pathological examination of brain tissue. RESULTS: The rats in DCE groups suffered decreased body weight with increasing DCE dose (P < 0.01), and brain water content rose with increasing DCEdose. The brain water content of middle-dose DCE group (80.09 ± 0.14%) and high-dose DCE group (80.28±0.10%) increased significantly as compared with that of the negative control group (79.46±0.23%) (P < 0.001). Optical microscopy discovered loose structure and vasodilation in the brain tissue of middle-dose DCE group, indicating obvious brain edema; the high-dose DCE group and positive control group had spongiform and vacuolated brain tissues with severe vascular dilation, indicating severe brain edema. CONCLUSION: A rat model of subacute toxic encephalopathy induced by 1, 2-dichloroethane has been successfully established.
Assuntos
Modelos Animais de Doenças , Dicloretos de Etileno/toxicidade , Síndromes Neurotóxicas , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To study toxic effects of 2,5-hexanedione (2,5-HD) on pathology and lipid peroxidation in mouse retina. METHODS: Forty-eight mice were randomly divided into blank control group (12 mice), negative control group exposed to normal solution (12 mice) and group exposed to 2,5-HD for 2. 4 and 8 weeks, respectively (24 mice) by intraperitoneal injection (2.5% 2,5-HD) at the dose of 400 mg/kg. The pathological changes of mouse retina were examined under light microscope. The activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) in mouse retina were detected. RESULTS: The retinal structure in the blank and negative control groups was normal. In mice exposed to 2,5-HD for 8 weeks, the swelling of outer and inner segments and disorder arrangement of the segments without clear boundary were found. The staining of outer plexiform layers was uneven and the irregular loose structure appeared. The hyperchromatic pyknotic and necrosis nuclei were presented in ganglion cells layer. Compared with the control and blank groups, the activities of SOD gradually and significantly reduced and the concentrations of MDA increased in group exposed to 2,5-HD (P < 0.05). CONCLUSION: 2,5-HD can induce the injury of retina tissues of mice, which may be associated with the lipid peroxidation.
Assuntos
Hexanonas/toxicidade , Retina/patologia , Animais , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos , Retina/efeitos dos fármacos , Retina/metabolismo , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: To study the effect of NP9 on the growth of transplanted nasopharyngeal carcinoma (NPC) in nude mice and explore the mechanisms involved. METHODS: Recombinant pRc/CMV2-NP9 plasmid was constructed and transfected into the NPC cell lines by lipofectamine 2000. Cell clones stably expressing NP9 were obtained by detecting the mRNA expression of NP9 in G418-resistant clones with RT-PCR. The tumorigenicity and size of transplanted tumors were assessed after inoculation of NPC cells and their transgene clones into Balb/C mice. The expression of PCNA and cyclin D1 in transplanted tumors was detected by immunohistochemistry. RESULTS: The expression of NP9 was detected in some of NP9 gene-transfected G418-resistant clones of CNE1 and SUNE1. In vivo experiments showed that the tumorigenicity of CNE19 clone was decreased significantly compared to that of CNE1 and its vector control, and the transplanted tumors grew more slowly from SUNE1/NP9 than from SUNE1 and SUNE1/vector. Compared with the vector control, the expression of cyclin D1 and PCNA in CNE1/NP9 transplants was decreased. CONCLUSION: NP9 inhibits tumorigenicity and growth of NPC transplanted tumor by down-regulating the expression of cyclin D1 and PCNA.
Assuntos
Retrovirus Endógenos/genética , Produtos do Gene env/genética , Genes Supressores de Tumor , Neoplasias Nasofaríngeas/genética , Animais , Ciclina D1/biossíntese , Ciclina D1/genética , Feminino , Produtos do Gene env/biossíntese , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Transplante de Neoplasias , Antígeno Nuclear de Célula em Proliferação/biossíntese , Antígeno Nuclear de Célula em Proliferação/genética , Células Tumorais CultivadasRESUMO
OBJECTIVE: To study the effect of occupational exposure to traffic exhaust and smoking on DNA damage in traffic policemen. METHODS: 812 traffic policemen (741 men and 71 women, 130 of office-work and 682 of outside work) from 8 districts in Guangzhou were investigated. Blood samples were taken by venipuncture and lymphocytes were collected by using lymphocyte separation medium and centrifugation. The comet assay was used to measure DNA damage. RESULTS: The office-work policemen [(37.7 +/- 9.5) years] were older than the outside-work ones [(32.3 +/- 8.1) years, P < 0.001]. No significant difference was observed in sex (P = 0.08) and age (P = 0.45). Comet assay showed that occupational exposure to traffic exhaust significantly increased tail length [4.20 micro m, 95% CI: (3.98 - 4.42) micro m vs 3.23 micro m, 95% CI: (2.82 - 3.7) micro m, P < 0.001]. Smokers had longer tail length [4.66 micro m, 95% CI: (4.37 - 4.97) micro m] than ex-smokers [3.28 micro m, 95% CI: (2.57 - 4.17) micro m] and nonsmokers [3.47 micro m, 95% CI: (3.21 - 3.75) micro m, P < 0.001]. In nonsmokers, significant increase in tail length was observed by passive smoking at home (P = 0.004) but not at work (P = 0.22). When out-door nonsmokers were excluded, passive smoking at work also significantly increased tail length (P = 0.007). Analysis of covariance showed that occupational exposure to traffic exhaust, tobacco smoking, and female had independent effect on lymphocyte DNA damage (P < 0.001) after these factors were adjusted. Passive smoking and age had no effect on lymphocyte DNA damage. CONCLUSIONS: Occupational exposure to traffic exhaust and tobacco smoking respectively increase lymphocyte DNA damage. Female traffic policemen may have more severe DNA damage than male.