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The objective of this study was to determine in a rat model of hepatocellular carcinoma (HCC) the effects of the antiangiogenic agent TNP-470 on cell proliferation and effectors of the apoptotic pathway, including p53, p21WAF1/CIP1, cyclin D, and cyclin E. Tumor was induced in male Wistar rats by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30 mg/kg, 3 times per week from 20 to 28 weeks. Serum levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor beta (HGFbeta) liver expression were increased by hepatocarcinogenesis (+38% and +183%, respectively), and treatment with TNP-470 was able to prevent the increase in these angiogenic factors induced by HCC. HCC coursed with reduced expression of p21WAF1/CIP1 and p53 (-63% and -60%, respectively). Hepatic expression of cyclin D and cyclin E were significantly increased in rats with HCC (+108% and +115%, respectively). In animals with experimental carcinogenesis, a significant increase in the expression of Cdk4 and CdK2 was also observed (+119% and +187%, respectively). These effects were prevented by TNP-470 administration. In conclusion, cell-cycle inhibition by TNP-470 is mediated at least in part by an activation of p21WAF1/CIP1 because of a p53-dependent mechanism, with reduction of the cyclin D-Cdk4 and cyclin E-Cdk 2 expression. These cytostatic effects should be considered when assessing the efficacy of TNP-470 for anti-angiogenic therapy. These findings may prove useful for the development of therapies for the treatment of human HCC. [ABSTRACT FROM AUTHOR]

Epomediol is a terpenoid compound that has been reported to reverse 17alpha-ethinylestradiol-induced cholestasis and to have a choleretic effect related to the biliary secretion of epomediol glucuronide. The aim of this study was to investigate the contribution of changes in bile acid metabolism to epomediol-induced effects on bile formation. Twenty-four-hour bile collections were performed in animals that had received intraperitoneal epomediol for five days at 100 mg/kg daily. Epomediol-treated rats had a 24% larger bile acid pool and 28% greater bile acid synthesis than controls when measured by the "washout" technique. There was no change in the fractional turnover rate and the cycling frequency of the pool. Both basal bile flow and bile acid secretion were significantly increased (+42% and +74%, respectively). Linear regression analysis between bile flow and bile acid secretion revealed that both bile acid-dependent fraction and bile acid-independent fraction were significantly increased (+40 and +27, respectively), with no change in the choleretic capacity of bile acids. Cholesterol secretion was increased by 42%, but there were no significant differences in phospholipid secretion. Cholesterol 7alpha-hydroxylase and HMG-CoA reductase activities were significantly higher in epomediol-treated rats (+39% and +97%, respectively). The activities of NADPH-cytochrome c reductase and aniline hydroxylase were also significantly elevated (+26% and +64%, respectively). It is concluded that epomediol treatment expands the bile acid pool through an enhanced bile acid synthesis. Choleresis induced by the drug is partly related to the increase in bile acid secretion. [ABSTRACT FROM AUTHOR]

The effects of aerobic and anaerobic physical conditioning on fibrinolysis were studied before and immediately after physical exercise. Moderately active controls (group A) were compared with aerobically- (group B) or anaerobically-conditioned (group C) subjects. Comparison of the resting parameters revealed that FgDP were significantly higher in group B as a compared to groups A and C. FbDP did not significantly differ between groups B and C and were significantly lower in group A. t-PA antigen and PAI antigen did not significantly differ between the three groups, but t-PA activity was elevated and PAI activity and t-PA/PAI complexes were reduced in group B. Following a maximal exercise test on the treadmill both FbDP and FgDP were significantly increased in all groups, although values for FbDP in group B and values for FgDP in group C reached a higher level than in group A. t-PA antigen and t-PA activity were also increased in the three groups. PAI activity was significantly reduced in groups A and C. t-PA/PAI complexes were significantly enhanced in all cases, but increased to a lower degree in group B. These results indicate that both aerobic and anaerobic physical conditioning induce activation of the fibrinolytic system. [ABSTRACT FROM AUTHOR]