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To design dual acting inhibitors that can block the enzyme estrone sulfatase (an enzyme involves in the in situ formation of estrogen in breast cancer cells) and act as antiestrogens. Scope: The design and synthesis of 30 dual inhibitors are proposed. The inhibitors contain 4 different structural core. The synthesized inhibitors will be tested on their ability to inhibit the enzyme estrone sulfatase and also their ability to inhibit the growth of breast cancer cells stimulated by estrone sulfate. In addition, selected inhibitors will be tested in vivo using NMU-induced mammary tumors in rats.

We have demonstrated that pretreatment with a lignan-enriched extract of Fructus schisandrae (FS) protected against physical exercise-induced muscle damage in rats. The muscle protection afforded by FS pretreatment was associated with a significant enhancement in hepatic antioxidant status, as assessed by hepatic glutathione (GSH) and malondialdehyde (MDA) levels. Pretreating rats with α-tocopherol acetate, though decreasing the MDA level in skeletal muscle, did not protect against exercise-induced muscle damage or improve hepatic antioxidant status in exercised rats. The results indicate that the protective effect of FS pretreatment on physical exercise-induced muscle damage may result from the enhancement of hepatic GSH status, thereby providing sufficient GSH for effective antioxidant protection of skeletal muscle during exercise. © 1996 by John Wiley & Sons, Ltd.

Sheng Mai San (SMS), a traditional Chinese formulation comprising Radix Ginseng, Fructus Schisandrae and Radix Ophiopogonis, is used for the treatment of coronary heart disease. The role of the lignans (lignan-enriched Fructus Schisandrae extract and Schisandrin B) in the cardioprotective effect of SMS was examined. Cardioprotective effects of chronic (7 g/kg/day x 30 day) and acute (17 g/kg/day x 3 day) lignan-enriched SMS (LgESMS) pretreatment in rats were observed in isoproterenol (in vivo) and ischemia-reperfusion (ex vivo) bioassay models. It is postulated that LgESMS plays a dual role in protecting the myocardium. LgESMS may provide a modulating effect in the β1-receptor mediated activity(ies) and at the same time it neutralizes the oxidative effects of free radicals. Schisandrin B present in the lignan-enriched Fructus Schisandrae extract, an constituent of LgESMS, may be responsible for the antioxidative action observed in LgESMS. Pretreatment of rats with Schisandri.n B at increasing oral daily doses of 0.3 - 0.9 mmol/kg for 3 days showed a dose-dependent protection against ischemia-reperfnsion injury. Further studies on the mechanisms of protection by Schisandrin B have provided evidences that Schisandrin B exerts its antioxidant effect by enhancing the endogenous glutathione and ascorbic acid content as well as glutathione peroxidase activity in the cardiomyocytes. These results showed obvious benefits of the lignans in the cardioprotective action of SMS. By enhancing the lignan content in SMS, we can have a fortified formulation of SMS which may improve the therapy and provide preventive measure of coronary heart disease.

Effects of Schisandrin B (Sch B) and alpha-tocopherol (alpha-TOC) on ferric chloride (Fe3+) induced oxidation of erythrocyte membrane lipids in vitro and carbon tetrachloride (CCl4) induced lipid peroxidation in vivo were examined. While alpha-TOC could produce prooxidant and antioxidant effect on Fe3+-induced lipid peroxidation, Sch B only inhibited the peroxidation reaction. Pretreatment with alpha-TOC (3 mmol/kg/day x 3) did not protect against CCl4-induced lipid peroxidation and hepatocellular damage in mice, whereas Sch B pretreatment (0.3 mmol/3.0 mmol/kg/day x 3) produced a dose-dependent protective effect on the CCl4-induced hepatotoxicity. The ensemble of results suggests that the ability of Sch B to inhibit lipid peroxidation, while in the absence of pro-oxidant activity, may at least in part contribute to its hepatoprotective action.

We have demonstrated that pretreatment with a lignan-enriched extract of Fructus schisandrae (FS) protected against physical exercise-induced muscle damage in rats. The muscle protection afforded by FS pretreatment was associated with a significant enhancement in hepatic antioxidant status, as assessed by hepatic glutathione (GSH) and malondialdehyde (MDA) levels. Pretreating rats with alpha-tocopherol acetate, though decreasing the MDA level in skeletal muscle, did not protect against exercise-induced muscle damage or improve hepatic antioxidant status in exercised rats. The results indicate that the protective effect of FS pretreatment on physical exercise-induced muscle damage may result from the enhancement of hepatic GSH status, thereby providing sufficient GSH for effective antioxidant protection of skeletal muscle during exercise.

Effects of Sheng Mai San (SMS), a traditional Chinese medicine used for the treatment of coronary heart disease, and the lignan-enriched extract of Fructus Schisandrae (FS), an antioxidant component of SMS, were examined in an in vivo model of myocardial infarction and an ex vivo model of myocardial ischemia-reperfusion injury in rats. Pretreatment with SMS (12 g/kg/day x 3, p.o.) or FS extract (0.8 g/kg/day x 3, p.o.) was found to protect against the isoproterenol-induced myocardial injury in rats and the ischemia-reperfusion injury in isolated perfused hearts prepared from the pretreated animals. Pretreatment with alpha-tocopherol (0.8 g/kg/day x 3, p.o.) produced similar beneficial effect on the myocardium. The myocardial protection afforded by SMS pretreatment is likely, at least in part, mediated by the FS-derived antioxidant activity.

Sheng-Mai-San (SMS), a traditional Chinese formulation used for the treatment of coronary heart disease, is comprised of Radix Ginseng, Fructus Schisandrae and Radix Ophiopogonis. Pretreatment with a lignan-enriched SMS (17 g/kg/day x 3, p.o.) was found effective in protection against isoproterenol-induced myocardial injury in rats, and in ischemia-reperfusion injury in isolated perfused hearts prepared from pretreated animals. Results obtained from pretreatment studies using extracts prepared by mixing various combinations of the three component herbs indicate that the major myocardial protective component in SMS is the lignan-enriched extract of Fructus Schisandrae.

Changes in tissue glutathione antioxidant system in streptozotocin-induced diabetic rats for a period of 15 weeks were examined. Total glutathione level was significantly increased in kidney tissue, but were slightly decreased and increased in liver and heart tissues, respectively. The small changes in total glutathione level in the liver and heart, though not statistically significant, were associated with reciprocal alterations in the activity of gamma-glutamylcysteine synthetase (GCS). While the GCS activity was not changed in kidney tissue, the activity of gamma-glutathione peroxidase was significantly increased in kidney tissue. Insulin treatment could completely or partly normalize almost all of these changes induced by diabetes. However, the decrease in hepatic glutathione S-transferases activity in diabetic rats was not reversed by the insulin treatment. The ensemble of results suggests that the diabetes-induced alterations in tissue glutathione antioxidant system may possibly reflect an inter-organ antioxidant response to a generalized increase in tissue oxidative stress associated with diabetes.

Exposure of liver homogenates to an in vitro tert-butyl hydroperoxide challenge can be used as a means for measuring the reduced glutathione regeneration capacity (GRC) of hepatic tissues. Pretreatment of rats with a lignan-enriched extract of Fructus Schisandrae (FS) caused a moderate enhancement of hepatic GRC in control rats, but the GRC enhancing effect of FS pretreatment on hepatic tissues was greatly exaggerated after CCl4 challenge. This in vitro bioassay can be used for investigating the hepatic GRC promoting action of orally active agents.