Duncan Hon Fai Mak

Alterations in tissue glutathione antioxidant system in streptozotocin-induced diabetic rats

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 γ-glutamylcysteine synthetase (GCS). While the GCS activity was not changed in kidney tissue, the activity of γ-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.

Myocardial protection against ischaemia-reperfusion injury by a Polygonum multiflorum extract supplemented `Dang-Gui Decoction for Enriching Blood', a compound formulation, ex vivo

‘Dang‐Gui Decoction for Enriching the Blood’ (BE), a traditional Chinese formulation comprising Angelica sinensis and Astragalus membranaceus, is used for stimulating red blood cell production as well as enhancing cardiovascular function. In the present study, we have demonstrated the myocardial protection afforded by BE pretreatment against ischaemia‐reperfusion (IR) injury in isolated‐perfused rat hearts. A more complete and potent myocardial protection against IR injury was also shown by a Polygonum multiflorum extract supplemented BE preparation (BEA). The results suggest that the more potent cardioprotective action of BEA may be related to its ability to sustain the myocardial glutathione antioxidant status under conditions of IR‐induced oxidative stress, which may possibly in turn result from the synergistic interaction between the BE and Polygonum extract. Copyright

Hepatoprotective mechanism of schisandrin B: Role of mitochondrial glutathione antioxidant status and heat shock proteins

In this study, the time course of schisandrin B- (Sch B-) induced changes in hepatic mitochondrial glutathione antioxidant status (mtGAS) and heat shock protein (HSP) 25/70 induction was examined to study their differential roles in the hepatoprotection afforded by Sch B pretreatment against carbon tetrachloride (CCl(4)) toxicity in mice. Dimethyl diphenyl bicarboxylate (DDB), a nonhepatoprotective analog of Sch B, was also included for comparison. The results indicate that Sch B treatment (2 mmol/kg) produced maximum enhancement in hepatic mtGAS and increases in both hepatic HSP 25 and HSP 70 levels at 24 h after dosing. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl(4) was found to correlate inversely with the elapsed time postdosing, the protective effect was associated with the ability to sustain mtGAS and/or HSP 70 levels in a CCl(4)-intoxicated condition. On the other hand, DDB (2 mmol/kg) treatment, which did not sustain mtGAS and HSP 70 level, could not protect against CCl(4) toxicity. Abolition of the Sch B-mediated enhancement of mtGAS by buthionine sulfoximine/phorone did not completely abrogate the hepatoprotective action of Sch B. The results indicate that Sch B pretreatment independently enhances mtGAS and induces HSP 25/70 production, particularly under conditions of oxidative stress, thereby protecting against CCl(4) hepatotoxicity.

Myocardial protective effect of Sheng Mai San (SMS) and a lignan-enriched extract of Fructus Schisandrae, in vivo and ex vivo.

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 × 3, p. o.) or FS extract (0.8 g/kg/day × 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 α-tocopherol (0.8 g/kg/day × 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.

Effects of Schisandrin B and alpha-tocopherol on lipid peroxidation, in vitro and in vivo.

Effects of Schisandrin B (Sch B) and α-tocopherol (α-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 α-TOC could produce prooxidant and antioxidant effect on Fe3+-induced lipid peroxidation, Sch B only inhibited the peroxidation reaction. Pretreatment with α-TOC (3 mmol/kg/day × 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 × 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.

Alterations in susceptibility to carbon tetrachloride toxicity and hepatic antioxidant/detoxification system in streptozotocin-induced short-term diabetic rats: effects of insulin and Schisandrin B treatment.

The streptozotocin-induced short-term (2 week) diabetic rats showed an increase in susceptibility to carbon tetrachloride (CCl4)-induced hepatocellular damage. This diabetes-induced change was associated with a marked impairment in the hepatic glutathione antioxidant/detoxification response to CCl4 challenge, as indicated by the abrogation of the increases in hepatic reduced glutathione (GSH) level, glucose-6-phosphate dehydrogenase and microsomal glutathione S-transferases (GST) activities upon challenge with increasing doses of CCl4. While the hepatic GSH level was increased in diabetic rats, the hepatic mitochondrial GSH level and Se-glutathione peroxidase activity were significantly reduced. Insulin treatment could reverse most of the biochemical alterations induced by diabetes. Both insulin and schisandrin B (Sch B) pretreatments protected against the CCl4 hepatotoxicity in diabetic rats. The hepatoprotection was associated with improvement in hepatic glutathione redox status in both cytosolic and mitochondrial compartments, as well as the increases in hepatic ascorbic acid level and microsomal GST activity. The ensemble of results suggests that the diabetes-induced impairment in hepatic mitochondrial glutathione redox status may at least in part be attributed to the enhanced susceptibility to CCl4 hepatotoxicity. Sch B may be a useful hepatoprotective agent against xenobiotics-induced toxicity under the diabetic conditions. (Mol Cell Biochem 175: 225–232, 1997)

Protective effect of a lignan-enriched extract of fructus schisandrae on physical exercise induced muscle damage 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.