| BackgroundsReactive oxygen species (ROS) are part of oxygen reduction products during oxidative stress in various cells. Components of ROS [super oxide anion (O-2·), hydrogen peroxide (H2O2), peroxinitrite anions (ONOO-), etc.] are produced by vesicular wall endothelial cells under the actions of NADPH oxygenize, hypoxanthine oxidize, lipoids and endothelial nitric oxide syntheses (eNOS) during aerobic respiration. Meanwhile, excessive oxidation can be protected by enzymatic mechanisms [super oxide disputes (SOD), catalane (CAT), glutathione peroxides (GPX), glutathione (GSH), vitamin C (Vit C), vitamin E (Vit E), etc.]) As well as non-enzymatic mechanisms of the body. Under physiologic conditions, dynamic equilibrium of ROS is maintained by continuous production and clearance of anti-oxidative system. Lipid hyper oxidation and irreversible lesion to cellular membranes, protein and DNA are both resulted from excessive production of ROS by vesicular wall endothelial cells that surpasses the protection capacity. Oxidative stress lesion to the vesicular wall, manifested as endothelial cell dysfunction, structural abnormality, migration of monocytes-macrophages, smooth muscle cells and fibroblasts hyperplasia and extra cellular component degradation, would ultimately progress to atherosclerosis (AS). Peter Libby et al revealed no significant correlation between pathogenesis of AS and macrophage uptake of low density lipoprotein (LDL) prototype, while significant positive correlation was found in uptake of oxidized LDL (ox-LDL). The increase in the level of ROS induced by oxidative stress could oxidize LDL into ox-LDL. However, promotion of excessive macrophage uptake of lipids is the not the single action that ox-LDL leads to AS. Recent studies revealed that AS could be initiated and promoted through formation of foam cells, cellular adhesion to endothelial cells and chemo taxis to sub-endothelium, degradation of macrophage proliferation, hyperplasia of endothelial cells, hyperplasia and migration of smooth muscle cells, formation of platelet adhesion, aggregation and thrombus, vasoconstriction, endothelial cell injury, worsening of AS inflammation and activation of NF-κBLipid per oxidation (LP) reactions could interfere hepatic lipid metabolism, and LP could also be exacerbated by excessive lipid storage, which would lead to vicious cycles. Microsomal cytochromase (CYP2E1 or P450ⅡE1) is the LP-related factor reported. It has been proved that hepatic cytochrome P450ⅡE1 plays a vital role in non-alcoholic fatty liver (FL) [3]. The decrease in anti-oxidative capability and exacerbation of LP are resulted from the increase in hepatic malondialdehyde (MDA) as well as the significant decrease in SOD, GSH and Vit E inside the cells as the expression of CYP2E1 increases. Studies abroad showed dose-response correlation between production of microsomal ROS and CYP2E1 in rats, which could exacerbate LP through promotion of free radicals. Lipid per oxidation, which refers to biomembrane oxidation due to ROS caused by enhanced oxidative stress, is another important pathogenesis. Lipid peroxidates, produced by per oxidation reactions of ROS and poly-unsaturated fatty acids of phospholipids in the membranes, could not only increase internal ROS and enhance toxicity, but also inhibit anti-oxidative capability and enhance the sensitivity to external proximate, thus leading to liver impairment and fatty liver. Production of free radicals increases as a consequence of enhanced LP reaction and decreased anti-oxidative capability. And impairment of hepatic cellular structure and function can be resulted from free radicals through oxidation of lipids in the cellular membranes.Reduced glutathione (GSH), which is comprised of glutamate, cysteine and alanine, is a determinant of intracellular oxidation or reduction state. It is present in all sorts of animal cells, and serves as the major intracellular non-protein mercaptal compounds. Due to its small molecular weight and high solubility in water, GSH tends to transmit through cellular membranes, capillary membranes, all sorts of biomembranes and blood-brain barrier easily. GSH plays a pivotal role in prevention of cellular lipid per oxidation injuries. As the product of GSH peroxides, it exerts it action on clearance of intracellular hydrogen peroxide and lipid peroxidates. On the other hand, it could independently react with many other free radicals, for instance, alkyl free radicals, peroxide free radicals, semiquinone free radicals. During the process above, intracellular GSH content decreases or will be transformed into oxidized disulfide compound (GSSG), which could again be transformed into GSH by GSH reductase with the assistance of reduced coenzymeⅡ(NADPH). Moreover, GSH participates in metabolism of Vit C and aid in protection of mercaptal group of protein, thus toxicity of external substances is reduced by GSH transferees.Objectives:1. To investigate the impact of reduced glutathione (GSH) on anti-oxidation action and blood lipid level in rats with hyperlipidemia.2. To investigate the synergistic modulation action of atrovastatin-GSH combination therapy on lipids and anti-oxidative capability.MethodsForty SD male rats were randomized into 5 groups, with 8 rats in each group. Among which atrovastatin was administered in group A, with the concentration of 2.1 mg/kg (20 mg/d was defined according to the dose for adults). Reduced glutathione was administered in group B, with the concentration of 126 mg/kg (1200 mg/d was defined according to the dose for adults). The combination of atrovastatin and reduced glutathione was administered in group C. And intragastric lipid-rich feedstuff was administered in group D, which was hyperlipidemia control group. Common feedstuff was administered in group E, which served as blank control group. At the end of the study(after fifty days), measurements of LDL, triglyceride (TG), total cholesterol (TC), aspartame aminotransferrase (AST), almandine aminotransferrase (ALT), MDA, high-density lipoprotein (HDL) and SOD were performed, and degradation of hepatic adipose tissue was examined.Statistical analysisStatistical analysis was performed using SPSS 13.0. All data were expressed as mean±standard deviation. One-way analysis of variance (ANOVA) was used for comparison among multiple groups, and least significant difference (LSD-t) test was adopted for comparison between two groups. Statistical difference was regarded when P <0.05.ResultsThe levels of LDL, TG, TC, ALT, AST and MDA were lower (P <0.05) and the levels of HDL and SOD in medication intervention groups were higher (P <0.05) compared with those in hyperlipidemia group. A more significant impact (P <0.05) was revealed in group C compared with that of group A and B. Pathological changes of liverVisual examination: Smooth reddish brown hepatic capsules with luster were observed in blank control group. Significantly diminished livers with intense capsule and blunt border were seen in hyperlipidemia group, and the livers appeared overall light yellow with adhesion to the peripheral tissues and lackluster fatty cutting surface. Diminished reddish brown livers with luster were observed in medication intervention groups.Microscopic examination: Swollen hepatic cells with hydropic degeneration and bolus hepatic cells with lipid degeneration predominated in hyperlipidemia group, with changes of intralobular spotty and focal necrosis as well as mononuclear cells infiltration. Minor fatty change was observed in both GSH group and atrovastatin group. Minor lesion with mild swollen hepatic cells and fatty changes was revealed in GSH/ atrovastatin combination group, no hepatic cell necrosis or inflammatory cell infiltration was discovered in all groups.Conclusions1. Protection to hepatic cells and lipid modulation of reduced glutathione might be associated with its anti-oxidative action.2. Synergistic action could be found in glutathione and atrovastatin. |
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