Antioxidant and hepatoprotective effects of Ginkgo biloba phytosomes in carbon tetrachloride-induced liver injury in rodents.

AIM: The protective effects of Ginkgo biloba phytosomes (GBP) on carbon tetrachloride (CCl4)-induced hepatotoxicity and the probable mechanism(s) involved in this protection were investigated in rats. METHODS: Liver damage was induced in Wistar rats by administering a 1:1 (v/v) mixture of CCl4 and olive oil (1 ml/kg, i.p.) once daily for 7 days. GBP at 25 mg/kg and 50 mg/kg, i.p. and reference drug silymarin (200 mg/kg, p.o.) were administered for 10 days to CCl4-treated rats, this treatment beginning 3 days prior to the commencement of CCl4 administration. The degree of protection was evaluated by determining the marker enzymes (SGOT, SGPT and SALP), albumin (Alb) and total proteins (TP). Further, the effects of GBP on lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) were estimated in liver homogenates to evaluate antioxidant activity. RESULTS: GBP (25 and 50 mg/kg) and silymarin elicited significant hepatoprotective activity by decreasing the activities of serum marker enzymes and lipid peroxidation and elevated the levels of GSH, SOD, CAT, GPX, GR, Alb and TP in a dose-dependent manner. CONCLUSION: The present findings indicate that the hepatoprotective effects of GBP against CCl4-induced oxidative damage may be due to its antioxidant and free radical-scavenging activity.     

Effects of extract from Ginkgo biloba on carbon tetrachloride-induced liver injury in rats

AIM: To study the effects of extract from Ginkgo biloba (EGb) containing 22% flavonoid and 5% terpenoid on chronic liver injury and liver fibrosis of rats induced by carbon tetrachloride (CCl4). METHODS: All rats were randomly divided into control group, CCl4-treated group, colchicine-treated group and EGb-protected group. Chronic liver injury was induced in experimental groups by subcutaneous injection of CCl4 and fed with chows premixed with 79.5% corn powder, 20% lard and 0.5% cholesterol (v/v). EGb-protected group was treated with EGb (0.5 g/kg body weight per day) for 7 wk. At the end of wk 8, all the rats were killed. Liver function, liver fibrosis, oxidative stress and expression of transforming growth factorβ1 (TGF-β1), a-smooth muscle actin (α-SMA) and typeⅠcollagens in liver were determined. In addition, pathology changes of liver tissue were observed under light microscope. RESULTS: The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (Alb) in EGb-protected group were notably improved as compared with the CCL4-treated group (P < 0.01). The contents of serum hyaluronic acid (HA), typeⅢprocollagen (PCⅢ), typeⅣcollagen (CIV) and the expression of hepatic tissue TGF-β1,α-SMA and typeⅠcollagen in EGb-protected group were significantly lower than those in CCL4-treated groups (P < 0.05, P < 0.01). The degrees of liver fibrosis in EGb-protected groups were lower than those in CCL4-treated groups (6.58±1.25 vs 9.52±2.06, P < 0.05). Compared to the CCL4-treated group, the levels of plasma glutathoine peroxidase (Se-GSH-Px), superoxide dismutase (SOD) and malondialdehyde (MDA) were strikingly improved also in EGb-protected group (P < 0.05, P < 0.01). CONCLUSION: EGb resists oxidative stress and thereby reduces chronic liver injury and liver fibrosis in rats with liver injury induced by CCl4     

Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride

We reported that melatonin prevents the progression of carbon tetrachloride (CCl4)-induced acute liver injury in rats possibly by attenuating enhanced lipid peroxidation and reduced glutathione depletion. Herein, we examined the effect of melatonin on the changes in hepatic reactive oxygen species (ROS) metabolism in rats with a single intraperitoneal injection of CCl4 (1.6 g/kg body weight); the intent was to clarify the therapeutic mechanism of the indoleamine on CCl4-induced acute liver injury. Rats with and without CCl4 treatment received a single oral dose of melatonin (10, 50 or 100 mg/kg body weight) 6 hr after CCl4 treatment. Hepatic concentrations of ascorbic acid (ASC) and vitamin E (VE) and hepatic activities of superoxide dismutase (SOD), catalase (CAT), Se-glutathione peroxidase (Se-GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PDH), and xanthine oxidase (XO) were determined 6 and 24 hr after CCl4 treatment. The liver of CCl4-treated rats showed reductions in ASC concentrations, and SOD activity and an increase in G-6-PDH activity at 6 hr after treatment and further decreases in ACS concentrations and SOD activity and also further increase in G-6-PDH activity in addition to decreases in CAT and GSSG-R activities and increases in VE concentrations and XO activity at 24 hr after treatment. Melatonin attenuated the reductions in hepatic ASC concentrations and SOD, CAT and GSSG-R activities and the increase in hepatic XO activity in a dose-dependent manner without affecting either hepatic Se-GSH-Px activity or the increased hepatic VE concentration and G-6-PDH activity at 24 hr after CCl4 treatment. No dose of melatonin influenced hepatic ACS and VE concentrations and SOD, CAT, Se-GSH-Px, G-6-PDH, and XO activities in CCl4-untreated rats. These results indicate that melatonin postadministered at pharmacological doses prevents the disruption of hepatic ROS metabolism associated with ASC, SOD, CAT, GSSG-R, and XO, in addition to reduced glutathione, in CCl4-treated rats.     

补肾养肝合剂对四氯化碳诱导大鼠急性肝损伤的防护作用

目的：探讨补肾养肝合剂萃取物对四氯化碳（CCl4）诱导大鼠急性肝损伤之影响。方法：用CCl4诱导急性肝损伤模型，造模前口服补肾养肝合剂萃取物（100，500mg／kg），适时检测血清中ALT、AST活性。结果：补肾养肝合剂可有效降低CCl4诱发之ALT、AST活性；提升肝脏中抗氧化酵素（酶）SOD、GPx、GR活性。结论：结果显示补肾养肝合剂萃取物对CCl4诱导急性肝损伤具有防护作用，其防护CCl4诱导急性肝损伤之机转与提升肝脏内抗氧化酵素（酶）GR、GPx与SOD活性有关。     

谷胱甘肽转移酶μ基因缺失和氧化损伤与系统性红斑狼疮相关性研究

目的　检测系统性红斑狼疮 (SLE)患者谷胱甘肽转移酶 μ(GSTμ)基因缺失及血中一氧化氮 (NO)、脂质过氧化物 (LPO)、超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GSH Px)和谷胱甘肽 (GSH)含量 ,分析其与SLE发病之间的关系。方法　用PCR法检测 87例SLE患者和 40名健康对照组的GSTμ基因 ,用化学分析法测上述 5项指标。 结果　SLE患者GSTμ基因缺失率达 6 9 0 % ,明显高于对照组的 47 5 %。SLE活动期NO(79± 18) μmol/L、LPO (10 4± 2 0 ) μmol/L明显高于稳定期和对照组的水平。SLE活动期SOD (12 86± 2 5 2 ) μU/L、GSH Px (78± 14)U/mg、GSH (0 37±0 0 5 )mg/ g明显低于稳定期及对照组水平。在SLE稳定期GSH (1 0 0± 0 14)mg/ g ,仍明显低于对照组水平。血清NO水平与LPO呈显著直线正相关 ,与SOD、GSH Px、GSH呈显著直线负相关。抗dsDNA与NO、LPO呈显著直线正相关。在SLE活动期 ,GSTμ基因缺失者LPO (11 4± 2 2 ) μmol/L明显高于GSTμ基因携带者的水平 ,SOD (1111± 2 18) μU/L、GSH Px (6 7± 14)U/mg、GSH (0 2 4±0 0 4)mg/g明显低于GSTμ基因携带者的水平。在SLE稳定期GSTμ基因缺失者的SOD和GSH水平仍低于GSTμ基因携带者。 结论　GSTμ基因缺失可能是SLE发病的遗传因素之一 ,SLE     

Correlation of EPHX1, GSTP1, GSTM1, and GSTT1 genetic polymorphisms with antioxidative stress markers in chronic obstructive pulmonary disease

This study was undertaken to ascertain if a relationship existed between oxidative status and polymorphisms of microsomal epoxide hydrolase X1 (EPHX1), glutathione S-transferase P1 (GSTP1), GSTM1, and GSTT1 in chronic obstructive pulmonary disease (COPD). Erythrocyte glutathione peroxidase (GSH-px), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and plasma GST activities and total antioxidant status (TAS) as antioxidative stress markers were determined and compared either with individual and combined genotypes of EPHX1 exon 3, GSTP1 exon 5, GSTM1, and GSTT1 polymorphisms in COPD patients and healthy controls from the central area of Tunisia. Statistical data processing revealed significantly lower GSH-px, GR, SOD, CAT, GST, and TAS values in COPD patients in comparison to the control group (P < .001). As for genotypes, there was a no significant association in each of the 6 parameters and individual genotypes (P > .05). A significant correlation between the studied parameters and combined null GSTM1/null GSTT1 (GSH-px: P < .001, GR: P = .026, CAT: P = .018, GST: P = .022, TAS: P = .046), His113His EPHX1/null GSTM1 (GSH-px: P = .001, GST: P = .0012, TAS: P = .013), His113His EPHX1/Val105Val GSTP1 (GSH-px: P = .048, CAT: P = .026, GST: P = .031), and null GSTM1/Val105Val GSTP1 (GSH-px: P = .011, GR: P = .0028, GST: P = .0054, TAS: P = .032) was found in patients. In conclusion, combined genetic polymorphisms of GSTM1, GSTT1, GSTP1, and EPHX1 may have favorable effects on redox balance in COPD patients.     

绞股蓝总皂苷对四氯化碳诱导大鼠肝纤维化的防治作用

目的:观察绞股蓝总皂苷对四氯化碳( CCl4)诱导的大鼠肝纤维化的防治作用.方法:采用CCl4诱导的大鼠肝纤维化模型,分为正常组(Z,n=6)、模型组(M,n=8)、绞股蓝总皂苷组(J,n=8)、秋水仙碱(Q,n=8).造模6周末开始给药(股蓝总皂苷200mg/kg体重、秋水仙碱0.1mg/kg体重),给药3周.观察:①大鼠体重、肝脾比值的变化;②血清丙氨酸氨基转移酶(ALT)、门冬氨酸氨基转移酶(AST)、谷氨酰转肽酶(GGT)活性、白蛋白( Alb)、总胆红素(TBil)含量、肝组织羟脯氨酸(Hyp)含量;③肝组织超氧化物歧化酶(SOD)活性及丙二醛(MDA)、还原型谷胱甘肽(GSH)、谷胱甘肽过氧化物酶(GSH-Px)含量;④肝组织病理及胶原沉积情况.结果:①M组大鼠血清ALT、AST、GGT、TBil显著升高,Alb显著降低;J和Q组大鼠血清ALT、AST、GGT、TBil显著下降,Alb显著升高;②M组大鼠肝组织Hyp含量显著升高,J组及Q组大鼠肝组织Hyp含量显著下降;③肝组织HE染色显示:M组大鼠肝细胞脂肪变性,大量纤维结缔组织增生,假小叶形成.J组及Q组大鼠肝细胞脂肪变性减轻,纤维增生减少,少见完整假小叶结构.天狼星红染色显示:M组大鼠肝窦周胶原沉积明显,形成较厚汇管区和中央静脉间的纤维间隔,J组和Q组大鼠肝脏汇管区胶原纤维染较M组明显减轻;④M组大鼠肝组织SOD活性及GSH含量明显降低,MDA含量显著升高.J组大鼠肝组织SOD活性显著提高.结论:绞股蓝总皂苷具有显著抗CCl4诱导的大鼠肝纤维化及氧化损伤的作用.     

Role of oxidative stress in lansoprazole-mediated gastric and hepatic protection in Wistar rats.

BACKGROUND AND AIM: Lansoprazole, a benzimidazole derivative, is a widely-used proton-pump inhibitor. In addition, it has been reported to have an independent gastroprotective action. Since free radicals and antioxidant mechanisms appear to counter-act tissue-related injury, we studied the effect of lansoprazole on oxidative stress in acid-ethanol gastric injury. As this drug is metabolized in the liver, we also studied its effect on the liver. METHODS: Wistar rats were divided into three groups: control group, group I (vehicle treatment) and group II (lansoprazole treatment for eight days). In all the groups, injury was induced by ethanol-HCl administration. The effect of lansoprazole on free-radical generation and various antioxidants, e.g. superoxide dismutase (SOD), catalase, reduced glutathione (GSH), glutathione-s-transferase (GST) and glutathione reductase was evaluated in the gastric mucosal and liver homogenates. RESULTS: Ethanol-HCl administration initiated injury as shown by increase in malondialdehyde (MDA) levels in both gastric mucosa and liver. There was an increase in SOD and GST activity and a decrease in catalase, glutathione reductase and GSH in the gastric mucosa. In liver, ethanol-HCl administration decreased the activity of SOD, catalase and GSH and increased GST activity. Lansoprazole pretreatment led to decrease in the levels of MDA and increase in SOD, catalase, GSH, glutathione reductase and GST in both the gastric mucosa and liver. CONCLUSIONS: Lansoprazole has a protective action on gastric mucosa and the liver. This protection is mediated by a decrease in oxidative stress and a concomitant in-crease in antioxidants.     

Efficient hepatoprotective activity of cranberry extract against CCl_4-induced hepatotoxicity in Wistar albino rat model: Down-regulation of liver enzymes and strong antioxidant activity

Objective: To investigate the hepatoprotective efficacy of cranberry extract(CBE)against carbon tetrachloride(CCl4)-induced hepatic injury using in-vivo animal model.Methods: The hepatoprotective efficacy of CBE(200 and 400 mg/kg) was investigated against CCl4(4 m L/kg)-induced hepatotoxicity, elevated liver enzymes [ALT(alanine aminotransferase), AST(aspartate aminotransferase), and alkaline phosphatase(ALP)],and total protein(TP) contents in the serum. Moreover, CBE-aided antioxidant defense against hepatotoxic insult of CCl4 was measured by evaluating a number of anti-oxidative biomarkers including reduced glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), and malondialdehyde(MDA) in the serum by using spectrophotometric analyses.Results: Results showed that the exposure of experimental animals to CCl4 did induce significant hepatotoxicity compared to the non-induced(untreated) group. The oral administration of CBE demonstrated a significant dose-dependent alleviation in the liver enzymes(AST, ALT, and ALP), increased antioxidant defense(GSH, SOD, and CAT),and reduced MDA levels in the serum of treated animals compared to the animals without treatment. The resulting data showed that the administration of CBE decreased the serum levels of ALT, AST, and ALP compared to the CCl4-induced group.Conclusions: The resulting data evidenced that CBE exhibits promising hepatoprotective potential against the chemical induced hepatotoxicity, maintains homeostasis in liver enzymes, and can provide significant antioxidant defense against free radicals-induced oxidative stress.     

Myocardial oxidative stress and antioxidants in hypertension as a result of nitric oxide synthase inhibition

Rats were made hypertensive by the administration of the nitric oxide synthase inhibitor nitro-L-arginine (LNA, 2.74 mmol/L) in drinking water for 7 d. Hearts from hemodynamically assessed animals were analyzed for lipid peroxidation (LPO), ψ-glutamylcysteine-synthetase (ψ-GCS), glutathione disulfide reductase (GR), glutathione peroxidase (GSHPx), catalase (CAT), superoxide dismutase (SOD), and total radical trapping potential (TRAP) activities. LNA treatment increased the mean arterial blood pressure by 46% and the heart rate by 22% without changing plasma renin activity. LNA treatment resulted in a 30% increase in LPO. ψ-GCS was reduced by 48% and GR by 36% in the cardiac tissue of hypertensive rats as compared to controls. The activity of nonselenium GSHPx was reduced by 27%, and selenium-dependent GSHPx activity in the heart was not affected by LNA treatment. In hypertensive rats, SOD activity was increased by 16%, and CAT was decreased by 46%. TRAP was lower (27%) in the myocardium of hypertensive rats than in that of controls. These data suggest that LNA-induced hypertension is associated with increased myocardial oxidative stress.     

Potent Induction of Total Cellular and Mitochondrial Antioxidants and Phase 2 Enzymes by Cruciferous Sulforaphane in Rat Aortic Smooth Muscle Cells: Cytoprotection Against Oxidative and Electrophilic Stress

Sulforaphane, a cruciferous isothiocyanate compound, upregulates cytoprotective genes in liver, but its effects on antioxidants and phase 2 defenses in vascular cells are unknown. Here we report that incubation of rat aortic smooth muscle A10 cells with sulforaphane (0.25-5 muM) resulted in concentration-dependent induction of a spectrum of important cellular antioxidants and phase 2 enzymes, including superoxide dismutase (SOD), catalase, the reduced form of glutathione (GSH), glutathione peroxidase, glutathione reductase (GR), glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1). Sulforaphane also increased levels/activities of SOD, catalase, GSH and GST in isolated mitochondria of aortic smooth muscle cells. Time-dependent sulforaphane-induced increases in the mRNA levels for MnSOD, catalase, the catalytic subunit of gamma-glutamylcysteine ligase, GR, GST-A1, GST-P1, and NQO1 were observed. Pretreatment with sulforaphane (0.5, 1, and 5 muM) protected aortic smooth muscle cells from oxidative and electrophilic cytotoxicity induced by xanthine oxidase (XO)/xanthine, H(2)O(2), SIN-1-derived peroxynitrite, 4-hydroxy-2-nonenal, and acrolein. Furthermore, sulforaphane pretreatment prevented intracellular accumulation of reactive oxygen species (ROS) after exposure of the cells to XO/xanthine, H(2)O(2), or SIN-1. Taken together, this study demonstrates that in the aortic smooth muscle cells sulforaphane at physiologically relevant concentrations potently induces a series of total cellular as well as mitochondrial antioxidants and phase 2 enzymes, which is accompanied by dramatically increased resistance of these vascular cells to oxidative and electrophilic stress.     

Impairment of Intestinal Mucosal Antioxidant Defense System During Salmonella typhimurium Infection

The mucosal pathology of Salmonella typhimuriuminfection may in part be due to the excessive productionof reactive oxygen species (ROS). The influence of S.typhimurium infection on the intestinal mucosal antioxidant defense system was investigated. Weinjected ligated rat ileal loops with Salmonella liveculture or toxin. After 18 hr of infection, the animalswere killed and enterocytes isolated from the ileal loops. The enterocyte-reduced glutathione(GSH) content and activities of the enzymes superoxidedismutase (SOD), glutathione peroxidase (GSH-Px),catalase, glutathione-S-transferase (GST), glutathione reductase (GR), and glucose-6-phosphatedehydrogenase (G6PDH) were spectrophotometricallyestimated. The vitamin E and A contents were determinedby high-performance liquid chromatography (HPLC). Inboth the Salmonella live culture and toxin-treatedgroups, the enterocyte GSH and vitamin E contents andactivities of the enzymes SOD, GSH-Px, catalase, GR, andG6PDH were significantly decreased as compared to the control group. However there was asignificant increase in the enterocyte activity of GST.There was no change in the vitamin A content of theenterocytes. These findings might indicate a decreased endogenous intestinal protection against ROS inS. typhimurium-mediated infection, which couldcontribute to the pathogenesis of the disease.     

Protective effect of selenium-enriched Lactobacillus on CCl4-induced liver injury in mice and its possible mechanisms

AIM: To study the protective effects and mechanisms of Se-enriched lactobacillus on liver injury caused by carbon tetrachloride (CCl4) in mice. METHODS: Seventy-two ICR mice were randomly divided into four groups: normal group, CCl4-induced model group, low Se-enriched lactobacillus treatment group (L-Se group), and high Se-enriched lactobacillus treatment group (H-Se group). During a 3-wk experimental period, the common complete diet was orally provided daily for normal group and model group, and the mice in L-Se and H-Se groups were given a diet with 2 and 4 mg of organoselenium from Se-enriched lactobacillus per kg feed, respectively. From the 2nd wk of experiment, the model group, L-Se group, and H-Se group received abdominal cavity injection of olive oil solution containing 500 mL/L CCl4 (0.07 mL/100 g body mass) to induce liver injury, and the normal group was given olive oil on every other day for over 2 wk. In the first 2 wk post injection with CCl4, mice in each group were killed. The specimens of blood, liver tissue, and macrophages in abdominal cavity fluid were taken. Then the activities of the following liver tissue injury-associated enzymes including glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as malondialdehyde (MDA) content were assayed. Changes of phagocytic rate and phagocytic index in macrophages were observed with Wright-Giemsa stain. Plasma TNF-alpha level was measured by radioimmunoassay. The level of intracellular free Ca2+ ([Ca2+]i) in hepatocytes was detected under a laser scanning confocal microscope. RESULTS: During the entire experimental period, the AST and ALT activities in liver were greatly enhanced by CCl4 and completely blunted by both low and high doses of Se-enriched lactobacillus. The Se-enriched lactobacillus-protected liver homogenate GSH-Px and SOD activities were higher or significantly higher than those in model group and were close to those in normal group. CCl4 significantly increased MDA content in liver homogenates, while administration of Se-enriched lactobacillus prevented MDA elevation. Phagocytic rate and phagocytic index of macro-phages decreased after CCl4 treatment compared to those in normal control, but they were dramatically rescued by Se-enriched lactobacillus, showing a greatly higher phagocytic function compared to model group. CCl4 could significantly elevate plasma TNF-alpha and hepatocyte [Ca2+]i level, which were also obviously prevented by Se-enriched lactobacillus. CONCLUSION: Se-enriched lactobacillus can intervene in CCl4-induced liver injury in mice by enhancing macrophage function activity to keep normal and beneficial effects, elevating antioxidant-enzyme activities and reducing lipid peroxidation reaction, inhibiting excessive release of TNF-alpha, preventing the dramatic elevation of [Ca2+]i in hepatocytes.     

核因子κB和转化生长因子β1在银杏叶提取物抗肝纤维化中的作用

目的观察银杏叶提取物（EGB）对大鼠肝纤维化的防治效果，探讨EGB抗肝纤维化的机制。方法采用四氯化碳诱导大鼠肝纤维化。EGB各组四氯化碳处理同模型组，另分别给予0．25、0．5、1．0g／kg EGB灌胃。8周末检测其肝功能以及血清透明质酸和层黏连蛋白。取肝组织进行氧化应激测定，免疫组织化学法检测核因子KB（NF-kB）P65和α-平滑且儿肌动蛋白的表达，逆转录聚合酶链反应法检测转化生长因子β1（TGF-β1）和Ⅰ型胶原mRNA的表达，凝胶电泳迁移率分析检测NF-kB的活性，并进行病理组织学检查。结果EGB组肝纤维化分级评分、肝功能以及血清透明质酸和层黏连蛋白较模型组明显改善；EGB能抑制氧化应激、肝星状细胞的活化、NF-kB P65的表达以及NF-kB活性。此外，EGB还可减低TGFβ1和1型胶原mRNA的表达。结论EGB可能通过抑制氧化应激和TGFβ1的表达，减弱NF-kB诱导的肝星状细胞活化，从而阻止四氯化碳诱导的大鼠肝纤维化的发生发展。     

Therapeutic effect of melatonin on carbon tetrachloride-induced acute liver injury in rats

The therapeutic effect of melatonin on acute liver injury was examined in rats intoxicated with carbon tetrachloride (CCl4). Melatonin (10, 50, or 100 mg/kg body weight [BW]) was intraperitoneally administered to male Wistar rats 6 hr after intraperitoneal injection of CCl4 (1.6 g/kg BW) at which time an apparent liver injury occurred. This post-melatonin administration dose dependently prevented the progression of liver injury at 24 hr after CCl4 injection, judging from the levels of serum transaminases, indices of liver cell damage. Rats injected with CCl4 alone showed an increase in liver lipid peroxide (LPO) content and a decrease in liver reduced glutathione content at 6 and 24 hr after the injection. The post-melatonin administration dose dependently ameliorated both changes found at 24 hr after CCl4 injection. Rats injected with CCl4 alone showed an increase in liver triglyceride (TG) content and decreases in serum TG concentration and liver tryptophan 2,3-dioxygenase (TDO) activity, a marker of the inhibition of liver protein synthesis by CCl4, at 6 and 24 hr after the injection, and also a decrease in serum albumin concentration at 24 hr. The changes in serum TG, albumin concentration, liver TG content, and TDO activity found at 24 hr after CCl4 injection were not ameliorated by the post-administration of melatonin. The same administration of melatonin dose dependently reduced liver LPO content in CCl4-untreated rats. These results indicate that melatonin exerts a therapeutic effect on CCl4-induced acute liver injury in rats, possibly through its antioxidant action.     

Lentivirus-mediated superoxide dismutase1 gene delivery protects against oxidative stress-induced liver injury in mice.

BACKGROUND: The exposure of liver to hepatotoxins, and their subsequent metabolism, results in increased reactive oxygen species (ROS), one of the major culprits in causing both acute liver cell injury and chronic liver diseases. The aim of this present study is to investigate the protective effects of lentiviral vector-mediated copper-zinc superoxide dismutase (LV-SOD1) gene transfer against ROS-induced cytotoxicity in Hep G2 cells and liver injury in mice. METHODS: In vitro SOD1 efficacy was tested against two ROS-generating systems: hypoxanthine/xanthine oxidase (HX/XO) and hydroxyethyl radicals (HER), whereas in vivo SOD1 efficacy was evaluated in carbon tetrachloride (CCl4)-induced liver injury in C57BL/6 mice. RESULTS: LV-SOD1 transduction in Hep G2 cells resulted in a significant increase in SOD activity in cell lysates, and it significantly decreased the toxicity induced by HX/XO and HER. High SOD1 expression in the liver was achieved via portal vein injection of LV-SOD1 in mice and these high levels were observed for 30 days, the length of the experiment to date. SOD1 overexpression significantly decreased the toxicity and restored liver function in the CCl4-treated mice. CONCLUSIONS: These findings demonstrate for the first time that LV transduction led to the long-term expression of fully functional transgene expression in both in vitro and in vivo systems.     

Effect of fermented Panax ginseng extract (GINST) on oxidative stress and antioxidant activities in major organs of aged rats

The intracellular levels of oxidant and antioxidant balances are gradually distorted during the aging process. An age associated elevation of oxidative stress occurring throughout the lifetime is hypothesized to be the major cause of aging. The present study was undertaken to evaluate the putative antioxidant activity of the fermented Panax ginseng extract (GINST) on lipid peroxidation and antioxidant status of major organs of aged rats compared to young rats. Increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine were observed in the serum of aged rats. Increased levels of malondialdehyde (MDA) and significantly lowered activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) were observed in the liver, kidneys, heart and lungs of aged rats, when compared with those in young rats. Quantitative analysis of the non-enzymatic antioxidants such as reduced glutathione (GSH), ascorbic acid and α-tocopherol levels showed significantly lower values in the liver, kidneys, heart and lungs of aged rats. On the other hand, administration of the fermented Panax ginseng extract (GINST) to aged rats resulted in increased activities of SOD, CAT, GPx, GR and GST as well as elevation in GSH, ascorbic acid and α-tocopherol levels. Besides, the level of MDA, AST, ALT, urea and creatinine were reduced on administration of GINST to aged rats. These results suggested that treatment of GINST can improve the antioxidant status during aging, thereby minimizing the oxidative stress and occurrence of age-related disorders associated with free radicals.     

Effects of hypoxia and hypoxic training on 8-hydroxydeoxyguanosine and glutathione levels in the liver

The effects of hypoxia and hypoxic training on 8-hydroxydeoxyguanosine (8-OHdG), reduced glutathione (GSH), and oxidized glutathione (GSSG) levels and on glutathione reductase (GR) activity in the liver of rats were evaluated. Rats were divided into 3 groups: a hypoxia and exercise (HE) group, a hypoxia and sedentary (HS) group, and a normoxia and sedentary (NS) group. The liver 8-OHdG levels were lower in the HE and HS groups compared with the NS group (P <.05). No significant difference between in the liver 8-OHdG levels in the HE and HS groups were found. However, the liver GSH level in the HS group was lower than that in the NS group (P <.05), and the HE group had significantly higher levels of liver GSH than the HS group (P <.01). The activity of liver GR in the HS group was lower than that of the NS group (P <.05). Moreover, the liver GR activity of the HE group was significantly higher than that of the HS group (P <.01). No significant difference in liver GR activity between the HE and NS groups was noted. In conclusion, the present study confirmed that moderate hypoxia and hypoxic training attenuated liver DNA damage and decreased liver GSH levels and GR activity. These results indicate that moderate hypoxia and hypoxic training result in decreased oxidative stress.     

VE、VC对大鼠肝、心组织中谷胱甘肽过氧化物酶、超氧化物歧化酶和过氧化脂质的影响

本实验研究选用14个月龄Wistar大白鼠,研究了VE、VC单独摄入与二者联合摄入后对谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)和过氧化脂质(LPO)的影响。结果表明,无论单独饲喂VE、VC或二者联合使用,肝LPO均低于对照组,差异非常显著。大剂量VC降低LPO的作用明显大于VE组。从GSH-Px和SOD的变化来看,VC具有明显提高GSH-Px和SOD活性的作用,与降低LPO的作用一致。     

Accelerated reversal of carbon tetrachloride-induced cirrhosis in rats by the endothelin receptor antagonist TAK-044

BACKGROUND: A multifunctional mediator, endothelin (ET)-1 is implicated in the pathophysiology of liver cirrhosis. Carbon tetrachloride (CCl4)-induced cirrhosis in rats resolves upon termination of CCl4 treatment. We determined the hepatic ET-1 system during such reversal and assessed whether ET-1 receptor antagonism enhances this process. METHODS: Cirrhosis was induced in rats by CCl4 treatment for 8 weeks. Treatment with an ETA/ETB antagonist TAK-044 (10 mg/kg per day) was then started and determinations were made at 1, 2 and 4 weeks. RESULTS: After termination of CCl4 treatment, accelerated normalization of liver architecture and portal hypertension occurred in TAK-044-treated rats compared with saline-treated rats. The increased hepatic hydroxyproline concentration and collagen I mRNA expression also declined to greater extents in the TAK-044-treated group. Higher collagenase activity in cirrhosis decreased in saline-treated rats, but did not reach basal values. In TAK-044-treated rats, collagenase activity tended to increase at weeks 2 and 4. Increased ET-1 concentration and ETA receptor density declined to normal values in both groups. In contrast, increased ETB receptor density did not change in saline-treated rats, but decreased to control values in TAK-044-treated rats. CONCLUSIONS: Our results emphasize the role of ET-1 in chronic liver disease and strongly indicate the potential for ET-1 receptor antagonists in its treatment.