Differential effect of schisandrin B and dimethyl diphenyl bicarboxylate (DDB) on hepatic mitochondrial glutathione redox status in carbon tetrachloride intoxicated mice

The effects of schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, and dimethyl diphenyl bicarboxylate (DDB), a synthetic intermediate of schisandrin C (also a dibenzocyclooctadiene derivative), on hepatic mitochondrial glutathione redox status in control and carbon tetrachloride (CCl₄)-intoxicated mice were examined. Treating mice with Sch B or DDB at a daily oral dose of 1 mmol/kg for 3 d did not produce any significant alterations in plasma alanine aminotransferase (ALT) and sorbital dehydrogenase (SDH) activities. CCl₄ treatment caused drastic increases in both plasma ALT and SDH activities in mice. Pretreating mice with Sch B or DDB at the same dosage regimen significantly suppressed the CCl₄-induced increase in plasma ALT activity, with the inhibitory effect of Sch B being much more potent. Sch B, but not DDB, pretreatment could also decrease the plasma SDH activity in CCl₄-intoxicated mice. The lowering of plasma SDH activity, indicative of hepatoprotection against CCl₄ toxicity, by Sch B pretreatment was associated with an enhancement in hepatic mitochondrial glutathione redox status as well as an increase in mitochondrial glutathione reductase (mtGRD) activity in both non-CCl₄ and CCl₄-treated mice. DDB pretreatment, though enhancing both hepatic mitochondrial glutathione redox status and mtGRD activity in control animals, did not produce any beneficial effect in CCl₄-treated mice. The difference in hepatoprotective action against CCl₄ toxicity between Sch B and DDB may therefore be related to their ability to maintain hepatic mitochondrial glutathione redox status under oxidative stress condition.     

Hepatoprotective action of schisandrin B against carbon tetrachloride toxicity was mediated by both enhancement of mitochondrial glutathione status and induction of heat shock proteins in mice

In the present study, we investigated the differential role of the mitochondrial glutathione status and induction of heat shock proteins (HSPs) 25/70 in protecting against carbon tetrachloride (CCl_4) hepatotoxicity in schisandrin B (Sch B)-pretreated mice. The time-course of Sch B-induced changes in these hepatic parameters were examined. Dimethyl diphenyl bicarboxylate (DDB), a non-hepatoprotective analog of Sch B, was studied for comparison. Sch B treatment (2 mmol/kg) produced maximal enhancement in hepatic mitochondrial glutathione status as well as increases in hepatic HSP 25/70 levels at 24 h post-dosing. The stimulatory effect of Sch B then gradually subsided, but the activities of hepatic mitochondrial glutathione reductase (GR) and glutathione S-transferases (GST) as well as the level of HSP 25 remained relatively high even at 72 h post-dosing. CCl_4 challenge caused significant impairment in mitochondrial glutathione status and a decrease in HSP 70 level, but the HSP 25 level was significantly elevated. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl_4 was found to inversely correlate with the time elapsed after the dosing, the protective effect was associated with the ability of Sch B to maintain the mitochondrial glutathione status and/or induce further production of HSP 25 in CCl_4-intoxicated condition. On the other hand, DDB treatment (2 mmol/kg), which did not increase mitochondrial GSH level and GST activity or induce further production of HSP 25 after CCl_4 challenge, could not protect against CCl_4 toxicity. The results suggest that the enhancement of mitochondrial glutathione status and induction of HSP 25/70 may contribute independently to the hepatoprotection afforded by Sch B pretreatment.     

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.     

Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress

This study aimed to investigate whether treatments with vitamin E, L-carnitine and melatonin can protect against CCl₄ and diabetes-induced hepatic oxidative stress. Hepatic oxidative stress was performed in rats through 50% v/v carbon tetrachloride (CCl₄) (1 ml/kg/3days, i.p.), and through diabetes mellitus induced by streptozotocin (STZ) (40 mg/kg, i.p.). Vitamin E (100 mg/kg/day, i.p), L-carnitine (300 mg/kg/day, i.p.) and melatonin (10 mg/kg/day, i.p.) were injected for a period of 6 weeks. Thereafter, changes in serum glucose level, liver function tests, hepatic malondialdehyde (MDA) content, hepatic reduced glutathione (GSH) content, hepatic superoxide dismutase (SOD) activity, and serum total antioxidant capacity (TAC) level were evaluated. In CCl₄-induced liver fibrosis, the efficacy order was melatonin > L-carnitine > vitamin E, while in STZ-induced diabetes, the efficacy order was vitamin E ≥ melatonin > L-carnitine. In conclusion, these data indicate that low dose of melatonin is more effective than high doses of vitamin E and L-carnitine in reducing hepatic oxidative stress induced by CCl₄ and diabetes. Moreover, the potent effect of vitamin E in ameliorating diabetes can be linked not only to the antioxidant actions, but also to the superior effect in reducing diabetes-induced hyperglycaemia. Meanwhile, potency of L-carnitine was nearly the same in CCl₄ and diabetes-induced liver damage.     

Protective Effects of Garlic and Silymarin on NDEA-Induced Rats Hepatotoxicity

Background ­— The present study was conducted to investigate the chemopreventive effects of garlic extract and silymarin on N-nitrosodiethylamine (NDEA) and carbon tetrachloride (CCl₄)-induced hepatotoxicity in male albino rats. Methods and Results — Animals were pretreated with garlic, silymarin or both for one week prior to the injection of NDEA. Then animals received a single injection of NDEA followed by weekly subcutaneous injections of CCl₄ for 6 weeks. Oral administration was then continued along with the injection of CCl₄ for the duration of the experiment. Serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), hepatic lipid peroxidation (LPO), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione-S-transferase (GST) and glutathione reductase (GSR) were measured. Injection of NDEA induced a significant elevation in serum AST, ALT and ALP. In the liver, NDEA increased oxidative stress through the increase in LPO and decrease in SOD, and GSH-dependent enzymes. Although administration of garlic or silymarin significantly reduced the liver toxicity, combined administration was more effective in preventing the development of hepatotoxicity. Conclusion — These novel findings suggest that silymarin and garlic have a synergistic effect, and could be used as hepatoprotective agents against hepatotoxicity.     

Schisandrin B enhances the glutathione redox cycling and protects against oxidant injury in different types of cultured cells

Tert-butylhydroperoxide (tBHP) challenge caused an initial depletion of cellular reduced glutathione (GSH), which was followed by a gradual restoration of cellular GSH in AML12, H9c2, and differentiated PC12 cells. The time-dependent changes in cellular GSH induced by tBHP were monitored as a measure of GSH recovery capacity (GRC), of which glutathione reductase (GR)-mediated glutathione redox cycling and γ-glutamate cysteine ligase (GCL)-mediated GSH synthesis were found to play an essential role. While glutathione redox cycling sustained the GSH level during the initial tBHP-induced depletion, GSH synthesis restores the GSH level thereafter. The effects of (-)schisandrin B [(-)Sch B] and its analogs (Sch A and Sch C) on GRC were also examined in the cells. (-)Sch B and Sch C, but not Sch A, ameliorated the extent of tBHP-induced GSH depletion, indicative of enhanced glutathione redox cycling. However, the degree of restoration of GSH post-tBHP challenge was not affected or even decreased. Pretreatment with (-)Sch B and Sch C, but not Sch A, protected against oxidant injury in the cells. The (-)Sch B afforded cytoprotection was abolished by N,N'-bis(chloroethyl)-N-nitrosourea pretreatment suggesting the enhancement of glutathione redox cycling is crucially involved in the cytoprotection afforded by (-)Sch B against oxidative stress-induced cell injury.     

Hepatoprotective effect of Origanum vulgare in Wistar rats against carbon tetrachloride-induced hepatotoxicity

The effect of an aqueous extract of Origanum vulgare (OV) leaves extract on CCl₄-induced hepatotoxicity was investigated in normal and hepatotoxic rats. To evaluate the hepatoprotective activity of OV, rats were divided into six groups: control group, O. vulgare group, carbon tetrachloride (CCl₄; 2 ml/kg body weight) group, and three treatment groups that received CCl₄ and OV at doses of 50, 100, 150 mg/kg body weight orally for 15 days. Alanine amino transferase (ALT), alkaline phosphatase (ALP), and aspartate amino transferase (AST) in serum, lipid peroxide (LPO), GST, CAT, SOD, GPx, GR, and GSH in liver tissue were estimated to assess liver function. CCl₄ administration led to pathological and biochemical evidence of liver injury as compared to controls. OV administration led to significant protection against CCl₄-induced hepatotoxicity in dose-dependent manner, maximum activity was found in CCl₄?+?OV3 (150 mg/kg body weight) groups and changes in the hepatocytes were confirmed through histopathological analysis of liver tissues. It was also associated with significantly lower serum ALT, ALP, and AST levels, higher GST, CAT, SOD, GPx, GR, and GSH level in liver tissue. The level of LPO also decreases significantly after the administration of OV leaves extract. The biochemical observations were supplemented with histopathological examination of rat liver sections. Thus, the study suggests O. vulgare showed protective activity against CCl₄-induced hepatotoxicity in Wistar rats and might be beneficial for the liver toxicity.     

Protective effects of ascorbic acid on hepatotoxicity and oxidative stress caused by carbon tetrachloride in the liver of Wistar rats

This study was planned to investigate the protective effect of l (+)‐ascorbic acid (Vit C) on CCl₄‐induced hepatotoxicity and oxidative stress in the liver of Wistar rats (Rattus Norvegicus, strain Wistar). Twenty‐four adult male Wistar rats were fed with standard rat chow diet for 10 days and randomly were divided into four groups of six each as follows: (1) control, (2) CCl₄, (3) “CCl₄ + Vit C”, (4) Vit C groups. CCl₄ was applied to rats belonging to CCl₄ and “CCl₄ + Vit C” groups subcutaneously at 1 mg kg^?1 dose CCl₄ for 3 days. Vit C applied to “CCl₄ + Vit C” and “Vit C” group rats intraperitoneally at 300 mg kg^?1 dose for 3 days. All rats were sacrificed and livers were quickly removed on the fourth day of the experiment. MDA, total glutathione (T.GSH) levels and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH‐PX) activities were measured in the liver of all groups of rats and also serum alanine amino transferase (ALT) and aspartate amino transferase (AST) activities were detected to determine liver functions in all groups of rats. Histopathological changes were evaluated by light and transmission electron microscopes. In “CCl₄ + Vit C” group, MDA level was significantly decreased (p < 0.05) and SOD, CAT, GSH‐PX activities were significantly increased (p < 0.005, 0.01, 0.05) respectively, T.GSH level was significantly increased (p < 0.005) and serum ALT and AST activities were significantly decreased (p < 0.01, 0.05), respectively, when compared with CCl₄ group. These results show that Vit C has a highly protective effect on hepatotoxicity and oxidative stress caused by CCl₄. Copyright © 2009 John Wiley & Sons, Ltd.     

Time-dependent enhancement in mitochondrial glutathione status and ATP generation capacity by schisandrin B treatment decreases the susceptibility of rat hearts to ischemia-reperfusion injury

In the present study, we examined the time-dependent changes in the mitochondrial glutathione status and ATP generation capacity in the myocardium as well as the susceptibility of the myocardium to ischemia-reperfusion (IR) injury in female Sprague Dawley rats treated with a single pharmacological dose (1.2 mmol/kg) of schisandrin B (Sch B). Sch B treatment produced a time-dependent enhancement in myocardial mitochondrial glutathione status, as evidenced by increases in myocardial mitochondrial reduced glutathione (GSH) level and activities of glutathione reductase, Se-glutathione peroxidase (GPX) and glutathione S-transferases, with the response reaching maximum at 48 h post-dosing and then declining gradually to the control level at 96 h post-dosing. The enhancement of mitochondrial glutathione status was associated with an increase in myocardial ATP generation capacity, with the value peaking at 72 h post-dosing. These beneficial effects of Sch B on the myocardium was paralleled by a time-dependent decrease in the susceptibility to IR injury, with the maximum protection demonstrable at 48 h post-dosing. The cardioprotection was associated with increases in myocardial GSH level and activities of glutathione antioxidant enzymes (except for GPX whose activity was suppressed) as well as tissue ATP level/ATP generation capacity. The results suggest that Sch B treatment can precondition the myocardium by enhancing the mitochondrial glutathione status and ATP generation capacity, thereby protecting against IR injury.     

Effect of three structurally related antimalarial drugs on liver microsomal components and lipid peroxidation in rats

Changes in microsomal drug oxidizing enzymes, microsomal lipids, hepatic glutathione (GSH), glutathione S-trans-ferase (GST) and malondialdehyde (MDA) formation following administration of rats with therapeutic doses of three structurally related antimalarial drugs, amodiaquine (AQ), mefloquine (MQ) and halofantrine (HF) were investigated. There was a significant decrease in the activities of aniline hydroxylase, p-nitroanisole O-demethylase and pentoxyresorufin O-dealkylase in AQ, MQ and HF treated rats. AQ elicited the greatest effect with 50, 37 and 67% reductions in the activities of aniline hydroxylase, p-nitroanisole O-demethylase and pentoxyresorufin O-dealkylase, respectively. All the drugs prolonged hexobarbital-sleeping time to varying extents. The three drugs increased significantly the cholesterol per phospholipid ratio. AQ, MQ and HF decreased significantly the GSH level, GST activity and increased the formation of MDA. The results indicate that the alterations in hepatic microsomal components and lipid peroxidation caused by the antimalarials are related to the structural differences in the compounds.     

Hepatoprotective effects of Solanum nigrum Linn extract against CCl(4)-induced oxidative damage in rats

Solanum nigrum L. (SN) is an herbal plant that has been used as hepatoprotective and anti-inflammation agent in Chinese medicine. In this study, the protective effects of water extract of SN (SNE) against liver damage were evaluated in carbon tetrachloride (CCl4)-induced chronic hepatotoxicity in rats. Sprague-Dawley (SD) rats were orally fed with SNE (0.2, 0.5, and 1.0 g kg(-1) bw) along with administration of CCl4 (20% CCl4/corn oil; 0.5 mL kg(-1) bw) for 6 weeks. The results showed that the treatment of SNE significantly lowered the CCl4-induced serum levels of hepatic enzyme markers (GOT, GPT, ALP, and total bilirubin), superoxide and hydroxyl radical. The hepatic content of GSH, and activities and expressions of SOD, GST Al, and GST Mu that were reduced by CCl4 were brought back to control levels by the supplement of SNE. Liver histopathology showed that SNE reduced the incidence of liver lesions including hepatic cells cloudy swelling, lymphocytes infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by CCl4 in rats. Therefore, the results of this study suggest that SNE could protect liver against the CCl4-induced oxidative damage in rats, and this hepatoprotective effect might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects.     

Protective Effects of the Flavonoid-Rich Fraction from Rhizomes of Smilax glabra Roxb. on Carbon Tetrachloride-Induced Hepatotoxicity in Rats

Hepatoprotective agents could prevent tissue damage and reduce morbidity and mortality rates; such agents may include folkloric or alternative treatments. The present study evaluated the protective effects of the flavonoid-rich fraction from rhizomes of Smilax glabra Roxb. (SGF) on carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Sprague-Dawley male rats were orally treated with SGF daily and received CCl₄ intraperitoneally twice a week for 4 weeks. Our results showed that SGF at doses of 100, 300 and 500 mg/kg significantly reduced the elevated activities of serum aminotransferases (ALT and AST), alkaline phosphatase and lactate dehydrogenase and the level of hepatic thiobarbituric acid–reactive substances compared to the CCl₄-treated group. Moreover, SGF treatment was also found to significantly increase the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and glutathione compared with CCl₄-induced intoxicated liver. Histopathologic examination revealed that CCl₄-induced hepatic damage was markedly reversed by SGF. The results suggest that SGF has hepatoprotective and antioxidant properties in CCl₄-induced liver injury in rats.     

Destruction of hepatic mixed-function oxygenase parameters by CCl4 in rats following acute treatment with chlordecone, Mirex, and phenobarbital

Previous work has established the marked potentiation of CCl4 hepatoxicity by prior exposure to chlordecone (CD). This study was conducted to determine if prior exposure to CD results in enhancement of CCl4-induced destruction of the hepatic microsomal mixed-function oxygenase (MFO) system. Male Sprague-Dawley rats received a single oral dose of CD (10 mg/kg) or corn oil vehicle alone (1 ml/kg) 24 hr prior to a single ip injection of CCl4 (0-100 microliter/kg). Mirex (M; 10 mg/kg) and phenobarbital (PB; 80 mg/kg/day for two days) were used as negative and positive controls respectively for the potentiation of CCl4 hepatotoxicity. Hepatotoxicity was evaluated 24 hrs after CCl4 administration by elevations of three serum enzymes (GPT, GOT, and ICD). The key hepatic microsomal MFO parameters measured were microsomal protein, cytochrome P-450 content, glucose-6-phosphatase (G-6-Pase), and aminopyrine demethylase (APD). As previously demonstrated using a subchronic dietary pretreatment protocol, CD potentiated CCl4 hepatotoxicity over a range of CCl4 doses to a greater extent than PB or M, as judged by elevations in serum enzymes. PB caused the greatest increase in total P-450 content and the greatest increase in CCl4-mediated destruction of microsomal protein and APD activity. M caused the least destruction of total hepatic cytochrome P-450, despite the same level of cytochrome P-450 as in the PB group. CD treatment caused the greatest decrease in G-6-Pase activity in comparison to PB or M pretreatments and a similar degree of P-450 destruction as observed with the PB group. These findings suggest that in general, CCl4-induced destruction of hepatic MFO parameters measured in this study is disproportional to the known degree of potentiated hepatotoxicity by the pretreatments and does not accurately reflect the potentiation of CCl4 hepatotoxicity by CD.     

Pleurotus ostreatus, an oyster mushroom, decreases the oxidative stress induced by carbon tetrachloride in rat kidneys, heart and brain

The present work is aimed at evaluating the protective effect of the oyster mushroom, Pleurotus ostreatus on carbon tetrachloride (CCl4)-induced toxicity in male Wistar rats. Significantly elevated mean levels (p<0.05) of malondialdehyde (MDA) and lowered mean levels (p<0.01) of reduced glutathione (GSH), vitamins C and E (p<0.05) were observed in kidneys, heart and brain of rats exposed to CCl4, when compared to values in normal rats. Quantitative and qualitative analysis of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (Gpx) and glutathione-S-transferase (GST) revealed lower activities of these antioxidant enzymes in the kidneys, heart and brain of rats exposed to CCl4. When the extract of P. ostreatus was used to treat rats with CCl4-induced toxicity, it lowered the mean level of MDA, elevated the mean levels of GSH and of vitamins C and E and enhanced the mean activities of CAT, SOD, Gpx and GST so that the values of most of these parameters did not differ significantly from those of normal rats. Histopathological studies confirmed the toxic effects of CCl4 on other organs such as kidneys, heart and brain and also tissue protective effect of the extract of P. ostreatus. These results suggest that an extract of P. ostreatus is able to alleviate the oxidative damage caused by CCl4 in the kidneys, heart and brain of Wistar rats.     

Protective Effects of Polydatin from Polygonum cuspidatum against Carbon Tetrachloride-Induced Liver Injury in Mice

Polydatin is one of main compounds in Polygonum cuspidatum, a plant with both medicinal and nutritional value. The possible hepatoprotective effects of polydatin on acute liver injury mice induced by carbon tetrachloride (CCl₄) and the mechanisms involved were investigated. Intraperitoneal injection of CCl₄ (50 µl/kg) resulted in a significant increase in the levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and hepatic malondialdehyde (MDA), also a marked enhancement in the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclearfactor-kappa B (NF-κB). On the other hand, decreased glutathione (GSH) content and activities of glutathione transferase (GST), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were observed following CCl₄ exposure. Nevertheless, all of these phenotypes were evidently reversed by preadministration of polydatin for 5 continuous days. The mRNA and protein expression levels of hepatic growth factor-beta1 (TGF-β₁) were enhanced further by polydatin. These results suggest that polydatin protects mice against CCl₄-induced liver injury through antioxidant stress and antiinflammatory effects. Polydatin may be an effective hepatoprotective agent and a promising candidate for the treatment of oxidative stress- and inflammation-related diseases.     

Effect of vitamin E on monosodium glutamate induced hepatotoxicity and oxidative stress in rats

Monosodium glutamate (MSG), administered to rats (by gavage) at a dose of 0.6 mg/g body weight for 10 days, significantly (P<0.05) induced lipid peroxidation (LPO), decreased reduced glutathione (GSH) level and increased the activities of glutathione-s-transferase (GST), catalase and superoxide dismutase (SOD) in the liver of the animals; these were observed 24 hr after 10 days of administration. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT) were also significantly increased in the serum, on MSG administration. Vitamin E (0.2 mg/g body wt) co-administered with MSG, significantly reduced the LPO, increased the GSH level and decreased the hepatic activities of GST, catalase and SOD. The activities of ALT, AST and GGT in the serum were also significantly reduced. The results showed that MSG at a dose of 0.6 mg/g body wt induced the oxidative stress and hepatotoxicity in rats and vitamin E ameliorated MSG-induced oxidative stress and hepatotoxicity.     

Biochemical studies on the mechanism of action of liver poisons III. Depletion of liver glutathione in ethionine poisoning

Administration of ethionine to female rats was followed by rapid fall of the hepatic reduced glutathione content, concomitant with a progressive impairment of the cell-free protein-synthesizing capacity and a decline of the ATP level.In male rats and in adrenalectomized female rats, the onset of the first two alterations was considerably delayed. In contrast, the time course and the severity of the ethionine-induced ATP depletion were essentially the same in all instances.Treatment with CCl₄, despite the similarity of its hepatotoxic effects to those of ethionine, resulted in no appreciable decrease of the liver reduced glutathione level.Administration of methionine counteracted both the reduced glutathione decline and the other biochemical lesions induced by ethionine, whereas injection of adenine, though preventing the ATP depletion, failed to reverse the depression of reduced glutathione.The available evidence suggests that the decrease in the reduced glutathione level reflects a diminished capacity of the liver for oxidized glutathione reduction and its resultant inability to compensate the normal process of continuous reduced glutathione oxidation.The possible role of the altered reduced glutathione metabolism in the pathogenesis of ethionine hepatotoxicity is discussed.     

Protective effects of cassia seed ethanol extract against carbon tetrachloride-induced liver injury in mice

Oxidative stress has been recognized as a critical pathogenetic mechanism for the initiation and the progression of hepatic injury in a variety of liver disorders. Antioxidants, including many natural compounds or extracts, have been used to cope with liver disorders. The present study was designed to investigate the hepatoprotective effects of cassia seed ethanol extract (CSE) in carbon tetrachloride (CCl(4))-induced liver injury in mice. The animals were pre-treated with different doses of CSE (0.5, 1.0, 2.0 g/kg body weight) or distilled water for 5 days, then were injected intraperitoneally with CCl(4) (0.1% in corn oil, v/v, 20 ml/kg body weight), and sacrificed at 16 hours after CCl(4) exposure. The serum aminotransferase activities, histopathological changes, hepatic and mitochondrial antioxidant indexes, and cytochrome P450 2E1 (CYP2E1) activities were examined. Consistent with previous studies, acute CCl(4) administration caused great lesion to the liver, shown by the elevation of the serum aminotransferase activities, mitochondria membrane permeability transition (MPT), and the ballooning degeneration of hepatocytes. However, these adverse effects were all significantly inhibited by CSE pretreatment. CCl(4)-induced decrease of the CYP2E1 activity was dose-dependently inhibited by CSE pretreatment. Furthermore, CSE dramatically decreased the hepatic and mitochondrial malondialdehyde (MDA) levels, increased the hepatic and mitochondrial glutathione (GSH) levels, and restored the activities of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione S-transferase (GST). These results suggested that CSE could protect mice against CCl(4)-induced liver injury via enhancement of the antioxidant capacity.     

Lipoic acid ameliorates oxidative stress and renal injury in alloxan diabetic rabbits

The therapeutic potential of lipoic acid (LA) in diabetes and diabetic nephropathy treatment was elucidated. Alloxan diabetic rabbits were treated daily for three weeks with either 10 or 50 mg of LA per kg body weight (i.p.). The following parameters were measured: 1) serum glucose, urea, creatinine and hydroxyl free radical (HFR) levels; 2) blood glutathione redox state; 3) urine albumin concentration; 4) hepatic and renal HFR levels, GSH/GSSG ratios, cysteine contents and the activities of the enzymes of glutathione metabolism; and 5) the activity of renal NADPH oxidase. Histological studies of kidneys were also performed. The treatment of diabetic rabbits with 50 mg of LA resulted in lethal hypoglycaemia in 50% of animals studied. Although the low dose of LA did not change serum glucose concentration, it decreased serum urea and creatinine concentrations, attenuated diabetes-induced decline in GSH/GSSG ratio and abolished hydroxyl free radicals accumulation in serum, liver and kidney cortex. LA did not change the activities of the enzymes of glutathione metabolism, but it elevated hepatic content of cysteine, which limits the rate of glutathione biosynthesis. Moreover, LA lowered urine albumin concentration and attenuated glomerulopathy characteristic of diabetes. However, it did not affect diabetes-stimulated activity of renal NADPH oxidase. In view of these data, it is concluded that low doses of LA might be useful for the therapy of diabetes and diabetic nephropathy. Beneficial action of LA seems to result mainly from direct scavenging of HFR and restoring glutathione redox state due to elevation of intracellular cysteine levels.     

Beneficial effect of (-)schisandrin B against 3-nitropropionic acid-induced cell death in PC12 cells

Huntington's disease (HD) is characterized by the dysfunction of mitochondrial energy metabolism, which is associated with the functional impairment of succinate dehydrogenase (mitochondrial complex II), and pyruvate dehydrogenase (PDH). Treatment with 3-nitropropionic acid (3-NP), a potent irreversible inhibitor of succinate dehydrogenase, replicates most of the pathophysiological features of HD. In the present study, we investigated the effect of (-)schisandrin B [(-)Sch B, a potent enantiomer of schisandrin B] on 3-NP-induced cell injury in rat differentiated neuronal PC12 cells. The 3-NP caused cell necrosis, as assessed by lactate dehydrogenase (LDH) leakage, and mitochondrion-dependent cell apoptosis, as assessed by caspase-3 and caspase-9 activation, in differentiated PC12 cells. The cytotoxicity induced by 3-NP was associated with a depletion of cellular reduced glutathione (GSH) as well as the activation of redox-sensitive c-Jun N-terminal kinase (JNK) pathway and the inhibition of PDH. (-)Sch B pretreatment (5 and 15 μM) significantly reduced the extent of necrotic and apoptotic cell death in 3-NP-challenged cells. The cytoprotection afforded by (-)Sch B pretreatment was associated with the attenuation of 3-NP-induced GSH depletion as well as JNK activation and PDH inhibition. (-)Sch B pretreatment enhanced cellular glutathione redox status and ameliorated the 3-NP-induced cellular energy crisis, presumably by suppressing the activated JNK-mediated PDH inhibition, thereby protecting against necrotic and apoptotic cell death in differentiated PC12 cells.