An insight into the possible protective effect of pyrrolidine dithiocarbamate against lipopolysaccharide-induced oxidative stress and acute hepatic injury in rats

Lipopolysaccharide (LPS) is a major cell wall molecule of Gram-negative bacteria known to stimulate the synthesis and secretion of several toxic metabolites, such as reactive oxygen species. In this study, the effect of pyrrolidine dithiocarbamate (PDTC), an antioxidant with nuclear factor-κB inhibitor activity, was evaluated in LPS-induced oxidative stress and acute hepatic injury in rats. Animals were pretreated for 3 consecutive days with PDTC (200 mg/kg/day, i.p.) or saline and animals were then challenged with LPS (6 mg/kg, i.p.) or saline. Six hours after LPS injection, animals were decapitated and blood and liver samples were collected to assess the chosen biochemical parameters. Saline-pretreated animals challenged with LPS revealed extensive liver damage, as evidenced by increases in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (γ-GT). Also, LPS treatment resulted in significant increases in serum lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α) and nitrite levels. Furthermore, LPS challenge caused oxidative stress as indicated by an increase in hepatic lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) and a decrease in hepatic reduced glutathione concentration (GSH) as well as decreased activities of superoxide dismutase (SOD) and catalase in hepatic tissues. The administration of PDTC prior to LPS challenge resulted in improved liver functions as evidenced by the decline in serum AST, ALT, γ-GT levels and reduction in serum LDH, TNF-α and nitrite levels. Moreover, PDTC reduced the chosen lipid peroxidation marker, TBARS and increased GSH concentration, and SOD and catalase activities in hepatic tissues. These results indicate that PDTC may be a useful pharmacological agent in alleviating LPS-induced oxidative stress and acute hepatic injury.     

Low dose docosahexaenoic acid protects normal colonic epithelial cells from araC toxicity

Background

CCl₄ is a well-established hepatotoxin inducing liver injury by producing free radicals. Exposure to CCl₄ also induces acute and chronic renal injuries. The present study was designed to establish the protective effect of hesperidin (HDN), a citrus bioflavonoid, on CCl₄-induced oxidative stress and resultant dysfunction of rat liver and kidney.

Methods

Animals were pretreated with HDN (100 and 200 mg/kg orally) for one week and then challenged with CCl₄ (2 ml/kg/s.c.) in olive oil. Rats were sacrificed by carotid bleeding under ether anesthesia. Liver enzymes, urea and creatinine were estimated in serum. Oxidative stress in liver and kidney tissue was estimated using Thiobarbituric acid reactive substances (TBARS), glutathione (GSH) content, superoxide dismutase(SOD), and Catalase (CAT)

Results

CCl₄ caused a marked rise in serum levels of ALT and AST (P < 0.05). TBARS levels were significantly increased whereas GSH, SOD and CAT levels decreased in the liver and kidney homogenates of CCl₄ treated rats. HDN (200 mg/kg) successfully attenuated these effects of CCl₄

Conclusion

In conclusion, our study demonstrated a protective effect of HDN in CCl₄ induced oxidative stress in rat liver and kidney. This protective effect of HDN can be correlated to its direct antioxidant effect.     

Tissue-specific gene expression of heme oxygenase-1 (HO-1) and non-specific delta-aminolevulinate synthase (ALAS-N) in a rat model of septic multiple organ dysfunction syndrome

Reactive oxygen species are thought to be involved in the pathogenesis of septic multiple organ dysfunction syndrome (MODS). It has been reported that heme oxygenase-1 (HO-1) (EC 1.14.99.3) is induced in septic animal models and is thought to confer protection against oxidative tissue injury. In this study, we examined changes in gene expression of HO-1 and non-specific delta-aminolevulinate synthase (ALAS-N) (EC 2.3.1.37), the rate-limiting enzymes in heme catabolism and heme synthesis, respectively, after intraperitoneal administration of bacterial lipopolysaccharide (LPS) to rats. LPS treatment caused the elevation of body temperature, increases in white blood cell counts, and marked elevation of serum interleukin-6 levels associated with liver, lung, and kidney injuries, characteristic of septic MODS. LPS administration significantly induced HO-1 mRNA, protein, and enzyme activity in the liver, lung, and kidney. In contrast, ALAS-N mRNA was decreased rapidly in the liver, followed by an oscillating recovery pattern. Induction of hepatic HO-1 mRNA and rapid suppression of ALAS-N mRNA were likely the result of a rapid increase in hepatic free heme concentration as judged by the increase in heme saturation of tryptophan pyrrolase. In contrast to that in the liver, the ALAS-N mRNA level in the lung and kidney was increased significantly after LPS administration, suggesting a novel mechanism of ALAS-N regulation in these tissues. These findings suggest that HO-1 and ALAS-N mRNA are regulated in a tissue-specific manner in a rat model of septic MODS.     

Protective effect of Rumex patientia (English Spinach) roots on ferric nitrilotriacetate (Fe-NTA) induced hepatic oxidative stress and tumor promotion response.

In this communication, we document the antioxidant potential of ethanolic extract of Rumex patientia L. (Polygonaceae) roots and its chemopreventive effects against Fe-NTA mediated hepatic oxidative stress, hepatotoxicity and tumor promotion response. The extract exhibited high polyphenolic content, potent reducing power and significantly scavenged free radicals (including several reactive oxygen species (ROS) and reactive nitrogen species (RNS)). The extract also significantly and dose dependently protected against oxidative damage to lipids and DNA. These results indicated R. patientia root extract to exert a potent antioxidant activity in vitro. The efficacy of extract was also evaluated in vivo and it was found to exert a potent protective affect in acute oxidative tissue injury animal model: ferric nitrilotriacetate (Fe-NTA) induced hepatotoxicity in mice. Administration of Fe-NTA (9 mg/kg body weight, i.p.) to mice led to a significant oxidative stress and allied damage in liver tissues and induced hyperproliferation. A significant depletion was observed in GSH content and enzymes implicated in its metabolism. Attenuation also occurred in activities of other hepatic antioxidant enzymes including SOD, CAT, and GPX. Fe-NTA also incited hyperproliferation response elevating ornithine decarboxylase activity and [(3)H]-thymidine incorporation into DNA. Histopathological investigations and liver function tests (LFT) indicated Fe-NTA to cause extensive hepatic damage. However, prophylactic treatment with R. patientia root extract at a dose regimen of 100-200mg/kg body weight for a week not only restored hepatic antioxidant armory close to normal, but also significantly precluded oxidative damage restoring normal hepatic architecture and levels of hepatic damage markers. The data obtained in the present study illustrates R. patientia roots to possess potent antioxidant and free radical scavenging activities and thwart oxidative damage and hyperproliferation in hepatic tissues.     

Cypermethrin-induced oxidative stress in rat brain and liver is prevented by vitamin E or allopurinol

Considering that the involvement of reactive oxygen species (ROS) has been implicated in the toxicity of various pesticides, this study was designed to investigate the possibility of oxidative stress induction by cypermethrin, a Type II pyrethroid. Either single (170 mg/kg) or repeated (75 mg/kg per day for 5 days) oral administration of cypermethrin was found to produce significant oxidative stress in cerebral and hepatic tissues of rats, as was evident by the elevation of the level of thiobarbituric acid reactive substances (TBARS) in both tissues, either 4 or 24 h after treatment. Much higher changes were observed in liver, increasing from a level of 60% at 4 h up to nearly 4 times the control at 24 h for single dose. Reduced levels (up to 20%) of total glutathione (total GSH), and elevation of conjugated dienes ( approximately 60% in liver by single dose at 4 h) also indicated the presence of an oxidative insult. Glutathione-S-transferase (GST) activity, however, did not differ from control values for any dose or at any time point in cerebral and hepatic tissues. Pretreatment of rats with allopurinol (100 mg/kg, ip) or Vitamin E (100 mg/kg per day, ig, for 3 days and a dose of 40 mg/kg on the 4th day) provided significant protection against the elevation of TBARS levels in cerebral and hepatic tissues, induced by single high dose of oral cypermethrin administration within 4 h. Thus, the results suggest that cypermethrin exposure of rats results in free radical-mediated tissue damage, as indicated by elevated cerebral and hepatic lipid peroxidation, which was prevented by allopurinol and Vitamin E.     

The effect of captopril on inflammation-induced liver injury in male rats

Abstract

Activation of macrophages-induced by lipopolysaccharide (LPS) is accompanied by the production of reactive oxygen species and inflammatory cytokines to induce hepatic injury. Renin–angiotensin system may play a role in liver damage. In the current study, the effect of captopril on the injury of inflammation-induced liver was investigated. The rats were divided into (1) Control, (2) LPS, and (3–5) LPS as well as 10, 50, or 100?mg/kg captopril for 2 weeks. Captopril decreased NO metabolites, IL-6, and MDA, while it increased CAT, SOD, and total thiol in the liver. Captopril also attenuated AST, ALT, and ALK-P, whereas it increased albumin and total protein in serum. As an ACE inhibitor, captopril improved liver function and attenuated inflammation and oxidative stress induced by LPS injection.     

The role of Salicornia herbacea in ovariectomy-induced oxidative stress

Ovarian hormone deficiency increases the generation of reactive oxygen species. Their excess induces oxidative stress, which results in the cell damage or death. It causes the aging diseases-atherosclerosis, rheumatoid arthritis, osteoporosis, etc. Ovariectomized rats are used as oxidative stress models. We verified the effects of ovariectomy-induced oxidative stress on free radical production as evaluated by DPPH elimination, lipoperoxidation evaluated by malondialdehyde levels, and antioxidant activation of superoxide dismutase, catalase, glutathione peroxidase, and estradiol in the liver and sera. Ovariectomized rats were given Salicornia herbacea (SH) intraperitoneally at the dose of 100 mg/kg daily for 2 months. Free radical-scavenging activity of SH was measured in comparison with that of L-ascorbic acid. The histopathology of liver tissue was also investigated. Antioxidative values in the ovariectomized group decreased, but those in the SH-treated group increased due to the free radical-scavenging activity of SH. Moreover, inflammation and cirrhosis in the liver tissue of SH-treated rats decreased significantly. These results suggest that SH may be a potential candidate for an antioxidative reagent.     

Assessment of the extent of oxidative stress induced by intravenous ferumoxytol, ferric carboxymaltose, iron sucrose and iron dextran in a nonclinical model

Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malondialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.     

Effects of acute dimethoate administration on antioxidant status of liver and brain of experimental rats

Organophosphorus compounds may induce oxidative stress leading to generation of free radicals and alterations in antioxidant and scavengers of oxygen free radicals. The present study demonstrates effect of acute exposure of dimethoate in causation of oxidative stress in male Wistar rats. Dimethoate was administered orally at doses 45, 75 and 90 mg/kg of body weight on the basis of LD(50) for 24 h. After administration of doses, the liver and brain homogenates were analyzed for various parameters of oxidative stress. The results indicated an increase in hepatic cytochrome P450, lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase in liver and brain at 90 and 75 mg/kg doses. There were no significant changes in the levels of glucose-6-phosphate dehydrogenase activity in both liver and brain. Similarly, there were no significant changes in hepatic glutathione and glutathione-S-transferase activities. However, there was a significant increase in glutathione and glutathione-S-transferase in brain at 90 mg/kg dose only. Erythrocyte acetylcholinesterase was inhibited at all doses used. Dose-dependent histopathological changes, observed in both liver and brain, are also described.     

Heat stress-induced hepatotoxicity and its prevention by resveratrol in rats

The high ambient temperature beyond the range of comfort zone or thermoneutral zone causes environmental heat stress (HST). It causes serious physiological dysfunction that may result in heat-related diseases and even death. The underlying mechanism in the pathogenesis of hepatic dysfunction following hyperthermic challenge and the possible involvement of oxidative stress to induce oxidative deterioration of liver functions in adult rats are investigated in this study. Cellular damage was assessed in terms of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histology of liver. The effect of hyperthermia in altering the oxidative stress was evaluated on the basis of its influence on hepatic lipid peroxidation and antioxidant status-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity. The current study demonstrated that HST is associated with a complex set of integrated alterations in liver, time-dependent rise in oxidative stress followed by distinct pattern of liver injury in animals. Heat-induced hepatotoxicity was assessed by increased lipid peroxidation, depletion of antioxidant enzyme activities such as SOD, CAT, GPx and tissue damages revealed by hepatic vacuolization, and widespread necrosis. The study also revealed that pretreatment with resveratrol resulted in normalizing these parameters appreciably, emphasizing the therapeutic potentials of this polyphenol. Taken together, the results suggest that an increase in free radical formation relative to loss of the antioxidant defense system during heat stress may render liver more susceptible to oxidative damage, leading to their functional inactivation. However, resveratrol supplementation can be an effective antidote in the treatment of HST-induced malfunction.     

Heat stress-induced hepatotoxicity and its prevention by resveratrol in rats

The high ambient temperature beyond the range of comfort zone or thermoneutral zone causes environmental heat stress (HST). It causes serious physiological dysfunction that may result in heat-related diseases and even death. The underlying mechanism in the pathogenesis of hepatic dysfunction following hyperthermic challenge and the possible involvement of oxidative stress to induce oxidative deterioration of liver functions in adult rats are investigated in this study. Cellular damage was assessed in terms of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histology of liver. The effect of hyperthermia in altering the oxidative stress was evaluated on the basis of its influence on hepatic lipid peroxidation and antioxidant status—superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity. The current study demonstrated that HST is associated with a complex set of integrated alterations in liver, time-dependent rise in oxidative stress followed by distinct pattern of liver injury in animals. Heat-induced hepatotoxicity was assessed by increased lipid peroxidation, depletion of antioxidant enzyme activities such as SOD, CAT, GPx and tissue damages revealed by hepatic vacuolization, and widespread necrosis. The study also revealed that pretreatment with resveratrol resulted in normalizing these parameters appreciably, emphasizing the therapeutic potentials of this polyphenol. Taken together, the results suggest that an increase in free radical formation relative to loss of the antioxidant defense system during heat stress may render liver more susceptible to oxidative damage, leading to their functional inactivation. However, resveratrol supplementation can be an effective antidote in the treatment of HST-induced malfunction.     

Effects of antioxidant vitamins on glutathione depletion and lipid peroxidation induced by restraint stress in the rat liver

BACKGROUND AND AIM: Stress as a cofactor has been reported to affect the progression and severity of several diseases. The influence of stress on the liver is of interest from the clinical point of view because stress plays a potential role in aggravating liver diseases in general and hepatic inflammation in particular, probably through generation of reactive oxygen species. The present study was undertaken to investigate the potential of the antioxidant vitamins A (retinol), E (tocopherol) and C (ascorbic acid) individually and in combination (vitamin E + C) to modulate restraint stress-induced oxidative changes. These effects were determined by measuring changes in hepatic levels of free radical scavenging enzymes such as superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase, as well as levels of total glutathione (GSH), malondialdehyde (MDA), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). METHODS: Immobilisation was achieved by placing the animals in wire mesh cages of their size. The rats were orally administered vitamins A, E and C individually and in combination (E + C) prior to and after 6 hours of immobilisation stress exposure. The hepatic levels of SOD, GST, catalase, GSH and MDA were determined by spectrophotometric methods. Liver SOD activity was assayed by monitoring the amount of enzyme required to inhibit autoxidation of pyrogallol by 50%. Hepatic GST was monitored by following the increase in absorbance at 340 nm of CDNB-GSH conjugate generated due to GST catalysis between GSH and CDNB. Catalase activity in liver tissues was determined using peroxidase as the substrate. Lipid peroxidation was measured by determining the level of thiobarbituric acid reactive substances. ALT and AST were determined by commercial kits. RESULTS: Six hours of immobilisation stress caused a decrease in liver levels of SOD (p = 0.001), catalase (p = 0.031), GST (p = 0.021) and GSH (0.013), while levels of MDA (p = 0.0015), AST (p = 0.05) and ALT (p = 0.046) were increased compared with non-stressed control rats. Both pre-vitamin stress and post-vitamin stress treatments either alone or in combination were associated with increased normalisation of these parameters towards control values, with post-vitamin treatment being the more effective of the two. Vitamins E and C individually were found to be more effective in restoring the endogenous antioxidant system than vitamin A. The combined vitamin (E + C) post-stress treatment was found to be effective but not additive in combating hepatic oxidative stress. The beneficial effects of these vitamin treatments were also reflected in reversions of altered AST and ALT levels towards their control values. CONCLUSION: Vitamins E or C alone or in combination can be given as prophylactic/therapeutic supplements for combating scavenging free radicals generated in liver tissue. This approach may reduce oxidative stress caused by diseases such as cirrhosis.     

Carnosic acid attenuates lipopolysaccharide-induced liver injury in rats via fortifying cellular antioxidant defense system

The study investigated the protective effects of carnosic acid (CA), the principal constituent of rosemary, on lipopolysaccharide (LPS)-induced oxidative/nitrosative stress and hepatotoxicity in rats. CA was administered orally to rats at doses of 15, 30 and 60 mg/kg body weight before LPS challenge (single intraperitoneal injection, 1 mg/kg body weight). The results revealed that CA inhibited LPS-induced liver damage and disorder of lipid metabolism, which were mainly evidenced by decreased serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. CA also inhibited LPS-induced oxidative/nitrosative stress by decreasing lipid peroxidation, protein carbonylation, and serum levels of nitric oxide. Histopathological examination demonstrated that CA could improve pathological abnormalities and reduce the immigration of inflammatory cells in liver tissues with LPS challenge. Concurrently, CA potently inhibited the LPS-induced rise in serum levels of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6. CA supplementation markedly enhanced the body’s cellular antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and glutathione in serum and liver after the LPS challenge. In conclusion, the present study suggests that CA successfully and dose dependently attenuates LPS-induced hepatotoxicity possibly by preventing cytotoxic effects of oxygen free radicals, NO and cytokines.     

Effect of glycine on oxidative stress in rats with alcohol induced liver injury

We studied the effect of administering glycine on tissue lipid peroxidation and enzymic and non-enzymic antioxidants in experimental hepatotoxic Wistar rats. Hepatotoxicity was induced by administering ethanol for 30 days by intragastric intubation. Glycine administered at a dose of 0.6 g kg(-1) body weight for 30 days significantly inhibited the severe oxidative stress as evidenced by the decreased levels of liver and brain thiobarbituric acid reactive substances (TBARS) and hydroperoxides compared to control. The activities of enzymic and non-enzymic antioxidants such as reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) in the liver and brain were significantly elevated on glycine supplementation as compared to the untreated alcohol fed rats. The levels of serum vitamin E and vitamin C were also increased to near normal levels on glycine treatment. Microscopic examination of alcohol treated rat liver showed inflammatory cell infiltrates and fatty changes, which were alleviated on treatment with glycine. Alcohol treated rat brain demonstrated oedma, which was significantly lowered on treatment with glycine. Thus our study shows that administering glycine to alcohol supplemented rats, markedly reduced the oxidative stress and elevated the enzymic and non-enzymic antioxidants in the liver and brain, which a was associated with a reversal of hepatic steatosis and cerebral oedma.     

Endotoxin potentiates the hepatotoxicity of cocaine in male mice

Cocaine produces hepatotoxicity by a mechanism that remains undefined but that has been linked to its oxidative metabolism. Endotoxin (lipopolysaccharide, LPS) is also a well-known cause of hepatic damage, where exposure to non-injurious doses of LPS increases the toxicity of certain hepatotoxins. This study was conducted to investigate the possible potentiation of cocaine-mediated hepatotoxicity (CMH) by LPS. Male CF-1 mice were administered oral cocaine hydrochloride for 5 consecutive days at a dose of 20 mg/kg with and without 12 x 10(6) EU LPS/kg given intraperitoneally 4 h after the last cocaine injection. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Blood and liver glutathione (GSH) levels were determined, as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured. The results demonstrate that endotoxin potentiated the hepatotoxicity of cocaine. Serum ALT and AST were significantly elevated with the combined cocaine and LPS treatment versus all other treatments. While cocaine alone resulted in centrilobular necrosis, the cocaine and LPS combination produced submassive necrosis. The increased hepatic GSH content and GRx activity observed with cocaine alone were not observed with the combination treatment, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the combination treatment. In conclusion, this study demonstrates that LPS potentiates the hepatotoxicity of cocaine as revealed by an array of biochemical and morphological markers.     

Protective effects of echinacoside on carbon tetrachloride-induced hepatotoxicity in rats

The aim of this study was to investigate the possible protective effects of echinacoside, one of the phenylethanoids isolated from the stems of Cistanches salsa, a Chinese herbal medicine, on the free radical damage of liver caused by carbon tetrachloride in rats. Treatment of rats with carbon tetrachloride produced severe liver injury, as demonstrated by dramatic elevation of serum ALT, AST levels and typical histopathological changes including hepatocyte necrosis or apoptosis, haemorrhage, fatty degeneration, etc. In addition, carbon tetrachloride administration caused oxidative stress in rats, as evidenced by increased reactive oxygen species (ROS) production and MDA concentrations in the liver of rats, along with a remarkable reduction in hepatic SOD activity and GSH content. However, simultaneous treatment with echinacoside (50mg/kg, intraperitoneally) significantly attenuated carbon tetrachloride-induced hepatotoxicity. The results showed that serum ALT, AST levels and hepatic MDA content as well as ROS production were reduced dramatically, and hepatic SOD activity and GSH content were restored remarkably by echinacoside administration, as compared to the carbon tetrachloride-treated rats. Moreover, the histopathological damage of liver and the number of apoptotic hepatocytes were also significantly ameliorated by echinacoside treatment. It is therefore suggested that echinacoside can provide a definite protective effect against acute hepatic injury caused by CCl(4) in rats, which may mainly be associated with its antioxidative effect.     

ENDOTOXIN POTENTIATES THE HEPATOTOXICITY OF COCAINE IN MALE MICE

Cocaine produces hepatotoxicity by a mechanism that remains undefined but that has been linked to its oxidative metabolism. Endotoxin (lipopolysaccharide, LPS) is also a well-known cause of hepatic damage, where exposure to non-injurious doses of LPS increases the toxicity of certain hepatotoxins. This study was conducted to investigate the possible potentiation of cocaine-mediated hepatotoxicity (CMH) by LPS. Male CF-1 mice were administered oral cocaine hydrochloride for 5 consecutive days at a dose of 20 mg/kg with and without 12 2 10 6 EU LPS/kg given intraperitoneally 4 h after the last cocaine injection. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Blood and liver glutathione (GSH) levels were determined, as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured. The results demonstrate that endotoxin potentiated the hepatotoxicity of cocaine. Serum ALT and AST were significantly elevated with the combined cocaine and LPS treatment versus all other treatments. While cocaine alone resulted in centrilobular necrosis, the cocaine and LPS combination produced submassive necrosis. The increased hepatic GSH content and GRx activity observed with cocaine alone were not observed with the combination treatment, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the combination treatment. In conclusion, this study demonstrates that LPS potentiates the hepatotoxicity of cocaine as revealed by an array of biochemical and morphological markers.     

Antioxidant effect of Coscinium fenestratum in carbon tetrachloride treated rats

Antioxidant effect of methanol extract of Coscinium fenestratum stem powder was examined using carbon tetrachloride-intoxicated rat liver as the experimental model. Hepatotoxic rats were treated with the methanol extract for 90 days (daily, orally at the dose of 60 mg/kg body weight). Lipid peroxidation in carbon tetrachloride-administered rats was evidenced by a marked elevation in the levels of thiobarbituric acid reactive substances and diene conjugates, and also a profound diminution in glutathione content in the liver. Rats co-administered with the methanol extract retained an almost normal level of these constituents. The decreased activities of antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in carbon tetrachloride-intoxicated rats, and its retrieval towards near-normalcy in the methanol extract co-administered animals revealed the effectiveness of Coscinium fenestratum in combating oxidative stress due to hepatic damage. The findings provide a rationale for further studies on isolation of active principles and its pharmacological evaluation.     

Nordihydroguairetic acid, a lignin, prevents oxidative stress and the development of diabetic nephropathy in rats

Recent evidences indicate a pivotal role of reactive oxygen species in etiology of diabetic nephropathy, an important microvascular complication of diabetes mellitus. Moreover, oxidative stress leads to an increased production of lipoxygenase derivatives which also play a role in diabetic nephropathy. The present study was thus designed to examine the effect of an antioxidant and a lipoxygenase inhibitor, nordihydroguairetic acid (NDGA), on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin (65 mg/kg) in rats. After the 4th week of STZ injection, NDGA (5 and 10 mg/kg) was given subcutaneously (s.c.) for another 4 weeks to both control and diabetic rats. At the end of the 8th week, diabetic rats exhibited renal dysfunction as evidenced by reduced creatinine and urea clearance along with enhanced albumin excretion rate as compared with control rats. Biochemical analysis of kidneys revealed a marked increase in oxidative stress demonstrated by increased lipid peroxidation and decreased activities of key antioxidant enzymes, glutathione (GSH), superoxide dismutase (SOD) and catalase in diabetic rats. Chronic treatment with NDGA in diabetic rats significantly prevented both renal dysfunction and oxidative stress as compared with vehicle-treated diabetic rats. The kidneys of diabetic rats showed morphological changes such as hyaline casts, glomerular thickening and moderate interstitial fibrosis and arteriolopathy, whereas NDGA administration in diabetic rats markedly prevented renal morphological alterations. These results emphasize the role of oxidative stress in the pathophysiology of diabetic nephropathy and point towards the potential of NDGA as a complementary therapy for the prevention/treatment of diabetic nephropathy.     

Effects of salvianolic acid a on oxidative stress and liver injury induced by carbon tetrachloride in rats

In the present study, we investigated the hepatoprotective effects of salvianolic acid A, a novel antioxidant, against oxidative stress and acute liver injury induced by carbon tetrachloride (CCl(4)) in rats, and the mechanisms underlying its protective effects. Administration of CCl(4) to rats caused severe hepatic damage, as demonstrated by the significant increase in the levels of serum alanine aminotransferase, aspartate aminotransferase and classic histological changes including hepatocyte necrosis or apoptosis, haemorrhage, fatty degeneration, etc. Co-treatment with salvianolic acid A (20 mg/kg, intraperitoneally), a water-soluble extract from a Chinese traditional drug, Radix Salvia miltiorrhiza, significantly decreased CCl(4)-induced hepatotoxicity. Salvianolic acid A not only decreased serum alanine aminotransferase, aspartate aminotransferas levels and ameliorated histopathological manifestations in CCl(4)-treated rats, but also reduced oxidative stress, as evidenced by decreased reactive oxygen species production and malondialdehyde concentrations in the liver tissues, combined with elevated hepatic superoxide dismutase activity and gluthathione content. In addition, salvianolic acid A treatment remarkably reduced intrahepatic tumour necrosis factor-alpha concentrations and caspase-3 activities as compared with the CCl(4)-treated rats. The results suggested that treatment with salvianolic acid A provides a potent protective effect against acute hepatic damage caused by CCl(4) in rats, which may mainly be related to its antioxidative effect.