N-acetylcysteine pretreatment attenuates paraquat-induced lung leak in rats

We investigated the effects of N-acetylcysteine (NAC) pretreatment on paraquat-induced lung inflammation and leak. We found that administering a single intravenous dose (60 mg/kg) of paraquat rapidly (2 h) increased lung leak, lung lavage cytokine-induced neutrophil chemoattractant (CINC) levels, and lung myeloperoxidase (MPO) activity in rats. Rats pretreated with NAC (150 mg/kg, intraperitoneally) had increased lung tissue glutathione (GSH + GSSG) levels compared to saline-pretreated rats. In addition, rats pretreated with NAC and then given paraquat 2.5 h later had decreased lung leak compared to saline-pretreated rats given paraquat. In contrast, NAC pretreated rats given paraquat had the same lung lavage CINC levels and lung tissue MPO activity as saline-pretreated rats given paraquat. Our results indicate that paraquat causes an oxidative injury which may be decreased by the GSH-increasing or other properties of NAC.     

Taurine protects against carbon tetrachloride toxicity in the cultured neurons and in vivo

Carbon tetrachloride (CCl4) has been found to induce cellular damage by generating oxygen free radicals. A study was carried out to investigate the effects of taurine (extracted from Pegasus laternarius Cuvier) on CCl4 intoxicated cultured neurons. CCl4 application (0.4 mmol x l(-1), 0.8 mmol x l( -1), 1.2 mmol x l (-1) and 1.6 mmol x l(-1 )) increased the lipid peroxidation product and decreased glutathione peroxidase (GPx) activity significantly in a concentration dependent manner. Pretreatment of cultures with taurine (10 micromol x l(-1), 30 micromol x l(-1) and 60 micromol x l(-1)) prevented the loss of GPx activity and lipid peroxidation. The effects of three different dosages of taurine (10 mg/kg body wt., 20 mg/kg body wt. and 40 mg/ kg body wt.) for 45 days on the activities of superoxide dismutase and glutathione peroxidase were examined in the cerebrum, cerebellum and medulla of normal and CCl4 treated mice. Treatment of mice with taurine provided protection against CCl4 toxicity as was evident by lipid peroxide status. Taurine was not so successful at inducing the activity of SOD in normal animals except in the medulla where it could increase the activity of SOD (p < 0.05). Taurine induces the GPx activity in a dose dependent manner in all regions of the brain studied. Also in the CCl4 poisoned mice taurine could augment the status of GPx activity in a dose dependent manner. Hence it is concluded that taurine can protects neurons from the oxidative stress induced by CCl4.     

Liver and colon pro- and anti-oxidant enzyme activities in rats after long-term ethylnitrosourea exposure

Liver and colon pro- and anti-oxidant enzyme activities were investigated in rats treated with ethylnitrosourea (ENU) (i.p.) (4 mg/kg body wt) for 6 months. The pro-oxidant enzymes (NADPH cytochrome c reductase, NADH cytochrome c reductase, NADH cytochrome b5 reductase and cytochrome P-4502E1and the antioxidant enzyme, superoxide dismutase (SOD) exhibited significantly increased activity in liver and colon. Glucose-6-phosphate dehydrogenase (G6PDH) and glutathione-S-transferase (GST) showed enhanced activity in liver, but decreased activity in colon. Glutathione peroxidase (GP) and glutathione reductase (GR) activities were significantly increased in colon, but decreased in liver. Catalase (CAT) activity while showed a significant increase in liver, exhibited only marginal increase in colon. Malondialdehyde (MDA) level was significantly elevated in both tissues.     

Curative effect of methionine on certain enzymes of chick kidney cortex under lanthanum toxicity situation.

Acute single dose administration of lanthanum chloride (250 mg/kg body wt, ip) to chicks have been found to alter the levels of enzymes of the antioxidant defence system of chick renal cortex fractions. Such changes involved significant decrease in activities of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase and catalase of kidney epithelial cells. However glutathione-S-transferase activity was not altered. Glutathione and total thiol contents were decreased while lipoperoxidative reactions in kidney-cortex was significantly enhanced. The data indicate that amelioration of lanthanum toxicity condition by methionine supplementation may be due to the methionine serving as a precursor of glutathione.     

Peroxisome proliferator perfluorodecanoic acid alters glutathione and related enzymes

Previously we have shown that treatment with the peroxisome proliferator perfluorodecanoic acid (PFDA) significantly increased hepatic reduced glutathione (GSH) content without altering the activity of selenium-glutathione peroxidase. In this study we examined some potential mechanisms by which PFDA treatment increases GSH levels. Male Sprague-Dawley rats were given a single injection of 0, 8.8, 17.5, and 35 mg PFDA in corn oil per kg body weight. Twelve days later the effects of PFDA on the activities of enzymes associated with GSH synthesis, utilization, and regeneration were assessed. The results showed that in a dose-dependent manner, PFDA treatment significantly decreased the activity of gamma-glutamylcysteine synthetase, while the activities of NADPH-generating enzymes, malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase were increased. PFDA treatment also dose dependently decreased cytosolic, but not microsomal, glutathione S-transferase activity, and the activity of glutathione reductase was decreased by the highest dose of PFDA. The data obtained suggest that increased hepatic GSH levels following PFDA treatment may result from increased regeneration and/or decreased utilization.     

Immuno-detection of aluminium and aluminium induced conformational changes in calmodulin - implications in Alzheimer's disease

Studies were conducted to ascertain any involvement of free radical mediated prooxidative processes in different brain regions following diazopam administration. A significant decrease in TBA reactive substance formation was observed in cerebral cortex, cerebellum and brain stem regions after single doses of 1.5, 3 and 6 mg/kg b.wt. For further studies rats were given diazepam (i.p.) at 3 mg/kg body weight dose and sacrificed after 1 h to follow changes in the pro/antioxidant status. An enhancement in the TBARS formation was found in the mitochondrial fractions from cerebral cortex and brain stem. This effect was highest in brain stem being 107% as compared to controls. In the post mitochondrial fraction, cerebellum showed 49% enhancement whereas decreased formation of thiobarbituric acid reactive substances was observed in cerebral cortex and brain stem. Isozymes of superoxide dismutase showed a decrease in activity which was region dependent. Even though, total thiols were not significantly altered, free thiols showed depletion in cerebellum (39.8%) and brain stem (50%). Glutathione reductase activity was also decreased in cerebellum and brain stem. The results indicate that a single dose of diazepam causes free radical mediated changes and the modulatory response of antioxidant defences appears to be region specific.     

Toxicity of endosulfan on kidney of male rats in relation to drug metabolizing enzymes and microsomal lipid peroxidation

Endosulfan administration (po, 15 and 30 days at 7.5 and 10 mg/kg body wt respectively) inhibited the activity of microsomal mixed function oxidases in kidney tissue of male rats. Microsomal and cytosolic protein contents of kidney were significantly increased following 30 days endosulfan exposures. Profound induction in the activity profiles of alcohol dehydrogenase and cytosolic glutathione s-transferase was noticed, however, no such change was apparent in the activity of aldehyde dehydrogenase. Microsomal preparations from treated animals showed a dose and duration dependent increase in spontaneous lipid peroxidation. The observed biochemical changes persisted even after 7 days normalcy allowance provided after the endosulfan (10 mg/kg body wt) withdrawl. The results suggest a substantial renal toxicity of endosulfan to male rats in relation to microsomal mixed function oxidases and associated functions which possibly resulted from lipid peroxidative damage of microsomal membrane in treated animals.     

Influence of ferulic acid on circulatory prooxidant-antioxidant status during alcohol and PUFA induced toxicity.

In recent years, there has been an escalation in alcohol abuse and inevitably, alcohol related disorders are becoming an increasingly important cause of morbidity and mortality. Alcohol is known to induce a dose dependent increase in lipid peroxidation. Alcohol related disabilities are more pronounced when taken along with diet rich in polyunsaturated fatty acid (PUFA). The present work aims at analysing the protective role of ferulic acid (FA), a naturally occurring nutritional component on alcohol and PUFA induced oxidative stress. Two different doses of ferulic acid, 20 mg/kg body weight and 40 mg /kg body weight were used for the study. The results showed that the levels of oxidative markers; thiobarbituric acid reactive substances (TBARS), hydroperoxides (HP) and levels of copper (Cu) and ferritin were increased significantly in plasma of alcohol, thermally oxidised PUFA (DeltaPUFA) and alcohol + DeltaPUFA groups, which were decreased significantly on treatment with both the doses of ferulic acid. The activities of enzymic antioxidants viz. superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and non enzymic antioxidants like vitamin C, vitamin E, and reduced glutathione (GSH) and the levels of zinc (Zn) were significantly decreased in alcohol, DeltaPUFA and alcohol + DeltaPUFA groups which were improved significantly on treatment with both the doses of FA. The reduction in oxidative stress was more significant in 20 mg/kg body weight treatment groups compared to 40 mg/kg body weight. Thus from the results obtained, we conclude that FA effectively protects the system against alcohol and PUFA induced oxidative stress.     

Developmental and reproductive toxicity studies on artemisone

BACKGROUND: In order to justify clinical studies in women of child-bearing age with artemisone, a new artimisinin derivative, studies to assess fertility and early embryonic development in rats, developmental toxicity in rats and rabbits, and peri-post natal development in rats were performed. METHODS AND RESULTS: In the study on fertility and early embryonic development (dose levels 0-5-20-80 mg/kg bw/day), doses inducing clinical and organ toxicity were used. Only in severe toxicity conditions, a reduction of the number of estruses, a prolonged time to insemination, decreased numbers of corpora lutea, implantation sites, and viable fetuses were found. Two developmental toxicity studies were performed in rats (dose levels 0-1-2 mg/kg bw/day) and rabbits (dose levels 0-2.5-5.0-7.5 mg/kg bw/day). It was shown that rats were about 5 times more sensitive than rabbits. In rats, artemisone induced total litter loss (late resorptions) at 2 mg/kg body weight and above with an increased incidence of a common vascular variation and retarded ossification at this dose. In rabbits, maternal toxicity, abortion and a slightly increased incidence of cardiac ventricular septal defects was observed at 7.5 mg/kg body weight. In a pre- and postnatal developmental toxicity study in rats (dose levels 0-1-2-4 mg/kg bw/day), 4 mg/kg body weight artemisone induced clinical symptoms and affected postnatal survival, body weight gain in the F1 pups, and motor activity. CONCLUSIONS: In summary, artemisone was shown to be embryo- and fetotoxic and induced cardiac ventricular septal defects and retarded ossification in dosages where total litter loss and abortions were observed. However, no effect on reproductive and developmental parameters below severe toxic dosages could be observed. Birth Defects Res (Part B)86: 131-143, 2009. © 2009 Wiley-Liss, Inc.     

Paraquat-generated oxidative stress in rat liver induces heme oxygenase-1 and aminolevulinic acid synthase

The in vivo effect of the known herbicide, paraquat, on both hepatic oxidative stress and heme metabolism was studied. A marked increase in lipid peroxidation and a decrease in reduced glutathione (GSH) content were observed 1 h after paraquat administration. The activity of liver antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase was decreased 3 h after paraquat injection. Heme oxygenase-1 induction started 9 h after treatment, peaking at 15 h. delta-aminolevulinic acid synthase induction occurred once heme oxygenase had been enhanced, reaching its maximum (1.5-fold of control) at 16 h. delta-aminolevulinic acid dehydratase activity was 40% inhibited at 3 h showing a profile similar to that of GSH, while porphobilinogenase activity was not modified along the whole period of the assay. Administration of alpha-tocopherol (35 mmol/kg body weight) 2 h before paraquat treatment entirely prevented the increase in thiobarbituric acid reactive substances (TBARS) content, the decrease in GSH levels as well as heme oxygenase-1 and delta-aminolevulinic acid synthase induction. This study shows that oxidative stress produced by paraquat leads to an increase in delta-aminolevulinic acid synthase and heme oxygenase-1 activities, indicating that the herbicide affects both heme biosynthesis and degradation.     

Influence of ethanol on methanol-induced oxidative stress and neurobehavioral deficits

The present study examines the efficacy of ethanol as an antidote in methanol neurotoxicity in terms of its effect on antioxidant defense system and behavior. It was observed that acute methanol exposure (7.5 g/kg body weight) led to an increase in lipid peroxidation in various regions of brain. Ethanol administration (7.5 g/kg body weight), on the other hand, was found to accentuate methanol-induced lipid peroxidation. Glutathione levels in brain were significantly reduced in methanol-exposed animals. However, in the coexposed animals, the levels of glutathione were comparable to those observed in controls. The activities of superoxide dismutase and catalase were decreased in the brain following methanol exposure, whereas in methanol- and ethanol-coexposed animals there was no significant effect on these enzymes as compared to methanol-exposed animals. The activity of acetylcholinesterase was significantly reduced in the methanol-exposed animals. On the other hand, acetylcholinesterase activity was not affected in the coexposed animals in comparison to methanol-treated group. Neurobehavioral studies revealed impaired motor and cognitive functions following methanol exposure. In contrast, ethanol exposure ameliorated the behavioral deficits induced by methanol. The findings from the present study suggest the beneficial effect of ethanol on neurobehavioral deficits induced by methanol along with intensification of methanol-induced oxidative stress.     

Effect of cisplatin on brush border membrane enzymes and anti-oxidant system of rat intestine

Cisplatin (CP) is a widely used antineoplastic agent which exhibits gastrointestinal toxicity. The present work was done to study the effect of administration of CP on brush border membrane (BBM) enzymes and anti-oxidant system of rat intestine. Male Wistar rats were given a single intraperitoneal dose of CP (6 mg/kg body weight) and then sacrificed 1, 3, 5 and 7 days after this treatment. Control animals were given saline only. The administration of CP led to significant decline in the specific activities of BBM enzymes both in the mucosal homogenates and isolated membrane vesicles. Kinetic studies showed that the V(max) of the enzymes was decreased in BBM vesicles from CP treated rats while the K(m) remained unchanged. The activities of catalase, Cu-Zn superoxide dismutase, glucose 6-phosphate dehydrogenase and glutathione reductase decreased while the activities of glutathione S-transferase and thioredoxin reductase increased in CP treated animals compared to the control group. Lipid peroxidation and total sulfhydryl groups were also altered upon CP treatment indicating the generation of oxidative stress. The maximum changes in all the parameters studied above were 3 days after administration of CP and then recovery took place on days 5 and 7. Thus, the administration of CP leads to significant alterations in the activities of BBM enzymes and the anti-oxidant status of rat intestine.     

Free radical scavenging activity of Cleome gynandra L. leaves on adjuvant induced arthritis in rats

The generation of free radicals has been implicated in the causation of several diseases of known and unknown etiologies such as, rheumatoid arthritis, diabetes, cancer, etc., and compounds that can scavenge free radicals have great potential in ameliorating these disease processes. The present study was aimed to investigate the possible anti-oxidant potential of Cleome gynandra leaf extract at a dose of 150 mg/kg body weight for 30 days on adjuvant induced arthritis in experimental rats. Oral administration of C. gynandra leaf extract significantly increased the levels of lipid peroxides and activities of catalase, glutathione peroxidase and decreased the levels of reduced glutathione and superoxide dismutase activity in arthritis induced rats. The free radical scavenging activity of the plant was further evidenced by histological observations made on the limb tissue. The presence of biologically active ingredients and vital trace elements in the leaves readily account for free radical scavenging property of C. gynandra. (Mol Cell Biochem 276: 71–80, 2005)     

Modification of cyclophosphamide-induced clastogenesis and apoptosis in rats by alpha-lipoic acid

The aim of the present study was to investigate the protective efficacy of alpha-lipoic acid (LA) on the cyclophosphamide (CP)-induced chromosomal aberrations (CA) and apoptosis in the bone marrow of rats. Male Wistar rats of 140+/-20 g were categorized into eight groups. Five groups were administered CP (40 mg/kg body weight, intraperitoneally) to induce toxicity; four of these groups received a single intraperitoneal injection of LA at a dose of either 100 or 200 mg/kg body weight, and either 30 or 60 min prior to CP administration. A vehicle-treated control group and LA control groups were also included. Twenty-four hours after CP treatment, the frequency of CA in bone marrow cells were significantly increased in comparison with the controls. The CP-induced CA were associated with significant increase in DNA damage in the bone marrow as evidenced by increased single strand breaks, whereas in rats treated with LA and CP, the frequency of CA and single strand breaks were significantly decreased in comparison to those given CP alone. CP administration distinctly triggered the apoptotic and necrotic cell death, and LA pretreatment affected cell death by decreasing the number of apoptotic and necrotic cells. The protective effect of LA was found to be stronger at a dose of 200 mg/kg body weight than 100 mg/kg body weight dosage, indicating the dose dependent protective effect of LA. However, the protection by LA was not dependent on the time intervals between LA and CP administration. The results of this study illustrate the protective effect of LA on the CA and apoptosis induced by CP in the erythropoietic system of rats.     

Central nervous system depressant activity of Russelia equisetiformis.

The central nervous system depressant activity of the crude methanol extract (REC) and fractions (RE1, RE2, and RE3) of Russelia equisetiformis were evaluated in mice using the following models: amphetamine-induced stereotypy, picrotoxin-induced convulsion and phenobarbitone sleeping time. At 200-400 mg/kg, REC significantly increased phenobarbitone-sleeping time [P < 0.05] in a dose- dependent manner and also reduced the sleep latency significantly [P < 0.05]. The fractions, at doses 1.5 mg/kg for RE1 and 20 mg/kg for RE2 and RE3 also significantly prolonged Phenobarbitone sleeping time and sleep latency [P < 0.05]. Picrotoxin-induced convulsion was not prevented by 100-400 mg/kg of REC but this dose range significantly prolonged seizure latency. A significant reduction [P < 0.05] in amphetamine-induced stereotype behavior was observed with 200 mg/kg REC, but there was no protection against amphetamine-induced mortality. The results of this study suggest that Russelia equisetiformis methanol extract possesses central nervous system depressant activities.     

腹腔注射乙酰唑胺对大鼠氧惊厥潜伏期的影响

为探讨脑血流调节与氧惊厥的关系,本研究在复制大鼠氧惊厥模型的基础上,采用行为学方法测定氧惊厥潜伏期,并测定脑皮质氧化指标内二醛（maleic dialdehyde,MDA）含量,采用腹腔注射不同剂量脑血管扩张药物乙酰唑胺（acetazolamide,ACZ）,以及联合注射ACZ及其拈抗刺吲哚美辛（indomethacin,IND）后,观察脑血管扩张对氧化状态以及氧惊厥潜伏期的影响。结果观察到：（1）腹腔注射ACZ（不小于7．5mg／kg体重）后,氧惊厥潜伏期明显缩短（P〈0．05）,剂量越大,缩短越明显。腹腔注射IND对氧惊厥潜伏期无显著影响。腹腔注射IND（20mg／kg体重）,30min后再注射ACZ（7．5mg／kg体重）,ACZ的氧惊厥潜伏期缩短作川被对抗（P〈0．05）。（2）腹腔注射ACZ7．5mg／kg后,与各组相比,6及16min暴露后,脑组织MDA含量明显增多（P〈0．01,P〈0．05）;腹腔注射IND对脑皮质MDA含量无显著影响;在预注射IND,再注射ACZ后,MDA含量显著降低（P〈0．01,P〈0．05）。结果表明,ACZ外周注射加重氧化损伤,缩短氧惊厥潜伏期;而IND可以对抗其氧惊厥潜伏期缩短作用以及氧化损伤加重作用,碳酸酐酶活力变化很可能是通过影响脑血管状态而影响氧化损伤以及氧惊厥潜伏期。     

Effect of testosterone on carboxypeptidase H activity in the murine hypothalamus and hypophysis

Effects of single intraperitoneal administration of testosterone propionate (3 or 30 mg/kg body weight) on activity of carboxypeptidase H in pituitary body and hypothalamus of female white mouse were studied. It was found that testosterone propionate treatment (3 and 30 mg/kg body weight) increased the carboxypeptidase H activity in pituitary through 0.5 hour and it decreased one in 24 hours after treatment. The carboxypeptidase H activity in hypothalamus was lower as compared with control animals in 24 hours after testosterone propionate treatment in the dose 3 mg/kg body weight. However, the carboxypeptidase H activity in hypothalamus was lower in 0.5 and 24 hours and it was higher in 4 h after testosterone propionate treatment in the dose 30 mg/kg body weight as compared with the control. These data suggest that testosterone affects the carboxypeptidase H activity by changing the level of enzyme gene expression.     

Protective effect of proanthocyanidins against doxorubicin‐induced nephrotoxicity in rats

Doxorubicin (DOX) exerts toxic effects in several organs particularly kidney. The present study aimed to assess the protective effect of proanthocyanidins (PAs) against DOX‐induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg, i.v.) significantly increased kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha levels, and kidney contents of malondialdehyde, nitric oxide, cyclooxygenase‐2, and caspase‐3 activity with significant reduction in final body weight, serum albumin, kidney contents of reduced glutathione (GSH), and superoxide dismutase activity as compared with control group. In contrast, pretreatment with PAs (200 mg/kg, p.o.) for 14 days before DOX and for 7 days after DOX ameliorated kidney function and oxidative stress parameters. Histopathological evidence confirmed the protective effects of PAs from the tissue damage induced by DOX. In conclusion, PAs have a multi‐nephroprotective effect that might be attributed to its antioxidant, anti‐inflammatory, and antiapoptoic activities.     

Effect of lupeol isolated from Crataeva nurvala Buch.-Ham. stem bark extract against free radical induced nephrotoxicity in rats

Lupeol, isolated from Crataeva nurvala stem bark in doses 40 and 80 mg/kg body weight, po, for 10 days, decreased the concentration of blood urea nitrogen, creatinine and lipid peroxidation and increased glutathione and catalase activities in cisplatin (5 mg/kg body weight, ip) induced nephrotoxicity in rats. The increased glutathione and catalase activities are indicative of antioxidant properties of lupeol.     

Effects of oral administration of nicotine on organ weight, serum testosterone level and testicular histology in adult male rats

This study investigated the effects of oral administration of nicotine on body and reproductive organ weight, serum testosterone level and testicular histology in adult male rats. Forty male rats divided into five groups and treated for a period of 30 days with 0.5mg/kg (low dose) and 1.0 mg/kg (high dose) body weight of nicotine while the control rats received 0.2 ml/kg normal saline. The fourth and fifth groups were gavaged with 0.5mg/kg and 1.0mg/kg body weight of nicotine but were left untreated for another 30 days. These groups served as the recovery groups.  At the end of each experimental period, the animals were scarified and their reproductive organs were removed and weighed immediately. There was no significant change in the body weight. There was a significant decrease (p <0.05) in the testicular and epididymal weight of rats for both treatments while the decrease in the seminal vesicle weight for both treatment groups was not significant. The prostate weight was not significantly increased in both groups. The recovery groups showed appreciable recovery in their organ weight. Serum level of testosterone of both groups was significantly decreased in a dose dependent manner when compared with those of the control rats. The histological section showed testicular degeneration and disorganization in the cytoarchitecture, as the observed changes were pronounced in the high dose group than the low dose group. However, there were both regeneration of the germinal epithelium and restructuring of the interstitum towards normal in the recovery groups. No lesion was observed in the epididymis of the rats. The results suggest that nicotine has deleterious effect on the male reproductive organ of albino rats ameliorated by nicotine cessation.