Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced oxidative cardiac injury

Cyclophosphamide (CP), one of the most widely prescribed antineoplastic drugs could cause a lethal cardiotoxicity. The present study is aimed at evaluating the role of DL-alpha-lipoic acid (LA) in oxidative cardiac damage induced by CP. Adult male Wistar rats were divided into four treatment groups. Two groups received single intraperitoneal injection of CP (200 mg/kg BW) to induce cardiotoxicity, one of these groups received LA treatment (25 mg/kg BW for 10 days). A vehicle treated control group and a LA drug control were also included. Cardiotoxicity, evident from increased activities of serum creatine phosphokinase, lactate dehydrogenase, aspartate transaminase and alanine transaminase in CP administered rats, was reversed by LA treatment. CP administered rats showed abnormal levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymic antioxidants (glutathione, vitamin C and vitamin E) along with high malondialdehyde levels. However, normalized lipid peroxidation and antioxidant defenses were reported in the LA treated rats. These findings highlight the efficacy of LA as a cytoprotectant in CP induced cardiotoxicity.     

Effect of DL-alpha-lipoic acid on cyclophosphamide induced lysosomal changes in oxidative cardiotoxicity

Cyclophosphamide (CP), one of the widely prescribed antineoplastic drugs can cause fatal cardiotoxicity. The present study is aimed at evaluating the cardioprotective role of lipoic acid in CP induced toxicity. Male albino rats of Wistar strain were divided into four groups and treated as follows: Group I served as control, Group II received a single dose of CP (200 mg/kg b.wt., i.p.), Group III received lipoic acid (25 mg/kg b.wt., orally) for 10 days, and Group IV received CP immediately followed by lipoic acid for 10 days. In CP administered rats, the levels of protein carbonyl and 8-hydroxy-2-deoxyguanosine were increased significantly (P<0.001) indicating oxidative changes in the heart tissue. The activities of lysosomal acid hydrolases, beta-Glu, beta-Gal, NAG, Cat-D and ACP increased significantly (P<0.001) in the serum as well as in the heart tissue after CP administration. An increase in hydroxyproline was observed in CP induced rats. Lipoic acid effectively reverted these abnormal biochemical changes to near normalcy. These observations highlight the protective role of lipoic acid in CP induced cardiotoxicity.     

Effects of vanadate on male rat reproductive tract histology, oxidative stress markers and androgenic enzyme activities

Vanadium has been recognized as industrial hazards that adversely affect male reproductive systems of humans and animals. However, less information is available concerning the underlying mechanism in the pathogenesis of male reproductive dysfunction. The present study investigated the possible involvement of oxidative stress to induce oxidative deterioration of testicular functions in adult rats. The results of in vitro and in vivo studies demonstrate that vanadium treatment resulted in a significant dose- and time-dependent increase in the testicular lipid peroxidation, marked inhibition in the level of superoxide dismutase and catalase activities, decreased sperm counts, and substantially inhibited the activities of Delta(5)3beta- and 17beta-hydroxysteroid dehydrogenase as well as serum testosterone level. Histopathological examination revealed inhibition of spermatogenesis and the preferential loss of maturing and elongated spermatids along with increased percent of abnormal sperm. Taken together, the results suggest that an increase in free radical formation relative to loss of antioxidant defense system during vanadium exposure may render testis more susceptible to oxidative damage leading to their functional inactivation. Thus the toxic effects of vanadium are cumulative and that vanadium produced damages in testes are dose- and time-dependent.     

trans,trans-2,4-decadienal induces mitochondrial dysfunction and oxidative stress

Lipid peroxidation produces a large number of reactive aldehydes as secondary products. We have previously shown that the reaction of cytochrome c with trans,trans-2,4-decadienal (DDE), an aldehyde generated as a product of lipid peroxidation in cell membranes, results in the formation of adducts. Mass spectrometry analysis indicated that His-33, Lys-39, Lys-72 and Lys-100 in cytochrome c were modified by DDE. In the present work, we investigated the effect of DDE on isolated rat liver mitochondria. DDE (162 μM) treatment increases the rate of mitochondrial oxygen consumption. Extensive mitochondrial swelling upon treatment with DDE (900 nM–162 μM) was observed by light scattering and transmission electron microscopy experiments. DDE-induced loss of inner mitochondrial membrane potentials, monitored by safranin O fluorescence, was also observed. Furthermore, DDE-treated mitochondria showed an increase in lipid peroxidation, as monitored by MDA formation. These results suggest that reactive aldehydes promote mitochondrial dysfunction.     

Ameliorating effects of troxerutin on nickel-induced oxidative stress in rats

Abstract

Objective

This study investigates the effects of troxerutin on nickel (Ni)-induced oxidative stress in rats.

Methods

Nickel as nickel sulfate (20 mg/kg body weight (b.w.)) was administered intraperitoneally for 20 days to induce toxicity in the subject rats. The levels of stress markers AST, ALT, ALP, LDH, and GGT in the hepatic tissue were significantly increased while a decrease in the levels of enzymic and non-enzymic antioxidants was observed in Ni intoxicated rats.

Results

Oral administration of troxerutin along with Ni for 20 days in a dose-dependent manner significantly reverted the stress markers in the liver tissue to near normal level. Troxerutin exhibited significant protection at 100 mg/kg b.w. Histopathological studies also supported the above findings.

Conclusions

Thus, we conclude that troxerutin preserved the histo-architecture and ameliorated stress markers in the liver tissue of Ni-intoxicated rats.     

Analysis of age-associated changes in mitochondrial free radical generation by rat testis

Throughout spermatogenesis, mitochondria undergo a morphological and functional differentiation. Mitochondria are involved in the production of reactive oxygen species (ROS), considered one of the mediators of ageing. Particularly, lipid peroxidation is regarded as a major phenomenon by which ROS can impair cellular function. In the present study, we examined the production of superoxide anion, superoxide dismutase activity and the effect of Fe²⁺/ascorbate induced-lipid peroxidation on the respiratory chain activities of testis mitochondria throughout the process of spermatogenesis and ageing. Mitochondria from rat testes generated superoxide anion, mainly using NADH as substrate, which increased according to age. The activity of SOD is age-dependent and greatly stimulated during the first wave of spermatogenesis, but decreases in adulthood and old age. TBARS concentration was also markedly increased by ageing. The activity of mitochondrial respiratory chain complexes is differentially affected by oxidative stress induced by iron/ascorbate, succinate-dehydrogenase activity being less vulnerable than that of NADH-dehydrogenase and cytochrome c oxidase. The data suggest that ageing is accompanied by reduced activity of SOD, leading to excessive oxidative stress and enhanced lipid peroxidation that compromises the functionality of the electron transport chain. The data support the concept that mitochondrial function is an important determinant in ageing.     

Aortic coarctation induces oxidative stress in rat tissues

The purpose of this study was to evaluate the induction of oxidative stress in heart and erythrocytes from rats with abdominal aorta coarctation (Coa) compared with sham-operated normotensive controls (Sham). The group of Coa animals developed myocardial hypertrophy, showing heart homogenates markedly increased levels of reduced glutathione (48%), lipid peroxidation (148%) and activation of superoxide dismutase and glutathione peroxidase (189% and 37%, respectively), compared with controls. Other oxidative stress indicators were also altered in erythrocytes from Coa rats: increased protein carbonyl content (141%) and total glutathione level (349%) were determined. Inactivation of the antioxidant enzymes catalase (27%), superoxide dismutase (58%) and glutathione peroxidase (25%) was observed in erythrocytes from the Coa group. Taken jointly our results provide strong evidence for the production of oxidative stress in heart and erythrocytes from aortic coarcted rats.     

Lipid peroxidation and decline in antioxidant status as one of the toxicity measures of diazinon in the testis

Abstract

The rapid emergence of various pesticides in the market is inevitable due to the demands from agriculture industries and domestic needs to control nuisance pests and to sustain green resources worldwide. However, long-term exposure to pesticide has led to adverse effects on male fertility. Organophosphate diazinon (O,O-diethyl-O-[2-isopropyl-6-methyl-4-pyrimidinyl] phosphorothiote) is an often abusively used pesticide, as it is effective and economical. This study is to determine the adverse effects of low-dose diazinon exposure on the male reproductive system. In this study, 72 Sprague–Dawley rats were segregated into 1, 2, and 8 weeks of exposure groups and further sub-grouped (n = 6) to receive 0, 10, 15, and 30 mg/kg body weight diazinon treatment. Rats were gavaged orally with diazinon and sacrificed under anaesthesia the day after the last exposure. Our results showed that consistent diazinon exposure decreased glutathione and catalase, and increased lipid peroxidation which together lead to diazinon-mediated oxidative stress. Additionally, diazinon increased serum lactate dehydrogenase and decreased serum testosterone, which may have caused sperm and histopathological anomalies. In conclusion, exposure to diazinon caused changes in lipid peroxidation and sperm, and these two effects might be causally linked.     

Combined effect of ascorbic acid and selenium supplementation on alcohol-induced oxidative stress in guinea pigs

Oxidative stress is a key step in the pathogenesis of ethanol associated liver injury. Ethanol administration induces an increase in lipid peroxidation either by enhancing the production of oxygen reactive species or by decreasing the level of endogenous antioxidants. In this present study, four groups of male guinea pigs (Cavia porcellus) were maintained for 45 days as follows: Control group (1 mg ascorbic acid (AA)/100 g body wt./day); Ethanol group (1 mg AA/100 g body wt./day+900 mg ethanol/100 g body wt./day); Selenium+AA group (25 mg AA+0.05 mg sodium selenite/100 g body wt./day); Ethanol+Se+AA group (25 mg AA+0.05 mg sodium selenite/100 g body wt.+900 mg ethanol/100 g body wt./day). Malondialehyde (MDA), hydroperoxides (HP) and conjugated dienes (CD) were significantly increased, while the activities of scavenging enzymes superoxide dismutase (SOD) and catalase were reduced in the alcohol administered groups. Co-administration of Se+AA along with alcohol increased the activities of scavenging enzymes and reduced the lipid peroxidation products level in hepatic tissues of guinea pigs. Activities of glutathione peroxidase (GPX) and glutathione reductase (GR) were enhanced in co-administered group. gamma-Glutamyl transpeptidase (GGT), a marker enzyme of alcohol induced toxicity, was also reduced, as was the glutathione content. This study suggests that the combined effect of Se+AA, provides protection against alcohol-induced oxidative stress as evidenced from the decreased levels of lipid peroxidation products and enhanced activities of scavenging enzymes.     

Neuroprotective effects of arachidonic acid against oxidative stress on rat hippocampal slices

Arachidonic acid (AA), 5,8,11,14-eicosateraenoic acid is abundant, active and necessary in the human body. In the present study, we reported the neuroprotective effects and mechanism of arachidonic acid on hippocampal slices insulted by glutamate, NaN(3) or H(2)O(2)in vitro. Different types of models of brain injury in vitro were developed by 1mM glutamate, 10mM NaN(3) or 2mM H(2)O(2). After 30 min of preincubation with arachidonic acid or linoleic acid, hippocampal slices were subjected to glutamate, NaN(3) or H(2)O(2), then the tissue activities were evaluated by using the 2,3,5-triphenyltetrazolium chloride method. Endogenous antioxidant enzymes activities (SOD, GSH-PX and catalase) in hippocampal slices were evaluated during the course of incubation. MK886 (5 microM; a noncompetitive inhibitor of proliferator-activated receptor [PPAR]alpha), BADGE (bisphenol A diglycidyl ether; 100 microM; an antagonist of PPARgamma) and cycloheximide (CHX; 30 microM; an inhibitor of protein synthesis) were tested for their effects on the neuroprotection afforded by arachidonic acid. Population spikes were recorded in randomly selected hippocapal slices. Arachidonic acid (1-10 microM) dose dependently protected hippocampal slices from glutamate and H(2)O(2) injury (P<0.01), and arachidonic acid (10 microM) can significantly improve the activities of Cu/Zn-SOD in hippocampal slices after 1h incubation. In addition, 10 microM arachidonic acid significantly increased the activity of Mn-SOD and catalase, and decreased the activities of Cu/Zn-SOD to control value after 3h incubation. These secondary changes of SOD during incubation can be reversed by indomethacine (10 microM; a nonspecific cyclooxygenase inhibitor) or AA 861 (20 microM; a 5-lipoxygenase inhibitor). Its neuroprotective effect was completely abolished by BADGE and CHX. These observations reveal that arachidonic acid can defense against oxidative stress by boosting the internal antioxidant system of hippocampal slices. Its neuroprotective effect may be mainly mediated by the activation of PPARgamma and synthesis of new protein in tissue.     

Inhibitory effect of carboxymethylpachymaran on cyclophosphamide-induced oxidative stress in mice

The aim of the present study was to investigate the immunomodulatory effect and antioxidant activity of carboxymethylpachymaran on cyclophosphamide-induced immunosuppression in mice in vivo. The results showed that carboxymethylpachymaran could be used to overcome the cyclophosphamide-induced immunosuppression in mice. Moreover, it significantly increased the thymus and spleen indices, lysozyme, catalase and superoxidase dismutase activities, and total antioxidant capacity. In contrast, it decreased xanthine oxidase activity and malondialdehyde levels. The results indicated that carboxymethylpachymaran might play an important role in the prevention of oxidative damage in the immunological system.     

Studies on the protective effects of betaine against oxidative damage during experimentally induced restraint stress in Wistar albino rats

Stress can be defined as physical and psychological modifications that disrupt the homeostasis and the balance of organisms. Stress is known as one of the most important reasons of several diseases. In the present study, the anti-stress effect of betaine was evaluated with reference to its antioxidant property. Wistar albino rats were divided into four groups such as control, betaine, restraint stress (6 h/day for 30 days), and betaine + restraint stress. The oxidative damage was assessed by measuring the protein and corticosterone in plasma, lipid peroxidation, non-enzymic (reduced glutathione), and enzymic antioxidants (glutathione peroxidase, glutathione-S-transferase, catalase, and superoxide dismutase) in the lymphoid organs of thymus and spleen. Followed by the induction of restraint stress, the non-enzymic and enzymic antioxidants were significantly decreased with concomitant increase observed in the levels of corticosterone and lipid peroxidation. Oral pretreatment with betaine (250 mg/kg body weight daily for a period of 30 days) significantly (P < 0.001) prevented the restraint stress-induced alterations in the levels of protein and corticosterone in plasma of experimental groups of rats. It counteracted the restraint stress-induced lipid peroxidation and maintained the antioxidant defense system in the lymphoid tissues at near normal. The findings suggest that betaine possesses significant anti-stress activity, which may be due to its antioxidant property.     

No evidence for oxidative stress as a mechanism of action of hyperhomocysteinemia in humans

Oxidative stress has been suggested as one of the physiopathologic conditions underlying the association of total plasma homocysteine (p-tHcy) with cardiovascular disease (CVD), but this hypothesis has not been validated in human epidemiological studies. We measured plasma and erythrocyte antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD), along with serum lipid-soluble antioxidants alpha-tocopherol, beta-carotene, lycopene and retinol, in a sample of 123 healthy elderly subjects (54 men, 69 women). Plasma malondialdehyde (p-MDA) was determined as a marker of lipid peroxidation, and p-tHcy was quantified by HPLC. No significant differences were found for p-MDA, GPx or SOD activities or serum antioxidant concentrations, in subjects with elevated p-tHcy (≥15 μmol/l) as compared to those with lower plasma homocysteine. Hyperhomocysteinemia did not lead to increased risk of having the highest p-MDA values, in either sex. We found no evidence that p-tHcy was associated with lipid peroxidation in this elderly human sample. Our results do not support the view that hyperhomocysteinemia would induce an adaptive response of antioxidant systems, either. More epidemiologic and clinical research is needed to clarify whether homocysteine promotes atherosclerosis by means of an oxidative stress mechanism.     

Ameliorative effect of kaempferol,a flavonoid,on oxidative stress in streptozotocin-induced diabetic rats

Abstract

Objective

The aim of the present study was to evaluate the protective effect of kaempferol against oxidative stress in streptozotocin (STZ)-induced diabetic rats.

Methods

Diabetes was induced in male, adult albino rats of the Wistar strain, by intraperitoneal administration of STZ (40 mg/kg body weight (BW)). Kaempferol (100 mg/kg BW) or glibenclamide (600 µg/kg BW) was administered orally once daily for 45 days to normal and STZ-induced diabetic rats.

Results

The STZ-induced diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes in plasma, liver, kidney, and heart whereas they showed significantly decreased level of plasma insulin. The levels of non-enzymic antioxidants (vitamin C, vitamin E, reduced glutathione) in plasma, liver, kidney, and heart and the activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) in liver, kidney, and heart were significantly decreased in diabetic rats. Administration of kaempferol to diabetic rats was showed brought back in plasma glucose, insulin, lipid peroxidation products, enzymatic, and non-enzymatic antioxidants to near normal.

Conclusion

The present study indicates that kaempferol has a good antioxidant property, as evidenced by its increase of antioxidant status and decrease of lipid peroxidation markers, thus providing protection from the risks of diabetic complications.     

Influence of the oxidative stress induced by the organophosphate pesticide bromopropylate on the mitochondrial respiratory chain in Trichoderma harzianum

The present study was designed to investigate the effect of bromopropylate on its own transport rate, glycolysis and tricarboxylic acid cycle metabolite levels, adenine nucleotides, and membrane lipid peroxidation (LPO) as well as the activities of mitochondrial electron transport chain (ETC) enzymes in eukaryotic Trichoderma harzianum. The transport rate of bromopropylate reached a maximum level within the first 24 h of incubation for all studied concentrations. The succinate dehydrogenase (SDH) and cytochrome c oxidase (CCO) activities reached their maxima at 72 h for 2.5 and 10 mg/L of bromopropylate, respectively. In addition, the intracellular pyruvate levels increased for bromopropylate concentrations up to 2.5 mg/L. The maximum intracellular α-ketoglutarate level was determined at 5 mg/L, while the intracellular fumarate and citrate levels reached their maximums at 7.5 mg/L of bromopropylate. The variations in the adenine nucleotide levels showed a positive correlation with both α-ketoglutarate and fumarate levels. Nevertheless, the LPO levels increased with increasing bromopropylate concentrations. These results may indicate that the membrane becomes more damaged from an impaired respiratory chain, which may then cause an increase in electron leakage.     

Inhibition of copper-induced lipid peroxidation by sinapic acid and its derivatives in correlation to their effect on the membrane structural properties

The efficiencies of sinapic acid and its derivatives syringic acid, syringaldehyde, three sinapoyl esters (ethyl, propyl, butyl sinapates), 4-vinylsyringol and sinapine were investigated for prevention of lipid peroxidation in correlation with their interactions with model lipid membrane systems. Significant antioxidant activities of propyl and butyl sinapates were seen by fluorimetric assay in phosphatidylcholine liposomes as model membrane using C11-BODIPY^581/591 lipophilic fluorescent probe. The sinapic acid esters also had the highest impact on membrane structural properties, as observed by differential scanning calorimetry and fluorescence polarisation measurements. The greatest protection of phospholipids from peroxidation by these esters correlated well with their polarity and insertion into the lipid bilayer.     

Ebselen attenuates cyclophosphamide-induced oxidative stress and DNA damage in mice

The role of selenium, a trace element in the human diet, has been extensively studied against cancer, immunity and infectious/inflammatory diseases. The purpose of the present study was to investigate the beneficial effect of ebselen, an organo-selenium compound, against cyclophosphamide-induced oxidative stress and DNA damage in mice. Malondialdehyde and total glutathione were estimated in the liver to detect the oxidative stress induced by cyclophosphamide. Standard and modified comet assays (the latter incorporated lesion-specific enzymes, formamidopyrimidine-DNA glycosylase and endonuclease-III) were used to detect the normal and oxidative stress-induced DNA damage by cyclophosphamide in the mouse bone marrow and the peripheral blood lymphocytes. In addition, a micronucleus assay capable of detecting DNA damage was also carried out in the mouse bone marrow and the peripheral blood reticulocytes induced by cyclophosphamide. The results confirm that pre-treatment with ebselen (2.5, 5 and 10 mg/kg) for 5 consecutive days decreased the oxidative stress induced by cyclophosphamide (100 mg/kg) based on the restoration in concentration of malondialdehyde and glutathione in the liver and decreased DNA damage and micronuclei count in the bone marrow and the peripheral blood. It is concluded that pre-treatment with ebselen attenuates cyclophosphamide-induced oxidative stress and the resultant DNA damage in mice.     

Effects of intermittent hypoxia different regimes on mitochondrial lipid peroxidation and glutathione-redox balance in stressed rats

The purpose of this study was to compare the influence of two regimes of intermittent hypoxia (IH) [repetitive 5 cycles of 5 min hypoxia (7% O₂ or 12% O₂ in N₂) followed by 15 min normoxia, daily for three weeks] on oxidative stress protective systems in liver mitochondria. To estimate the effectiveness of hypoxia adaptation at the early and late preconditioning period, we exposed rats to acute 6-h immobilization at the 1^st and 45^th days after cessation of IH. We showed that severity of hypoxic episodes during IH might initiate different adaptive programs. Moderate hypoxia during IH prevents mitochondrial glutathione pool depletion induced by immobilization stress, maintains GSH-redox cycle via activation of glutathione peroxidase, glutathione-S-transferase, glutathione reductase, NADP⁺-dependent isocitrate dehydrogenase, and increases Mn-SOD activity. Such regimen of hypoxic preconditioning caused the decrease of mitochondrial superoxide anion generation as well as of basal and stimulated in vitro lipid peroxidation and this protective effect remained for 45 days under renormoxic conditions. Hypoxic adaptation in a more severe regimen exerted beneficial effects on the mitochondrial antioxidant defense system only at its later phase.     

Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice

The present study investigated the prophylactic influence of melatonin against cyclophosphamide-induced oxidative stress in mouse tissues. Lipid peroxidation, reduced glutathione (GSH), glutathione disulphide (GSSG), glutathione peroxidase (GSH-Px) and serum phosphatase levels were analyzed in brain, spleen liver, lungs, kidney and testes. Fifteen days oral administration with melatonin (0.1 mg/kg bw per day) before treatment checked the augmentation of the level of lipid peroxidation, blood GSSG and acid phosphatase caused by an acute treatment with a radiomimetic drug, cyclophosphamide (75 mg/kg bw). Cyclophosphamide-induced depletion in the level of GSH, GSH-Px and alkaline phosphatase was made up statistically significant by chronic melatonin administration given orally. The results indicate the antioxidative properties of melatonin resulting into its prophylactic property against the cyclophosphamide-induced biochemical alterations. The finding support the idea that melatonin is a potent free-radical scavenger and antioxidant.