Prevention of chromate induced oxidative stress by alpha-lipoic acid

The parenteral administration of alpha-lipoic acid (LA) protected against chromate induced oxidative stress in mouse liver. A shift in Cr induced pro-oxidant state to antioxidant-state by LA was noteworthy. The degree of protection was significant and similar in different LA administration regimens (prior-, co- and post- parenteral Cr exposure) explored. An improved status of the tissue antioxidants by LA appeared to be the mechanism of mitigation. The results are of chemopreventive value and suggest a possible alternative to ascorbic acid for abrogation of Cr toxicity.     

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.     

Rapid oxidative stress induced by N-nitrosamines

We have investigated the generation of prooxidant state shortly after administration of N-nitrosamines (NA) to rats. N-Nitrosodimethylamine (NDMA) was found to increase ethane exhalation (EE) rapidly in a dose-related manner. EE remained elevated for several days after single doses of NDMA. Similarly, lipid peroxidation (LP) in the liver (measured by four methods) increased rapidly showing a peak 20 min after NDMA dose. The increase of LP was preceded by a decrease in retinol concentration in the liver. N-Nitrosodiethanolamine, too, increased EE and LP in the liver, whereas N-nitrosomethylbenzylamine had no effect. Thus, hepatocarcinogenic NA induced LP in their target tissue, and the LP enhancing effects of NA were not related to their acute toxic effects.     

Amelioration of salt-induced oxidative stress in eggplant by application of 24-epibrassinolide

The effects of exogenous 24-epibrassinolide (EBR) on the growth, oxidative damage, antioxidant system and ion contents in eggplant (Solanum melongena L.) seedlings under salt stress were investigated. Eggplant seedlings were exposed to 90 mM NaCl with 0, 0.025, 0.05, 0.10 and 0.20 mg dm⁻³ EBR for 10 d. EBR, especially at concentration 0.05 mg dm⁻³, alleviated growth suppression caused by NaCl stress, decreased electrolyte leakage, superoxide production and content of malondialdehyde and H₂O₂ in NaCl-treated plants. EBR also increased activities of superoxide dismutase, guaiacol peroxidase, catalase and ascorbate peroxidase and the contents of ascorbic acid and reduced glutathione. Furthermore, we also found that Na⁺, Cl⁻ contents were decreased, K⁺, Ca²⁺ contents and K⁺/Na⁺, Ca²⁺/Na⁺ ratios were increased in the presence of EBR under salt stress.     

Amelioration of alcohol-induced oxidative stress by Emblica officinalis (amla) in rats

The present study was aimed at investigating the ameliorative effect of Emblica (Phyllanthus Emblica L) fruit extract (EFE) against alcohol-induced oxidative changes in plasma biochemical profile in rats. Alcohol administration (5 g/kg body wt/day) for 60 days resulted in significantly (P<0.05) higher levels of plasma nitrite/nitrate (NOx), total bilirubin, creatinine, and abnormalities in lipid and lipoproteins. Moreover, alcohol receiving rats showed significantly (P<0.05) lowered plasma total protein, albumin/globulin (A/G) ratio and uric acid, with no significant change in glucose level. The EFE administration (250 mg/kg body wt/day) to alcohol-administered rats significantly modulated plasma lipids and lipoprotein patterns and also decreased nitrite/nitrate, total bilirubin and creatinine levels. EFE administration to alcohol receiving rats showed a significant (P<0.05) increase in plasma total protein, A/G ratio and uric acid levels. Total cholesterol (r = 0.466), triglycerides (r = 0.574), VLDL-C (r = 0.578), LDL-C (r = 0.225) and total bilirubin (r = 0.419) showed a stronger positive correlation with that of NOx in alcohol-treated rats. The concentration of nitric oxide (NOx) was negatively correlated with HDL-C (r = -0.285) and uric acid (r = 0.392) in alcohol-treated rats. The amelioration of alcohol-induced oxidative stress might be due to the combined effect of phytophenols, such as tannins and flavonoid compounds and vitamin C.     

Suicidal oxidative stress induced by certain antioxidants

Well known antioxidants-coumarins (7,8-dihydroxy-4-methyl coumarin-DHMC and 7,8-diacetoxy-4-methyl coumarin-DAMC) and flavonoids (quercetin-Q and quercetin penta-acetate-QPA) were investigated for their pro-oxidant effects in two human tumor cell lines. The breast carcinoma cell line (MDA-MB-468) was found to be more sensitive to treatment by the drugs-DAMC, Q and QPA at 10 microM than the glioma cell line (U-87MG), while DHMC was non toxic in both cell lines at this concentration. In MDA-MB-468 distinct growth inhibition was observed by 48 hr post treatment. Paradoxically, an increase in the formazan production was revealed by MTT assay at this time indicating an increase in the production of free radicals. An increase in the levels of reactive oxygen species (ROS) was also confirmed by DCFH-DA assay. In cells treated with DAMC, Q and QPA an increase in the percentage of cells with the hypodiploid DNA content was suggestive of apoptotic cell death. Taken together, these results suggest that an increase in oxidative stress caused by the pro-oxidant action of these drugs is responsible for cell death.     

Gallic acid modulates purine metabolism and oxidative stress induced by ethanol exposure in zebrafish brain

Gallic acid (GA) is a secondary metabolite found in plants. It has the ability to cross the blood-brain barrier and, through scavenging properties, has a protective effect in a brain insult model. Alcohol metabolism generates reactive oxygen species (ROS); thus, alcohol abuse has a deleterious effect on the brain. The zebrafish is a vertebrate often used for screening toxic substances and in acute ethanol exposure models. The aim of this study was to evaluate whether GA pretreatment (24 h) prevents the changes induced by acute ethanol exposure (1 h) in the purinergic signaling pathway in the zebrafish brain via degradation of extracellular nucleotides and oxidative stress. The nucleotide cascade promoted by the nucleoside triphosphate diphosphohydrolase (NTPDase) and 5′-nucleotidase was assessed by quantifying nucleotide metabolism. The effect of GA alone at 5 and 10 mg L^?1 did not change the nucleotide levels. Pretreatment with 10 mg L^?1 GA prevented an ethanol-induced increase in ATP and ADP levels. No significant difference was found between the AMP levels of the two pretreatment groups. Pretreatment with 10 mg L^?1 GA prevented ethanol-enhanced lipid peroxidation and dichlorodihydrofluorescein (DCFH) levels. The higher GA concentration was also shown to positively modulate against ethanol-induced effects on superoxide dismutase (SOD), but not on catalase (CAT). This study demonstrated that GA prevents the inhibitory effect of ethanol on NTPDase activity and oxidative stress parameters, thus consequently modulating nucleotide levels that may contribute to the possible protective effects induced by alcohol and purinergic signaling.

     

Retinal oxidative stress induced by high intraocular pressure

Glaucoma is an optic neuropathy in which retinal ganglion cells die probably through an apoptotic process. Apoptosis is known to involve free radicals in several systems including the retina. In this context, the aim of the present work was to analyze retinal oxidative damage in rats with glaucoma induced by the chronic injection of hyaluronic acid in the eye anterior chamber. The results showed a significant decrease in total retinal superoxide dismutase and catalase activities after 6 and 3 weeks of treatment with hyaluronic acid, respectively. Also, although GPX activity increased after 10 weeks of ocular hypertension, GSH levels significantly decreased at 6 weeks of treatment with hyaluronic acid. Moreover, retinal lipid peroxidation significantly increased in a time-of-hypertension-dependent manner. On the other hand, a significant decrease in both diurnal and nocturnal retinal melatonin content was detected at 3, 6, or 10 weeks of treatment with hyaluronic acid. The present results suggest that retinal oxidative stress may be involved in glaucomatous cell death. Thus, manipulation of intracellular redox status using antioxidants may be a new therapeutic tool to prevent glaucomatous neurodegeneration.     

Amelioration of diet-induced nonalcoholic steatohepatitis in rats by Mn-salen complexes via reduction of oxidative stress

Background

Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis (accumulation of triacylglycerols within hepatocytes) along with inflammation and ballooning degeneration. It has been suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. The aim of present study was to determine whether antioxidant supplementations using EUK-8, EUK-134 and vitamin C could improve the biochemical and histological abnormalities associated with diet-induced NASH in rats.

Methods

NASH was induced in male N-Mary rats by feeding a methionine - choline deficient (MCD) diet. The rats were fed either normal chow or MCD diet for 10 weeks. After NASH development, the MCD-fed rats were randomly divided into four groups of six: the NASH group that received MCD diet, the EUK-8 group which was fed MCD diet plus EUK-8, the EUK-134 group which was fed MCD diet plus EUK-134 and the vitamin C group which received MCD diet plus vitamin C. EUK-8, EUK-134 and vitamin C (30 mg/kg body weight/day) were administered by gavage for eight weeks.

Results

Treatment of MCD-fed rats with salens reduced the sera aminotransferases, cholesterol, low density lipoprotein contents, the extent of lipid peroxidation and protein carbonylation whereas the HDL-C cholesterol levels were significantly increased. In addition, EUK-8 and EUK-134 improved steatosis, ballooning degeneration and inflammation in liver of MCD-fed rats.

Conclusion

Antioxidant (EUK-8, EUK-134 and vitamin C) supplementation reduces NASH-induced biochemical and histological abnormalities, pointing out that antioxidant strategy could be beneficial in treatment of NASH.     

d-Aspartic acid induced oxidative stress and mitochondrial dysfunctions in testis of prepubertal rats

Previously we demonstrated the potential of d-aspartic acid (d-Asp), an acidic amino acid to induce oxidative response in prepubertal rat testis in vitro. In the present study, we determined the extent of oxidative stress in the testis of prepubertal rats that were administered d-Asp (100 and 500 mg/kg bw/d, i.p. 7 days). d-Asp treatment significantly elevated the levels of reactive oxygen species, malondialdehyde and hydroperoxide in cytosol and mitochondria of testis, which were accompanied by enhanced glutathione levels, elevated activities of glutathione-dependent enzymes and catalase suggesting a state of oxidative stress. Further, the activities of d-aspartate oxidase and 3β-hydroxy steroid dehydrogenase were elevated in the testis. The testis mitochondria of d-Asp-treated rats showed altered citric acid and complex enzyme activities, reduction in membrane potential, increased permeability and intracellular Ca²⁺ levels. Collectively, these findings suggest the potential of d-Asp to induce oxidative perturbations in the testis of prepubertal rats and this mechanism may in part be responsible for the observed physiological effects.     

Compensatory responses induced by oxidative stress in Alzheimer disease

Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibrillary tangles and senile plaques. In the first stage of development of the disease, amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative damage. These findings suggest that Alzheimer disease is associated with a novel balance in oxidant homeostasis.     

Vitamin C prevents DNA mutation induced by oxidative stress

The precise role of vitamin C in the prevention of DNA mutations is controversial. Although ascorbic acid has strong antioxidant properties, it also has pro-oxidant effects in the presence of free transition metals. Vitamin C was recently reported to induce the decomposition of lipid hydroperoxides independent of metal interactions, suggesting that it may cause DNA damage. To directly address the role of vitamin C in maintaining genomic integrity we developed a genetic system for quantifying guanine base mutations induced in human cells under oxidative stress. The assay utilized a plasmid construct encoding the cDNA for chloramphenicol acetyl transferase modified to contain an amber stop codon, which was restored to wild type by G to T transversion induced by oxidative stress. The mutation frequency was determined from the number of plasmids containing the wild type chloramphenicol acetyl transferase gene rescued from oxidatively stressed cells. Cells were loaded with vitamin C by exposing them to dehydroascorbic acid, thereby avoiding transition metal-related pro-oxidant effects of ascorbic acid. We found that vitamin C loading resulted in substantially decreased mutations induced by H(2)O(2). Depletion of glutathione led to cytotoxicity and an increase in H(2)O(2)-induced mutation frequency; however, mutation frequency was prominently decreased in depleted cells preloaded with vitamin C. The mutation results correlated with a decrease in total 8-oxo-guanine measured in genomic DNA of cells loaded with vitamin C and oxidatively stressed. These findings directly support the concept that high intracellular concentrations of vitamin C can prevent oxidation-induced mutations in human cells.     

Protection of arsenic-induced testicular oxidative stress by arjunolic acid

Arsenic-induced tissue damage is a major concern to the human population. An impaired antioxidant defense mechanism followed by oxidative stress is the major cause of arsenic-induced toxicity, which can lead to reproductive failure. The present study was carried out to investigate the preventive role of arjunolic acid, a triterpenoid saponin isolated from the bark of Terminalia arjuna, against arsenic-induced testicular damage in mice. Administration of arsenic (in the form of sodium arsenite, NaAsO(2), at a dose of 10 mg/kg body weight) for 2 days significantly decreased the intracellular antioxidant power, the activities of the antioxidant enzymes, as well as the levels of cellular metabolites. In addition, arsenic intoxication enhanced testicular arsenic content, lipid peroxidation, protein carbonylation and the level of glutathione disulfide (GSSG). Exposure to arsenic also caused significant degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. Pretreatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days could prevent the arsenic-induced testicular oxidative stress and injury to the histological structures of the testes. Arjunolic acid had free radical scavenging activity in a cell-free system and antioxidant power in vivo. In summary, the results suggest that the chemopreventive role of arjunolic acid against arsenic-induced testicular toxicity may be due to its intrinsic antioxidant property.     

Mitochondrial calcium, oxidative stress and apoptosis in a neurodegenerative disease model induced by 3-nitropropionic acid

Intracellular calcium homeostasis is important for cell survival. However, increase in mitochondrial calcium (Ca2+m) induces opening of permeability transition pore (PTP), mitochondrial dysfunction and apoptosis. Since alterations of intracellular Ca2+ and reactive oxygen species (ROS) generation are involved in cell death, they might be involved in neurodegenerative processes such as Huntington's disease (HD). HD is characterized by the inhibition of complex II of respiratory chain and increase in ROS production. In this report, we studied the correlation between the inhibitor of the complex II, 3-nitropropionic acid (3NP), Ca2+ metabolism, apoptosis and behavioural alterations. We showed that 3NP (1 mm) is able to release Ca2+m, as neither Thapsigargin (TAP, 2 microm) nor free-calcium medium affected its effect. PTP inhibitors and antioxidants inhibited this process, suggesting an increase in ROS generation and PTP opening. In addition, 3NP (0.1 mm) also induces apoptotic cell death. Behavioural changes in animals treated with 3NP (20 mg/kg/day for 4 days) were also attenuated by pre- and co-treatment with vitamin E (VE, 20 mg/kg/day). Taken together, our results show that complex II inhibition could involve Ca2+m release, oxidative stress and cell death that may precede motor alterations in neurodegenerative processes such as HD.     

Amelioration of age-dependent increase in oxidative stress markers in male mice by extract of Potentilla fulgens

Objective: To investigate the effect of Potentilla fulgens extract on lipid peroxidation and antioxidant status in male mice as a function of age.

Methods: Eighteen-month-old Swiss albino male mice were administered the dichloromethane-methanol extract of P. fulgens (250?mg/kg b.w.) on alternate days via intraperitoneal route for a period of 14 days. Lipid peroxidation and activities of catalase (CAT) and glutathione peroxidase (GPx1) in liver and kidney were measured and serum oxygen radical absorbance capacity (ORAC) assay was estimated. Phytochemical analysis of P. fulgens extract using high performance thin layer chromatography (HPTLC) was carried out with gallic acid, quercetin, catechin, and epicatechin as markers.

Results: Significant increase in level of thiobarbituric acid-reactive substances (TBARS), decreased GPx1, and CAT activities as well as reduction in ORAC were observed in 18-month-old mice as compared to that of 2-month-old mice. Treatment with P. fulgens extract significantly lowered TBARS level, ameliorated CAT, and GPx1 activities in liver and kidney and improved serum ORAC in aging mice. HPTLC studies revealed well resolved bands of P. fulgens extract containing epicatechin and catechin.

Discussion: This study showed that P. fulgens is a potent antioxidative agent, which can emerge as a promising candidate in alleviating the age-associated oxidative stress and related diseases.     

Protective effect of ascorbic acid against oxidative stress induced by inorganic arsenic in liver and kidney of rat

Ascorbic acid treatment in arsenic trioxide treated rats increased arsenic excretion, inhibited lipid peroxidation, improved GSH status, regulated GSSG turnover and also restored glutathione-S-transferases activity in liver and kidney. Suitable mechanisms leading to ascorbic acid protection have been discussed. Upregulation of GSH dependent enzymes was found to be necessary for a protective effect. Protection is finally attributed to higher GSH levels observed in the liver and kidney of ascorbic acid and inorganic arsenic treated rats. It is also concluded that ascorbic acid protection is influenced by gender dependent factors. Arsenic poisoning is a global problem now. Gender differences need to be considered while applying therapeutic measures.     

Ferulic acid inhibits oxidative stress and cell death induced by Ab oligomers: Improved delivery by solid lipid nanoparticles

Oxidative stress and dysfunctional mitochondria are among the earliest events in AD, triggering neurodegeneration. The use of natural antioxidants could be a neuroprotective strategy for blocking cell death. Here, the antioxidant action of ferulic acid (FA) on different paths leading to degeneration of recombinant β-amyloid peptide (rAβ42) treated cells was investigated. Further, to improve its delivery, a novel drug delivery system (DDS) was used. Solid lipid nanoparticles (SLNs), empty or containing ferulic acid (FA-SNL), were developed as DDS. The resulting particles had small colloidal size and highly negative surface charge in water. Using neuroblastoma cells and rAβ42 oligomers, it was demonstrated that free and SLNs-loaded FA recover cell viability. FA treatment, in particular if loaded into SLNs, decreased ROS generation, restored mitochondrial membrane potential (Δψ_m) and reduced cytochrome c release and intrinsic pathway apoptosis activation. Further, FA modulated the expression of Peroxiredoxin, an anti-oxidative protein, and attenuated phosphorylation of ERK1/2 activated by Aβ oligomers.