Endogenous Antioxidant Capacity Research Articles

EDITORIAL (Hot Topic: Recognition of Functional Roles of Free Radicals)

Although free radicals are traditionally regarded as harmful by-products of aerobic cellular metabolism, this view has recently essentially changed and it is now evident that production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are strongly regulated processes that play central roles in most cell signaling. During physiological and pathophysiology processes, ROS and RNS can act as secondary messengers and control gene expression, apoptosis, cell growth, cell cycle, cell adhesion, chemotaxis, protein-protein interactions and enzymatic functions, Ca2+ and redox homeostasis, to name but a few functions [1, 2]. In addition, the generation of reactive oxygen species is cell-specific [3]. ROS and RNS also act as signaling molecules in cerebral circulation and are required for signal processes such as synaptic plasticity, memory formation, and regulated production, release, and uptake of neurotransmitters [4, 5]. In addition, it is less known and seldom stressed that catecholamines and serotonin have significant free radical scavenging and neuroprotective abilities [5] that indicate redox regulation can also play key roles in neurotransmission. The average lifetime of free radicals is 10-9 - 10-6 sec, but under physiological conditions, in tissues and cells, it may be 1-2 orders of magnitude greater, because the physiological oxygen concentration is ≈ 10-25 µM, while in in vitro experiments oxygen concentration is ≈ 220 µM [6]. Thus, under physiological circumstances, ROS could carry long-distance signals in cells. Several recent studies suggest that regulated radical signal formation can be realized, for example, by redoxosomes (redox-active endosomes) that can spatially and temporally control ROS production to generate precise ROS gradients at sites of receptor signaling [7]. Lipid rafts (plasma membrane-localized microdomains) can have significant roles in formation of redoxosomes. It appears, however, that antioxidant supplements do not provide adequate protection against oxidative stress and do not lead to an increase of the lifespan. Some current studies revealed that antioxidant treatment has either no effect or can even enhance mortality [2]. Because ROS plays a key signaling role in cells, the imbalance of the increased antioxidant potential, (antioxidative stress), can also be dangerous. Recent experiments revealed that integral mitochondrial Manganese superoxide dismutase µMnSOD) protein possesses peroxidase activity when the enzyme is overexpressed in mitochondria [8]. It may seem paradoxical that diverse ROS-mediated mechanisms protect cells against ROS-induced oxidative stress and can restore redox homeostasis. Based on the classical physiological concept of hormesis (hormesis is a biological response when a beneficial effect (stress tolerance, longevity, etc.) is due to the exposition to low doses of an agent that is otherwise toxic or lethal at higher doses), Finkel and Holbrook [9] claim that the best strategy to enhance endogenous antioxidant capacity may be oxidative stress itself. ROS with low doses and short dynamic duration can exhibit hormesis effects, although higher ROS doses are indisputably detrimental [10]. Ca2+ and ROS are two cross-talking secondary messengers in numerous cellular processes. Functionally, interactions between Ca2+ and ROS signaling systems can be both stimulatory and inhibitory. There is a delicate balance between the beneficial and detrimental consequences of Ca2+ and ROS regarding the mitochondrial function [11]. It is probable that free radical generation is one of the most regulated processes in cells and that oxidative stress is a secondary consequence of cellular malfunctions produced by intrinsic and extrinsic factors. Protein-folding malfunctions play key roles in numbers of disorders and the metal coordination is a key structural and functional factor in most proteins [12]. It is more probable that various stresses, for example, can produce defective structure formations of proteins that perturb homeostasis of transition metals (mainly Cu+ or Fe2+). Subsequently, perturbed homeostasis produces free metal ions (or labile ions [13]), which create an unregulated production of extremely reactive hydroxyl radicals that can damage carbohydrates, DNA, lipids and proteins. However, it is highly unlikely that evolution could not have taken care of precise and regulated production of the most reactive signaling molecules in cells. It seems that the redox age (recognition of functional roles of free radicals) has opened new avenues for investigations of basic research, therapies, and drug development. We hope this special issue may significantly contribute towards these goals so that we can understand regulated free radical mechanisms in neural processes that work for us.

Abstract 185: Whole Body Periodic Acceleration (pGz) in Mice Increases Antioxidant Enzymes in the Heart

BACKGROUND: Mild to moderate exercise produces cardio and neuroprotection. Exercise increases pulsatile shear stress that provide several cytoprotective and signaling substances from muscle and endothelium. Some beneficial effects of exercise on cytoprotection are derived from increased antioxidant capacity. pGz is a passive exercise strategy that moves the body in a sinusoidal head to foot motion, adding pulses to the circulation thereby increasing pulsatile, cyclical shear stress to the endothelium. pGz activates the PI3/Akt eNOS pathway and increases release of eNO and its enzyme (eNOS), and other cytoprotective signaling and substances, and decreases reperfusion injury. Optimum frequency of pGz has been established in our laboratory for various animal species and humans. We tested the hypothesis that repeated exposure to pGz in mice would increase antioxidant enzymes, and determined its time course. METHODS: Acclimated awake mice (n=48) where exposed to shear stress at f ƒ=480 cpm, Gz ± 3mt/sec 2 (pGz) 1 hr daily sessions of 1, 2, and 4 weeks of pGz. Myocardial tissue was harvested prior to pGz (BL) and 24 hrs after the last pGz treatment for proteins via Western Blot analyses: Glutathioneperoxidase-1(GPX1), Superoxide Dismutase -1 (Cu-Zn SOD), Superoxide Dismutase -2 (mitochondrial or Mn-SOD) and Catalase (Cat) , Protein content was normalized to GAPDH. RESULTS:One to four weeks of pGz increased GPX1, Cat and SOD1 from BL levels, whereas SOD2 remained unchanged. 4 weeks of pGz increased GPX1, Cat and SOD1, by 110%, 80% and 240% of basal enzyme levels. (Data= mean ± SEM, Figure † p< 0.01 BL vs. 1,2,4 wks) CONCLUSIONS: One hour daily pGz increases cardiac antioxidant enzymes and may serve as a method to augment endogenous antioxidant capacity, and decrease reperfusion injury.

Coconut kernel-derived proteins enhance hypolipidemic and antioxidant activity in alloxan-induced diabetic rats

Impaired lipid levels and oxidative stress are indicative of malfunction of endogenous antioxidant capacity. The aim of this study was to determine the effect of coconut kernel protein (CKP) on the lipid peroxides and antioxidant enzyme activities in diabetic rats. Diabetes was induced prior to feeding by injecting a single dose of alloxan (150 mg/kg body weight) intraperitoneally. CKP (8% w/w) was administered to these rats along with a semi-synthetic diet for 45 days. After the experimental period, peroxide products and antioxidant enzyme activities were determined. Results show that CKP maintained the antioxidant enzyme activities and levels of peroxides to the normal levels in treated group compared to diabetic rats. This study clearly show that CKP has potential effect in lowering oxidative stress associated with diabetes. This beneficial effect of CKP may be due to the high amount of biologically potent arginine present in it.

Peroxiredoxins and sports: new insights on the antioxidative defense

Peroxiredoxins (PRDXs) are multifunctional proteins that have recently received much attention. They are part of the endogenous antioxidative capacity and function as efficient scavengers, especially for hydrogen peroxides. Studies show that physical training can induce an upregulation of PRDX isoform contents in the long term. This might help counteract chronic diseases that are causally linked to a high amount of free radicals, e.g., diabetes mellitus. Furthermore, it has been demonstrated that PRDX can overoxidize under pathological conditions during acute exercise. Overoxidized PRDXs could be useful because they act as protective chaperones. Taken together, it can be speculated that physical activity has a positive effect on the PRDX system and thereby prevents cells from free radical-induced damage.

The Nrf2-ARE Pathway: A Valuable Therapeutic Target for the Treatment of Neurodegenerative Diseases

Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer's disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.

Evaluation of the effect of glutathione on cisplatin antitumor activity and kidney injury at different administration times

Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most potent anticancer drugs. However, the therapeutic value of CDDP is greatly compromised by its dose-limiting nephrotoxicity. This study was performed to investigate whether reduced glutathione (GSH) was able to reduce the kidney injury induced by CDDP and whether it affected the anticancer activity of CDDP in vivo and invitro. In invivo experiments, mice were divided into five groups: control, CDDP only and three GSH treatment groups. Blood samples were collected 72h after CDDP administration to determine the levels of blood urea nitrogen (BUN) and plasma creatinine(Cr). In addition, we examined antioxidative parameters, malondialdehyde (MDA) levels and histopathological changes in the kidney. In order to investigate whether GSH affected the anticancer activity of CDDP, we performed a sulforhodamineB (SRB) assay to determine the anti-proliferative effect in three tumor cell lines of treatment with CDDP alone or combined with GSH and examined the cell morphology. The results revealed that GSH decreased the BUN and Cr levels in plasma, ameliorated the pathological changes induced by CDDP and enhanced the endogenous antioxidant capacities in all three GSH groups. Furthermore, GSH significantly inhibited the growth of the three tumor cell lines when combined with CDDP and did not affect the inhibitory effect of CDDP on the carcinoma cell proliferation. In addition, we found no differences among the three GSH groups. These findings suggest that GSH is able to attenuate the nephrotoxicity induced by CDDP, not only when administered prior to CDDP, but also when administered at the same time as or subsequent to CDDP administration, without affecting the anticancer activity of CDDP. Thus, the administration of GSH is a promising approach for attenuating the nephrotoxicity caused by CDDP.

Western-style diet modulates contractile responses to phenylephrine differently in mesenteric arteries from senescence-accelerated prone (SAMP8) and resistant (SAMR1) mice

The influence of two known cardiovascular risk factors, aging and consumption of a high-fat diet, on vascular mesenteric artery reactivity was examined in a mouse model of accelerated senescence (SAM). Five-month-old SAM prone (SAMP8) and resistant (SAMR1) female mice were fed a Western-type high-fat diet (WD; 8 weeks). Mesenteric arteries were dissected, and vascular reactivity, protein and messenger RNA expression, superoxide anion (O 2 (·-) ) and hydrogen peroxide formation were evaluated by wire myography, immunofluorescence, RT-qPCR, ethidium fluorescence and ferric-xylenol orange, respectively. Contraction to KCl and relaxation to acetylcholine remained unchanged irrespective of senescence and diet. Although similar contractions to phenylephrine were observed in SAMR1 and SAMP8, accelerated senescence was associated with decreased eNOS and nNOS and increased O 2 (·-) synthesis. Senescence-related alterations were compensated, at least partly, by the contribution of NO derived from iNOS and the enhanced endogenous antioxidant capacity of superoxide dismutase 1 to maintain vasoconstriction. Administration of a WD induced qualitatively different alterations in phenylephrine contractions of mesenteric arteries from SAMR1 and SAMP8. SAMR1 showed increased contractions partly as a result of decreased NO availability generated by decreased eNOS and nNOS and enhanced O 2 (·-) formation. In contrast, WD feeding in SAMP8 resulted in reduced contractions due to, at least in part, the increased functional participation of iNOS-derived NO. In conclusion, senescence-dependent intrinsic alterations during early stages of vascular senescence may promote vascular adaptation and predispose to further changes in response to high-fat intake, which may lead to the progression of aging-related cardiovascular disease, whereas young subjects lack the capacity for this adaptation.

β-Sitosterol Prevents Lipid Peroxidation and Improves Antioxidant Status and Histoarchitecture in Rats with 1,2-Dimethylhydrazine-Induced Colon Cancer

Oxidative stress has become widely viewed as an underlying condition in diseases such as ischemia/reperfusion disorders, central nervous system disorders, cardiovascular disease, cancer, diabetes, etc. The role that antioxidants play in the process of carcinogenesis has recently gained considerable attention. β-Sitosterol, a naturally occurring sterol molecule, is a relatively mild to moderate antioxidant and exerts beneficial effects in vitro by decreasing the level of reactive oxygen species. The present study evaluated the antioxidant potential of β-sitosterol in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. The enzymatic and nonenzymatic antioxidants and lipid peroxides in colonic and hepatic tissues were evaluated. Generation of reactive oxygen species, beyond the body's endogenous antioxidant capacity, causes a severe imbalance of cellular antioxidant defense mechanisms. Elevated levels of liver lipid peroxides by DMH induction were effectively decreased by β-sitosterol supplementation. β-Sitosterol also exhibited a protective action against DMH-induced depletion of antioxidants such as catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, and reduced glutathione in colonic and hepatic tissues of experimental animals. Supplementation with β-sitosterol restored the levels of nonenzymatic antioxidants (vitamin C, vitamin E, and glutathione). Histopathological alterations in DMH-induced animals were restored to near normal in rats treated with β-sitosterol. Thus, β-sitosterol by virtue of its antioxidant potential may be used as an effective agent to reduce DMH-induced oxidative stress in Wistar rats and may be an effective chemopreventive drug for colon carcinogenesis.

Neuroprotective effect of fucoidan on H2O2-induced apoptosis in PC12 cells via activation of PI3K/Akt pathway.

One of the plausible ways to prevent the reactive oxygen species (ROS)-mediated cellular injury is dietary or pharmaceutical augmentation of endogenous antioxidant defense capacity. In this study, we investigated the neuroprotective effect of fucoidan on H(2)O(2)-induced apoptosis in PC12 cells and the possible signaling pathways involved. The results showed that fucoidan inhibited the decrease of cell viability, scavenged ROS formation and reduced lactate dehydrogenase release in H(2)O(2)-induced PC12 cells. These changes were associated with an increase in superoxide dismutase and glutathione peroxidase activity, and reduction in malondialdehyde. In addition, fucoidan treatment inhibited apoptosis in H(2)O(2)-induced PC12 cells by increasing the Bcl-2/Bax ratio and decreasing active caspase-3 expression, as well as enhancing Akt phosphorylation (p-Akt). However, the protection of fucoidan on cell survival, p-Akt, the Bcl-2/Bax ratio and caspase-3 activity were abolished by pretreating with phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002. In consequence, fucoidan might protect the neurocytes against H(2)O(2)-induced apoptosis via reducing ROS levels and activating PI3K/Akt signaling pathway.

Protective Effects of Tannic Acid against Methomyl-Induced-Oxidative Stress

Methomyl carbamate is a pesticide widely used in the control of insects. The present work aims at studying the effect of tannic acid on the antioxidant system of methomyl-treated-mice. Swiss albino mice were intraperitoneally administered a single dose of methomyl (7 mg/Kg b.wt). Mice of another group were injected with tannic acid (20 mg/ Kg b.wt.) 3 hrs before methomyl intoxication. After 24 hours, methomyl exposure resulted in significant increase in lactic dehydrogenase activity (LDH). The antioxidant capacity of hepatic cells in terms of the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione (GSH) content was diminished. It appears that methomyl exerts its toxic effect via peroxidative damage to hepatic, renal and splenic cell membranes. Also, methomyl induced DNA damage in these organs as detected by alkaline filter elution technique. The distribution of methomyl in different organs of mice was detected by HPLC. Tannic acid administration prior to methomyl injection produced pronounced protective action against methomyl effects. It is observed that tannic acid enhances the endogenous antioxidant capacity of the cells by increasing the activities of SOD, CAT, GR and GST as well as increasing GSH content. The activity of LDH was decreased in liver and the damage of DNA was suppressed comparable to controls. In conclusion, this study concludes that tannic acid has a potential in mitigating most of the adverse effects induced by methomyl toxicity.

The effect of endogenous hydrogen peroxide induced by cold treatment in the improvement of tissue regeneration efficiency

We propose that oxidative stress resulting from an imbalance between generation and scavenging hydrogen peroxide contributes to tissue regeneration efficiency during somatic embryogenesis of hexaploid winter wheat (Triticum aestivum cv. Kamila) and organogenesis of faba bean (Vicia faba ssp. minor cv. Nadwislanski). Endogenous hydrogen peroxide content and antioxidant capacity of cells were determined in initial explants and callus cultures derived from these explants. Regeneration-competent explants (immature embryos) contained more endogenous H2O2 than explants initiated from regeneration-recalcitrant tissue (mature wheat embryos and faba bean epicotyls). Higher H2O2 levels were observed despite the higher activity of antioxidative enzymes (superoxide dismutase and catalase) and the induction of their gene expression. Calli originating from immature embryos retained the capacity of the initial explants: high H2O2 production was observed during the whole culture period. Low temperature treatment (4°C) was found to be an effective factor, which improved both regeneration ability and H2O2 production. Exogenous application to the medium of H2O2 and catalase blocker (3-aminotriazole), but not FeEDTA and superoxide dismutase blocker (diethyldithiocarbamate), also resulted in the enhancement of regeneration efficiency. These results clearly indicate that plant regeneration is specifically regulated by endogenous H2O2 and by factors, which improve its accumulation. Moreover, a study of the activity of various SOD isoforms suggests that not only the absolute concentration of H2O2, but also its localisation might be responsible for controlling regeneration processes.

Oral preoperative antioxidants in pancreatic surgery: A double-blind, randomized, clinical trial

ObjectiveOxidative stress due to ischemia/reperfusion injury increases systemic inflammation and impairs immune defenses. Much interest has developed for the administration of antioxidant substrates in surgical patients. The purpose of this study was to perform a pilot evaluation of the impact of a carbohydrate- containing preconditioning oral nutritional supplement (pONS) enriched with glutamine, antioxidants, and green tea extract on postoperative oxidative stress. MethodsWe performed a double-blind placebo-controlled randomized clinical trial, involving 36 cancer patients undergoing pancreaticoduodenectomy. Patients were randomized to receive either pONS or placebo twice the day before surgery and once 3 hours before surgery. Total endogenous antioxidant capacity (TEAC), plasma levels of vitamin C, vitamin E, selenium, zinc, F2-isoprostanes, and C-reactive protein were measured at baseline and on postoperative day (POD) 1, 3, and 7. ResultsAt surgery, the mean gastric residual volume (mL) was 54.2 in the pONS group versus 51.3 in the placebo group (P = NS). On POD 1 plasma levels of vitamin C (P = 0.001), selenium (P = 0.07), and zinc (P = 0.06) were higher in the pONS group compared to placebo. TEAC was improved on POD 1, 3, and 7 in the pONS group compared to placebo (P = 0.01). No difference was found in plasma C-reactive protein levels after surgery in both groups. ConclusionsPerioperative pONS administration positively affected plasma vitamin C levels and improved TEAC shortly after surgery, but did not reduce oxidative stress and systemic inflammation markers.

Protective effect of aescin from the seeds of Aesculus hippocastanum on liver injury induced by endotoxin in mice

To investigate the effect and underlying mechanism of aescin on acute liver injury induced by endotoxin, liver injury was established by injecting lipopolysaccharide (LPS) in mice. Animals were assigned to seven groups: the control group and groups treated with LPS (40 mg/kg), aescin (3.6 mg/kg), LPS plus dexamethasone (4 mg/kg) and LPS plus aescin (0.9, 1.8 or 3.6 mg/kg). Hepatic histopathological changes were examined under a light microscope. Activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were determined. Levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO) and antioxidative parameters in liver homogenate were measured. Glucocorticoid receptor (GR), 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expressions in liver were determined by western blotting. Treatment with escin could inhibit immigration of inflammatory cells, alleviate the degree of necrosis, and decrease serum ALT and AST activities. Aescin also down-regulated levels of inflammation mediators (TNF-α, IL-1β and NO) and 11β-HSD2 expression in liver, up-regulated GR expression, enhanced endogenous antioxidative capacity, but have no obvious effect on 11β-HSD1 expression in liver. The findings suggest aescin has protective effects on endotoxin-induced liver injury, and the underlying mechanisms were associated with its anti-inflammatory effects, up-regulating GR expression, down-regulating 11β-HSD2 experssion, and antixoidation.

Modifications on antioxidant capacity and lipid peroxidation in mice under fraxetin treatment.

Fraxetin belongs to an extensive group of natural phenolic antioxidants. We have investigated the modifications in endogenous antioxidant capacity; superoxide dismutase (SOD), catalase (CAT), total and selenium-dependent glutathione peroxidases (GPx) and glutathione reductase (GR) and stress index; glutathione disulphide (GSSG)/reduced glutathione (GSH) ratio and thiobarbituric acid-reactive substances (TBARs) in liver and brain supernatants of C57BL/6J male 12-month-old mice under fraxetin treatment for 30 days. Liver SOD and GPx (total and Se-dependent) activities were not significantly affected by fraxetin, whereas they were increased in the brain compared with control animals. GR activity increased significantly only in the liver of treated mice. Fraxetin treatment-related decreases were shown for GSSG/GSH ratio and rate of accumulation of TBARs (not significant in TBARs) in both tissues. We concluded that the net effect of fraxetin treatment on endogenous antioxidant capacity suggests that this compound might provide an important resistance to, or protection against, free-radical-mediated events which contribute to degenerative diseases of ageing.

Moderate aerobic exercise reduces ozone‐produced oxidative stress in rats

Nitric oxide (NO) increases as a result of exercise adaptation. Moderate exercise produces oxidative stress (OS) that stimulates endogenous antioxidant capacity. We previously found that ozone (O3) produced OS and endothelial dysfunction in rats. O3 has been related to increased all‐cause mortality in humans, and aerobic exercise reduced this relationship. The goal of this study was to determine if moderate aerobic exercise reduced OS produced by O3. Male Wistar rats (230–250 g, 10‐weeks old, n=12) were trained to swim 90 min daily (14 days). Six of the rats were exposed to O3 (0.5 ppm, 4 h/day) one hour before exercise. Two groups of sedentary rats (n=6, each) were used as control, one of which was exposed to O3. At the end of the experiment blood was taken from the carotid artery and the animals were euthanized. Measurements were made on the plasma. O3 decreased reduced nitrates (indirect measurement of NO) and produced OS manifested by increased plasma malondialdehyde and 8‐isoprostane, and decreased superoxide dismutase (SOD) activity. Exercise significantly blocked O3 effects, although SOD was also decreased by exercise (the greater drop was in the O3 group).ConclusionAerobic exercise protects against OS produced by O3 and the effect is independent of SOD. Future studies will determine if exercise effects remain after long O3 exposure and if other antioxidants are responsible for those effects

Protective Effects of 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone to PC12 Cells against Cytotoxicity Induced by Hydrogen Peroxide

Oxidative stress has been considered as a major cause of cellular injuries in various clinical abnormalities. One of the possible ways to prevent reactive oxygen species (ROS)-mediated cellular injury is dietary or pharmaceutical therapies to augment the endogenous antioxidant defense capacity. The present study found that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a chalcone isolated from the buds of Cleistocalyx operculatus, possessed cytoprotective activity in PC12 cells treated with H(2)O(2). The results showed that DMC could effectively increase cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) reduction], decrease the cell apoptotic percentage [annexin V/propidium iodide (AV/PI) assay], prevent the membrane from damage [lactate dehydrogenase (LDH) release], scavenge ROS formation, reduce caspase-3 activity, and attenuate the decrease of mitochondrial membrane potential (MMP) in PC12 cells treated with H(2)O(2). Meanwhile, DMC increased the catalytic activity of superoxide dismutase (SOD) and the cellular amount of glutathione (GSH), decreased the cellular amount of malondialdehyde (MDA), and decreased the production of lipid peroxidation in PC12 cells treated with H(2)O(2).

Escin attenuates acute lung injury induced by endotoxin in mice

Endotoxin causes multiple organ dysfunctions, including acute lung injury (ALI). The current therapeutic strategies for endotoxemia are designed to neutralize one or more of the inflammatory mediators. Accumulating experimental evidence suggests that escin exerts anti-inflammatory and antiedematous effects. The aim of this study was to evaluate the effect of escin on ALI induced by endotoxin in mice. ALI was induced by injection of lipopolysaccharide (LPS) intravenously. The mice were given dexamethasone or escin before injection of LPS. The mortality rate was recorded. Tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and nitric oxide (NO) were measured. Pulmonary superoxide dismutase (SOD), glutathione peroxidase (GPx) activity, glutathione (GSH), malondialdehyde (MDA) contents, and myeloperoxidase (MPO) activity were also determined. The expression of glucocorticoid receptor (GR) level was detected by Western blotting. Pretreatment with escin could decrease the mortality rate, attenuate lung injury resulted from LPS, down-regulate the level of the inflammation mediators, including NO, TNF-α, and IL-1β, enhance the endogenous antioxidant capacity, and up-regulating the GR expression in lung. The results suggest that escin may have potent protective effect on the LPS-induced ALI by inhibiting of the inflammatory response, and its mechanism involves in up-regulating the GR and enhancing the endogenous antioxidant capacity.

Protective effects of the citrus flavanones to PC12 cells against cytotoxicity induced by hydrogen peroxide

Oxidative stress has been considered as a major cause of cellular injuries in a variety of clinical abnormalities. One of the plausible ways to prevent the reactive oxygen species (ROS)-mediated cellular injury is dietary or pharmaceutical augmentation of endogenous antioxidant defense capacity. In this study, we investigated the protective actions of citrus flavanones naringin and nobiletin against the cytotoxicity induced by exposure to hydrogen peroxide (H 2O 2) (150 μM, 3 h) in PC12 cells. The results showed that naringin and nobiletin inhibited the decrease of cell viability (MTT reduction), prevented membrane damage (LDH release), scavenged ROS formation, reduced caspase-3 activity, and attenuated the decrease of mitochondrial membrane potential (MMP), respectively, in H 2O 2-induced PC12 cells. Meanwhile, naringin and nobiletin increased superoxide dismutase (SOD) and glutathione (GSH) activity, while decreased malondialdehyde (MDA), the production of lipid peroxidation, in H 2O 2-induced PC12 cells. In addition, the percentage of cells undergoing H 2O 2-induced apoptosis was decreased in the presence of naringin and nobiletin. These results first demonstrate that naringin and nobiletin, even at physiological concentrations, have neuroprotective effects against H 2O 2-induced cytotoxicity in PC12 cells. All the above results suggest that these dietary antioxidants are potential candidates for use in the intervention for neurodegenerative diseases.

Effects of exposure to BDE-99 on oxidative status of liver and kidney in adult rats

Little is known about the potential toxicity of polybrominated diphenyl ethers (PBDEs) on hepatic and renal tissues. In this study, we investigated the modifications in endogenous antioxidant capacity and oxidative damage in liver and kidney of rats by exposure to one of the most persistent PBDE congeners, the 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99). Adult male rats (10 per group) received BDE-99 by gavage at a single dose of 0, 0.6, and 1.2 mg/kg body weight. Forty-five days after exposure, liver and kidney were removed and processed to examine the following oxidative stress (OS) markers: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). In liver, BDE-99 significantly increased SOD activity, GSSG levels, and GSSG/GSH ratio, while GSH levels decreased. Moreover, CAT activity was only reduced at the highest BDE-99 dose. In kidney, CAT activity was significantly decreased, while GSSG/GSH ratio significantly increased following BDE-99 exposure at 1.2 mg/kg body weight. Histological examination of tissues showed phagolysosomes in the kidneys of BDE-99-exposed rats. The results of this investigation suggest that acute oral BDE-99 exposure causes renal and liver impairment, being oxidative damage a potential mechanism for nephrotoxicity and hepatotoxicity.

Antioxidants in Treating Pathologies Involving Oxidative Damage: An Update on Medicinal Chemistry and Biological Activity of Stobadine and Related Pyridoindoles

Pathologies involving oxidative stress are indicative of malfunction of endogenous antioxidant capacity. Numerous efforts were made to design and synthesize biologically active antioxidants and free oxygen radical scavenging substances that could improve the endogenous antioxidant status. The antioxidant and reactive-oxygen-species-scavenging activity of STB was well demonstrated in many in vitro and in vivo studies. These properties of STB seem to be closely related to its beneficial effects in models of oxidative-stress-involving pathologies, including myocardial infarction, stroke, neurodegenerative disorders, hypoxic-ischemic tissue injury, diabetic complications, chronic inflammation, etc. STB has a good affinity to lipids and exerts its protective activity against free-radical-mediated damage by preventing lipid peroxidation. Rather than interacting with the radicals initiating lipid peroxidation, STB was shown to act in its propagation stage via scavenging peroxyl and/or alkoxyl radicals. STB was also found to protect proteins, predominantly by a mechanism involving protection of thiol groups and by preventing oxidation of amino acids. The first findings on antioxidant and pharmacodynamic effects of STB, tested in a variety of biological models, were summarized in 1998. Recently, chemical modification of STB, which we considered as the leading structure, led to the synthesis of pyridoindole derivatives with significantly increased intrinsic antiradical activity and overall antioxidant efficacy compared to the parental molecule. The present paper provides a complete overview of the literature published since 1998 on both STB and STB congeners. Moreover, appropriate structural modifications of STB provided the opportunity to modulate lipophilicity and acidobasic behavior, thus optimizing bioavailability of the novel derivatives and attenuating their unwanted sideeffects, with the result of decreased toxicity. Hence, STB congeners might be prospectively used as medicinal antioxidants, i.e. remedies effective in conditions involving oxidative stress-mediated injury.