Alcohol, oxidative stress and free radical damage

The involvement of free radical mechanisms in the pathogenesis of alcoholic liver disease (ALD) is demonstrated by the detection of lipid peroxidation markers in the liver and the serum of patients with alcoholism, as well as by experiments in alcohol-feed rodents that show a relationship between alcohol-induced oxidative stress and the development of liver pathology. Ethanol-induced oxidative stress is the result of the combined impairment of antioxidant defences and the production of reactive oxygen species by the mitochondrial electron transport chain, the alcohol-inducible cytochrome P450 (CYP) 2E1 and activated phagocytes. Furthermore, hydroxyethyl free radicals (HER) are also generated during ethanol metabolism by CYP2E1. The mechanisms by which oxidative stress contributes to alcohol toxicity are still not completely understood. The available evidence indicates that, by favouring mitochondrial permeability transition, oxidative stress promotes hepatocyte necrosis and/or apoptosis and is implicated in the alcohol-induced sensitization of hepatocytes to the pro-apoptotic action of TNF-alpha. Moreover, oxidative mechanisms can contribute to liver fibrosis, by triggering the release of pro-fibrotic cytokines and collagen gene expression in hepatic stellate cells. Finally, the reactions of HER and lipid peroxidation products with hepatic proteins stimulate both humoral and cellular immune reactions and favour the breaking of self-tolerance during ALD. Thus, immune responses might represent the mechanism by which alcohol-induced oxidative stress contributes to the perpetuation of chronic hepatic inflammation. Together these observations provide a rationale for the possible clinical application of antioxidants in the therapy for ALD.     

Oxidative stress and antioxidant defense in alcoholic liver disease and chronic hepatitis C

In the past decade it became accepted that free radicals, lipid peroxidation and antioxidant defense play a role in various tissues damages, thus in certain liver diseases as well. Since only limited data have been reported concerning the oxidative stress in viral hepatitis, a comparative study was performed in patients (pts) with chronic hepatitis C and alcoholic liver disease. In addition, the effects of a flavonolignan drug silymarin were assessed. 10 pts with chronic hepatitis C, 5 pts with alcoholic hepatitis and 13 pts with alcoholic cirrhosis have been investigated. Biochemical liver tests (serum bilirubin, aminotransferases, ALT, AST, lactate dehydrogenase (LDH), pseudocholinesterase, prothrombin), malandialdehyde (MDA) levels in plasma and red blood cell (RBC) hemolysate, superoxide radical generating capacity of stimulated polymorphonuclear granulocytes (PMN), plasma concentrations of reduced (GSH) and oxidized (GSSG) glutathione, vitamin A, luteine and beta carotene, furthermore RBC superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase activities were determined. The level of plasma MDA--as the marker of lipid peroxidation--was highest in alcoholic cirrhosis (five times of normal) (p < 0.05), the RBC hemolysate MDA was most elevated in chronic hepatitis C (p < 0.05). The mean PMNs' superoxide radical generating capacity was 116.6% of normal control in alcoholic hepatitis, where the mean GSH level was the lowest (89.8% of normal). Plasma vitamin A content was lowest in alcoholic cirrhosis (68% of control) (p < 0.05). SOD activity was elevated in both chronic hepatitis C and alcoholic cirrhosis, where GPx activity was decreased (p < 0.05). There was a correlation between LDH and SOD activities (r = 0.77, p = 0.015). Silymarin treatment of one month duration resulted in normalization of serum bilirubin in 55% of treated pts, AST became normal in 45%, and RBC hemolyzate MDA level normalized in similar rate. A significant increase in both GSH and retinoids was found. Alterations in oxidative stress and antioxidant defense system were shown in chronic hepatitis C, not only in alcoholic liver disease. The parameters of lipid peroxidation and antioxidant defense may be useful surrogate markers for monitoring pts with liver disease during hepatoprotective treatment.     

Intestinal permeability and oxidative stress in patients with alcoholic pellagra

BACKGROUND & AIMS: Increased intestinal permeability is one of the grastointestinal changes observed in alcoholic patients. However, there are no objective definitions as yet of how alcohol induces pathological changes in the various organs. The action of oxygen-free radicals during ethanol metabolism has been considered a determinant factor of these alterations. The present study was undertaken to determine the effect of niacin supplementation on intestinal permeability and oxidative stress in patients with alcoholic pellagra. METHODS: The study was divided into two phases: in Phase 1 we studied ten patients with pellagra before treatment with niacin, and in Phase 2 we studied the same patients after 27 days of treatment with niacin. Intestinal permeability was assessed by the (51)CrEDTA test and the antioxidant action of niacin supplementation was assessed by the determination of lipid peroxidation (plasma malondialdehyde, MDA), protein oxidation (plasma carbonyl group) and of the antioxidants plasma vitamin E and erythrocyte glutathione peroxidase. RESULTS: Comparison of intestinal permeability by the (51)CrEDTA test before and after niacin treatment showed a significant decrease in permeability from 4.29+/-1.92% to 1.90+/-1.19% (P<0.05). Assessment of oxidative stress showed a significant decrease (P<0.05) in lipid and protein peroxidation (MDA: 1.19+/-0.40-0.89+/-0.27 micromol/l; carbonyl groups: 2.22+/-0.36-1.84+/-0.40 nmol/mg protein). CONCLUSIONS: The results suggest that niacin and vitamin E deficiency in patients with pellagra could be important factors in increased intestinal permeability and decreased antioxidant conditions, recovering to normal values after treatment with niacin, associated to alcohol abstinence and a balanced diet.     

一氧化碳对CYP2E1介导的微粒体酒精氧化应激的保护作用

目的探讨诱导I型血红素氧合酶(heme oxygenase-1,HO-1)催化血红素产生的代谢产物一氧化碳(CO)对大鼠肝微粒体细胞色素P4502E1(cytochrome P4502E1,CYP2E1)酶活性影响及其介导的酒精性氧化应激的保护作用。方法超速离心法制备大鼠肝脏微粒体,加入血红素(hemin)、血红蛋白(Hb)、不同剂量的CO释放剂CORM-2(carbonmonoxide-releasing molecules-2),检测CYP2E1酶活性;在微粒体酒精氧化反应体系中加入血红素、血红蛋白及CORM-2,检测微粒体超氧化物歧化酶(SOD)活力及谷胱甘肽(GSH)、丙二醛(MDA)及氧自由基(ROS)水平。结果 hemin处理后肝微粒体CYP2E1的酶活性下降,联合Hb后CYP2E1酶活性明显升高,外源性CO则显示出类似的CYP2E1酶抑制效应;针对乙醇孵育的肝微粒体,hemin处理后明显抑制了肝微粒体MDA和ROS水平的升高,有效维持了GSH水平和SOD活力,联合Hb处理后明显抑制了上述保护效应,外源性CORM-2也显示出类似的保护效应,而灭活的CORM-2则无明显的保护效应。结论 CO对大鼠肝微粒体酒精性氧化应激具有保护作用,其机制可能与CO对CYP2E1酶活性的直接抑制有关。     

Protective role of vitamin E on the microcystin-induced oxidative stress in tilapia fish (Oreochromis niloticus)

Microcystins (MCs) are potent hepatotoxins produced by cyanobacteria in water systems that induce oxidative stress in fish. The present study investigated the effect of vitamin E pretreatment on MC-induced oxidative damage in the liver, kidneys, and gills of tilapia fish (Oreochromis niloticus). Groups of fish were fed vitamin E supplements (200 or 700 mg per kilogram of diet) for 7 d or received only commercial fish food and then were exposed to a single oral dose of cyanobacterial cells (120 microg of MC-LR [2:Leu, 4:Arg] per fish), and were sacrificed in 24 h. The potential benefits of vitamin E were evaluated based on lipid peroxidation (LPO), protein oxidation, catalase (CAT, Enzyme Commission [EC] 1.11.1.6), superoxide dismutase (EC 1.15.1.1), glutathione peroxidase (EC 1.11.1.9), glutathione reductase (EC 1.8.1.7), and the ratio of reduced glutathione to oxidized glutathione (GSH/GSSG). Microcystins induced a 1.6-fold increase in LPO values in liver, whereas vitamin E-pretreated fish showed no alteration on this biomarker. Enzyme activities levels were also ameliorated by the chemoprotectant, whereas protein oxidation and GSH/GSSG did not show any significant change. The higher vitamin E dose used proved to have the greater protective effects, particularly on the biomarkers LPO and CAT. The results show that vitamin E could have a potential use as a preventive or therapeutic measure in MC-exposed fish.     

Dietary saturated fat reduces alcoholic hepatotoxicity in rats by altering fatty acid metabolism and membrane composition

Rats fed a saturated fat diet are protected from experimentally induced alcoholic liver disease, but the molecular mechanisms underlying this phenomenon remain in dispute. We fed male Sprague-Dawley rats intragastrically by total enteral nutrition using diets with or without ethanol. In 1 control and 1 ethanol group, the dietary fat was corn oil at a level of 45% of total energy. In other groups, saturated fat [18:82 ratio of beef tallow:medium-chain triglyceride (MCT) oil] was substituted for corn oil at levels of 10, 20, and 30% of total energy, while keeping the total energy from fat at 45%. After 70 d, liver pathology, serum alanine aminotransferase (ALT), biochemical markers of oxidative stress, liver fatty acid composition, cytochrome P450 2E1 (CYP2E1) expression and activity and cytochrome P450 4A (CYP4A) expression were assessed. In rats fed the corn oil plus ethanol diet, hepatotoxicity was accompanied by oxidative stress. As dietary saturated fat content increased, all measures of hepatic pathology and oxidative stress were progressively reduced, including steatosis (P < 0.05). Thus, saturated fat protected rats from alcoholic liver disease in a dose-responsive fashion. Changes in dietary fat composition did not alter ethanol metabolism or CYP2E1 induction, but hepatic CYP4A levels increased markedly in rats fed the saturated fat diet. Dietary saturated fat also decreased liver triglyceride, PUFA, and total FFA concentrations (P < 0.05). Increases in dietary saturated fat increased liver membrane resistance to oxidative stress. In addition, reduced alcoholic steatosis was associated with reduced fatty acid synthesis in combination with increased CYP4A-catalyzed fatty acid oxidation and effects on lipid export. These findings may be important in the nutritional management and treatment of alcoholic liver disease.     

Effect of vitamin E and C supplements on antioxidant defense system in cardiovascular disease patients in Zahedan, southeast Iran

Oxidative stress plays an important role in the pathogenesis of cardiovascular disease (CVD). Growing evidence suggest that antioxidant vitamins might reduce the risk of disease outcomes by their ability to scavenge free radicals. The aim of the present study was to evaluate the supplementation of vitamins E and C on oxidant and antioxidant status in CVD patients. We conducted a case-control study with vitamin E (400 IU/d) and vitamin C (500 mg/d) supplementation in 40 CVD patients for 2 mo. Antioxidant (enzymatic and non-enzymatic) and oxidant status were analyzed pre and post supplementation. In the initial stage the activity of both enzymatic and non-enzymatic antioxidants were lower, while the malondialdehyde (MDA) level was elevated (p<0.0001). After intervention, a significant increase in superoxide dismutase (SOD) activity (61.7%), glutathione peroxidase (GPx) activity (59.3%), the levels of vitamin E (83.7%), C (145.3%), total antioxidant capacity (TAC) (62.8%) and a significant decrease in MDA (40%) value were observed (p<0.0001). There was a significant negative correlation between MDA and TAC. The results suggest that supplementation with a combination of vitamins E and C reduced lipid peroxidation and strengthened the antioxidant defense system. Hence, there will be beneficial effects on the heart by reducing oxidative stress in CVD patients.     

Individual susceptibility and alcohol effects:biochemical and genetic aspects

The large interethnic and interindividual variability in alcohol-induced toxic effects comes from a combination of genetic and environmental factors, influencing ethanol toxicokinetics. The hepatic enzymatic systems involved in ethanol metabolism are alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and microsomal P4502E1 (CYP2E1). ADH oxidizes ethanol to acetaldehyde, which is very efficiently oxidized to acetate by ALDH. About 10% of moderate quantities of ethanol is metabolised by CYP2E1; the percentage increases when ADH is saturated. During ethanol metabolism reactive oxygen species and hydroxyethyl radicals are generated, causing oxidative stress, responsible for most ethanol-induced liver damage. For their critical role in detoxifying radicals, glutathione S-transferase are gaining attention in the etiology of alcoholism. All these enzymes have been shown to be polymorphic, giving rise to altered phenotypes. For this reason recent studies have looked for a correlation between metabolic variability and differences in alcohol abuse-related effects.     

维生素E和C对肺癌介入化疗患者血浆LPO及红细胞SOD水平的影响

观察了20例使用和19例未使用维生素E(VE)和维生素C(VC)的肺癌患者在介入化学疗法(支气管动脉内药物注射)前后血浆LPD(过氧化脂质,lipid peroxide)和红细胞SOD(超氧化物歧化酶;superoxide dismutase)水平的变化,结果:1)未使用VE、VC的肺癌患者在介入化学疗法后血浆LPO水平明显上升(P<0.02)、红细胞SOD水平显著下降(P<0.01);2)使用VE、VC的患者在介入化学疗法后血浆LPO明显下降(P<0.05),红细胞SOD水平上升,但差异无显著性(P>0.05);3)血浆LPO水平和VC摄入量之间有明显负相关,r=-0.55(P<0.01),而和VE间无明显负相关,r=-0.02(P>0.05)。     

Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis.

Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase-mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinucleotide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-terminal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leakage. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidylcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment.     

Protective role of vitamin E on the oxidative stress in Hansen's disease (Leprosy) patients

BACKGROUND: A constellation of reactive oxygen species (ROS) capable of damaging cellular constituents generated in excess during the chronic, inflammatory, neurodegenerative disease process of leprosy. The consequences of this leads to enhanced oxidative stress and lower antioxidant status. Enzymatic antioxidants provide first line defense against ROS. We have measured the levels of oxidative stress indices like lipid peroxidation (LPO), protein carbonyls together with enzymatic antioxidants in the blood samples of control and leprosy patients. Nutritional rehabilitation by way of exogenous supplementation of functionally efficient antioxidants like vitamin E reactivates the enzymatic antioxidant system and guards against the insult caused by ROS during the pathogenesis of the disease and antileprosy chemotherapy. DESIGN: Untreated leprosy patients were selected on the basis of clinical examination and skin smear. All diagnosed untreated leprosy patients received multi drug therapy (MDT) consisting of rifampicin, dapsone and clofazimine as recommended by World Health Organization. A small number of untreated cases were selected for co-supplementation of vitamin E along with MDT. Oxidative stress indices, enzymatic and nonenzymatic antioxidant status were assayed in untreated, MDT treated and those supplemented vitamin E along with MDT. STATISTICAL METHODS: We have compared the significance in the mean+/-s.d. values of the oxidative stress indices and the levels of antioxidants using one way analysis of variance (ANOVA) between control, untreated, MDT treated and those supplemented vitamin E with MDT and the results were significant at P < 0.05. Statistical analysis of the results suggests that oral administration of vitamin E lowers oxidative stress and augments antioxidant status in affected individuals.Results:Enhanced oxidative stress as evidenced by increased LPO and protein carbonyl in leprosy cases lowers the antioxidant status. Treatment with MDT has a limited impact on increased oxidative stress and decreased antioxidant status. Coadministration of vitamin E along with MDT decreases oxidative stress and activate the antioxidant status. DISCUSSION: The excess production of ROS as seen in leprosy cases could lead to degeneration of tissues and derangement of internal organs. The possible reason for the decreased antioxidant status in leprosy cases may be increased production of ROS, deranged liver function, and the free radical producing ability of drugs used in MDT of leprosy. Intervention with antioxidant supplementation like vitamin E prevents oxidative stress mediated through ROS and activates the net antioxidant status during the chronic course of the disease and antileprosy chemotherapy.     

Oxidative stress in humans during work at moderate altitude.

Increased oxidative stress has been associated with work at high altitude; however, it is not known whether oxidative stress is a significant problem at moderate altitudes. The oxidative stress indicators, breath pentane (BP), 8-hydroxydeoxyguanosine (8-OHdG), oxygen radical absorption capacity (ORAC), 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and lipid peroxides (LPO) were measured in breath, blood and urine samples of U.S. Marines engaged in moderate altitude ( approximately 3000 m) cold weather field training. The test subjects were divided into a placebo and four antioxidant supplement groups (n = 15/group) and received the following supplements for 28 d: 1) vitamin E, 440 alpha-tocopherol equivalents (alpha-TE); 2) vitamin A, 2000 retinol equivalents (RE) of beta-carotene; 3) vitamin C, 500 mg ascorbic acid; 4) a mixture of 440 alpha-TE, 2000 RE of beta-carotene, 500 mg ascorbic acid, 100 microg selenium and 30 mg zinc daily. Strenuous work ( approximately 23 MJ/d) in cold weather at moderate altitude was accompanied by increases in several indicators of oxidative stress that were not effectively controlled by conventional antioxidant supplements. The group receiving the antioxidant mixture exhibited lower BP (P < 0. 05) compared with those receiving single antioxidant supplements; however, not all markers of oxidative stress responded like BP. Because these markers did not respond in the same manner, it is important to include markers from more than one source to assess the effect of supplemental dietary antioxidants.     

急性敌百虫中毒与氧化应激及自由基损伤的关系

目的探讨急性敌百虫中毒与氧化应激和自由基损伤的关系。方法采用随机对照设计,用分光光度分析法检测了2002年7月至2003年6月抢救的82例急性敌百虫中毒者和92例健康成人志愿者的血浆维生素C、维生素E、红细胞过氧化脂质(LPO)水平和超氧化物歧化酶(SOD)、乙酰胆碱酯酶(AChE)活性。结果中毒组的维生素C为(3735±998)μmol/L,维生素E为(1657±454)μmol/L,SOD为(1785±154)U/gHb,AChE为(2131±576)U/gHb,志愿组的维生素C为(5534±1598)μmol/L,维生素E为(2566±724)μmol/L,SOD为(2124±185)U/gHb,AChE为(3053±836)U/gHb,中毒组上述指标均显著低于志愿组;中毒组的LPO为(3520±529)nmol/gHb,显著高于志愿组的(2787±466)nmol/gHb。控制年龄的偏相关分析结果表明,中毒组的AChE值与LPO值呈负相关,与维生素C、维生素E和SOD值呈正相关。结论急性敌百虫中毒者体内存在着严重的氧化应激和自由基损伤。     

Role of dietary vitamin E in cadmium-induced oxidative damage in rabbit's blood, liver and kidneys

The aim of this work was to determine the effect of dietary vitamin E intake on lipid peroxidation (LPO) by measuring thiobarbituric acid reactive substances (TBARS), vitamin E and reduced glutathione (GSH) levels, and glutathione peroxidase (GSH-Px: EC 1.11.1.9) activity in plasma, red blood cells (RBC), livers, and kidneys of rabbits dosed with cadmium (Cd). Six-month-old clinically healthy New Zealand White rabbits (8 in each group) were given tap water only, containing 1 g CdCl2/L, or tap water with CdCl2 plus vitamin E (100 mg dl-alpha-tocopheryl acetate in 0.2 mL corn oil) daily for 30 days. The vitamin E level in the plasma, liver, and kidneys was significantly higher in the control than in the Cd-only group, and TBARS levels were significantly lower. There were no statistical differences between the control and Cd-only groups GSH-Px activities and GSH levels in RBC, liver, and kidneys. Vitamin E levels in plasma, liver, and kidneys and GSH-Px activity in RBC were higher in the vitamin E group than in both control and Cd-only groups. However, the TBARS levels of RBC, liver, and kidneys in vitamin E administered group were decreased. Therefore, the present study demonstrates the effectiveness of vitamin E in reducing oxidative stress in Cd-treated rabbits and suggests that reductions in increased TBARS due to Cd toxicity may be an important factor in the action of vitamin E.     

S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings.

In patients with severe alcoholic liver disease (i.e., cirrhosis), a deficiency of S-adenosylmethionine (SAMe) develops as a result of decreased SAMe synthetase activity. Whether a sizeable SAMe depletion occurs already at earlier stages of alcoholic liver disease has been the subject of debate. To address this issue, rats were fed alcohol (or isocaloric carbohydrate) in Lieber-DeCarli liquid diets containing adequate amounts of protein, vitamins, and lipotropic factors, including methionine. Alcohol feeding resulted in hepatic steatosis (without fibrosis) and unchanged SAMe synthetase activity, yet SAMe concentration was already greatly decreased. This most likely resulted from oxidative stress associated with the metabolism of alcohol and the induction of cytochrome P4502E1 (CYP2E1), which generates free radicals. Indeed, the decrease in hepatic SAMe correlated with parameters of oxidative stress, such as increased 4-hydroxynonenal (measured by gas chromatography-mass spectrometry) and diminished glutathione (GSH). Decreased GSH, occurring as a result of excessive GSH consumption caused by the oxidative stress, probably generated by enhanced utilization of SAMe, a precursor of GSH, thereby explaining the depletion of SAMe. In view of the known differences between rodents and primates in the metabolism of lipotropes, my colleagues and I have also studied the interaction between alcohol and SAMe in baboons and found again that, at early stages preceding the development of cirrhosis, there was already a significant lowering of hepatic SAMe concentration, associated with a striking oxidative stress documented by decreased levels and accelerated turnover of GSH. This was associated with increased lipid peroxidation and damage to cellular membranes, including those of the mitochondria, assessed by electron microscopy. Oral administration of SAMe resulted in its hepatic repletion with a corresponding attenuation of the ethanol-induced oxidative stress and liver injury, with significantly less GSH depletion, less increases in plasma aspartate aminotransferase (AST) levels, less leakage of mitochondrial glutamic dehydrogenase into the plasma, and fewer megamitochondria. In conclusion, (1) both in rodents and in non-human primates, significant SAMe depletion occurs already at early stages of alcoholic liver disease, despite the consumption of adequate diets; (2) the decreased hepatic SAMe concentration and the associated liver lesions, including mitochondrial injury, can be corrected with SAMe supplementation; and (3) accordingly, therapeutic administration of SAMe should be the subject of a comprehensive clinical trial to assess its capacity to attenuate early stages of alcoholic liver injury in human beings.     

Iron supplementation increases disease activity and vitamin E ameliorates the effect in rats with dextran sulfate sodium-induced colitis

Inflammatory bowel disease is often associated with iron deficiency anemia and oral iron supplementation may be required. However, iron may increase oxidative stress through the Fenton reaction and thus exacerbate the disease. This study was designed to determine in rats with dextran sulfate sodium (DSS)-induced colitis whether oral iron supplementation increases intestinal inflammation and oxidative stress and whether the addition of an antioxidant, vitamin E, would reduce this detrimental effect. Four groups of rats that consumed 50 g/L DSS in drinking water were studied for 7 d and were fed: a control, nonpurified diet (iron, 270 mg, and dl-alpha-tocopherol acetate, 49 mg/kg); diet + iron (iron, 3000 mg/kg); diet + vitamin E (dl-alpha-tocopherol acetate, 2000 mg/kg) and the diet + both iron and vitamin E, each at the same concentrations as above. Body weight change, rectal bleeding, histological scores, plasma and colonic lipid peroxides (LPO), plasma 8-isoprostane, colonic glutathione peroxidase (GPx) and plasma vitamin E were measured. Iron supplementation increased disease activity as demonstrated by higher histological scores and heavier rectal bleeding. This was associated with an increase in colonic and plasma LPO and plasma 8-isoprostane as well as a decrease in colonic GPx. Vitamin E supplementation decreased colonic inflammation and rectal bleeding but did not affect oxidative stress, suggesting another mechanism for reducing inflammation. In conclusion, oral iron supplementation resulted in an increase in disease activity in this model of colitis. This detrimental effect on disease activity was reduced by vitamin E. Therefore, the addition of vitamin E to oral iron supplementation may be beneficial.     

Evaluation of dietary factors in relation to the biomarkers of oxidative stress and inflammation in breast cancer risk

Objective

This study was conducted to evaluate blood concentrations of inflammatory cytokines and oxidative stress-related biomarkers as risk factors of breast cancer and to determine the relation between these markers and antioxidant nutrient intake.

Methods

Study subjects were 134 patients with breast cancer and 149 controls. Total antioxidant capacity and concentrations of 8-isoprostane, 8-hydroxy-2′-deoxyguanosine, interleukin (IL)-1β, IL-6, and IL-8 of blood samples were determined. A food-frequency questionnaire was used to assess nutrient intake.

Results

Patients with breast cancer had significantly higher blood levels of oxidative stress markers compared with control subjects. Plasma concentrations of IL-1β and IL-6 were significantly higher in patients with breast cancer compared with those of control subjects. In the pooled analysis, total antioxidant capacity was significantly decreased with increasing quartiles of carbohydrate intake but was increased with increasing quartiles of total vitamin A intake and vitamin C intake. In addition, 8-hydroxy-2′-deoxyguanosine concentration was decreased with increasing quartiles of vitamin A and β-carotene. No significant association was found between nutrient intake and cytokine concentrations.

Conclusions

These results suggest that oxidative stress and inflammation may be associated with the risk of breast cancer. Total vitamin A intake was negatively related to oxidative stresses, possibly modifying the risk of breast cancer.     

维生素Ｅ对1，2-二氯乙烷中毒性脑水肿保护作用的研究

目的探讨维生素E (vitamin E,Vit E)对1,2-二氯乙烷(1,2-dichloroethane,1,2-DCE)中毒性脑水肿的保护作用。方法将雌性昆明种小鼠随机分为空白对照组、Vit E对照组、1,2-DCE单纯染毒组及Vit E低、中和高剂量干预组。连续给予药物灌胃4 d后,采取静式吸入方式染毒3. 5 h/d,持续3 d。结果与空白对照组相比,单纯染毒组小鼠脑组织呈现明显脑水肿病理改变,脑含水量、脑组织中丙二醛(malondialdehyde,MDA)含量及细胞色素P450 2E1 (cytochrome P450 2E1,CYP2E1)蛋白和mRNA表达水平显著升高,脑组织中还原型谷胱甘肽(glutathione,GSH)含量、超氧化物歧化酶(superoxide dismutase,SOD)和过氧化氢酶(catalase assay kit,CAT)活性、Occludin蛋白和mRNA及Claudin 5蛋白表达水平显著降低。与单纯染毒组相比,各干预组小鼠的脑含水量、脑组织MDA含量、CYP2E1蛋白和mRNA表达水平显著降低,GSH含量、Occludin蛋白及mRNA水平显著升高;中和高剂量干预组的小鼠脑组织中SOD和CAT活性及Claudin 5蛋白表达水平亦显著升高(P0. 05)。结论单纯1,2-DCE染毒可引起小鼠脑水肿,诱导脑组织中CYP2E1的表达,诱发脑组织氧化损伤,破坏紧密连接蛋白,并抑制Occludin和Claudin 5的表达;而Vit E干预可显著抑制CYP2E1的表达,缓解CYP2E1介导的氧化损伤,有效预防1,2-DCE引起的中毒性脑水肿。     

Oxidative stress and antioxidant capacity in smoking and nonsmoking men with HIV/acquired immunodeficiency syndrome.

BACKGROUND: Past studies document decreased levels of antioxidants and selenium and increased levels of oxidative stress in people living with HIV/acquired immunodeficiency syndrome (AIDS). Cigarette smoking is another source of oxidative stress. Excessive oxidative stress can induce HIV replication, resulting in disease progression. The purpose of this study was to determine whether subjects with HIV/AIDS who smoke cigarettes have increased oxidative stress and decreased antioxidant status compared with nonsmokers with HIV/AIDS. METHODS: Thirty-one men with HIV/AIDS (adhering to highly active antiretroviral therapy for the previous 3 months) were recruited during regular visits to a Veterans Affairs Medical Center Infectious Disease Clinic in a southeastern US city. Plasma was obtained from a 1-time blood draw for this comparison study. Plasma lipid peroxide (LPO) was used as a marker of oxidative stress. Indicators of antioxidant capacity included plasma glutathione peroxidase (GPx, the functional indicator of selenium status), vitamin C, and antioxidant potential (AOP). RESULTS: Fifteen smokers and 10 nonsmokers with HIV/AIDS were enrolled. Median plasma LPO level was above the normal range of 0-1.3 micromol/L in both nonsmokers (2.5 [0-23.4] micromol/L, median [range]) and smokers (4.0 [0-47.5] micromol/L), but there was no difference between groups. Plasma GPx concentration was significantly lower in smokers (169 [118-295] mumol/min/L) compared with nonsmokers (197 [149-414] micromol/min/L). Vitamin C and AOP levels were not different between groups. CONCLUSIONS: This pilot study suggests that effects of smoking on oxidative stress are not additive, as no striking differences were observed in oxidative stress or antioxidant capacity between clinically stable smoking and nonsmoking men with HIV/AIDS.