Alpha-tocopherol Supplementation Research Articles

Manganese superoxide dismutase (MnSOD) polymorphism, alpha-tocopherol supplementation and prostate cancer risk in the alpha-tocopherol, beta-carotene cancer prevention study (Finland).

Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that plays a key role in protecting the cell from oxidative damage. A polymorphism in the mitochondrial targeting sequence (a valine to alanine substitution), thought to alter transport of the enzyme into mitochondria, has been associated with increased risk for breast cancer with a more pronounced association among women with low intake of dietary antioxidants. We examined the role of MnSOD in the development of prostate cancer in a large, randomized cancer prevention trial of male smokers, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. We hypothesized that MnSOD may be associated with prostate cancer and that long-term antioxidant supplementation (alpha-tocopherol 50 mg/day for five to eight years) could modify the effect on risk. Logistic regression was used to estimate these associations among 197 cases and 190 controls genotyped and matched for age, intervention group, and clinic. Men homozygous for the MnSOD ala allele had a 70% increase in risk over men homozygous for the val allele (odds ratio, OR = 1.72, 95% confidence interval, CI = 0.96-3.08, p = 0.07). Supplementation with alpha-tocopherol had no impact on the MnSOD-prostate cancer association. Although there was no difference in the association with disease stage, men homozygous for MnSOD ala (compared to MnSOD val/val or val/ala) showed a three-fold risk increase for high-grade tumors (OR = 2.72, 95% CI: 1.15-6.40, p = 0.02). These data suggest an effect of the MnSOD ala/ala genotype on the development of prostate cancer. Our observation of a stronger association with high-grade tumors may have prognostic implications that should also be pursued.

Increased Immunity in Weaned Piglets by Daily Dosing of d-alpha-Tocopherol in the Drinking Water

The critically important role of vitamin E, i.e., alpha-tocopherol, in enhancing both humoral and cellmediated immunity has been demonstrated in various species. In weaned piglets, however, the utilization of acetate-form of supplemental vitamin E in feed is less than 10% during the 1st week following weaning, and only approximately 20-25% during the 2nd and 3rd week post-weaning. This results in critically low concentrations of plasma alpha-tocopherol. A clinical field study was conducted to measure the effectiveness of liquid natural-source vitamin E (d-alpha-tocopherol) in weaned piglets with a history of E. coli diarrhea. Three hundred ten 28-day old weaned piglets were divided into two groups, i.e., a control group of 155 piglets and a treatment group of 155 piglets with each group consisting of 4 pens of approximately 40 piglets per pen. All piglets received dl-alphatocopheryl acetate in the diet (125 mg/kg). The natural Vitamin E treated piglets received an extra daily administration of a d-alpha-tocopherol (NATUR-E Micelle, 500 I.U. d-alpha-tocopherol per ml, NETTOVET A/S) at a dose of 1 ml per 200 kg body weight for 10 days after weaning. The product was mixed with drinking water daily and offered in drinking troughs placed in the test pens. All piglets had equal access to the water troughs. Control piglets were also offered non-fortified water through drinking troughs. To entice intake of water, a small amount of milk replacer was added to the water for both groups. Plasma samples were collected at random from 10 piglets in both groups at weaning, and 1, 2, and 3 weeks following weaning and analyzed for alpha-tocopherol. Oral antibiotic treatment through drinking water (Neomycin Sulphate) was used only in pens with clinical signs of diarrhea. At weaning and prior to treatment, mean plasma alpha-tocopherol concentration was 4.5 mg/l in both groups. In control piglets, mean plasma alpha-tocopherol decreased to 1.4 mg/l and 1.2 mg/l at 1 and 2 weeks after weaning, respectively. In test animals, the supplementation of natural alpha-tocopherol through drinking water resulted in mean plasma alpha-tocopherol of 2.7 mg/l at 1 week following weaning. Since daily supplementation stopped 10 days after weaning, weeks 2 and 3 mean plasma alpha-tocopherol levels decreased to 2.0 mg/l and 1.4 mg/l, respectively. Vitamin E supplementation appeared to reduce incidence and severity of diarrhea. Control piglets first showed severe diarrhea 3-4 days after weaning, and 12 piglets died during the first two weeks (7.7% mortality). Vitamin E-supplemented piglets first showed signs of diarrhea 9 days post-weaning, and 3 piglets died during the 2nd week of weaning (1.9% mortality). Under the study condition employed, it can be concluded that daily addition of natural alpha-tocopherol to the drinking water to weaned piglets at a dose of 1 ml per 200 kg body weight for 10 days following weaning had a positive impact on plasma vitamin E status and subsequently immunity. Compared to control animals, the onset of diarrhea in test animals was postponed up to 6 days and was less severe; and mortality due to diarrhea was statistically significant reduced (p=0.017, relative risk=1.65). 286

Comparison of the antioxidant effects of Concord grape juice flavonoids α-tocopherol on markers of oxidative stress in healthy adults

Concord grape juice (CGJ) is a rich source of flavonoids, which have greater antioxidant efficacy in vitro than does alpha-tocopherol; however, the efficacies of flavonoids and alpha-tocopherol in vivo have not been compared. We compared the in vivo antioxidant efficacy of CGJ with that of alpha-tocopherol in healthy adults. Subjects were randomly assigned to receive either 400 IU RRR-alpha-tocopherol/d (n = 17) or 10 mL CGJ. kg(-1). d(-1) (n = 15) for 2 wk. Serum oxygen radical absorbance capacity, plasma protein carbonyls, urinary F(2)-isoprostanes, and resistance of LDL to ex vivo oxidation were measured before and after supplementation as markers of antioxidant status and oxidative stress. After supplementation, plasma alpha-tocopherol increased 92% in subjects who received alpha-tocopherol (P < 0.001); plasma total and conjugated phenols increased 17% (P < 0.01) and 22% (P < 0.001), respectively, in subjects who received CGJ. There was a significant change in plasma triacylglycerols in both groups, but the concentrations were within the normal range. CGJ supplementation was associated with significantly higher triacylglycerols than was alpha-tocopherol supplementation. Both supplementation regimens significantly increased serum oxygen radical absorbance capacity (P < 0.001) and LDL lag time (P < 0.001) and significantly decreased the LDL oxidation rate (P < 0.01), with no significant difference in effectiveness. Protein carbonyl concentrations in native plasma decreased 20% after CGJ supplementation, which was a significantly different response than that after alpha-tocopherol supplementation (P < 0.05). In healthy adults, 10 mL CGJ. kg(-1). d(-1) increased serum antioxidant capacity and protected LDL against oxidation to an extent similar to that obtained with 400 IU alpha-tocopherol/d but decreased native plasma protein oxidation significantly more than did alpha-tocopherol. CGJ flavonoids are potent antioxidants that may protect against oxidative stress and reduce the risk of free radical damage and chronic diseases.

Effects of ascorbic acid and alpha-tocopherol on arsenic-induced oxidative stress.

Arsenic is an ubiquitous element in the environment causing oxidative burst in the exposed individuals leading to tissue damage. Antioxidants have long been known to reduce the free radical-mediated oxidative stress. Therefore, the present study was designed to determine whether supplementation of alpha-tocopherol (400 mg/kg body weight) and ascorbic acid (200 mg/kg body weight) to arsenic-intoxicated rats (100 ppm in drinking water) for 30 days affords protection against the oxidative stress caused by the metalloid. The arsenic-treated rats showed elevated levels of lipid peroxide, decreased levels of non-enzymatic antioxidants and activities of enzymatic antioxidants. Administration of alpha-tocopherol and ascorbic acid to arsenic-exposed rats showed a decrease in the level of lipid peroxidation (LPO) and enhanced levels of total sulfhydryls, reduced glutathione, ascorbic acid and alpha-tocopherol and so do the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase to near normal. These findings suggest that alpha-tocopherol and ascorbic acid prevent LPO and protect the antioxidant system in arsenic-intoxicated rats.

Monocyte and neutrophil adhesion molecule expression during acute hyperglycemia and after antioxidant treatment in type 2 diabetes and control patients.

We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive. Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (P<0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (P=0.03). Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.

Effects of α-tocopherol supplementation and continuous subcutaneous insulin infusion on oxidative stress in Korean patients with type 2 diabetes

Most Koreans with type 2 diabetes are insulin deficient and insulin resistant. Continuous subcutaneous insulin infusion (CSII) provides a suitable amount of insulin to overcome insulin deficiency and achieve near-normal blood glucose concentrations. Our previous study showed, however, that CSII does not reduce oxidative stress even though it normalizes blood glucose concentrations. The purpose of this study was to determine whether CSII plus alpha-tocopherol supplementation for 2 mo would alter oxidative stress in Korean patients with type 2 diabetes. Ninety-eight subjects received CSII plus either 200 mg alpha-tocopherol/d (n = 48) or a placebo (n = 50) for 2 mo. The general characteristics (age, duration of diabetes, body mass index, and blood glucose concentrations) of the 2 groups were not significantly different. Fasting and postprandial blood glucose concentrations of all subjects were normalized after CSII. Fasting plasma insulin concentrations did not differ significantly between the 2 groups after CSII. Lipid peroxide concentrations in plasma and red blood cells decreased and alpha-tocopherol concentrations in plasma and red blood cells increased after alpha-tocopherol supplementation. However, these changes were not affected significantly by CSII. Plasma vitamin C concentrations increased significantly after CSII plus alpha-tocopherol supplementation. However, the activities of antioxidant enzymes in red blood cells did not change significantly after CSII plus alpha-tocopherol supplementation. alpha-Tocopherol supplementation was beneficial in decreasing blood lipid peroxide concentrations without altering antioxidant enzyme activities in Korean patients with type 2 diabetes treated with CSII.

Modulation of monocyte-macrophage function with alpha-tocopherol: implications for atherosclerosis.

Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. Monocyte-macrophages are crucial cells in atherogenesis. Several lines of evidence suggest that antioxidants, especially alpha-tocopherol, have beneficial effects with regard to cardiovascular disease. Alpha-tocopherol has beneficial effects on cell functions that are pivotal in atherogenesis. Alpha-tocopherol inhibits platelet aggregation and proinflammatory activity of monocytes. In vitro data also support an effect of alpha-tocopherol on smooth muscle cell proliferation and endothelial function. Finally, recent data support an effect of alpha-tocopherol on macrophage function. The mounting evidence from in vitro and in vivo studies provides a sound scientific basis for alpha-tocopherol supplementation. Further clinical trials are required, however, before a definitive recommendation can be made for primary and secondary prevention of heart disease.

Incorporation of alpha-tocopherol in marine lipid-based liposomes: in vitro and in vivo studies.

Liposomes made from a natural marine lipid extract and containing a high polyunsaturated n-3 fatty lipid ratio were envisaged as oral route vectors and a potential alpha-tocopherol supplement. The behavior of vesicles obtained by simple filtration and of giant vesicles prepared by electroformation was investigated in gastrointestinal-like conditions. The influence of alpha-tocopherol incorporation into liposomes was studied on both physical and chemical membrane stability. Propanal, as an oxidation product of n-3 polyunsaturated fatty acids, was quantified by static headspace gas chromatography when alpha-tocopherol incorporation into liposome ratios ranged from 0.01 to 12 mol%. Best oxidative stability was obtained for liposomes that contained 5 mol% alpha-tocopherol. Compared to the other formulas, propanal formation was reduced, and time of the oxidation induction phase was longer. Moreover, alpha-tocopherol induced both liposome structural modifications, evidenced by turbidity, and phospholipid chemical hydrolysis, quantified as the amount of lysophospholipids. This physicochemical liposome instability was even more pronounced in acid storage conditions, i.e., alpha-tocopherol incorporation into liposome membranes accelerated the structural rearrangements and increased the rate of phospholipid hydrolysis. In particular, giant vesicles incubated at pH 1.5 underwent complex irreversible shape transformations including invaginations. In parallel, the absorption rate of alpha-tocopherol was measured in lymph-cannulated rats when alpha-tocopherol was administrated, as liposome suspension or added to sardine oil, through a gastrostomy tube. Alpha-tocopherol recovery in lymph was increased by almost threefold, following liposome administration. This may be related to phospholipids that should favor alpha-tocopherol solubilization and to liposome instability in the case of a high amount of alpha-tocopherol in the membranes. A need to correlate results obtained from in vitro liposome behavior with in vivo lipid absorption was demonstrated by this study.

Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosis.

Alcohol misusers frequently have difficulties in gait, and various muscle symptoms such as cramps, local pain and reduced muscle mass. These symptoms are common in alcoholic patients and have previously been ascribed as neuropathological in origin. However, biochemical lesions and/or the presence of a defined myopathy occur in alcoholics as a direct consequence of alcohol misuse. The myopathy occurs independently of peripheral neuropathy, malnutrition and overt liver disease. Chronic alcoholic myopathy is characterized by selective atrophy of Type II fibres and the entire muscle mass may be reduced by up to 30%. This myopathy is arguably the most prevalent skeletal muscle disorder in the Western Hemisphere and occurs in approximately 50% of alcohol misusers. Alcohol and acetaldehyde are potent inhibitors of muscle protein synthesis, and both contractile and non-contractile proteins are affected by acute and chronic alcohol dosage. Muscle RNA is also reduced by mechanisms involving increased RNase activities. In general, muscle protease activities are either reduced or unaltered, although markers of muscle membrane damage are increased which may be related to injury by reactive oxygen species. This supposition is supported by the observation that in the UK, alpha-tocopherol status is poor in myopathic alcoholics. Reduced alpha-tocopherol may pre-dispose the muscle to metabolic injury. However, experimental alpha-tocopherol supplementation is ineffective in preventing ethanol-induced lesions in muscle as defined by reduced rates of protein synthesis and in Spanish alcoholics with myopathy, there is no evidence of impaired alpha-tocopherol status. In conclusion, by a complex series of mechanisms, alcohol adversely affects skeletal muscle. In addition to the mechanical changes to muscle, there are important metabolic consequences, by virtue of the fact that skeletal muscle is 40% of body mass and an important contributor to whole-body protein turnover.

Novel Tocotrienols of Rice Bran Inhibit Atherosclerotic Lesions in C57BL/6 ApoE-Deficient Mice

We are studying novel tocotrienols, which have a number of activities that might interfere with the formation of atherosclerotic plaques, including hypocholesterolemic, antioxidant, anti-inflammatory and antiproliferation effects. This study compared the effects of alpha-tocopherol, the tocotrienol-rich fraction (TRF(25)) and didesmethyl tocotrienol (d-P(25)-T3) of rice bran on the pathogenesis of atherosclerotic lesions in C57BL/6 apolipoprotein (apo)E-deficient (-/-) mice. These mice are an excellent model because they become hyperlipidemic even when they consume a low fat diet and they develop complex atherosclerotic lesions similar to those of humans. These compounds were also tested in wild-type C57BL/6 apoE (+/+) and (+/-) mice fed low or high fat diets. When a high fat diet was supplemented with alpha-tocopherol, TRF(25) or d-P(25)-T3 and fed to mice (+/+) for 24 wk, atherosclerotic lesion size was reduced 23% (P = 0.33), 36% (P = 0.14) and 57% (P < 0.02), respectively, and in mice (+/-) fed for 18 wk, lesions were reduced by 19% (P = 0.15), 28% (P < 0.01) and 33% (P < 0.005), respectively, compared with mice fed a control diet. A low fat diet did not cause atherosclerotic lesions in these mice. The low fat diet supplemented with TRF(25) or d-P(25)-T3 fed to apoE-deficient (-/-) mice for 14 wk decreased atherosclerotic lesion size by 42% (P < 0.04) and 47% (P < 0.01), respectively, whereas alpha-tocopherol supplementation resulted in only an 11% (P = 0.62) reduction. These results demonstrate the superior efficacy of tocotrienols compared with alpha-tocopherol. Although tocotrienols decreased serum triglycerides, total and LDL cholesterol levels, the decreases in atherosclerotic lesions seem to be due to the other activities. Serum tocol concentrations in various groups are also described. This is the first report of a significant reduction in the atherosclerotic lesion size in all three genotypes of apoE mice fed a novel tocotrienol (d-P(25)-T3) of rice bran. Dietary tocotrienol supplements may provide a unique approach to promoting cardiovascular health.

Failure to demonstrate a major anti-inflammatory effect with alpha tocopherol supplementation (400 IU/day) in normal subjects

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Educational differences in lung cancer mortality in male smokers

To assess the extent of lung cancer mortality differentials by education while adjusting for exposure to tobacco smoke and asbestos based on survey questions. Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study of 50-69-year-old Finnish male smokers enrolled 1985-1988. These analyses are based on the placebo group and the alpha-tocopherol supplementation group, altogether 14 011 men, with full information on tobacco smoking. Mortality follow-up was to the end of April 1993 and it was based on the complete death certificate register of the Statistics Finland. Lung cancer mortality of basic-educated men was 32% (rate ratio [RR] = 1.32; 95% CI : 0.93-1.87) higher than that of better-educated men in the ATBC Study. The excess is practically unchanged when additional adjustment was made for age at initiation, duration of smoking, current smoking at baseline and at first follow-up, smoke inhalation, occupational exposure to asbestos and interactions between asbestos exposure and all smoking variables. This excess mortality was about 40% of the similar excess observed in the general population of men of similar age. Educational differences in lung cancer mortality in the total Finnish population are likely to be mainly caused by differences in exposure, particularly to active smoking. Further understanding of the determinants and consequences of socioeconomic differences in smoking behaviour are of major scientific and public health importance.

Progression after release of obstructive nephropathy

Progressive glomerular and tubulointerstitial fibrosis develop in 1-year-old rats even after relief (R) of unilateral ureteral obstruction (UUO) at 5 days of age. The present study investigated whether a progressive renal injury model of UUO could be achieved after reversal of UUO (RUUO) in adult instead of neonatal rats. The potential for alpha-tocopherol modulation of mRNA for the fibrogenic cytokine, transforming growth factor-beta1 (TGFbeta1), apoptosis (TUNEL assay), and the presence of the stress protein, heat shock protein-70 (HSP-70), was also studied in this post-obstructive model. Male Sprague-Dawley rats weighing 125-150 g were randomly assigned to groups of 4 animals each for durations of 7 or 14 days of alpha-tocopherol supplementation after RUUO. The groups included: (i) sham, regular chow; (ii) RUUO, regular chow; (iii) RUUO, contralateral nephrectomy (NX); and (iv) RUUO, NX plus alpha-tocopherol supplementation. We found a significant increase in the ratio of kidney weight/body weight in the RUUO+NX group at 14 days compared with the sham and RUUO groups. This rise in the RUUO+NX group was significantly reduced after 14 days of alpha-tocopherol administration. The elevated level of kidney TGFbeta1 mRNA in the RUUO+NX group was only partially reduced at 7 days. But at 14 days this became significantly reduced with the continued alpha-tocopherol treatment. The HSP-70 staining and the apoptosis of the kidney showed results parallel to those of TGFbeta mRNA at 14 days. To separate the effects of hypertrophy after unilateral NX from the RUUO studies, we carried out a second experiment in control animals subjected to NX, with and without alpha-tocopherol supplementation. Fourteen days after NX, the apoptosis and TGFbeta1 mRNA showed no significant differences from the control animals. Our data suggest that a model of progressive renal injury in RUUO can be established in adult rats. After contralateral NX, the progressive injury is evidenced by the increase in the ratio of kidney weight/total body weight, the apoptotic counts, as well as fibrogenic cytokine TGFbeta1 mRNA in the post-obstructed kidney. Finally, our data also support the concept that alpha-tocopherol is renal protective, as judged by TGFbeta1 mRNA, apoptosis, and HSP-70 staining, even in the progressive disease process of the post-obstructed model.

Is there a vitamin E paradox?

In addition to epidemiologic studies that suggest a benefit for high intakes of alpha-tocopherol, studies of supplementation in humans have clearly shown that alpha-tocopherol decreases lipid peroxidation, platelet aggregation, and functions as a potent anti-inflammatory agent. In the five large prospective clinical trials with alpha-tocopherol therapy, four have shown a beneficial effect on cardiovascular end-points (two studies on a primary end-point and two studies on other cardiovascular end-points). Thus, the totality of evidence based on the epidemiologic data, in-vitro studies and animal models, and the clinical trials appears to support a benefit for alpha-tocopherol supplementation in patients with pre-existing cardiovascular disease. However, definitive recommendations must await ongoing clinical trials.

Alpha-tocopherol and atherosclerosis.

Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. There is compelling evidence incriminating oxidative stress in the pathogenesis of the atherosclerotic lesion. Several lines of evidence suggest that antioxidants, especially alpha-tocopherol, have potential beneficial effects with regard to cardiovascular disease. In vitro, alpha-tocopherol has been shown to inhibit platelet adhesion and aggregation and smooth muscle cell proliferation, exert anti-inflammatory effects on monocytes, and improve endothelial function. Also, supplementation with alpha-tocopherol has been shown to decrease lipid peroxidation, platelet aggregation, and pro-inflammatory activity of monocytes. However, clinical trials with alpha-tocopherol supplementation to date have been equivocal. Thus, although mounting in vitro evidence and animal models provide a sound scientific basis for alpha-tocopherol supplementation, further clinical trials are required before a definitive recommendation can be made with respect to the primary and secondary prevention of heart disease.

Intake of flavonols and flavones and risk of coronary heart disease in male smokers.

Flavonols and flavones are antioxidant polyphenolic compounds found in tea, vegetables, fruits, and wine. In experimental studies they have been effective free radical scavengers, metal chelators, and antithrombotic agents. In the few epidemiologic studies of these agents, some have suggested an inverse association between intake of flavonols and flavones and the risk of cardiovascular disease. Our study population comprised 25,372 male smokers, 50-69 years of age, with no previous myocardial infarction. They were participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, which was a randomized, double-blind, placebo-controlled trial with daily supplementation of alpha-tocopherol (50 mg per day) and/or beta-carotene (20 mg per day). The men completed a validated dietary questionnaire at baseline. After 6.1 years of follow-up, there were 1,122 nonfatal myocardial infarctions and 815 coronary deaths. In the multivariate model, the relative risk of nonfatal myocardial infarction was 0.77 (95% confidence interval = 0.64-0.93) among men in the highest (median 18 mg per day) compared with the lowest (median 4 mg per day) quintile of flavonol and flavone intake. The respective relative risk for coronary death was 0.89 (95% confidence interval = 0.71-1.11). Thus, intake of flavonols and flavones was inversely associated with nonfatal myocardial infarction, whereas there was a weaker association with coronary death.

In Vivo Rates of Skeletal Muscle Protein Synthesis in Rats Are Decreased by Acute Ethanol Treatment but Are Not Ameliorated by Supplemental α-Tocopherol

Some studies have shown that reductions in tissue protein synthesis, under a variety of cytotoxic conditions, are ameliorated by alpha-tocopherol (ATC) supplementation. We have also shown evidence of increased oxidative stress and reduced protein synthesis rates in alcohol-exposed muscle. Serum levels of ATC fall and rates of muscle protein synthesis are reduced in patients with alcoholic myopathy. We therefore tested the hypothesis that treatment with ATC could ameliorate the ethanol-induced changes in muscle protein synthesis, a contributory event in the pathogenesis of alcoholic muscle disease. Studies were carried out on gastrocnemius (Type II fiber-predominant and usually considered representative of the musculature as a whole), soleus (Type I fiber-predominant) and plantaris (Type II fiber-predominant) muscles. For comparative purposes, we also investigated the liver. Young male Wistar rats (90 g body weight) were injected intraperitoneally (i.p.) daily with ATC (30 mg/kg body weight) in Intralipid fat emulsion (0.1 mL/100 g body, i.p.) for 5 d. Controls were similarly injected with the Intralipid vehicle alone. After ATC supplementation, rats were given ethanol (75 mmol/kg body weight, i.p., 2.5 h) or saline (0.15 mol/L NaCl, i. p.). Fractional rates of tissue protein synthesis (i.e., the percentage of the tissue protein pool renewed each day, k(s), %/d) and RNA activities [i.e., the amount of protein synthesis each day per unit RNA, k(RNA), mg protein/d/mg RNA)] were then measured. Supplementation increased ATC concentrations in plasma, gastrocnemius and liver. There was no effect of ATC supplementation alone on k(s) in any of the tissues. ATC supplementation in the absence of alcohol increased k(RNA) in the plantaris muscle. In nonsupplemented groups, acute ethanol treatment reduced skeletal muscle (soleus, plantaris and gastrocnemius) k(s). Hepatic k(s) was not altered by ethanol, although ATC concentrations in this tissue increased due to ethanol. However, none of the changes in muscle k(s) or k(RNA) due to ethanol were significantly affected by ATC supplementation. In conclusion, ATC supplementation does not appear beneficial in ameliorating acute alcohol toxicity in skeletal muscle as defined by reductions in protein synthesis.

Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients

Type 2 diabetic subjects have an increased propensity to premature atherosclerosis. Alpha tocopherol (AT), a potent antioxidant, has several anti-atherogenic effects. There is scanty data on AT supplementation on inflammation in Type 2 diabetic subjects. The aim of the study was to test the effect of RRR-AT supplementation (1200 IU/d) on plasma C-reactive protein (CRP) and interleukin-6 (IL-6) release from activated monocyte in Type 2 diabetic patients with and without macrovascular complications compared to matched controls. The volunteers comprised Type 2 diabetic subjects with macrovascular disease (DM2-MV, n = 23), Type 2 diabetic subjects without macrovascular complications (DM2, n = 24), and matched controls (C, n = 25). Plasma high sensitive CRP (Hs-CRP) and Monocyte IL-6 were assayed at baseline, following 3 months of supplementation and following a 2 month washout phase. DM2-MV subjects have elevated HsCRP and monocyte IL-6 compared to controls. AT supplementation significantly lowered levels of C-reactive protein and monocyte interleukin-6 in all three groups. In conclusion, AT therapy decreases inflammation in diabetic patients and controls and could be an adjunctive therapy in the prevention of atherosclerosis.

Alpha-tocopherol modulates lipoprotein cytotoxicity in obstructive nephropathy.

Oxidative stress in unilateral ureteral obstruction (UUO) contributes to the development of glomerular and tubulointerstitial lesions. The present study investigated whether oxidized low-density lipoprotein (oLDL) contributes to the pathogenesis of kidney injury in UUO, and whether alpha-tocopherol modulates such cytotoxicity and promotes repair. Male Sprague-Dawley rats weighing 100-125 g were assigned to three groups of 6 animals each: (1) sham, regular chow; (2) UUO, regular chow; and (3) UUO, alpha-tocopherol supplementation. We found a significant increase in the level of oxidative stress in the UUO group as measured by malondialdehyde (MDA) content in both plasma and kidneys. The LDL isolated from this group was cytotoxic to rat mesangial cells. The level of oxidation and cytotoxicity was significantly reduced when animals were treated with alpha-tocopherol. Plasma cholesterol concentration, kidney MDA, and transforming growth factor beta1 mRNA expression were all significantly increased in the UUO animals, and partially reduced in alpha-tocopherol-treated animals. Our data suggest that oxidative modification of LDL is associated with the renal injury in UUO. Taken together, our data support the concept that alpha-tocopherol can modulate LDL oxidation and its cytotoxic effects on rat mesangial cells in vitro.

The effect of beta-carotene and alpha-tocopherol supplementation on accelerated atherosclerosis in diabetic apoE deficient mice

The effect of beta-carotene and alpha-tocopherol supplementation on accelerated atherosclerosis in diabetic apoE deficient mice