Vitamin E and atherosclerosis

Vitamin E was advocated as an effective treatment for heart disease by Dr. Even Shute of London, Ontario more than 50 years ago. His pioneering claims, which were unacceptable to the medical community at large, have been confirmed by recent findings from epidemiologic studies and clinical trials. This review integrates our current knowledge of atherogenesis with the biological functions of vitamin E. The response-to-injury hypothesis explains atherosclerosis as a chronic inflammatory response to injury of the endothelium, which leads to complex cellular and molecular interactions among cells derived from the endothelium, smooth muscle and several blood cell components. Inflammatory and other stimuli trigger an overproduction of free radicals, which promote peroxidation of lipids in LDL trapped in the subendothelial space. Products of LDL oxidation are bioactive, and they induce endothelial expression and secretion of cytokines, growth factors and several cell surface adhesion molecules. The last-mentioned are capable of recruiting circulating monocytes and T lymphocytes into the intima where monocytes are differentiated into macrophages, the precursor of foam cells. In response to the growth factors and cytokines, smooth muscle cells proliferate in the intima, resulting in the narrowing of the lumen. Oxidized LDL can also inhibit endothelial production of prostacyclin and nitric oxide, two potent autacoids that are vasodilators and inhibitors of platelet aggregation. Evidence is presented that vitamin E is protective against the development of atherosclerosis. Vitamin E enrichment has been shown to retard LDL oxidation, inhibit the proliferation of smooth muscle cells, inhibit platelet adhesion and aggregation, inhibit the expression and function of adhesion molecules, attenuate the synthesis of leukotrienes and potentiate the release of prostacyclin through up-regulating the expression of cytosolic phospholipase A2 and cyclooxygenase. Collectively, these biological functions of vitamin E may account for its protection against the development of atherosclerosis.     

Vitamin E and selenium deficiency induces expression of the ubiquinone-dependent antioxidant system at the plasma membrane

We have used a model of dietary deficiency that leads to a chronic oxidative stress to evaluate responses that are adaptations invoked to boost cellular defense systems. Long-Evans hooded rats were fed with a diet lacking vitamin E (E) and selenium (Se) for 7 wk from weaning leading to animals deficient in both nutrients (-E -Se). In the absence of an electron donor, liver plasma membranes from these rats were more sensitive to lipid peroxidation, although they contained 40% greater amounts of ubiquinone than the plasma membranes from rats consuming diets with sufficient vitamin E and Se (+E +Se). The incubation of plasma membranes with NAD(P)H resulted in protection against peroxidation, and this effect was more pronounced in -E -Se membranes. Deficiency was accompanied by a twofold increase in redox activities associated with trans plasma membrane electron transport such as ubiquinone reductase and ascorbate free radical reductase. Staining with a polyclonal antibody against pig liver cytochrome b5 reductase, which acts as one ubiquinone reductase in the plasma membrane, showed an increased expression of the enzyme in membranes from -E -Se rats. Little DT-diaphorase activity was measured in +E +Se plasma membranes, but this activity was dramatically increased in -E -Se plasma membranes. No such increase was found in liver cytosols, which contained elevated activity of calcium-independent phospholipase A2. Thus, ubiquinone-dependent antioxidant protection in +E +Se plasma membranes is based primarily on NADH-cytochrome b5 reductase, whereas additional protection needed in -E -Se plasma membranes is supported by the increase of ubiquinone levels, increased expression of the cytochrome b5 reductase, and translocation of soluble DT-diaphorase to the plasma membrane. Our results indicate that, in the absence of vitamin E and Se, enhancement of ubiquinone-dependent reductase systems can fulfill the membrane antioxidant protection.     

Vitamin D receptor expression as a predictive marker of biological behavior in human colorectal cancer

To date, none of the potential biological markers in colorectal cancer attempts to link the epidemiological data with the molecular biology of the disease. In an attempt to link dietary and epidemiological factors and to obtain a better understanding of the molecular biology of colorectal cancer, we measured vitamin D receptor (VDR) expression in 75 human colorectal cancers as a potential predictive marker of the biological behavior of the disease. Our results showed that a high level of VDR expression was associated with a favorable prognosis. The results of the studies reinforce the potential role that VDR may play in the development of the pathogenesis of colorectal cancer. Larger studies looking exclusively at stage I and stage II disease will hopefully lead to the development of a sensitive hormonal marker that can be used to predict the biological behavior of colorectal cancer, identifying at-risk patients in need of adjuvant treatment.     

Use of topiramate, a new anti-epileptic as a mood stabilizer

2-Hydroxycarbazole was shown to induce Ca2+ release from skeletal muscle and cardiac muscle sarcoplasmic reticulum at concentrations between 100-500 microM. This release was blocked by both 1 mM tetracaine and 30 microM ruthenium red which inhibit the ryanodine receptor or by pre-treatment with 10 mM caffeine which depletes the ryanodine receptor-containing Ca2+ stores. This, in addition to the fact that 2-hydroxycarbazole has little effect on Ca2+ ATPase activity, indicates that it activates Ca2+ release through the ryanodine receptor. The apparent EC50 value for release from both skeletal muscle and cardiac muscle sarcoplasmic reticulum was approximately 200 microM and maximal release occurred at 400-500 microM, making it approximately 20 times more potent than caffeine. The dose-dependency in the extent of Ca2+ release induced by 2-hydroxycarbazole was also apparently highly cooperative for both preparations. That 2-hydroxycarbazole was able to mobilize Ca2+ from non-muscle cell microsomes and in intact TM4 cells (which contain ryanodine receptors), makes this compound a more potent and commercially available alternative to caffeine in studying the role of this intracellular Ca2+ channel in a variety of systems.     

Action of nitric oxide as an antioxidant against oxidation of soybean phosphatidylcholine liposomal membranes

Giant liposomes were made from a mixture of asolectin phospholipid vesicles and presynaptic plasma membranes isolated from Torpedo cholinergic nerve endings. Acetylcholine filled giant liposomes were able to release neurotransmitter upon stimulation by the Ca2+ ionophore A23187 and Ca2+. Botulinum neurotoxin type A inhibited this Ca(2+)-dependent acetylcholine transport. Additionally, Botulinum toxin type A decreased membrane fluidity of liposomes. These results suggest that Botulinum toxin can interact directly with components of the presynaptic plasma membrane and inhibit acetylcholine translocation. Furthermore, since the reconstituted liposomes do not have synaptic vesicle components, the observed effects may account for the action of Botulinum toxin on the non-quantal release of acetylcholine from motor nerve terminals.     

Personality trait structure as a human universal.

Patterns of covariation among personality traits in English-speaking populations can be summarized by the five-factor model (FFM). To assess the cross-cultural generalizability of the FFM, data from studies using 6 translations of the Revised NEO Personality Inventory (P. T. Costa & R. R. McCrae, 1992) were compared with the American factor structure. German, Portuguese, Hebrew, Chinese, Korean, and Japanese samples (N?=?7,134) showed similar structures after varimax rotation of 5 factors. When targeted rotations were used, the American factor structure was closely reproduced, even at the level of secondary loadings. Because the samples studied represented highly diverse cultures with languages from 5 distinct language families, these data strongly suggest that personality trait structure is universal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"Vitamin CE," a novel prodrug form of vitamin E

Reaction of 5a-bromo-alpha-tocopherol with ascorbic acid produces 5a-tocopheryl ascorbate which is designated "vitamin CE." This novel tocopherol derivative represents an interesting prodrug form of alpha-tocopherol (vitamin E) that is stable under acidic conditions, but regenerates finely dispersed vitamin E in basic media. The reaction mechanism of the base-induced decomposition of vitamin CE involves elimination of ascorbate and production of an ortho-quinone methide intermediate that oxidizes ascorbate, and is reduced to vitamin E. Kinetic experiments showed reaction to proceed in the pH range of 8 to 11 under physiological conditions. Tissue culture measurements demonstrated that vitamin E generated from the novel derivative is absorbed at much higher rates than conventional preparations and can even be absorbed under simulated conditions of malabsorption where there is no uptake of conventional vitamin E medications.     

Vitamin C attenuates nitrate tolerance independently of its antioxidant effect

In LLC-PK1 kidney epithelial cells, a 5-h pretreatment with glyceryl trinitrate (GTN) resulted in substantial desensitization of the intracellular cyclic GMP response to a subsequent 10-min challenge with GTN (1 microM). GTN-tolerant cells were fully sensitive to the spontaneous nitric oxide (NO) donor spermine NONOate, which does not require enzymatic bioactivation. Cyclic GMP stimulation by GTN was up to 3.1-fold higher when vitamin C (1-10 mM) was present during the pretreatment period. In contrast, other oxygen radical scavengers such as tiron or dimethylsulfoxide and the NO scavenger PTIO left tolerance induction unaltered. Together, our results suggest that reactive oxygen species or NO do not contribute to the development of nitrate tolerance. Tolerance reduction by vitamin C may be due to a stabilizing effect on enzymes involved in the bioconversion of GTN to NO.     

Novel chelate-induced magnetic alignment of biological membranes

A phospholipid chelate complexed with ytterbium (DMPE-DTPA:Yb3+) is shown to be readily incorporated into a model membrane system, which may then be aligned in a magnetic field such that the average bilayer normal lies along the field. This so-called positively ordered smectic phase, whose lipids consist of less than 1% DMPE-DTPA:Yb3+, is ideally suited to structural studies of membrane proteins by solid-state NMR, low-angle diffraction, and spectroscopic techniques that require oriented samples. The chelate, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine diethylenetriaminepentaacetic acid, which strongly binds the lanthanide ions and serves to orient the membrane in a magnetic field, prevents direct lanthanide-protein interactions and significantly reduces paramagnetic shifts and line broadening. Similar low-spin lanthanide chelates may have applications in field-ordered solution NMR studies of water-soluble proteins and in the design of new magnetically aligned liquid crystalline phases.     

Pain as a biological phenomenon of consciousness

Pain has not to be considered a false step of nature. On the contrary, it is an extremely effective warning mechanism through which the individual becomes aware of a danger to its own physical integrity from inside the body or from the environment. Pain therefore belongs to the biological devices for evading bodily danger. The conscious experience of pain is the most sophisticated stage of evolution of warning systems, whose simplest form is represented by an unicellular organism which moves away if it anticipates danger from an environmental state. Similar to all qualia, conscious experience of pain cannot be fully explained in terms of neurophysiological events. Conscious pain is a complex perceptual and affective experience influenced not by the amount of the bodily lesion alone, but also by the whole personality of the sufferer. This often makes surgical, medical and psychological treatment of pain difficult and disappointing.     

Vitamin B6 deficiency affects antioxidant defences in rat liver and heart

We have evaluated the effects of a diet containing normal amounts of lipids and a marginal content of vitamin B6 on lipid peroxidation. Pyridoxal phosphate concentrations of plasma and liver indicated that an initial deficiency state was reached. Vitamin B6 deficiency led to peroxidative stress: TBARS production was higher in the liver (+18.6%) and even more in the heart (+61%) of deficient rats as compared with controls. Furthermore, significant stimulation of glutathione-dependent enzymes occurred in both heart and liver of deficient rats: glutathione peroxidase activity increased in heart (+144%) and liver (+505%); glutathione reductase increased in heart (+54.9%) and liver (+15.5%). No difference in the total glutathione content of the organs of the two groups was observed. The reduced glutathione/oxidized glutathione ratio was significantly lower in deficient rats. Although the activity of glutathione-dependent enzymes was significantly greater in deficient rats than in controls, this stimulation was only partially able to counteract the peroxidative damage due to vitamin B6 deficiency.     

Vitamin E in therapy of rheumatic diseases]

Methyl t-butyl ether (MTBE) and ethyl t-butyl ether (ETBE) are commonly used in unleaded gasoline to increase the oxygen content of fuel and to reduce carbon monoxide emissions from motor vehicles. This study was undertaken to investigate: (1) the effect of administration to rats of ETBE and its metabolite, t-butanol, on the induction and/or inhibition of hepatic P450 isoenzymes; (2) the oxidative metabolism of MTBE and ETBE by liver microsomes from rats pretreated with selected P450 inducers and purified rat P450(s), (2B1, 2E1, 2C11, 1A1). ETBE administration by gavage at a dose of 2 ml/kg for 2 days induced hepatic microsomal P4502E1-linked p-nitrophenol hydroxylase and the P4502B1/2-associated PROD and 16beta-testosterone hydroxylase, verified by immunoblot experiments. t-Butanol treatments at doses of 200 and 400 mg/kg i.p. for 4 days did not alter any liver microsomal monoxygenases. Both MTBE and ETBE were substrates for rat liver microsomes and were oxidatively dealkylated to yield formaldehyde and acetaldehyde, respectively. The dealkylation rates of both MTBE and ETBE were increased c. fourfold in phenobarbital (PB)-treated rats. In rats pretreated with pyrazole, an inducer of 2E1, only the demethylation of MTBE was increased (c. twofold). When the oxidations of MTBE and ETBE were investigated with purified P450(s) in a reconstituted system, it was found that P4502B1 had the highest activities towards both solvents, whereas 1A1 and 2C1 were only slightly active; P4502E1 had an appreciable activity on MTBE but not against ETBE. Metyrapone, a potent inhibitor of P450 2B, consistently inhibited both the MTBE and ETBE dealkylations in microsomes from PB-treated rats. Furthermore, 4-methylpyrazole (a probe inhibitor of 2E1) and anti-P4502E1 IgG showed inhibition, though modest, only on MTBE demethylation, but not on ETBE deethylation. Inhibition experiments have also suggested that rat 2A1 may exert an important role in MTBE and ETBE oxidation. Taken together, these results indicate that 2B1, when expressed, is the major enzyme involved in the oxidation of these two solvents and that 2E1 may have a role, although minor, in MTBE demethylation. The implications of these data for MTBE and ETBE toxicity remain to be established.