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Alpha-Tocopherol
The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Angelo Azzi – 1st expert on this subject based on the ideXlab platform
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The role of Alpha-Tocopherol in preventing disease.
European journal of nutrition, 2020Co-Authors: Angelo AzziAbstract:A role of oxidative stress in atherosclerosis lies on experimental results carried out in vitro and in animal models. In humans, the supplementation with the antioxidant vitamin E has given in some cases supportive results and in others no effects. From in vitro studies, a large amount of data has shown that Alpha-Tocopherol (the major component of vitamin E) regulates key events in the cellular pathogenesis of atherosclerosis. We first described the inhibition of protein kinase C (PKC) activity by Alpha-Tocopherol to be at the basis of the vascular smooth muscle cell growth inhibition by this compound. Subsequently, PKC was recognized to be the target of Alpha-Tocopherol in different cell types, including monocytes, macrophages, neutrophils, fibroblasts and mesangial cells. Inhibiting the activity of protein kinase C by Alpha-Tocopherol results in different events in different cell types: inhibition of platelet aggregation, of nitric oxide production in endothelial cells, of superoxide production in neutrophils and macrophages as well as impairment of smooth muscle cell proliferation. Adhesion molecule expression and inflammatory cell cytokine production are also influenced by Alpha-Tocopherol. Scavenger receptors, particularly important in the formation of atherosclerotic foam cells, are also modulated by Alpha-Tocopherol. The oxidized LDL scavenger receptors SR-A and CD36 are down regulated at the transcriptional level by Alpha-Tocopherol. The relevance of CD36 expression in the onset of atherosclerosis has been indicated by the protection against atherosclerosis by CD36 knockout mice. In conclusion, the effect of Alpha-Tocopherol against atherosclerosis is not due only to the prevention of LDL oxidation but also to the down regulation of the scavenger receptor CD36 and to the inhibition of PKC activity.
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Regulation of gene expression by Alpha-Tocopherol
Biol Chem, 2004Co-Authors: Angelo Azzi, René Gysin, P Kempna, Adrian Munteanu, L Villacorta, T Visarius, J M ZinggAbstract:Several genes are regulated by tocopherols which can be categorized, based on their function, into five groups: genes that are involved in the uptake and degradation of tocopherols (Group 1) include Alpha-Tocopherol transfer protein (alpha-TTP) and cytochrome P450 (CYP3A); genes that are associated with lipid uptake and atherosclerosis (Group 2) include CD36, SR-BI and SR-AI/II. Genes that modulate the expression of extracellular proteins (Group 3) include tropomyosin, collagen(alpha1), MMP-1, MMP-19 and connective tissue growth factor (CTGF). Genes that are related to inflammation, cell adhesion and platelet aggregation (Group 4) include E-selectin, ICAM-1, integrins, glycoprotein IIb, II-2, IL-4 and IL-beta. Group 5 comprises genes coding for proteins involved in cell signaling and cell cycle regulation and consists of PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27 and CD95 (Apo-1/Fas ligand). The expression of P27, Bcl2, alpha-TTP, CYP3A, tropomyosin, II-2, PPAR-gamma, and CTGF appears to be up-regulated by one or more tocopherols whereas all other listed genes are down-regulated. Several mechanisms may underlie tocopherol-dependent gene regulation. In some cases protein kinase C has been implicated due to its deactivation by Alpha-Tocopherol and its participation in the regulation of a number of transcription factors (NF-kappaB, AP-1). In other cases a direct involvement of PXR/RXR has been documented. The antioxidant responsive element (ARE) appears in some cases to be involved as well as the transforming growth factor beta responsive element (TGF-beta-RE). This heterogeneity of mediators of tocopherol action suggests the need of a common element that could be a receptor or a co-receptor, able to interact with tocopherol and with transcription factors directed toward specific regions of promoter sequences of sensitive genes. Here we review recent results of the search for molecular mechanisms underpinning the central signaling mechanism.
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Non-antioxidant molecular functions of Alpha-Tocopherol (vitamin E).
FEBS letters, 2002Co-Authors: Angelo Azzi, Roberta Ricciarelli, J M ZinggAbstract:Alpha-Tocopherol (the major vitamin E component) regulates key cellular events by mechanisms unrelated with its antioxidant function. Inhibition of protein kinase C (PKC) activity and vascular smooth muscle cell growth by Alpha-Tocopherol was first described by our group. Later, Alpha-Tocopherol was shown to inhibit PKC in various cell types with consequent inhibition of aggregation in platelets, of nitric oxide production in endothelial cells and of superoxide production in neutrophils and macrophages. Alpha-Tocopherol diminishes adhesion molecule, collagenase and scavenger receptor (SR-A and CD36) expression and increases connective tissue growth factor expression.
J M Zingg – 2nd expert on this subject based on the ideXlab platform
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Regulation of gene expression by Alpha-Tocopherol
Biol Chem, 2004Co-Authors: Angelo Azzi, René Gysin, P Kempna, Adrian Munteanu, L Villacorta, T Visarius, J M ZinggAbstract:Several genes are regulated by tocopherols which can be categorized, based on their function, into five groups: genes that are involved in the uptake and degradation of tocopherols (Group 1) include Alpha-Tocopherol transfer protein (alpha-TTP) and cytochrome P450 (CYP3A); genes that are associated with lipid uptake and atherosclerosis (Group 2) include CD36, SR-BI and SR-AI/II. Genes that modulate the expression of extracellular proteins (Group 3) include tropomyosin, collagen(alpha1), MMP-1, MMP-19 and connective tissue growth factor (CTGF). Genes that are related to inflammation, cell adhesion and platelet aggregation (Group 4) include E-selectin, ICAM-1, integrins, glycoprotein IIb, II-2, IL-4 and IL-beta. Group 5 comprises genes coding for proteins involved in cell signaling and cell cycle regulation and consists of PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27 and CD95 (Apo-1/Fas ligand). The expression of P27, Bcl2, alpha-TTP, CYP3A, tropomyosin, II-2, PPAR-gamma, and CTGF appears to be up-regulated by one or more tocopherols whereas all other listed genes are down-regulated. Several mechanisms may underlie tocopherol-dependent gene regulation. In some cases protein kinase C has been implicated due to its deactivation by Alpha-Tocopherol and its participation in the regulation of a number of transcription factors (NF-kappaB, AP-1). In other cases a direct involvement of PXR/RXR has been documented. The antioxidant responsive element (ARE) appears in some cases to be involved as well as the transforming growth factor beta responsive element (TGF-beta-RE). This heterogeneity of mediators of tocopherol action suggests the need of a common element that could be a receptor or a co-receptor, able to interact with tocopherol and with transcription factors directed toward specific regions of promoter sequences of sensitive genes. Here we review recent results of the search for molecular mechanisms underpinning the central signaling mechanism.
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Non-antioxidant molecular functions of Alpha-Tocopherol (vitamin E).
FEBS letters, 2002Co-Authors: Angelo Azzi, Roberta Ricciarelli, J M ZinggAbstract:Alpha-Tocopherol (the major vitamin E component) regulates key cellular events by mechanisms unrelated with its antioxidant function. Inhibition of protein kinase C (PKC) activity and vascular smooth muscle cell growth by Alpha-Tocopherol was first described by our group. Later, Alpha-Tocopherol was shown to inhibit PKC in various cell types with consequent inhibition of aggregation in platelets, of nitric oxide production in endothelial cells and of superoxide production in neutrophils and macrophages. Alpha-Tocopherol diminishes adhesion molecule, collagenase and scavenger receptor (SR-A and CD36) expression and increases connective tissue growth factor expression.
A Tasinato – 3rd expert on this subject based on the ideXlab platform
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RRR-Alpha-Tocopherol regulation of gene transcription in response to the cell oxidant status.
Zeitschrift fur Ernahrungswissenschaft, 1998Co-Authors: A Azzi, D Boscoboinik, A Fazzio, D Marilley, P Maroni, N K Ozer, S Spycher, A TasinatoAbstract:RRR-Alpha-Tocopherol, but not RRR-beta-tocopherol, negative regulates proliferation of vascular smooth muscle cells at physiological concentrations. At the same concentrations RRR-Alpha-Tocopherol inhibits protein kinase C activity, whereas RRR-beta-tocopherol is ineffective. Furthermore, RRR-beta-tocopherol prevents the inhibition of cell growth and of protein kinase C activity caused by RRR-Alpha-Tocopherol. The negative regulation by RRR-Alpha-Tocopherol of protein kinase C activity appears to be the cause of smooth muscle cell growth inhibition. RRR-Alpha-Tocopherol does not act by binding to protein kinase C directly but presumably by preventing protein kinase C activation. A second RRR-Alpha-Tocopherol effect has been found at the level of AP 1, the latter becoming activated by RRR-Alpha-Tocopherol under condition of protein kinase C inhibition or down regulation. AP-1 inhibition by RRR-Alpha-Tocopherol is seen, however, under condition of protein kinase C stimulation. Compositional changes of AP-1 have been found to be at the basis of the RRR-Alpha-Tocopherol effects. RRR-beta-tocopherol, provided with similar antioxidant properties, not only it does not affect AP 1 but it prevents the effects of RRR-Alpha-Tocopherol. Moreover, it has been observed that RRR-Alpha-Tocopherol is able to affect TRE regulated gene transcription. It is concluded that RRR-Alpha-Tocopherol acts specifically in vascular smooth muscle cells, by controlling a signal transduction pathway leading to cell proliferation by a non-antioxidant mechanism.
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Signalling functions of Alpha-Tocopherol in smooth muscle cells.
International Journal for Vitamin and Nutrition Research, 1997Co-Authors: Angelo Azzi, A Tasinato, Daniel Boscoboinik, Sophie Clément, Nesrin Kartal Ozer, Roberta Ricciarelli, Achim Stocker, Onder SirikciAbstract:Alpha-Tocopherol but not beta-tocopherol, activates protein phosphatase 2A, decreases protein kinase C activity and attenuates smooth muscle cell proliferation at physiological concentrations. beta-Tocopherol prevents the effects of Alpha-Tocopherol. Inhibition of protein kinase C alpha, but not of the other isoforms, by the inhibitor Go6976 prevents the effect of Alpha-Tocopherol. Protein kinase C alpha, immunoprecipitated from Alpha-Tocopherol treated cells, is less phosphorylated and inactive. It is proposed that the specific activation of protein phosphatase 2A by Alpha-Tocopherol results in dephosphorylation and inactivation of protein kinase C alpha. Finally, this cascade of events leads to smooth muscle cell proliferation inhibition.
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Alpha-Tocopherol as a modulator of smooth muscle cell proliferation.
Prostaglandins leukotrienes and essential fatty acids, 1997Co-Authors: A Azzi, D Boscoboinik, D Marilley, N K Ozer, Sophie Clément, Roberta Ricciarelli, A TasinatoAbstract:The effects of Alpha-Tocopherol and beta-tocopherol have been studied in rat and human aortic smooth muscle cells. Alpha-Tocopherol, but not beta-tocopherol, inhibited smooth muscle cell proliferation and protein kinase C in a dose-dependent manner, at concentrations ranging from 10 to 50 microM. Beta-tocopherol added simultaneously with Alpha-Tocopherol prevented both proliferation and protein kinase C inhibition. Protein kinase C inhibition was cell cycle-dependent and it was prevented by okadaic acid, a protein phosphatase inhibitor. Protein kinase C activity measured from aortas of cholesterol-fed rabbits was also inhibited by Alpha-Tocopherol. By using protein kinase C (PKC) isoform-specific inhibitors and immunoprecipitation reactions it was found that PKC-alpha was selectively inhibited by Alpha-Tocopherol. Further, an activation of protein phosphatase 2A by Alpha-Tocopherol was found, which caused PKC-alpha dephosphorylation and inhibition. Ultimately, this cascade of events at the level of cell signal transduction leads to the inhibition of smooth muscle cell proliferation.