Synaptic Membrane Synthesis in Rats Depends on Dietary Sufficiency of Vitamin C, Vitamin E, and Selenium: Relevance for Alzheimer’s Disease.

Cansev M, Turkyilmaz M, Sijben JWC, Sevinc C, Broersen LM, van Wijk N.

J Alzheimers Dis. 2017 Jun 9. doi: 10.3233/JAD-170081. [Epub ahead of print]

Abstract

Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors’ effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer’s disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants.

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Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E).

Bartolini D, Torquato P, Barola C, Russo A, Rychlicki C, Giusepponi D, Bellezza G, Sidoni A, Galarini R, Svegliati-Baroni G, Galli F.

J Nutr Biochem. 2017 Jun 7;47:120-131. doi: 10.1016/j.jnutbio.2017.06.003. [Epub ahead of print]

Abstract

This study aims to investigate in in vivo and in vitro models of nonalcoholic fatty liver disease (NAFLD) the enzymatic metabolism of α-tocopherol (vitamin E) and its relationship to vitamin E-responsive genes with key role in the lipid metabolism and detoxification of the liver. The experimental models included mice fed a high-fat diet combined or not with fructose (HFD+F) and HepG2 human hepatocarcinoma cells treated with the lipogenic agents palmitate, oleate or fructose. CYP4F2 protein, a cytochrome P-450 isoform with proposed α-tocopherol ω-hydroxylase activity, decreased in HFD and even more in HFD+F mice liver; this finding was associated with increased hepatic levels of α-tocopherol and decreased formation of the corresponding long-chain metabolites α-13-hydroxy and α-13-carboxy chromanols. A decreased expression was also observed for PPAR-γ and SREBP-1 proteins, two vitamin E-responsive genes with key role in lipid metabolism and CYP4F2 gene regulation. A transient activation of CYP4F2 gene followed by a repression response was observed in HepG2 cells during the exposure to increasing levels of the lipogenic and cytotoxic agent palmitic acid; such gene repression effect was further exacerbated by the co-treatment with oleic acid and α-tocopherol and was also observed for PPAR-γ and the SREBP isoforms 1 and 2. Such gene response was associated with increased uptake and ω-hydroxylation of α-tocopherol, which suggests a minor role of CYP4F2 in the enzymatic metabolism of vitamin E in HepG2 cells. In conclusion, the liver metabolism and gene response of α-tocopherol are impaired in experimental NAFLD.

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Enhanced antitumor activity of surface-modified iron oxide nanoparticles and an α-tocopherol derivative in a rat model of mammary gland carcinosarcoma.

Horák D, Pustovyy VI, Babinskyi AV, Palyvoda OM, Chekhun VF, Todor IN, Kuzmenko OI.

Int J Nanomedicine. 2017 Jun 6;12:4257-4268. doi: 10.2147/IJN.S137574. eCollection 2017.

Abstract

Maghemite (γ-Fe2O3) nanoparticles were obtained by coprecipitation of ferrous and ferric salts in an alkaline medium followed by oxidation; the nanoparticles were coated with poly(N,N-dimethylacrylamide) (PDMA) and characterized by transmission electron microscopy, attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering, thermogravimetric and elemental analyses, and magnetic measurements in terms of particle morphology, size, polydispersity, amount of coating, and magnetization, respectively. The effects of α-tocopherol (Toc) and its phenolic (Toc-6-OH) and acetate (Toc-6-Ac) derivatives on Fe2+ release from γ-Fe2O3@PDMA, as well as from γ-Fe2O3 and CuFe2O4 nanoparticles (controls), were examined in vitro using 1,10-phenanthroline. The presence of tocopherols enhanced spontaneous Fe2+ release from nanoparticles, with Toc-6-OH exhibiting more activity than neat Toc. All of the nanoparticles tested were found to initiate blood lipid oxidation in a concentration-dependent manner, as determined by analysis of 2-thiobarbituric acid reactive species. Wistar rats with Walker-256 carcinosarcoma (a model of mammary gland carcinosarcoma) received Toc-6-Ac, magnetic nanoparticles, or their combination per os, and the antitumor activity of each treatment was determined in vivo. γ-Fe2O3@PDMA nanoparticles exhibited increased antitumor activity compared to both commercial CuFe2O4 particles and the antitumor drug doxorubicin. Moreover, increased antitumor activity was observed after combined administration of γ-Fe2O3@PDMA nanoparticles and Toc-6-Ac; however, levels of bilirubin, aspartate aminotransferase, and white bloods normalized and did not differ from those of the intact controls. The antitumor activity of the γ-Fe2O3 nanoparticles strongly correlated with Fe2+ release from the nanoparticles but not with nanoparticle-initiated lipid peroxidation in vitro.

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Interaction Between the Haptoglobin Genotype and Vitamin E on Cardiovascular Disease in Diabetes

Hochberg I, Berinstein EM, Milman U, Shapira C, Levy AP

Curr Diab Rep. 2017 Jun;17(6):42. doi: 10.1007/s11892-017-0868-1.

Abstract

PURPOSE OF REVIEW:

Despite compelling evidence regarding the importance of oxidant stress in the development of vascular complications and observational studies suggesting that vitamin E may be protective from these complications, multiple clinical trials have failed to show benefit from vitamin E supplementation in the prevention of vascular complications in diabetes. One possible explanation for this failure of vitamin E may have been inappropriate patient selection. This review seeks to provide the clinical evidence and mechanistic basis for why a subset of individuals defined by their haptoglobin (Hp) genotype may derive cardiovascular protection by vitamin E supplementation.

RECENT FINDINGS:

Clinical trial data from the HOPE, ICARE, and WHS studies is presented showing a pharmacogenomic interaction between the Hp genotype and vitamin E on the development of CVD. Specifically, in individuals with diabetes and the Hp2-2 genotype, vitamin E has been shown to be associated with an approximately 35% reduction in CVD. Cardioprotection by vitamin E in individuals with the Hp2-2 genotype appears to be mediated in part by an improvement in HDL functionality as demonstrated in three independent trials in both type 1 diabetes and type 2 diabetes. Vitamin E may provide benefit in reducing CVD in Hp2-2 individuals with diabetes. However, in order for this pharmacogenomic algorithm to be accepted as a standard of care and used clinically, an additional large prospective study will need to be performed.

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Protective effects of Vitamin E on CCl4-induced testicular toxicity in male rats.

El-Faras AA, Sadek IA, Ali YE, Khalil M, Mussa EB.

Physiol Int. 2016 Jun 1;103(2):157-168. doi: 10.1556/036.103.2016.2.3.

Abstract

The increased generation of free radicals plays an important role in testicular damage. The present study aimed to investigate the adverse effects of carbon tetrachloride (CCl4) on the reproductive system of male rats as well as to examine whether Vitamin E (VE) is able to ameliorate these effects. The rats were equally divided into three groups: control, CCl4-treated, and CCl4 + VE-treated groups. After 4 weeks of treatment, the decrease in body and testes weights, sperm parameters, and the decrease in serum levels of testosterone, luteinizing hormone, and follicle-stimulating hormone of CCl4-treated rats were ameliorated by VE treatment. The co-administration of VE with CCl4significantly decreased the level of lipid peroxidation production (malondialdehyde) and increased the activity of anti-oxidant enzymes (superoxide dismutase and catalase) when compared with the CCl4 group. Moreover, VE prevented CCl4-induced severe testicular histopathological lesions and deformities in spermatogenesis. The results demonstrate that VE augments the anti-oxidants’ defense mechanism against CCl4-induced reproductive toxicity suggesting a therapeutic role in free radical-mediated infertility.

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Diacylglycerol Kinase alpha is Involved in the Vitamin E-Induced Amelioration of Diabetic Nephropathy in Mice.

Hayashi D, Yagi K, Song C, Ueda S, Yamanoue M, Topham M, Suzaki T, Saito N, Emoto N, Shirai Y.

Sci Rep. 2017 Jun 1;7(1):2597. doi: 10.1038/s41598-017-02354-3.

Abstract

Diabetic nephropathy (DN) is one of vascular complications of diabetes and is caused by abnormal protein kinase C activation as a result of increased diacylglycerol (DG) production in diabetic hyperglycaemia. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. Therefore, it is expected that the activation of DGK would ameliorate DN. Indeed, it has been reported that vitamin E (VtE) ameliorates DN in rat by activating DGK, and we recently reported that VtE specifically activates DGKα isoform in vitro. However, whether DGKα is involved in the VtE-induced amelioration of DN in vivo remains unknown. Therefore, we investigated the VtE-induced amelioration of DN in wild-type (DGKα+/+) and DGKα-deficient (DGKα-/-) mice in which diabetes was induced by streptozocin. Several symptoms of DN were ameliorated by VtE treatment in the DGKα+/+ mice but not in the DGKα-/- mice. Moreover, transmission electron microscopy of glomeruli and immunofluorescent staining of glomerular epithelial cells (podocytes) indicated that VtE ameliorates podocyte pathology and prevents podocyte loss in the DGKα+/+ mice but not in the DGKα-/- mice. We showed that VtE can ameliorate DN in mice and that DGKα is involved in the VtE-induced amelioration of DN in vivo, suggesting that DGKα is an attractive therapeutic target for DN.

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Synergistic protective effect of FTY720 and vitamin E against simulated cerebral ischemia in vitro.

Pang X, Hou X

Mol Med Rep. 2017 May 11. doi: 10.3892/mmr.2017.6572. [Epub ahead of print]

Abstract

The purpose of the present study was to explore the combination effect of FTY720 and vitamin E on cerebral ischemia. Astrocytes were isolated from newborn Sprague‑Dawley rats and were subjected to FTY720, vitamin E, or combination of the two. The astrocyte cultures were then exposed to oxygen‑glucose deprivation (OGD) to simulate an ischemic model in vitro. Cell viability, lactate dehydrogenase (LDH) leakage and cell apoptosis were detected following 12 h of exposure to OGD. In addition, the levels of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6, IL‑1β, total antioxidant capacity, intercellular adhesion molecule (ICAM)‑1, vascular cell adhesion molecule (VCAM)‑1, chemokine (C‑X‑C motif) ligand (CXCL)‑10, heme oxygenase (HO)‑1 and superoxide dismutase (SOD)‑1 were measured. Pre‑treatment with FTY720 or vitamin E significantly elevated the cell viability and decreased LDH release and number of apoptotic cells. Combination treatment with FTY720 and vitamin E demonstrated a synergistic protective effect on OGD‑induced cell viability, toxicity and apoptosis. Pre‑treatment with FTY720 markedly reduced the release of IL‑1β, TNF‑α, IL‑6, ICAM‑1, VCAM‑1 and CXCL‑10, and pre‑treatment with vitamin E increased the levels of antioxidant, HO‑1 and SOD‑1. However, pre‑treatment with FTY720 combined with vitamin E revealed a synergistic effect. Pre‑treatment with FTY720 combined with vitamin E exerts synergistic neuroprotective effects in the simulated cerebral ischemia in vitro.

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δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis.

Husain K, Centeno BA, Coppola D, Trevino J, Sebti SM, Malafa MP

Oncotarget. 2017 May 9;8(19):31554-31567. doi: 10.18632/oncotarget.15767.

Abstract

The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells. VEDT inhibited the viability, survival, self-renewal, and expression of Oct4 and Sox2 transcription factors in 3 models of PDAC stem-like cells. In addition, VEDT inhibited the migration, invasion, and several biomarkers of epithelial-to-mesenchymal transition and angiogenesis in PDAC cells and tumors. These processes are critical for tumor metastases. Furthermore, in the L3.6pl orthotopic model of PDAC metastases, VEDT significantly inhibited growth and metastases of these cells. Finally, in an orthotopic xenograft model of human PDAC stem-like cells, we showed that VEDT significantly retarded the growth and metastases of gemcitabine-resistant PDAC human stem-like cells. Because VEDT has been shown to be safe and to reach bioactive levels in humans, this work supports investigating VEDT for chemoprevention of PDAC metastases.

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Alterations of plasma concentrations of lipophilic antioxidants are associated with Guillain-Barre syndrome.

Tang HY, Ho HY, Chiu DT, Huang CY, Cheng ML, Chen CM

Clin Chim Acta. 2017 May 2;470:75-80. doi: 10.1016/j.cca.2017.05.001. [Epub ahead of print]

Abstract

BACKGROUND:

Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy resulting in demyelination in peripheral nervous system. Myelin enriched in lipids is easily oxidized by reactive oxygen species during inflammation. Oxidative stress and lipophilic anti-oxidative capacities in GBS patients have not been fully explored. To evaluate the redox status of GBS patients, we measured malondialdehyde (MDA), myeloperoxidase (MPO), lipophilic antioxidants, and tocopherols concentrations in plasma from GBS patients and age-matched healthy controls.

RESULTS:

Concentrations of γ-tocopherol and δ-tocopherol decreased significantly, and α-carotene significantly increased in GBS patients compared to healthy controls. However, no significant changes in MDA and MPO concentrations were detected. In GBS patients, the γ-tocopherol concentration correlated positively with concentrations of δ-tocopherol, α-tocopherol, lutein, Q10, and γ-CEHC, respectively. Similarly, the δ-tocopherol concentration correlated positively with γ-tocopherol, α-tocopherol, lutein, Q10, δ-CEHC, and γ-CEHC concentrations, respectively. The receiver operating characteristics curve analysis showed that γ-tocopherol may serve as a good predictor for GBS.

CONCLUSIONS:

Diminished lipophilic antioxidant defense, mainly γ-tocopherol and δ-tocopherol, in GBS patients accounting for their lowered resistance to reactive oxygen species is probably associated with pathogenesis of GBS, and potentially useful for the development of therapeutic strategies.

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Synergistic Impact of d-δ-Tocotrienol and Geranylgeraniol on the Growth and HMG CoA Reductase of Human DU145 Prostate Carcinoma Cells.

Yeganehjoo H, DeBose-Boyd R, McFarlin BK, Mo H

Nutr Cancer. 2017 May-Jun;69(4):682-691. doi: 10.1080/01635581.2017.1299876. Epub 2017 Mar 31.

Abstract

The growth-suppressive effect of d-δ-tocotrienol and geranylgeraniol is at least partially attributed to their impact on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the posttranslational modification of growth-related proteins including RAS. We hypothesize that these agents synergistically impact cell growth based on their complementary mechanisms of action with HMG CoA reductase. d-δ-tocotrienol (0-40 µmol/L; half maximal inhibitory concentration [IC50] = 15 µmol/L) and geranylgeraniol (0-100 µmol/L; IC50 = 60 µmol/L) each induced concentration-dependent suppression of the growth of human DU145 prostate carcinoma cells. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values ranging 0.67-0.75. While 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol individually had no impact on cell cycle distribution in DU145 cells, a blend of the agents induced cell cycle arrest at the G1 phase. The synergistic downregulation of the expression of HMG CoA reductase by 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol was accompanied by a reduction in membrane K-RAS protein. Our finding supports the cancer chemopreventive action of plant-based diets and their isoprenoid constituents. Properly formulated isoprenoids and derivatives may provide novel approaches in prostate cancer prevention and therapy.

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