Molecular Understanding of the Cardiomodulation in Myocardial Infarction and the Mechanism of Vitamin E Protections

Zarkasi KA, Jen-Kit T, Jubri Z

Mini Rev Med Chem. 2019;19(17):1407-1426. doi: 10.2174/1389557519666190130164334.


Myocardial infarction is a major cause of deaths globally. Modulation of several molecular mechanisms occurs during the initial stages of myocardial ischemia prior to permanent cardiac tissue damage, which involves both pathogenic as well as survival pathways in the cardiomyocyte. Currently, there is increasing evidence regarding the cardioprotective role of vitamin E in alleviating the disease. This fat-soluble vitamin does not only act as a powerful antioxidant; but it also has the ability to regulate several intracellular signalling pathways including HIF-1, PPAR-γ, Nrf-2, and NF-κB that influence the expression of a number of genes and their protein products. Essentially, it inhibits the molecular progression of tissue damage and preserves myocardial tissue viability. This review aims to summarize the molecular understanding of the cardiomodulation in myocardial infarction as well as the mechanism of vitamin E protection.

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Neuroprotective and Anti-Obesity Effects of Tocotrienols

Fukui K.

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S185-S187. doi: 10.3177/jnsv.65.S185.


Vitamin E is a natural lipophilic vitamin, and the most famous function of vitamin E is an antioxidant activity. Because we have α-tocopherol transfer protein, many vitamin E-related reports are about α-tocopherol. Recently, other vitamin E isoforms, tocotrienols are focusing. Because tocotrienols have unique biological functions such as induction of apoptosis, neuroprotective and anti-obesity effects. Tocotrienols contain in annatto, palm, whole wheat and rice bran. Rice is a typical food in the East Asian countries and Japan. Recently, intake of whole rice is a popular in young women of Japan. Previously, we demonstrated that treatment with tocotrienols on the neuronal cells shows a strong antioxidant effect compared to the tocopherols. In this review, I introduce about neuroprotective and anti-obesity effects of tocotrienols. I would like to show daily intake of whole rice is very good for our health in this review.

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Protective Effect of Tocotrienol on In Vitro and In Vivo Models of Parkinson’s Disease.

Matsura T.

J Nutr Sci Vitaminol (Tokyo). 2019;65(Supplement):S51-S53. doi: 10.3177/jnsv.65.S51.


Parkinson’s disease (PD) is a common progressive neurodegenerative disease. It has been reported that oxidative stress contributes, at least in part, to its pathogenesis. Although dietary epidemiological studies suggest that sufficient intake of vitamin E may prevent the onset of PD, antioxidative therapy for PD with exogenous antioxidants involving α-tocopherol has not been successful in the clinical setting thus far. In recent years, the non-antioxidant activities of vitamin E have been given attention to. In the present study, to determine the antioxidant-independent cytoprotective activity of vitamin E, we investigated whether tocotrienols (T3s), another members of vitamin E family, exhibit the neuroprotective effect in cell and mouse models of PD independently of their antioxidant activities. Treatment with T3s, especially γ- and δ-T3s, exhibited cytoprotective effects via activation of PI3K/Akt signaling pathway in a cellular PD model. We also identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling and demonstrated the direct binding of T3 to ERβ in vitro. Silencing expression of caveolin suppressed the cytoprotective effects of T3, indicating that caveola formation plays an important role in the cytoprotection by T3 via ERβ/PI3K/Akt signaling pathway. Thus it has been shown that T3 exerts cytoprotective function by a novel mechanism, which includes membrane ERβ/PI3K/Akt signaling via caveola formation as well as its antioxidant activity. Furthermore, we revealed that δ-T3 treatment relieved PD-related symptoms in PD model mice. These results suggest that T3 elicits the cytoprotective effects via ERβ/PI3K/Akt signaling pathway in cellular and murine PD models.

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Hydrogen produced in rat colon improves in vivo redox balance due to induced regeneration of α-tocopherol

Ishida Y, Hino S, Morita T, Ikeda S, Nishimura N

Br J Nutr. 2019 Dec 3:1-25. doi: 10.1017/S0007114519003118.


We investigated whether non-digestible saccharide fermentation-derived hydrogen molecules (H2) in rat colon could improve the in vivo reduction-oxidation balance via regeneration of α-tocopherol, by assessing their effect on hydroxyl radicals, the α-tocopherol concentration and the reduction-oxidation balance. In experiment 1, a Fenton reaction with phenylalanine (0 or 1.37 mmol/L of H2) was conducted. In experiment 2, rats received intraperitoneally 400 mg/kg of corn oil containing phorone, 7 days after drinking ad libitum water containing 0 or 4% fructooligosaccharides (groups CP and FP, respectively). In experiment 3, rats unable to synthesise ascorbic acid, drank ad libitum for 14 days, water with 240 mg/L (group AC), 20 mg of ascorbic acid/L (group DC) or 20 mg of ascorbic acid/L and 4% fructooligosaccharides (group DCF). In the Fenton reaction, H2 reduced tyrosine produced from phenylalanine to 72% when platinum was added and to 92% when platinum was excluded. In experiment 2, liver glutathione was depleted by administration of phorone to rats. However, compared with CP, no change in the m-tyrosine concentration in the liver of FP was detected. In experiment 3, net H2 excretion was higher in DCF than in the other rats, 3 days after the experiment ended. Furthermore, the concentrations of H2 and α-tocopherol and the reduction-oxidation glutathione ratio in perirenal adipose tissue of rats were significantly higher and lower, respectively, in DCF than in DC. To summarise, in rat colon, fermentation-derived H2 further reduced the reduction-oxidation balance in perirenal adipose tissue through increased regeneration of α-tocopherol.

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Differentially expressed plasma proteins of β-thalassemia/hemoglobin E patients in response to curcuminoids/vitamin E antioxidant cocktails

Panachan J, Chokchaichamnankit D, Weeraphan C, Srisomsap C, Masaratana P, Hatairaktham S, Panichkul N, Svasti J, Kalpravidh RW

Hematology. 2019 Dec;24(1):300-307. doi: 10.1080/16078454.2019.1568354.



Iron overload and oxidative stress are the major causes of serious complications and mortality in thalassemic patients. Our previous work supports the synergistic effects of antioxidant cocktails (curcuminoids or vitamin E, N-acetylcysteine, and deferiprone) in treatment of β-thalassemia/Hb E patients. This further 2-DE-based proteomic study aimed to identify the plasma proteins that expressed differentially in response to antioxidant cocktails.


Frozen plasma samples of ten normal subjects and ten β-thalassemia/Hb E patients at three-time points (baseline, month 6, and month 12) were reduced the dynamic range of proteome using ProteoMiner kit and separated proteins by two-dimensional gel electrophoresis. Differentially expressed proteins were identified using tandem mass spectrometry. Several plasma proteins were validated by ELISA and Western blot analysis.


Thirteen and 11 proteins were identified with altered expression levels in the curcuminoids- and vitamin E cocktail groups, respectively. The associations between vitronectin (VTN) expression and total bilirubin levels, as well as between serum paraoxonase/arylesterase 1 (PON1) expression and blood reactive oxygen species were observed. Validation results were consistent with proteomics results.


These plasma proteins may provide better understanding of the mechanisms underlying the therapeutic effects of antioxidant cocktails in thalassemic patients.

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Adjuvant therapy with γ-tocopherol-induce apoptosis in HT-29 colon cancer via cyclin-dependent cell cycle arrest mechanism

Bazzaz R, Bijanpour H, Pirouzpanah SMB, Yaghmaei P, Rashtchizadeh N

J Biochem Mol Toxicol. 2019 Nov;33(11):e22399. doi: 10.1002/jbt.22399.


Resistance to chemotherapy with 5-fluorouracil (5-FU) in patients with colorectal cancer (CRC) is the major obstacle to reach the maximum efficiency of CRC treatment. Combination therapy has emerged as a novel anticancer strategy. The present study evaluates the cotreatment of γ-tocopherol and 5-FU in enhancing the efficacy of chemotherapy against HT-29 colon cancer cells. Cytotoxic effect of this combination was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a synergistic effect was evaluated by a combination index technique. Nuclear morphology was studied via 4′,6-diamidino-2-phenylindole staining and flow cytometric assays were conducted to identify molecular mechanisms of apoptosis and cell cycle progression. We investigated the expression of Cyclin D1, Cyclin E, Bax, and Bcl-2 by a quantitative real-time polymerase chain reaction. The IC50 values for 5-FU and γ-tocopherol were 21.8  ± 2.5 and 14.4 ± 2.6 μM, respectively, and also this combination therapeutic increased the percentage of apoptotic cells from 35% ± 2% to 40% ±  4% (P  <  .05). Furthermore, incubation HT-29 colon cells with combined concentrations of two drugs caused significant accumulation of cells in the subGsubG1 phase. Our results presented the combination therapy with 5-FU and γ-tocopherol as a novel therapeutic approach, which can enhance the efficacy of chemotherapy.

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ROS-induced NLRP3 inflammasome priming and activation mediate PCB 118- induced pyroptosis in endothelial cells.

Long Y, Liu X, Tan XZ, Jiang CX, Chen SW, Liang GN, He XM, Wu J, Chen T, Xu Y

Ecotoxicol Environ Saf. 2019 Nov 27:109937. doi: 10.1016/j.ecoenv.2019.109937.


Growing epidemiological evidence has shown that exposure to polychlorinated biphenyls (PCBs) is harmful to the cardiovascular system. However, how PCB 118-induced oxidative stress mediates endothelial dysfunction is not fully understood. Here, we explored whether and how PCB 118 exposure-induced oxidative stress leads to NLRP3 inflammasome-dependent pyroptosis in endothelial cells. As expected, PCB 118 was cytotoxic to HUVECs and induced caspase-1 activation and cell membrane disruption, which are characteristics of pyroptosis. Moreover, PCB 118-induced pyroptosis may have been due to the activation of the NLRP3 infammasomes. PCB 118 also induced excessive reactive oxygen species (ROS) in HUVECs. The ROS scavenger (±)-α-tocopherol and the NFκB inhibitor BAY11-7082 reversed the upregulation of NLRP3 expression and the increase in NLRP3 inflammasome activation induced by PCB 118 exposure in HUVECs. Additionally, PCB 118-induced oxidative stress and pyroptosis were dependent on Aryl hydrocarbon receptor (AhR) activation and subsequent cytochrome P450 1A1 upregulation, which we confirmed by using the AhR selective antagonist CH 223191. These data suggest that PCB 118 exposure induces NLRP3 inflammasome activation and subsequently leads to pyroptosis in endothelial cells in vitro and in vivo. AhR-mediated ROS production play a central role in PCB 118-induced pyroptosis by priming NFκB-dependent NLRP3 expression and promoting inflammasome activation.

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Palm Tocotrienol-Adjuvanted Dendritic Cells Decrease Expression of the SATB1 Gene in Murine Breast Cancer Cells and Tissues

Abdul Hafid SR, Radhakrishnan AK

Vaccines (Basel). 2019 Nov 27;7(4). pii: E198. doi: 10.3390/vaccines7040198.


The aim of this study was to evaluate the effectiveness of immunotherapy using dendritic cells (DC) pulsed with tumor lysate (a DC vaccine) in combination with daily supplementation of tocotrienol-rich fraction (TRF) to potentiate anti-tumor immune responses. We had previously reported that DC-vaccine immunotherapy together with TRF supplementation induced protective immunity to tumor challenge. Breast cancer was induced in female BALB/c mice. The mice were randomly assigned into the treatment groups. At autopsy, peripheral blood was collected in heparinized tube and the expression of cell surface molecules (CD40, CD80, CD83, and CD86) that are crucial for T-cell activation and survival were analyzed by flow cytometry. Tumor was excised from each animal and snap-frozen. Total RNA was extracted from each tumor tissue for microarray and gene expression analysis. Total protein was extracted from tumor tissue for protein expression studies using Western blotting. The results show that systemic administration of 1 mg TRF daily in combination with DC-vaccine immunotherapy (DC + TL + TRF) caused a marked reduction (p < 0.05) of tumor size and increased (p < 0.05) the survival rates of the tumor-inoculated mice. The expression of CD40, CD80, CD83, and CD86 were upregulated in peripheral blood from the DC + TL + TRF group compared to other groups. In addition, there was higher expression of FasL in tumor-excised mice from the DC + TL + TRF group compared to other groups. FasL plays an important role in maintaining immune privilege and is required for cytotoxic T-lymphocyte (CTL) activity. Microarray analysis identified several genes involved in the regulation of cancer. In this study, we focused on the special AT rich binding protein 1 (SATB1) gene, which was reported to have dual functions, one of which was to induce aggressive growth in breast cancer cells. Tumors from DC + TL + TRF mice showed lower (p < 0.05) expression of SATB1 gene. Further study will be conducted to investigate the molecular functions of and the role of SATB1 in 4T1 mammary cancer cells and DC. In conclusion, TRF supplementation can potentiate the effectiveness of DC-vaccine immunotherapy.

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Association of vitamin E on the risk of ovarian cancer: A meta-analysis

Leng Y, Zhou H, Meng F, Tian T, Xu J, Yan F

Biosci Rep. 2019 Nov 27. pii: BSR20193311. doi: 10.1042/BSR20193311.


Many researches were conducted to assess the association of vitamin E intake on the risk of ovarian cancer, with conflict results. The current meta-analysis of published observational studies aimed to investigate the effect of vitamin E intake on ovarian cancer risk. The summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were calculated to measure the effectiveness of vitamin E intake on ovarian cancer risk using a random-effects model. As a result, fourteen studies including 4597 patients were identified. Eleven studies reported about total vitamin E intake, eight studies about vitamin E intake from food only and five studies about vitamin E intake from supplement only on the risk of ovarian cancer. Overall, the summary RRs on ovarian cancer risk was 0.95 (95%CIs= 0.78-1.16) in total vitamin E intake, 0.99 (95%CIs= 0.77-1.27) in vitamin E intake from food only and 0.82 (95%CIs= 0.54-1.25) in vitamin E intake from supplement only. Results in subgroup analyses by study design and geographic location were consistent with overall result. In conclusions, the findings of this meta-analysis suggested that high intake of vitamin E from food or vitamin E supplement had no significant effect on the risk of ovarian cancer.

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Synthesis, DFT Calculations, and In Vitro Antioxidant Study on Novel Carba-Analogs of Vitamin E

Baj A, Cedrowski J, Olchowik-Grabarek E, Ratkiewicz A, Witkowski S

Antioxidants (Basel). 2019 Nov 26;8(12). pii: E589. doi: 10.3390/antiox8120589.


Vitamin E is the most active natural lipophilic antioxidant with a broad spectrum of biological activity. α-Tocopherol (α-T), the main representative of the vitamin E family, is a strong inhibitor of lipid peroxidation as a chain-breaking antioxidant. Antioxidant and antiradical properties of vitamin E result from the presence of a phenolic hydroxyl group at the C-6 position. Due to stereoelectronic effects in the dihydropyranyl ring, the dissociation enthalpy for phenolic O-H bond (BDEOH) is reduced. The high chain-breaking reactivity of α-T is mainly attributed to orbital overlapping of the 2p-type lone pair on the oxygen atom (O1) in para position to the phenolic group, and the aromatic π-electron system. The influence of the O1 atom on the antioxidant activity of vitamin E was estimated quantitatively. The all-rac-1-carba-α-tocopherol was synthesized for the first time. Along with model compounds, 1-carba-analog of Trolox and its methyl ester were screened for their in vitro antioxidant activity by inhibition of styrene oxidation, and for the radical-reducing properties by means of 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) scavenging assay. To study the antioxidant activity, density functional theory (DFT) was also applied. Reaction enthalpies related to HAT (hydrogen atom transfer), SET-PT (sequential electron transfer-proton transfer), and SPLET (sequential proton loss-electron transfer) mechanisms were calculated.

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