γ-Tocotrienol as a Promising Countermeasure for Acute Radiation Syndrome: Current Status.

Singh VK, Hauer-Jensen M.

Int J Mol Sci. 2016 May 3;17(5). pii: E663. doi: 10.3390/ijms17050663. Review.

Abstract

The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and Drug Administration (U.S. FDA) has approved only two growth factors, Neupogen (granulocyte colony-stimulating factor (G-CSF), filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy Rule. Promising radioprotective efficacy results of γ-tocotrienol (GT3; a member of the vitamin E family) in the mouse model encouraged its further evaluation in the nonhuman primate (NHP) model. These studies demonstrated that GT3 significantly aided the recovery of radiation-induced neutropenia and thrombocytopenia compared to the vehicle controls; these results particularly significant after exposure to 5.8 or 6.5 Gray (Gy) whole body γ-irradiation. The stimulatory effect of GT3 on neutrophils and thrombocytes (platelets) was directly and positively correlated with dose; a 75 mg/kg dose was more effective compared to 37.5 mg/kg. GT3 was also effective against 6.5 Gy whole body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a single administration of GT3 without any supportive care was equivalent, in terms of improving hematopoietic recovery, to multiple doses of Neupogen and two doses of Neulasta with full supportive care (including blood products) in the NHP model. GT3 may serve as an ultimate radioprotector for use in humans, particularly for military personnel and first responders. In brief, GT3 is a promising radiation countermeasure that ought to be further developed for U.S. FDA approval for the ARS indication.

Tintino SR, Morais-Tintino CD, Campina FF, Pereira RL, Costa Mdo S, Braga MF, Limaverde PW, Andrade JC, Siqueira-Junior JP, Coutinho HD, Balbino VQ, Leal-Balbino TC, Ribeiro-Filho J, Quintans-Júnior LJ.

EXCLI J. 2016 Apr 29;15:315-22. doi: 10.17179/excli2016-277.

Abstract

Alpha-tocopherol is one the most abundant and biologically active isoforms of vitamin E. This compound is a potent antioxidant and one of most studied isoforms of vitamin E. Vitamin D3 (cholecalciferol) is an important nutrient for calcium homeostasis and bone health, that has also been recognized as a potent modulator of the immune response. Methicillin-resistant Staphylococcus aureus (MRSA) is the most important causative agent of both nosocomial and community-acquired infections. The aim of this study was to evaluate the inhibitory effect of alpha-tocopherol and cholecalciferol on both S. aureus and multidrug resistant S. aureus efflux pumps. The RN4220 strain has the plasmid pUL5054 that is the carrier of gene that encodes the macrolide resistance protein (an efflux pump) MsrA; the IS-58 strain possesses the TetK tetracycline efflux protein in its genome and the 1199B strain resists to hydrophilic fluoroquinolones via a NorA-mediated mechanism. The antibacterial activity was evaluated by determining the Minimal Inhibitory Concentration (MIC) and a possible inhibition of efflux pumps was associated to a reduction of the MIC. In this work we observed that in the presence of the treatments there was a decrease in the MIC for the RN4220 and IS-58 strains, suggesting that the substances presented an inhibitory effect on the efflux pumps of these strains. Significant efforts have been done to identify efflux pump inhibitors (EPIs) from natural sources and, therefore, the antibacterial properties of cholecalciferol and alpha-tocopherol might be attributed to a direct effect on the bacterial cell depending on their amphipathic structure.

Duan L, Yan Y, Liu J, Wang B, Li P, Hu Q, Chen W.

Sci Rep. 2016 Apr 26;6:24867. doi: 10.1038/srep24867.

Abstract

RNA interference (RNAi) represents a promising strategy for the treatment of HCV infection. However, the development of an effective system for in vivo delivery of small interfering RNA (siRNA) to target organ remains a formidable challenge. Here, we develop a unique nanoparticle platform (VE-DC) composed of α-tocopherol (vitamin E) and cholesterol-based cationic liposomes (DOTAP-Chol) for systemic delivery of siRNAs to the liver. A HCV-replicable cell line, Huh7.5.1-HCV, and a transient HCV core expressing cell line, Huh7.5.1-Core, were constructed and used to assess the in vitro anti-HCV activity of VE-DC/siRNAs. A transient in vivo HCV model was also constructed by hydrodynamic injection of pCDNA3.1(+)-3FLAG-Core (pCore-3FLAG) plasmid expressing core protein or pGL3-5’UTR-luciferase (pGL3-5’UTR-luc) plasmid expressing luciferase driven by HCV 5’UTR. Nanoscale VE-DC/siRNA was intravenously injected to assess the liver-targeting property as well as antiviral activity. The nanoscale VE-DC effectively exerted an anti-HCV activity in the in vitro cell models. Post-administration of VE-DC/siRNAs also effectively delivered siRNAs to the liver, suppressing core protein production and firefly luciferase activity, without inducing an innate immunity response or off-target and toxicity effects. The VE-DC platform has high potential as a vehicle for delivery of siRNAs to the liver for gene therapy for targeting hepatitis C.

Cervinkova B, Krcmova LK, Solichova D, Melichar B, Solich P.

Anal Bioanal Chem. 2016 Apr;408(10):2407-24. doi: 10.1007/s00216-015-9214-0. Review.

Abstract

Vitamin E comprises eight related compounds: α-, β-, γ-, δ-tocopherols and α-, β-, γ-, δ-tocotrienols. In the past, α-tocopherol has been the isomer that was studied most, and its anti-inflammatory and anti-proliferative effects have been described. Therefore, many prevention trials have investigated the effect of α-tocopherol on human health. Current research studies have also defined the important roles of other tocopherols, such as anti-inflammatory, anti-proliferative and cancer preventative effects. Knowledge of the individual tocopherols could help to understand their roles in various metabolic pathways. This review summarizes the recent trends in sample pretreatment, liquid chromatography and selected applications of the determination of tocopherols in various biological materials. The relationship between tocopherol isomers and serious diseases is also described. Graphical Abstract Article structure.

Ramis MR, Sarubbo F, Terrasa JL, Moranta D, Aparicio S, Miralles A, Esteban S.

Rejuvenation Res. 2016 Apr;19(2):159-71. doi: 10.1089/rej.2015.1685.

Abstract

Limiting enzymes in the synthesis of brain monoamines seems to be susceptible to oxidative damage, one of the most important factors in aging. It has been suggested that the use of anti-oxidants can reduce the rate of free radical production related with aging and the associated damage. Therefore, this study aims to analyze the effects of the chronic treatments with the anti-oxidant α-tocopherol (vitamin E) on central monoamines (high-performance liquid chromatography [HPLC] analysis) mediating cognitive functions, as well as on the evaluation of memory and motor abilities in old rats measured by radial maze, Barnes maze, novel object recognition test, and rotarod test. Results show that α-tocopherol significantly increased in a dose- and/or time-dependent manner the synthesis rate and the levels of monoaminergic neurotransmitters (serotonin, dopamine, and noradrenaline) in the hippocampus and striatum, brain regions involved in memory processing and motor coordination. These positive neurochemical effects, largely due to an increased activity of the limiting enzymes in monoamines synthesis, tryptophan hydroxylase and tyrosine hydroxylase, were accompanied by an improvement in cognitive and motor abilities in old rats. Altogether these findings suggest that α-tocopherolexhibits neuroprotective actions in old rats; thus, diets with α-tocopherol might represent a promising strategy to mitigate or delay the cognitive and motor decline associate with aging and related-diseases.

Takemoto K, Doi W, Masuoka N.

Biochim Biophys Acta. 2016 Apr;1862(4):647-50. doi: 10.1016/j.bbadis.2015.12.022.

Abstract

Alloxan induces oxidative stress and hyperglycemia in animal models. Acatalasemic (catalase deficiency) mice are susceptible to alloxan-induced hyperglycemia. As the incidence of hyperglycemia induced by alloxan was reportedly improved when mice were fed a vitamin E supplemented diet, this protective effect was examined. Acatalasemic and normal mice fed a vitamin E supplemented diet were treated with alloxan. The pancreas were examined with microscopy. We also isolated pancreatic islets of normal mice treated with alloxan. The glucose stimulated insulin secretion was examined. Results showed Vitamin E powerfully ameliorated the increase in apoptosis. Vitamin E increases insulin amounts secreted from pancreatic cells, but does not ameliorate the regulation of the glucose stimulated insulin secretion. In conclusion, it is suggested that the difference in the mice fed vitamin E supplemented diet is due to an increase of insulin secretion and that vitamin E supplementation may have a role in helping to slow the stages of diabetes mellitus.

Abdala-Valencia H, Soveg F, Cook-Mills JM.

Am J Physiol Lung Cell Mol Physiol. 2016 Apr 15;310(8):L759-71. doi: 10.1152/ajplung.00301.2015.

Abstract

γ-Tocopherol increases responses to allergen challenge in allergic adult mice, but it is not known whether γ-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether γ-tocopherolaugments development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with γ-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to allergen challenge. The γ-tocopherol supplementation of allergic female mice increased the numbers of eosinophils twofold in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also about a twofold increase in pup lung CD11b(+) subsets of CD11c(+) dendritic cells and in numbers of these dendritic cells expressing the transcription factor IRF4. There was no change in several CD11b(-) dendritic cell subsets. Furthermore, maternal supplementation with γ-tocopherolincreased the number of fetal liver CD11b(+)CD11c(+) dendritic cells twofold in utero. In the pups, γ-tocopherol increased lung expression of the inflammatory mediators CCL11, amphiregulin, activin A, and IL-5. In conclusion, maternal supplementation with γ-tocopherol increased fetal development of subsets of dendritic cells that are critical for allergic responses and increased development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with γ-tocopherol in prenatal vitamins.

Pires Medeiros JF, Ribeiro KD, Lima MS, das Neves RA, Lima AC, Dantas RC, da Silva AB, Dimenstein R.

Br J Nutr. 2016 Apr;115(8):1424-30. doi: 10.1017/S0007114516000477.

Abstract

We evaluated the effect of maternal vitamin E supplementation on the α-tocopherol concentrations of colostrum, transitional milk and mature milk of women who had given birth prematurely. This longitudinal randomised-controlled trial divided eighty-nine women into two groups: a control group and a supplemented group. Blood and breast milk were collected from all the participants after delivery. Next, each woman in the supplemented group received 400 IU of RRR-α-tocopheryl acetate. Further breast milk samples were collected 24 h after the first collection, as well as 7 and 30 d after delivery. α-Tocopherol concentrations were determined by HPLC. The baseline α-tocopherol concentrations in the maternal serum of the two groups were similar: 1159·8 (sd 292·4) μg/dl (27·0 (SD 6·8) μmol/l) for the control group and 1128·3 (sd 407·2) μg/dl (26·2 (SD 9·5) μmol/l) for the supplemented group. None of the women was vitamin E deficient. Breast milk α-tocopherol concentrations increased by 60 % 24 h after supplementation in the intervention group and did not increase at all in the control group. α-Tocopherol concentration of the transitional milk in the supplemented group was 35 % higher compared with the control group. α-Tocopherol concentrations of the mature milk in both groups were similar. Maternal supplementation with 400 IU of RRR-α-tocopherol increased the vitamin E concentrations of the colostrum and transitional milk, but not of the mature milk. This study presents relevant information for the design of strategies to prevent and combat vitamin Edeficiency in the risk group of preterm infants.

Azzi A, Meydani SN, Meydani M, Zingg JM.

Arch Biochem Biophys. 2016 Apr 1;595:100-8. doi: 10.1016/j.abb.2015.11.010. Review.

Abstract

This review deals with the expectations of vitamin E ability of preventing or curing, as a potent antioxidant, alleged oxidative stress based ailments including cardiovascular disease, cancer, neurodegenerative diseases, cataracts, macular degeneration and more. The results obtained with clinical intervention studies have highly restricted the range of effectiveness of this vitamin. At the same time, new non-antioxidant mechanisms have been proposed. The new functions of vitamin E have been shown to affect cell signal transduction and gene expression, both in vitro and in vivo. Phosphorylation of vitamin E, which takes place in vivo, results in a molecule provided with functions that are in part stronger and in part different from those of the non-phosphorylate compound. The in vivo documented functions of vitamin E preventing the vitamin E deficiency ataxia (AVED), slowing down the progression of non-alcoholic steato-hepatitis (NASH), decreasing inflammation and potentiating the immune response are apparently based on these new molecular mechanisms. It should be stressed however that vitamin E, when present at higher concentrations in the body, should exert antioxidant properties to the extent that its chromanol ring is unprotected or un-esterified.

Sato A, Ueno H, Takase A, Ando A, Sekine Y, Yano T.

Anticancer Res. 2016 Apr;36(4):1527-33.

Abstract

De novo synthesis of proteins is regulated by cap-dependent protein translation. Aberrant activation of the translation is a hallmark of many cancer types including malignant mesothelioma (MM). We previously reported that a redox-silent analog of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) induces potent cytotoxicity against human MM cells. However, the detailed mechanism of cytotoxicity of T3E remains unclear. In this study, we investigated if T3E induced potent cytotoxicity aganist MM cells. T3E reduced the formation of the cap-dependent translation complex and induced inactivation of oncogene from rat sarcoma virus (RAS). These events were associated with T3E cytotoxicity in MM cells. Furthermore, atorvastatin, an inhibitor of RAS function, had similar effects on MM cells. Moreover, 4EGI-1, a specific inhibitor of the cap-dependent translation complex, induced severe cytotoxicity in MM cells. Overall, T3E had a cytotoxic effect on MM cells via disruption of the activated cap-dependent translation complex through inactivation of RAS.