The potentiation of the radioprotective efficacy of two medical countermeasures, gamma-tocotrienol and amifostine, by a combination prophylactic modality.

Singh VK, Fatanmi OO, Wise SY, Newman VL, Romaine PL, Seed TM.

Radiat Prot Dosimetry. 2016 Aug 19. [Epub ahead of print]

Abstract

This study was designed to evaluate the possible potentiation of survival protection afforded by relatively low-dose amifostine prophylaxis against total body irradiation in combination with a protective, less toxic agent, gamma-tocotrienol (GT3). Mice were administered amifostine and/or GT3, then exposed to 9.2 Gy ⁶⁰Co γ-irradiation and monitored for survival for 30 days. To investigate cytokine stimulation, mice were administered amifostine or GT3; serum samples were collected and analyzed for cytokines. Survival studies show single treatments of GT3 or amifostine significantly improved survival, compared to the vehicle, and combination treatments resulted in significantly higher survival compared to single treatments. In vivo studies with GT3 confirmed prior work indicating GT3 induces granulocyte colony-stimulating factor (G-CSF). This approach, the prophylactic combination of amifostine and GT3, which act through different mechanisms, shows promise and should be investigated further as a potential countermeasure for acute radiation syndrome.

Singh VK, Fatanmi OO, Verma A, Newman VL, Wise SY, Romaine PL, Berg AN.

Health Phys. 2016 Aug;111(2):85-92. doi: 10.1097/HP.0000000000000458.

Abstract

This article reviews studies of progenitor mobilization with gamma-tocotrienol (GT3), a tocol under advanced development as a radiation countermeasure for acute radiation syndrome (ARS). GT3 protects mice against high doses of ionizing radiation and induces high levels of granulocyte colony-stimulating factor (G-CSF). GT3-induced G-CSF in conjunction with AMD3100 (a chemokine receptor antagonist clinically used to improve the yield of mobilized progenitors) mobilizes progenitors; these mobilized progenitors mitigate injury when infused to mice exposed to acute, high-dose ionizing radiation. The administration of a G-CSF antibody to GT3-injected donor mice abrogated the radiomitigative efficacy of blood or peripheral blood mononuclear cells (PBMC) in irradiated recipient mice. The efficacy of GT3-injected donor mice blood or PBMC was comparable to a recently published article involving blood or mononuclear cells obtained from mice injected with G-CSF. The injected progenitors were found to localize in various tissues of irradiated hosts. The authors demonstrate the efficacy of a bridging therapy in a preclinical animal model that allows the lymphohematopoietic system of severely immunocompromised mice to recover. This suggests that GT3 is a highly effective agent for radioprotection and mobilizing progenitors with significant therapeutic potential. Therefore, GT3 may be considered for further translational development and ultimately for use in humans.

Li Y, Bharath LP, Qian Y, Ruan T, Anandh Babu PV, Bruno RS, Symons JD, Jalili T.

Exp Biol Med (Maywood). 2016 Jul 27. pii: 1535370216661780. [Epub ahead of print]

Abstract

Endothelial dysfunction occurs when there are imbalances between factors that regulate the synthesis and degradation of nitric oxide (NO^•), and has been reported in patients with hyperglycemia and insulin resistance. We reported that supplementation with γ-tocopherol (γ-T) in humans limits impairments in endothelial function otherwise induced by postprandial hyperglycemia. Given the rapid metabolism of γ-T into γ-carboxyethyl hydroxychroman (γ-CEHC), we hypothesized that the vasoprotective activities of γ-T could be attributed to its metabolite γ-CEHC. To test this, human aortic endothelial cells (HAECs) treated with 0 (vehicle control) or 3 µM γ-CEHC for 24 h prior to incubation with normal (5 mM) or high (25 mM) glucose for 48 h. High-glucose increased levels of uncoupled endothelial nitric oxide synthase (eNOS) as evidenced by reduced (p < 0.05) eNOS dimer:monomer. High glucose also prevented insulin-stimulated increases in p-Akt^Ser473: total Akt, p-eNOS^Ser1177: total eNOS, and NO^• production. These adverse changes were accompanied by increased (p < 0.05) reactive oxygen species and mRNA expression of inflammatory mediators (VCAM-1, E-selectin, IL-8). However, each deleterious response evoked by high glucose was prevented when HAECs were incubated with γ-CEHC prior to the high glucose challenge. Taken together, our data support the hypothesis that vascular protection provided by γ-T in vivo may be elicited through the bioactivity of its metabolite, γ-CEHC. Furthermore, it is possible that the antioxidant and anti-inflammatory activities of γ-CEHC may mediate this protective activity.

Montagnani Marelli M, Marzagalli M, Moretti RM, Beretta G, Casati L, Comitato R, Gravina GL, Festuccia C, Limonta P.

Sci Rep. 2016 Jul 27;6:30502. doi: 10.1038/srep30502.

Abstract

Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.

Araoud M, Neffeti F, Douki W, Khaled L, Najjar MF, Kenani A, Houas Z.

Environ Toxicol. 2016 Jul;31(7):842-54. doi: 10.1002/tox.22095.

Abstract

The role of alpha-tocopherol on nephrotoxicity and hepatotoxicity induced by methamidophos (MT) was investigated in wistar rats. Animals were given via gavage, for four weeks, a low dose of MT (MT1), a high dose of MT (MT2), vitamin E (200 mg/kg of bw) or both MT2 plus vitamin E (Vit E) and control group was given distillate water. MT treatment resulted in a significant decrease in the body weight of MT2-treated group. Moreover, MT-treated groups had significantly lower butyrylcholinesterase (p < 0.01) and paraoxonase 1 (PON1) activities compared with the control group (p < 0.05). However, MT2-treated group had significantly higher alkaline phosphatase activity compared with untreated rats (p < 0.05). Both MT-treated groups had significantly higher urea (p < 0.01) and uric acid levels (p < 0.05) compared with the control group. However, significant low uric acid level (p < 0.05) was noted in MT2 plus vit E-treated rats compared with MT2-treated group. Histopathological changes in organ tissues were observed in both MT-treated groups and MT2 plus vit E-treated rats. However, the damage was reduced in MT2 plus vit E-treated rats. Therefore, this study deduces that alpha-tocopherol administration may ameliorate the adverse effects of subacute exposure to MT on rat liver and kidney and this antioxidant can protect PON1 from oxidative stress induced by this organophosphorus pesticide.

Kuchan MJ, Jensen SK, Johnson EJ, Lieblein-Boff JC.

Br J Nutr. 2016 Jul;116(1):126-31. doi: 10.1017/S0007114516001719.

Abstract

α-Tocopherol is the principal source of vitamin E, an essential nutrient that plays a crucial role in maintaining healthy brain function. Infant formula is routinely supplemented with synthetic α-tocopherol, a racaemic mixture of eight stereoisomers with less bioactivity than the natural stereoisomer RRR-α-tocopherol. α-Tocopherol stereoisomer profiles have not been previously reported in the human brain. In the present study, we analysed total α-tocopherol and α-tocopherol stereoisomers in the frontal cortex (FC), hippocampus (HPC) and visual cortex (VC) of infants (n 36) who died of sudden infant death syndrome or other conditions. RRR-α-tocopherol was the predominant stereoisomer in all brain regions (P<0·0001) and samples, despite a large intra-decedent range in total α-tocopherol(5-17 μg/g). Mean RRR-α-tocopherol concentrations in FC, HPC and VC were 10·5, 6·8 and 5·5 μg/g, respectively. In contrast, mean levels of the synthetic stereoisomers were RRS, 1-1·5; RSR, 0·8-1·0; RSS, 0·7-0·9; and Σ2S 0·2-0·3 μg/g. Samples from all but two decedents contained measurable levels of the synthetic stereoisomers, but the intra-decedent variation was large. The ratio of RRR:the sum of the synthetic 2R stereoisomers (RRS+RSR+RSS) averaged 2·5, 2·3 and 2·4 in FC, HPC and VC, respectively, and ranged from 1 to at least 4·7, indicating that infant brain discriminates against synthetic 2R stereoisomers in favour of RRR. These findings reveal that RRR-α-tocopherol is the predominant stereoisomer in infant brain. These data also indicate that the infant brain discriminates against the synthetic 2R stereoisomers, but is unable to do so completely. On the basis of these findings, investigation into the impact of α-tocopherol stereoisomers on neurodevelopment is warranted.

Kim SK, Im GJ, An YS, Lee SH, Jung HH, Park SY.

Int J Pediatr Otorhinolaryngol. 2016 Jul;86:9-14. doi: 10.1016/j.ijporl.2016.04.008.

Abstract

Alpha-tocopherol is a class of methylated phenols, known as fat-soluble antioxidants, and is a different form of vitamin E, which reduces free radicals and acts as an antioxidant. We hypothesized that the antioxidative effect of α-tocopherol could protect against cisplastin-induced cytotoxicity, and thus evaluated its effects on cisplatin-induced ototoxicity in HEI-OC1 auditory cells. As a result, D-α-tocopherol succinate significantly reduced a cisplatin-induced hair cell loss in HEI-OC1 cell lines. These effects were mediated by its scavenging activity against reactive oxygen species (ROS) and inhibition of apoptosis.

A Systematic Review of Global Alpha-Tocopherol Status as Assessed by Nutritional Intake Levels and Blood Serum Concentrations.

Péter S, Friedel A, Roos FF, Wyss A, Eggersdorfer M, Hoffmann K, Weber P.

Int J Vitam Nutr Res. 2016 Jul 14:1-21. [Epub ahead of print]

Abstract

The purpose of this study is to systematically review the published literature reporting vitamin E intake levels and serum concentrations in order to obtain a global overview of α-tocopherol status. Articles published between 2000 and 2012 were considered; 176 articles referring to 132 single studies were included. Applying an RDA (recommended daily allowance) of 15 mg/day and EAR (estimated average requirement) of 12 mg/day to all populations with a minimum age of 14 years, 82 and 61% of mean and median data points were below the RDA and the EAR, respectively. Regarding serum concentrations, globally 13% of the included data points were below the functional deficiency threshold concentration of 12 μmol/L, mostly for newborns and children. Several prospective observational studies suggest that a serum α-tocopherol concentration of ≥30 μmol/L has beneficial effects on human health. Of the reported study populations and subpopulations, only 21% reached this threshold globally. This systematic review suggests that the α-tocopherol status is inadequate in a substantial part of the studied populations.

Jansen E, Viezeliene D, Beekhof P, Gremmer E, Ivanov L.

Int J Mol Sci. 2016 Jul 19;17(7). pii: E1166. doi: 10.3390/ijms17071166.

Abstract

A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third group received a high dose of vitamin E (25× RDI), close to the upper limit of toxicity (UL), but still recommended and considered to be harmless and beneficial. The high dose of vitamin E caused a number of beneficial, but also adverse effects. Different biomarkers of tissue toxicity, oxidative stress related processes and inflammation were determined. These biomarkers did not change in plasma and erythrocytes to a large extent. In the liver of male mice, some beneficial effects were observed by a lower concentration of several biomarkers of inflammation. However, in the kidney of male mice, a number of biomarkers increased substantially with the higher dose of vitamin E, indicating tissue toxicity and an increased level of inflammation. Since this dose of vitamin E, which is lower than the UL, cause some adverse effects, even after a short exposure period, further studies are required to reconsider the UL for vitamin E.

Wu YM, Xue ZW, Zhang LL, Gao NM, Du XM, Zhang XY, Zhang ZH, Zhang ZG.

Adv Clin Exp Med. 2016 Jul-Aug;25(4):643-8. doi: 10.17219/acem/41191.

Abstract

Bronchial asthma is one of the world’s most common chronic disorders dangerous to human health. It has been hypothesized that the increased number of asthma sufferers may be due to changing antioxidant intake or vitamin deficiency. However, the influence of vitamins on asthma has rarely been considered. The aim of this study was to explore the effects of γ-tocopherols, a specific form of vitamin E, on asthma remission together with the possible mechanism behind the process. The cell counting results showed that γ-tocopherols possesses the capability to reduce the number of eosinophils. Moreover, the exudation of inflammatory cells together with the hyperplasia of goblet cells was also found to experience significant inhibition when treated with γ-tocopherols. Furthermore, the high levels of eotaxin and IL-4 in the asthma group were evidently reduced under the treatment of γ-tocopherols which was comparable with hexadecadrol. In conclusion, γ-tocopherols can remit asthma by regulating the level of eotaxin and IL-4. Moreover, γ-tocopherols may be regarded as a potential candidate for asthma treatment after much deeper explorations.