Vitamin E: Emerging aspects and new directions.

Galli F, Azzi A, Birringer M, Cook-Mills JM, Eggersdorfer M, Frank J, Cruciani G, Lorkowski S, Özer NK.

Free Radic Biol Med. 2016 Nov 2;102:16-36. doi: 10.1016/j.freeradbiomed.2016.09.017. [Epub ahead of print]

Abstract

The discovery of vitamin E will have its 100th anniversary in 2022, but we still have more questions than answers regarding the biological functions and the essentiality of vitamin E for human health. Discovered as a factor essential for rat fertility and soon after characterized for its properties of fat-soluble antioxidant, vitamin E was identified to have signaling and gene regulation effects in the 1980s. In the same years the cytochrome P-450 dependent metabolism of vitamin E was characterized and a first series of studies on short-chain carboxyethyl metabolites in the 1990s paved the way to the hypothesis of a biological role for this metabolism alternative to vitamin E catabolism. In the last decade other physiological metabolites of vitamin E have been identified, such as α-tocopheryl phosphate and the long-chain metabolites formed by the ω-hydroxylase activity of cytochrome P-450. Recent findings are consistent with gene regulation and homeostatic roles of these metabolites in different experimental models, such as inflammatory, neuronal and hepatic cells, and in vivo in animal models of acute inflammation. Molecular mechanisms underlying these responses are under investigation in several laboratories and side-glances to research on other fat soluble vitamins may help to move faster in this direction. Other emerging aspects presented in this review paper include novel insights on the mechanisms of reduction of the cardiovascular risk, immunomodulation and antiallergic effects, neuroprotection properties in models of glutamate excitotoxicity and spino-cerebellar damage, hepatoprotection and prevention of liver toxicity by different causes and even therapeutic applications in non-alcoholic steatohepatitis. We here discuss these topics with the aim of stimulating the interest of the scientific community and further research activities that may help to celebrate this anniversary of vitamin E with an in-depth knowledge of its action as vitamin.

Pathak R, Ghosh SP, Zhou D, Hauer-Jensen M.

Int J Mol Sci. 2016 Nov 18;17(11). pii: E1937.

Abstract

Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) and strongly induce endothelial thrombomodulin (TM); which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member gamma-tocotrienol (GT3) also suppresses HMGCR activity and induces TM expression without causing significant adverse side effects; even at high concentrations. To investigate the synergistic effect of statins and GT3 on TM; a low dose of atorvastatin and GT3 was used to treat human primary endothelial cells. Protein-level TM expression was measured by flow cytometry. TM functional activity was determined by activated protein C (APC) generation assay. Expression of Kruppel-like factor 2 (KLF2), one of the key transcription factors of TM, was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). TM expression increased in a dose-dependent manner after both atorvastatin and GT3 treatment. A combined treatment of a low-dose of atorvastatin and GT3 synergistically up-regulated TM expression and functional activity. Finally; atorvastatin and GT3 synergistically increased KLF2expression. These findings suggest that combined treatment of statins with GT3 may provide significant health benefits in treating a number of pathophysiological conditions; including inflammatory and cardiovascular diseases.

Ding Y, Peng Y, Deng L, Fan J, Huang B.

J Steroid Biochem Mol Biol. 2016 Nov 15. pii: S0960-0760(16)30323-5. doi: 10.1016/j.jsbmb.2016.11.009. [Epub ahead of print]

Abstract

In addition to its antioxidant properties, γ-tocotrienol also has the ability to inhibit HMG-CoA reductase, which is the key enzyme in the mevalonate pathway for cholesterol biosynthesis. Statins, the competitive inhibitors of HMG-CoA reductase, display potent anticancer activity and reversal ability of multidrug resistance in a variety of tumor cells, which is believed to be due to their inhibition of HMG-CoA reductase. Here, we determined the role of the mevalonate pathway in γ-tocotrienol-mediated reversal of multidrug resistance in cancer cells. We found both γ-tocotrienol and atorvastatin effectively reversed multidrug resistance of MCF-7/Adr and markedly inhibited the intracellular levels of FPP and GGPP. Exogenous addition of mevalonate or FPP and GGPP almost completely prevented the reversal ability of atorvastatin but only partly attenuated the reversal effect of γ-tocotrienol on doxorubicin resistance. In addition, γ-tocotrienol actively inhibited the expression of P-gp and increased the accumulation of doxorubicin in cells, which led to the enhanced G2/M arrest and cell apoptosis. Taken together, γ-tocotrienol reversed the multidrug resistance of MCF-7/Adr with a mechanism distinct from that of atorvastatin. Instead of the mevalonate pathway, the inhibition of P-gp expression is a potential mechanism by which γ-tocotrienol reverses multidrug resistance in MCF-7/Adr.

Ibrahim NF, Yanagisawa D, Durani LW, Hamezah HS, Damanhuri HA, Wan Ngah WZ, Tsuji M, Kiuchi Y, Ono K, Tooyama I.

Alzheimers Dis. 2016 Nov 19;55(2):597-612.

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.

Torshabi M, Esfahrood ZR, Gholamin P, Karami E.

J Basic Clin Physiol Pharmacol. 2016 Nov 1;27(6):595-602. doi: 10.1515/jbcpp-2015-0143.

Abstract

Evidence shows that oxidative stress induced by nicotine plays an important role in bone loss. Vitamin E with its antioxidative properties may be able to reverse the effects of nicotine on bone. This study aimed to assess the effects of nicotine in the presence and absence of vitamin E on morphology, viability and osteogenic gene expression in MG-63 (osteosarcoma) human osteoblast-like cells.

We treated the cells with 5 mM nicotine. The viability and morphology of cells were evaluated respectively using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) and crystal violet assays. The effect of nicotine on osteogenic gene expression in MG-63 cells was assessed by real-time reverse-transcription polymerase chain reaction of osteoblast markers, namely, alkaline phosphatase, osteocalcin and bone sialoprotein.

The results revealed that survival and proliferation of MG-63 cells were suppressed following exposure to nicotine, and cytoplasm vacuolization occurred in the cells. Nicotine significantly down-regulated the expression of osteogenic marker genes. Such adverse effects on morphology, viability and osteogenic gene expression of MG-63 cells were reversed by vitamin E therapy.

In conclusion, vitamin E supplementation may play a role in proliferation and differentiation of osteoblasts, and vitamin E can be considered as an anabolic agent to treat nicotine-induced bone loss.

Wang J, Ma W, Guo Q, Li Y, Hu Z, Zhu Z, Wang X, Zhao Y, Chai X, Tu P.

Int J Nanomedicine. 2016 Nov 7;11:5851-5870. eCollection 2016.

Abstract

Tumor-targeted delivery system has been developed as an attractive strategy for effective tumor therapy. In this study, in order to enhance the antitumor effects of doxorubicin (DOX), amphiphilic hyaluronic acid (HA)-conjugated vitamin E succinate (VES) copolymers (HA-VES) with different degrees of substitution (DS) were prepared with synergistic antitumor effects and active targeting activities, and utilized as nanocarriers for the efficient delivery of DOX. DOX-loaded HA-VES polymeric micelles (HA-VES/DOX) self-assembled from dual-functional HA-VES copolymer and exhibited excellent loading efficiency and superior colloidal stability. In vitro, HA-VES/DOX displayed enhanced cytotoxicity with synergistic anticancer effects of HA-VES copolymer, high apoptosis-inducing activities of tumor cells, and reversal effects of DOX on multidrug resistance, in comparison with DOX. Also, in vitro cellular uptake and subcellular localization studies revealed that HA-VES/DOX could more efficiently internalize into cancer cells and selectively release DOX within lysosomes, thereby enhancing the distribution of DOX in nuclei and facilitating its interactions with DNA. Specifically, HA-VES/DOX decreased the activity of CD44 mRNA and improved the targeting efficiency on MCF-7 cells, based on the active recognition between HA and CD44 receptor. More importantly, HA-VES/DOX displayed better tumor accumulation and targeting, and enhanced antitumor efficacy with reduced systemic toxicity in 4T1 tumor-bearing mice. In summary, the developed HA-VES-based drug delivery system, which increased drug targeting on the tumor site and exhibited preferable anticancer activity, could hold great potential as an effective and promising strategy for efficient tumor therapy.

Prathipati P, Zhu J, Dong X.

Eur J Pharm Biopharm. 2016 Nov;108:126-135. doi: 10.1016/j.ejpb.2016.08.005. Epub 2016 Aug 12.

Abstract

Nerve Growth Factor (NGF) is one of the members of the neurotrophin family with multifaceted functions. However, clinical application of NGF is hurdled by the challenge on formulation development. The objective of this study was to develop novel high-density lipoproteins (HDL)-mimicking nanoparticles (NPs) coated with α-tocopherol to incorporate NGF by a self-assembly approach. The NPs were prepared by an optimized self-assembly method that is simple and scalable. The composition of HDL-mimicking NPs was optimized. The prototype of the HDL-mimicking α-tocopherol-coated NPs contained phosphatidylserine (a negative charged phospholipid) and d-α-Tocopheryl polyethylene glycol succinate (a source of vitamin E) to enhance the entrapment efficiency of apolipoprotein A-I in the NPs. The entrapment efficiency of apolipoprotein A-I was about 30%. The NPs had particle size about 200nm with a relatively narrow size distribution. Finally, cationic ion-pair agents were optimized to form ion-pairs with NGF to facilitate the incorporation of NGF into the NPs. Protamine sodium salt USP formed an optimal ion-pair complex with NGF. The results showed that the novel HDL-mimicking α-tocopherol-coated NPs successfully encapsulated NGF with over 65% entrapment efficiency by using this ion-pair strategy. In vitro release studies demonstrated a slow release of NGF from NGF NPs in PBS containing 5% BSA at 37°C for 72 h. Further biodistribution studies showed that intravenously injected NGF NPs significantly increased NGF concentration in plasma and decreased the uptake in liver, spleen and kidney, compared to free NGF in mice.

Asemi Z, Soleimani A, Shakeri H, Mazroii N, Esmaillzadeh A.

Int Urol Nephrol. 2016 Nov;48(11):1887-1895. Epub 2016 Aug 23.

Abstract

The current study was carried out to assess the effects of omega-3 fatty acid and alpha-tocopherol co-supplementation on malnutrition-inflammation score (MIS), biomarkers of inflammation and oxidative stress in chronic hemodialysis (HD) patients.

In a randomized double-blind placebo-controlled clinical trial, 120 patients with chronic HD were included. Patients were randomly allocated into four groups to receive: (1) 1250 mg/day omega-3 fatty acid containing 600 mg EPA and 300 mg DHA + alpha-tocopherol placebo (n = 30); (2) 400 IU/day alpha-tocopherol + omega-3 fatty acids placebo (n = 30); (3) 1250 mg omega-3 fatty acids/day + 400 IU/day alpha-tocopherol (n = 30); and (4) omega-3 fatty acids placebo + alpha-tocopherol placebo (n = 30) for 12 weeks.

After 12 weeks of intervention, all three groups of alpha-tocopherol only, individual omega-3 fatty acids, and combined omega-3 fatty acids and alpha-tocopherol experienced a significant improvements in MIS compared with the placebo group; however, improvements were much greater in the individual omega-3 fats (-1.4 ± 1.4) and combined omega-3 fats and alpha-tocopherol (-1.1 ± 2.3) groups compared with alpha-tocopherol group alone (-0.5 ± 1.7, P = 0.004). Furthermore, both individual and combined intervention with omega-3 fats and alpha-tocopherol led to a significant increase in plasma nitric oxide (NO) (combined group: +17.6 ± 29.3; alpha-tocopherol: +43.1 ± 36.3; omega-3 fats: +31.0 ± 40.0; and placebo: -0.5 ± 18.5 µmol/L, respectively, P < 0.001) and total antioxidant capacity (TAC) (+64.9 ± 113.6, +53.0 ± 144.6, +57.6 ± 157.8 and -69.9 ± 215.1 mmol/L, respectively, P = 0.004) levels.

Overall, omega-3 fatty acids and alpha-tocopherol co-supplementation for 12 weeks among HD patients improved MIS, plasma NO and TAC levels. Future studies with longer duration of the intervention are needed to confirm the validity of our findings. CLINICAL REGISTRATION: www.irct.ir as IRCT201410245623N28.

Kim JE, Ferruzzi MG, Campbell WW.

Nutr. 2016 Nov;146(11):2199-2205. Epub 2016 Sep 21.

Abstract

Most people living in the United States underconsume vitamin E, and dietary approaches to increase the absorption of vitamin E may help individuals to meet their body’s needs. In this study, we assessed the effect of adding cooked whole egg to a raw mixed-vegetable salad on α-tocopherol and γ-tocopherol absorption.

With the use of a randomized-crossover design, 16 healthy young men [mean ± SD age: 24 ± 4 y; mean ± SD body mass index (in kg/m²): 24 ± 2] consumed the same salad (all served with 3 g canola oil) with no egg [control (CON)], with 75 g cooked egg [low egg (LE)], or with 150 g cooked egg [high egg (HE)]; a 1-wk dietary washout period was included between trials. For the first 7 d of each trial, participants consumed a low-vitamin E diet to reduce plasma vitamin E concentrations. Blood was collected hourly for 10 h and the triacylglycerol-rich lipoprotein fractions (TRLs) were isolated. α-Tocopherol and γ-tocopherol concentrations in TRLs were analyzed and composite areas under the curve (AUCs) were calculated.

Results showed that the consumption of cooked whole eggs is an effective way to increase the absorption of α-tocopherol and γ-tocopherol from a co-consumed meal that naturally contains vitamin E, such as a raw mixed-vegetable salad, in healthy young men. This trial was registered at clinicaltrials.gov as NCT01951313.