Antioxidant status following postprandial challenge of two different doses of tocopherols and tocotrienols

Fairus S, Cheng HM, Sundram K

Integr Med. 2020 Jan;18(1):68-79. doi: 10.1016/j.joim.2019.11.005. Epub 2019 Nov 23.

Abstract

OBJECTIVE:

Tocotrienols (T3s) have been hypothesized to have greater antioxidant capacity than tocopherols (Ts) due to differences in biokinetics that affect their absorption and function. The present trial compares the antioxidant effectiveness following postprandial challenge of two different doses of α-T or palm T3-rich fraction (TRF) treatments and evaluates their dose-response effects on antioxidant status.

METHODS:

Ten healthy volunteers were given four different doses of vitamin E formulations (268 mg α-T, 537 mg α-T, 263 mg TRF or 526 mg TRF) in a cross-over postprandial trial. Blood was sampled at 0, 2, 4, 5, 6 and 8 hours after meal consumption and plasma antioxidant status including total glutathione, superoxide dismutase, malondialdehyde (MDA), ferric reducing antioxidant potential and trolox-equivalent antioxidant capacity, was analyzed.

RESULTS:

Supplementation with the different doses of either α-T or TRF did not significantly improve overall antioxidant status. There was no significant difference in overall antioxidant status among treatments at the different doses compared. However, a significant dose-response effect was observed for plasma MDA throughout the 8-hour postprandial period. MDA was significantly lower after the 537 mg α-T treatment, compared to the 268 mg α-T treatment; it was also lower after the 526 mg TRF treatment compared to the 263 mg TRF treatment (P < 0.05).

CONCLUSION:

T3 and α-T demonstrated similar antioxidant capacity, despite markedly lower levels of T3 in blood and lipoproteins, compared to α-T.

Zheng L, Jin J, Shi L, Huang J, Chang M, Wang X, Zhang H, Jin Q

Crit Rev Food Sci Nutr. 2020 Jan 20:1-15. doi: 10.1080/10408398.2020.1711704. [Epub ahead of print]

Abstract

Gamma-tocopherol (γ-T), the major form of vitamin E in many plant seeds and products derived from them, has been attracting increasing attention because of its health-promoting roles. However, the underlying molecular mechanisms are still unclear, to some degree. Furthermore, its dimmers and quinones are expected to be potential nutritious and pharmaceutical agents, however, the knowledge about these dimmers (γ-TBD and γ-TED) and quinones (para– and ortho-quinones) is relatively limited. Thus, a comprehensive summary of the history, chemical structure, source, determination, absorption, transport, and metabolism of its dimmers and quinones compared to γ-T has been reviewed. In addition, the antioxidant activity (AOA) and non-AOA activity of these substances are highlighted. It is suggested that more special attention be paid to the dimmers and quinones for better understanding and further applications.

Liu X1,, Poddar S, Song L, Hendrickson H, Zhang X, Yuan Y, Zhou D, Zheng G

ChemMedChem. 2020 Jan 19. doi: 10.1002/cmdc.201900676.

Abstract

A fluoro-substituted δ-tocotrienol derivative, DT3-F2, was synthesized. This compound was designed to stabilize the metabolically labile terminal methyl groups of δ-tocotrienol by replacing one C-H bond on each of the two methyl groups with a C-F bond. However, in vitro metabolic stability studies using mouse liver microsomes revealed an unexpected rapid enzymatic C-F bond hydrolysis of DT3-F2. To the best of our knowledge, this is the first report of an unusual metabolic hydrolysis of allylic C-F bonds.

Wong SK, Kamisah Y, Mohamed N, Muhammad N, Masbah N, Fahami NAM, Mohamed IN, Shuid AN, Saad QM, Abdullah A, Mohamad NV, Ibrahim NI, Pang KL, Chow YY, Thong BKS, Subramaniam S, Chan CY, Ima-Nirwana S, Chin AK

Nutrients. 2020 Jan 19;12(1). pii: E259. doi: 10.3390/nu12010259.

Abstract

Tocotrienol (T3) is a subfamily of vitamin E known for its wide array of medicinal properties. This review aimed to summarize the health benefits of T3, particularly in prevention or treatment of non-communicable diseases (NCDs), including cardiovascular, musculoskeletal, metabolic, gastric, and skin disorders, as well as cancers. Studies showed that T3 could prevent various NCDs, by suppressing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the mevalonate pathway, inflammatory response, oxidative stress, and alternating hormones. The efficacy of T3 in preventing/treating these NCDs is similar or greater compared to tocopherol (TF). TF may lower the efficacy of T3 because the efficacy of the combination of TF and T3 was lower than T3 alone in some studies. Data investigating the effects of T3 on osteoporosis, arthritis, and peptic ulcers in human are limited. The positive outcomes of T3 treatment obtained from the preclinical studies warrant further validation from clinical trials.

Asay S, Graham A, Hollingsworth S, Barnes B, Oblad RV, Michaelis DJ, Kenealey JD

Molecules. 2020 Jan 18;25(2). pii: E398. doi: 10.3390/molecules25020398.

Abstract

Prostate cancer is the second most commonly diagnosed cancer in men, and metastatic prostate cancer is currently incurable. Prostate cancer frequently becomes resistant to standard of care treatments, and the administration of chemotherapeutic drugs is often accompanied by toxic side effects. Combination therapy is one tool that can be used to combat therapeutic resistance and drug toxicity. Vitamin E (VE) compounds and analogs have been proposed as potential non-toxic chemotherapeutics. Here we modeled combination therapy using mixture design response surface methodology (MDRSM), a statistical technique designed to optimize mixture compositions, to determine whether combinations of three chemotherapeutic agents: γ-tocotrienol (γ-T3), α-tocopherol ether acetate (α-TEA), and docetaxel (DOC), would prove more effective than docetaxel alone in the treatment of human prostate cancer cells. Response surfaces were generated for cell viability, and the optimal treatment combination for reducing cell viability was calculated. We found that a combination of 20 µM γ-T3, 30 µM α-TEA, and 25 nm DOC was most effective in the treatment of PC-3 cells. We also found that the combination of γ-T3 and α-TEA with DOC decreased the amount of DOC required to reduce cell viability in PC-3 cells and ameliorated therapeutic resistance in DOC-resistant PC-3 cells.

Vineetha RC, Hariharan S, Jaleel A, Chandran M, Nair RH

Iran J Kidney Dis. 2020 Jan;14(1):26-30.

Abstract

Chemosensitization is an effective strategy to overcome the drawbacks of arsenic trioxide (As₂O₃) treatment, which may be possible through the use of dietary supplements in combination. The present investigation evaluates the synergistic mechanism of action of vitamins, such as L-ascorbic acid (L-AA) and α-tocopherol (α-TOC) in As₂O₃ chemotherapy using human leukemia (HL-60) cells. In vitro assays on the cytotoxicity of As₂O₃ and vitamins and cellular apoptotic evidences were done; a proteomic investigation with mass spectrometry was also performed. The combination of L-AA and α-TOC potentiates As₂O₃ cytotoxicity in HL-60 cells, substantiated by depletion in antioxidant status, mitochondrial transmembrane potential, and inhibition of nuclear factor erythroid 2-related factor 2 and B-cell lymphoma 2 transcription factors. Mass spectrometry results showed decreased expression of proteins regulating cell cycle and translation in cells treated with As₂O₃, L-AA, and α-TOC when compared with As₂O₃-treated sample. In addition, this combination treatment identified numerous proteins associated with apoptosis and cell stress. HL-60 cells became more prone to As₂O₃ on exposure to L-AA and α-TOC, indicating that this combination may be a promising approach to increase the outcome of As₂O₃ chemotherapy.

Park HA, Mnatsakanyan N, Broman K, Davis AU, May J, Licznerski P, Crowe-White KM, Lackey KH, Jonas EA

Int J Mol Sci. 2019 Dec 28;21(1). pii: E220. doi: 10.3390/ijms21010220.

Abstract

B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunction and neuronal death. In this study, we hypothesized that the generation of reactive oxygen species (ROS) during excitotoxicity leads to formation of ∆N-Bcl-xL. We further proposed that the application of an antioxidant with neuroprotective properties such as α-tocotrienol (TCT) will prevent ∆N-Bcl-xL-induced mitochondrial dysfunction via its antioxidant properties. Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both. Glutamate challenge significantly increased cytosolic and mitochondrial ROS and ∆N-Bcl-xL levels. ∆N-Bcl-xL accumulation was accompanied by intracellular ATP depletion, loss of mitochondrial membrane potential, and cell death. α-TCT prevented loss of mitochondrial membrane potential in hippocampal neurons overexpressing ∆N-Bcl-xL, suggesting that ∆N-Bcl-xL caused the loss of mitochondrial function under excitotoxic conditions. Our data suggest that production of ROS is an important cause of ∆N-Bcl-xL formation and that preventing ROS production may be an effective strategy to prevent ∆N-Bcl-xL-mediated mitochondrial dysfunction and thus promote neuronal survival.

Tan GCJ, Tan SMQ, Phang SCW, Ng YT, Ng EY, Ahmad B, Palamisamy UDM, Kadir KA

Ther Adv Endocrinol Metab. 2019 Dec 25;10:2042018819895462. doi: 10.1177/2042018819895462. eCollection 2019.

Abstract

Chronic hyperglycemia in type 2 diabetes mellitus increases oxidative stress and inflammation which contributes to long-term diabetic kidney disease. Tocotrienol-rich vitamin E, as Tocovid, has been shown to reduce oxidative stress and inflammation to ameliorate diabetes in rat models and human subjects. In this prospective, multicenter, double-blinded, placebo-controlled clinical trial, 54 patients (duration = 18.4 years, HbA1c = 8.8%) with diabetic nephropathy were randomized to receive Tocovid 200 mg or placebo for 12 weeks. Fasting blood samples were taken to measure HbA1c, serum creatinine, estimate glomerular filtration rate (eGFR), urine albumin:creatinine ratio, malondialdehyde, tumor necrosis factor receptor-1, vascular cell adhesion molecule-1 (VCAM-1), and thromboxane-B2. Patients were reassessed 6-9 months post-washout. After 12 weeks of supplementation, Tocovid significantly decreased serum creatinine levels (mean difference: -3.3 ± 12.6 versus 5.4 ± 14.2, p = 0.027) and significantly increase eGFR (mean difference: 1.5 ± 7.6 versus -2.9 ± 8.0, p = 0.045) compared with placebo. There were no significant changes in HbA1c, blood pressure, and other parameters. Subgroup analysis revealed that in patients with low serum vitamin E concentrations at baseline, Tocovid reduced serum creatinine, eGFR, and VCAM-1 significantly. After 6-9 months of washout, persistent difference in serum creatinine remained between groups (mean difference: 0.82 ± 8.33 versus 11.26 ± 15.47, p = 0.031), but not eGFR. Tocovid at 400 mg/day significantly improved renal function in 12 weeks of supplementation, as assessed by serum creatinine and eGFR, which remained significant 6-9 months post-washout.

Akdogan M, Polat O

Med Hypothesis Discov Innov Ophthalmol. 2019 Winter;8(4):291-297.

Abstract

Treatment strategy for retinopathy of prematurity (ROP) includes anti-vascular endothelial growth factor (anti-VEGF) and/or laser therapy. The aim of this study was to investigate the clinical effects of topical Coqun® eye drop (CoQ10 and Vitamin-E) on the progression and treatment of ROP. One hundred and ten infants with type 1 ROP who received Coqun® (Coqun group) and 131 infants with type 1 ROP who did not receive Coqun® (control group) were included in this retrospective analysis. All patients were follow-up until retinal vascular maturation was complete. Intravitreal bevacizumab (IVB) injection or laser photocoagulation (LPC) were apply if needed. Treatment frequency, treatment response and mean follow-up time were compare. The number of IVB was similar between the groups, but infants in the Coqun group underwent significantly fewer LPC procedure than those in the control group (P = 0.022). The mean follow-up time was significantly shorter in infants receiving Coqun® in stage 1 ROP (P = 0.017) and similar in stages 2-4 ROP and aggressive posterior retinopathy of prematurity (APROP). The number of LPC procedure was fewer in the Coqun group in APROP (P = 0.043). These results indicate that faster retinal vascular maturation in infants with low-grade ROP and lower number of treatments with APROP could be achieve with Coqun® therapy.

Ramdas P, Radhakrishnan AK, Abdu Sani AA, Kumari M, Anandha Rao JS, Abdul-Rahman PS

Biomolecules. 2019 Dec 21;10(1). pii: E19. doi: 10.3390/biom10010019.

Abstract

Tocotrienol, an analogue of vitamin E has been known for its numerous health benefits and anti-cancer effects. Of the four isoforms of tocotrienols, gamma-tocotrienol (γT3) has been frequently reported for their superior anti-tumorigenic activity in both in vitro and in vivo studies, when compared to its counterparts. In this study, the effect of γT3 treatment in the cytoplasmic and nuclear fraction of MDA-MB-231 human breast cancer cells were assessed using the label-free quantitative proteomics analysis. The cytoplasmic proteome results revealed the ability of γT3 to inhibit a group of proteasome proteins such as PSMA, PSMB, PSMD, and PSME. The inhibition of proteasome proteins is known to induce apoptosis in cancer cells. As such, the findings from this study suggest γT3 as a potential proteasome inhibitor that can overcome deficiencies in growth-inhibitory or pro-apoptotic molecules in breast cancer cells. The nuclear proteome results revealed the involvement of important nuclear protein complexes which hardwire the anti-tumorigenesis mechanism in breast cancer following γT3 treatment. In conclusion, this study uncovered the advancing roles of γT3 as potential proteasomes inhibitor that can be used for the treatment of breast cancer.