Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial

Pei Fen Chuar, Yeek Tat Ng, Sonia Chew Wen Phang, Yan Yi Koay, J-Ian Ho, Loon Shin Ho, Nevein Philip Botross Henien, Badariah Ahmad, Khalid Abdul Kadir

Nutrients . 2021 Oct 25;13(11):3770. doi: 10.3390/nu13113770.

Abstract

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid Suprabio^TM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFβ-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

You Zhuan Lee, Eng Kwong Seow, Sheau Chin Lim, Kah Hay Yuen, Nurzalina Abdul Karim Khan

Pharmaceutics . 2021 Oct 25;13(11):1777. doi: 10.3390/pharmaceutics13111777.

Abstract

Self-emulsifying drug delivery systems (SEDDS) can improve the oral bioavailability of poorly water-soluble drugs. Solid self-emulsifying drug delivery systems (s-SEDDS) offer several advantages including improved drug stability, ease of administration, and production. Most compounds employed in developing s-SEDDS are solid in nature, with a high amount of surfactants added. The aim of this study was to develop an s-SEDDS using a tocotrienol-rich fraction (TRF) as the model liquid active substance via a simple adsorption method. The solid formulation was developed using magnesium aluminosilicate as the carrier with 70% TRF and 30% surfactants (poloxamer and Labrasol^®). The formulation showed good self-emulsification efficiency with stable emulsion formed, excellent powder flowability, and small emulsion droplet size of 210-277 nm. The s-SEDDS with combined surfactants (poloxamer and Labrasol^®) showed a faster absorption rate compared to preparations with only a single surfactant and enhanced oral bioavailability (3.4-3.8 times higher) compared to the non-self-emulsifying oily preparation when administered at a fasted state in rats. In conclusion, an s-SEDDS containing a high amount of TRF was successfully developed. It may serve as a useful alternative to a liquid product with enhanced oral bioavailability and the added advantage of being a solid dosage form.

Na-Young Park, Suji Im, Qing Jiang

J Nutr Biochem . 2021 Oct 25;100:108884. doi: 10.1016/j.jnutbio.2021.108884. Online ahead of print.

Abstract

Cyclooxygenase (COX-1 and COX-2)- and 5-lipoxygenase (5-LOX)-catalyzed biosynthesis of eicosanoids play important roles in inflammation and chronic diseases. The vitamin E family has four tocopherols and tocotrienols. We have shown that the metabolites of δ-tocopherol (δT) and δ-tocotrienol (δTE), i.e., δT-13′-carboxychromanol (COOH) and δTE-13′-COOH, respectively, inhibit COX-1/-2 and 5-LOX activity, but the nature of how they inhibit 5-LOX is not clear. Further, the impact of tocopherols and tocotrienols on COX-1/-2 or 5-LOX activity has not been fully delineated. In this study, we found that tocopherols and tocotrienols inhibited human recombinant COX-1 with IC50s of 1-12 µM, and suppressed COX-1-mediated formation of thromboxane in collagen-stimulated rat’s platelets with IC50s of 8-50 µM. None of the vitamin E forms directly inhibited COX-2 activity. 13′-COOHs inhibited COX-1 and COX-2 enzyme activity with IC50s of 3-4 and 4-10 µM, respectively, blocked thromboxane formation in collagen- and ionophore-stimulated rats’ platelets with IC50s of 1.5-2.5 µM, and also inhibited COX-2-mediated prostaglandins in stimulated cells. Using enzyme kinetics, we observed that δT-13′-COOH, δTE-13′-COOH and δTE competitively inhibited 5-LOX activity with Ki of 1.6, 0.8 and 2.2 µM, respectively. These compounds decreased leukotriene B₄ from stimulated neutrophil-like cells without affecting translocation of 5-LOX from cytosol to the nucleus. Our study reveals inhibitory effects of vitamin E forms and 13′-COOHs on COX-1 activity and thromboxane formation in platelets, and elucidates mechanisms underlying their inhibition of 5-LOX. These observations are useful for understanding the role of these compounds in disease prevention and therapy.

Maret G Traber, Brian Head

Free Radic Biol Med . 2021 Oct 23;177:212-225. doi: 10.1016/j.freeradbiomed.2021.10.028. Online ahead of print.

Abstract

α-Tocopherol (α-T) is a required dietary nutrient for humans and thus is a vitamin. This narrative review focuses on vitamin E structures, functions, biological determinants and its deficiency symptoms in humans. The mechanisms for the preferential α-T tissue enrichment in the human body include the α-T transfer protein (TTPA) and the preferential metabolism of non-α-T forms. Potential new α-T biomarkers, pharmacokinetic data, and whether there are better approaches to evaluate and set the α-T dietary requirement are discussed. Finally, the possible role of α-T supplements in delay of chronic diseases and the evaluation of vitamin E safety are considered.

Masaki Tanito

Free Radic Biol Med . 2021 Oct 22;177:100-119. doi: 10.1016/j.freeradbiomed.2021.10.027. Online ahead of print.

Abstract

Cataract and glaucoma are the major causes of severe visual loss and blindness in older adults. This review article describes the currently available basic and clinical evidence regarding vitamin E protection against these eye diseases in the chronologic order of the publications. Experimental evidence has suggested both that oxidative stress due to the accumulation of free radicals plays a role in the pathogenesis of cataracts and glaucoma and that the process can be prevented or ameliorated by vitamin E. The results of observational studies have been inconsistent regarding the association between blood vitamin E levels and the risk of age-related cataract or glaucoma. Despite the encouraging effects of vitamin E from case series, case-control studies, and cross-sectional studies in humans, the effects on cataract formation and/or progression have not been consistent among prospective and randomized control studies; few randomized control studies have tested the effects of supplemental vitamin E on glaucoma development or progression. Given the high prevalence of cataract and glaucoma in the elderly population, even a modest reduction in the risk for these eye diseases would potentially have a substantial public health impact; however, the potential benefits of vitamin E on cataract or glaucoma remain inconclusive and need to be carefully considered.

Chikako Kiyose

Free Radic Biol Med . 2021 Oct 20;S0891-5849(21)00766-8. doi: 10.1016/j.freeradbiomed.2021.10.016. Online ahead of print.

Abstract

Vitamin E has eight different naturally occurring forms: four tocopherols and four tocotrienols. Because α-tocopherol has three asymmetric carbons, both natural α-tocopherol (RRR-α-tocopherol) and synthetic α-tocopherol (all-rac-α-tocopherol) are utilized in both pharmaceutical products and food additives. Therefore, determining the distribution of vitamin E in the body is very important. With regard to absorption, and transportation of vitamin E, it is suggested that the pathways mediated by three proteins (CD36, SR-BI, and NPC1L1) as well as passive diffusion affect absorption of vitamin E. Vitamin E homologs are mainly transported by very low-density lipoprotein (VLDL) with the α-tocopherol being recognized by the α-tocopherol transfer protein in liver. However, it is also suggested that chylomicrons (CMs) and high-density lipoprotein (HDL) are involved in transportation of vitamin E homologs from the small intestine to each section of peripheral tissue. In particular, it is speculated that vitamin E homologs transportation by CMs and HDL from enterocytes to peripheral tissues such as adipose tissue greatly affects the distribution of vitamin E homologs, excluding α-tocopherol. However, how lipoprotein lipase affects the incorporation of vitamin E homologs containing lipoprotein into peripheral tissues is unclear. Whether there is biodiscrimination when vitamin E homologs are incorporated into peripheral tissues from lipoprotein is an interesting question. It is likely that future research will reveal how individual vitamin E homologs are incorporated into peripheral tissue, especially the brain, adipose tissue, and skin.

Zhenou Sun, Shutao Yin, Chong Zhao, Li Hong Fan, Hongbo Hu

Carcinogenesis . 2021 Oct 17;bgab096. doi: 10.1093/carcin/bgab096. Online ahead of print.

Abstract

Numerous studies have shown that the different isoforms vitamin E have distinct activity on carcinogenesis. α-Tocopherol (α-T), the most abundant vitamin E in certain types of food and animal tissues, has demonstrated a cancer-promoting effect in a number of human clinical trials and pre-clinical studies, whereas the γ- and δ- forms of Tocopherols and Tocotrienols have exhibited significant anticancer effect in various pre-clinical studies. However, the mechanisms underlying the tumorigenic effect of α-T have not yet been fully understood. In the present study, we found that α-T was able to activate Programmed death-ligand 1 (PD-L1)-mediated tumor-intrinsic signaling and immune suppression via JAK/STAT3-dependent transcriptional and ERK-dependent posttranscriptional mechanism. In line with PD-L1 induction, α-T treatment increased cancer cell viability in vitro and promoted tumor growth in LLC xenograft mouse model. The findings of the present study for the first time provided evidence that PD-L1-mediated tumor-intrinsic and immune escape mechanism contributed to the tumorigenic effect of α-T.

Alexander Montoya-Arroyo, Tanja Wagner, Nadine Sus, Marco Müller, Alexander Kröpfl, Walter Vetter, Jan Frank

Free Radic Biol Med . 2021 Oct 16;S0891-5849(21)00768-1. doi: 10.1016/j.freeradbiomed.2021.10.018. Online ahead of print.

Abstract

Contrary to the major vitamin E congener α-tocopherol, which carries a saturated sidechain, and α-tocotrienol, with a threefold unsaturated sidechain, little is known about the intracellular fate of α-tocomonoenol, a minor vitamin E derivative with a single double bond in C11′-position of the sidechain. We hypothesized that, due to structural similarities, the uptake and metabolism of α-tocomonoenol will resemble that of α-tocopherol. Cytotoxicity, cellular uptake of α-tocomonoenol, α-tocopherol and α-tocotrienol and conversion into the short-chain metabolites αCEHC and αCMBHC were studied in HepG2 cells. α-Tocomonoenol did not show significant effects on cell viability and its uptake was similar to that observed for α-tocopherol and significantly lower than for α-tocotrienol. α-Tocomonoenol was mainly metabolized to αCMBHC in liver cells, but to a lower extent than α-tocotrienol, while α-tocopherol was not metabolized in quantifiable amounts at all. In summary, the similarities in the cytotoxicity, uptake and metabolism of α-tocomonoenol and α-tocopherol suggest that this minor vitamin E congener deserves more attention in future research with regard to its potential vitamin E activity.

Enzo Berardesca, Norma Cameli

Dermatol Ther . 2021 Oct 16;e15160. doi: 10.1111/dth.15160. Online ahead of print.

Abstract

Vitamin E is a powerful lipophilic antioxidant that protects membranes from lipid peroxidation, and consequently, oxidative damage. Oxidative stress plays a role in the development of neurodegenerative diseases. Vitamin E supplementation is recommended in patients with vitamin E deficiency due to fat malabsorption. The addition of vitamin E to the diet slows Alzheimer’s disease progression and protects older patients against respiratory infections. Recent studies also point to the involvement of oxidative stress in the pathology of immune-mediated skin diseases, such as atopic dermatitis and psoriasis. We reviewed the available clinical trials that investigated the role of vitamin E supplementation in preventing and treating atopic dermatitis and psoriasis. Data from these studies point to a positive role of vitamin E supplementation in these diseases. Still, due to limitations in study design, further evidence is needed to reach a definite conclusion.

Irina Zueva, Sofya Lushchekina, Polina Shulnikova, Oksana Lenina, Konstantin Petrov, Elena Molochkina, Patrick Masson

Chem Biol Interact . 2021 Oct 1;348:109646. doi: 10.1016/j.cbi.2021.109646. Epub 2021 Sep 8.

Abstract

Acetylcholinesterase (AChE) is reversibly inhibited by α-tocopherol (α-T). Steady state kinetic analysis shows that α-T is a mixed slow-binding inhibitor of type A of human enzyme (K_ci = 0.49 μM; K_ui = 1.6 μM) with a residence time of 2 min on target. Molecular dynamics (MD) simulations support this mechanism, and indicate that α-T first forms multiple non-specific interactions with AChE surface near the gorge entrance, then binds to the peripheral side with alkylene chain slowly sliding down the gorge, inducing no significant conformational change. α-T slightly modulates the progressive inhibition of AChE by the cyclic organophosphorus, cresyl saligenylphosphate, accelerating the fast pseudo-first order process of phosphorylation. A moderate accelerating effect of α-T on phosphorylation by paraoxon was also observed after pre-incubation of AChE in the presence of α-T. This accelerating effect of α-T on ex vivo paraoxon-induced diaphragm muscle weakness was also observed. The effect of α-T on AChE phosphylation was interpreted in light of molecular modeling results. From all results it is clear that α-T does not protect AChE against phosphylation by organophosphorus.