A Phase IIb Randomized Controlled Trial Investigating the Effects of Tocotrienol-Rich Vitamin E on Diabetic Kidney Disease

Yan Yi Koay, Gerald Chen Jie Tan, Sonia Chew Wen Phang, J-Ian Ho, Pei Fen Chuar, Loon Shin Ho, Badariah Ahmad, Khalid Abdul Kadir

Nutrients . 2021 Jan 18;13(1):258. doi: 10.3390/nu13010258.

Abstract

Diabetic kidney disease (DKD) is a debilitating complication of diabetes, which develops in 40% of the diabetic population and is responsible for up to 50% of end-stage renal disease (ESRD). Tocotrienols have shown to be a potent antioxidant, anti-inflammatory, and antifibrotic agent in animal and clinical studies. This study evaluated the effects of 400 mg tocotrienol-rich vitamin E supplementation daily on 59 DKD patients over a 12-month period. Patients with stage 3 chronic kidney disease (CKD) or positive urine microalbuminuria (urine to albumin creatinine ratio; UACR > 20-200 mg/mmol) were recruited into a randomized, double-blind, placebo-controlled trial. Patients were randomized into either intervention group (n = 31) which received tocotrienol-rich vitamin E (Tocovid SupraBioTM; Hovid Berhad, Ipoh, Malaysia) 400 mg daily or a placebo group which received placebo capsules (n = 28) for 12 months. HbA1c, renal parameters (i.e., serum creatinine, eGFR, and UACR), and serum biomarkers were collected at intervals of two months. Tocovid supplementation significantly reduced serum creatinine levels (MD: -4.28 ± 14.92 vs. 9.18 ± 24.96), p = 0.029, and significantly improved eGFR (MD: 1.90 ± 5.76 vs. -3.29 ± 9.24), p = 0.011 after eight months. Subgroup analysis of 37 patients with stage 3 CKD demonstrated persistent renoprotective effects over 12 months; Tocovid improved eGFR (MD: 4.83 ± 6.78 vs. -1.45 ± 9.18), p = 0.022 and serum creatinine (MD: -7.85(20.75) vs. 0.84(26.03), p = 0.042) but not UACR. After six months post washout, there was no improvement in serum creatinine and eGFR. There were no significant changes in the serum biomarkers, TGF-β1 and VEGF-A. Our findings verified the results from the pilot phase study where tocotrienol-rich vitamin E supplementation at two and three months improved kidney function as assessed by serum creatinine and eGFR but not UACR.

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Application of Partial Hydrogenation for the Generation of Minor Tocochromanol Homologs and Functional Evaluation of Hydrogenated Tocotrienol-rich Vitamin E Oil in Diabetic Obese Mice

Fumiaki Beppu, Aimi Sakuma, Satoshi Kasatani, Yoshinori Aoki, Naohiro Gotoh

J Oleo Sci . 2021;70(1):103-112. doi: 10.5650/jos.ess20233.

Abstract

Recent research has identified minor homologs of vitamin E with one or two double bonds in the side-chain, namely tocomonoenol (T1) and tocodienol (T2), in natural products. We first explored the effectiveness of partial hydrogenation for generating minor tocochromanols from tocotrienol (T3). During hydrogenation with pure α-T3 as a substrate, the side-chain was partially saturated in a time-dependent manner, and a large amount of α-T1 and α-T2 was obtained. To investigate the beneficial effects of the hydrogenated product, we fed diabetic obese KK-A y mice with a hydrogenated T3 mixture (HT3). Feeding HT3 revealed tissue-specific accumulation of tocochromanols, ameliorated hyperglycemia and improved ratio of high-density lipoprotein cholesterol to total cholesterol in serum, with invariant body weight and fat mass. Hence, we propose that hydrogenation is a useful method for generating T1 and T2 homologs, which can be applied to explore the structure-related function of tocochromanols.

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Study of vitamin E microencapsulation and controlled release from chitosan/sodium lauryl ether sulfate microcapsules

Jelena Milinković Budinčić, Lidija Petrović, Ljiljana Đekić, Jadranka Fraj, Sandra Bučko, Jaroslav Katona, Ljiljana Spasojević

Carbohydr Polym . 2021 Jan 1;251:116988. doi: 10.1016/j.carbpol.2020.116988. Epub 2020 Aug 30.

Abstract

Potential benefit of microencapsulation is its ability to deliver and protect incorporated ingredients such as vitamin E. Microcapsule wall properties can be changed by adding of coss-linking agents that are usually considered toxic for application. The microcapsules were prepared by a spray-drying technique using coacervation method, by depositing the coacervate formed in the mixture of chitosan and sodium lauryl ether sulfate to the oil/water interface. All obtained microcapsules suspensions had slightly lower mean diameter compared to the starting emulsion (6.85 ± 0.213 μm), which shows their good stability during the drying process. The choice and absence of cross-linking agents had influence on kinetics of vitamin E release. Encapsulation efficiency of microcapsules without cross-linking agent was 73.17 ± 0.64 %. This study avoided the use of aldehydes as cross-linking agents and found that chitosan/SLES complex can be used as wall material for the microencapsulation of hydrophobic active molecules in cosmetic industry.

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Vitamin E-infused highly cross-linked polyethylene did not reduce the number of in vivo wear particles in total knee arthroplasty

Kumi Orita, Yukihide Minoda, Ryo Sugama, Yoichi Ohta, Hideki Ueyama, Susumu Takemura, Hiroaki Nakamura

Carbohydr Polym . 2021 Jan 1;251:116988. doi: 10.1016/j.carbpol.2020.116988. Epub 2020 Aug 30.

Abstract

Aims: Vitamin E-infused highly cross-linked polyethylene (E1) has recently been introduced in total knee arthroplasty (TKA). An in vitro wear simulator study showed that E1 reduced polyethylene wear. However there is no published information regarding in vivo wear. Previous reports suggest that newly introduced materials which reduce in vitro polyethylene wear do not necessarily reduce in vivo polyethylene wear. To assist in the evaluation of the newly introduced material before widespread use, we established an in vivo polyethylene wear particle analysis for TKA. The aim of this study was to compare in vivo polyethylene wear particle generation between E1 and conventional polyethylene (ArCom) in TKA.

Methods: A total of 34 knees undergoing TKA (17 each with ArCom or E1) were investigated. Except for the polyethylene insert material, the prostheses used for both groups were identical. Synovial fluid was obtained at a mean of 3.4 years (SD 1.3) postoperatively. The in vivo polyethylene wear particles were isolated from the synovial fluid using a previously validated method and examined by scanning electron microscopy.

Results: The total number of polyethylene wear particles obtained from the knees with E1 (mean 6.9, SD 4.0 × 107 counts/knee) was greater than that obtained from those with ArCom (mean 2.2, SD 2.6 × 107 counts/knee) (p = 0.001). The particle size (equivalent circle of diameter) from the knees with E1 was smaller (mean 0.5 μm, SD 0.1) than that of knees with ArCom (mean 1.5, SD 0.3 μm) (p = 0.001). The aspect ratio of particles from the knees with E1 (mean 1.3, SD 0.1) was smaller than that with ArCom (mean 1.4, SD 0.1) (p < 0.001 ).

Conclusion: This is the first report of in vivo wear particle analysis of E1. E1 polyethylene did not reduce the number of in vivo polyethylene wear particles compared with ArCom in early clinical stage. Further careful follow-up of newly introduced E1 for TKA should be carried out. Cite this article: Bone Joint J 2020;102-B(11):1527-1534.

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Involvement of miR-190b in Xbp1 mRNA Splicing upon Tocotrienol Treatment

Roberto Ambra, Sonia Manca, Guido Leoni, Barbara Guantario, Raffaella Canali, Raffaella Comitato

Molecules . 2020 Dec 31;26(1):163. doi: 10.3390/molecules26010163.

Abstract

We previously demonstrated that apoptosis induced by tocotrienols (γ and δT3) in HeLa cells is preceded by Ca2+ release from the endoplasmic reticulum. This event is eventually followed by the induction of specific calcium-dependent signals, leading to the expression and activation of the gene encoding for the IRE1α protein and, in turn, to the alternative splicing of the pro-apoptotic protein sXbp1 and other molecules involved in the unfolded protein response, the core pathway coping with EndoR stress. Here, we showed that treatment with T3s induces the expression of a specific set of miRNAs in HeLa cells. Data interrogation based on the intersection of this set of miRNAs with a set of genes previously differentially expressed after γT3 treatment provided a few miRNA candidates to be the effectors of EndoR-stress-induced apoptosis. To identify the best candidate to act as the effector of the Xbp1-mediated apoptotic response to γT3, we performed in silico analysis based on the evaluation of the highest ∆ in Gibbs energy of different mRNA-miRNA-Argonaute (AGO) protein complexes. The involvement of the best candidate identified in silico, miR-190b, in Xbp1 splicing was confirmed in vitro using T3-treated cells pre-incubated with the specific miRNA inhibitor, providing a preliminary indication of its role as an effector of EndoR-stress-induced apoptosis.

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Pharmacology and Pharmacokinetics of Vitamin E: Nanoformulations to Enhance Bioavailability

Anis Syauqina Mohd Zaffarin, Shiow-Fern Ng, Min Hwei Ng, Haniza Hassan, Ekram Alias

Int J Nanomedicine . 2020 Dec 8;15:9961-9974. doi: 10.2147/IJN.S276355. eCollection 2020.

Abstract

Vitamin E belongs to the family of lipid-soluble vitamins and can be divided into two groups, tocopherols and tocotrienols, with four isomers (alpha, beta, gamma and delta). Although vitamin E is widely known as a potent antioxidant, studies have also revealed that vitamin E possesses anti-inflammatory properties. These crucial properties of vitamin E are beneficial in various aspects of health, especially in neuroprotection and cardiovascular, skin and bone health. However, the poor bioavailability of vitamin E, especially tocotrienols, remains a great limitation for clinical applications. Recently, nanoformulations that include nanovesicles, solid-lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and polymeric nanoparticles have shown promising outcomes in improving the efficacy and bioavailability of vitamin E. This review focuses on the pharmacological properties and pharmacokinetics of vitamin E and current advances in vitamin E nanoformulations for future clinical applications. The limitations and future recommendations are also discussed in this review.

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Synthesis of [ 18 F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics

Peter Roselt, Carleen Cullinane, Wayne Noonan, Hassan Elsaidi, Peter Eu, Leonard I Wiebe

Molecules . 2020 Dec 3;25(23):5700. doi: 10.3390/molecules25235700.

Abstract

Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, β-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E’s biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[18F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([18F]F-γ-T-3) was prepared for this purpose. [18F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [18F]fluoride in DMF/K222. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [18F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [18F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [18F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.

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Stereological and histopathological evaluation of doxorubicin-induced toxicity in female rats’ ovary and uterus and palliative effects of quercetin and vitamin E

M Samare-Najaf, F Zal, S Safari, F Koohpeyma, N Jamali

Hum Exp Toxicol . 2020 Dec;39(12):1710-1724. doi: 10.1177/0960327120937329. Epub 2020 Jul 15.

Abstract

Doxorubicin (DOX) is a widely used chemotherapeutic agent with demonstrated reproductive toxicity. This study sought to determine the DOX-induced toxicity in the ovary and uterus and the preventive effects of quercetin (QCT) and vitamin E (Vit.E). Female rats were divided into six groups as follows: control, QCT (20 mg/kg), Vit.E (200 mg/kg), DOX (accumulative 15 mg/kg), DOX/QCT, and DOX/Vit.E. After 3 weeks, the toxicity of DOX in ovarian and uterine tissues and the potential palliative effects of QCT and Vit.E were evaluated by histopathological-stereological methods. The findings indicate a dramatic decline in the number of ovarian follicles (p < 0.001), ovarian and its associated structures volume, the volume of the uterus, its layers, and related structures (p < 0.05). Coadministration of QCT and Vit.E with DOX-treated rats demonstrated an alleviative effect on most of the studied parameters. Nevertheless, few adverse effects were recognized concerning these antioxidants administration (p < 0.05). In conclusion, the findings of this study support the protective role of these dietary supplements in the prevention of DOX-induced toxicity in uterine and ovarian tissues.

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Epidermal Growth Factor and Tocotrienol-Rich Fraction Cream Formulation Accelerates Burn Healing Process Based on Its Gene Expression Pattern in Deep Partial-Thickness Burn Wound Model

Hui-Fang Guo, Razana Mohd Ali, Roslida Abd Hamid, Sui Kiat Chang, Mohammed Habibur Rahman, Zaida Zainal, Huzwah Khaza'ai

Int J Low Extrem Wounds . 2020 Nov 26;1534734620971066. doi: 10.1177/1534734620971066. Online ahead of print.

Abstract

Our previous study has demonstrated that epidermal growth factor (EGF) with tocotrienol-rich fraction (TRF) cream formulation accelerating postburn wound healing with deep partial-thickness burn in rats. Current study was conducted to determine the gene expression levels related to burn wound healing process. A total of 180 Sprague-Dawley rats were randomly divided into 6 groups: untreated control, treated with Silverdin cream, base cream, base cream with 0.00075% EGF, base cream with 3% TRF or base cream with 0.00075% EGF, and 3% TRF, respectively. Burn wounds were created and the above-mentioned creams were applied once daily. Six animals from each group were sacrificed on days 3, 7, 11, 14, and 21 postburn. RNA was extracted from wound tissues and quantitative real-time polymerase chain reaction was performed to analyze the 9 wound healing-related genes against time postburn. Results demonstrated that topically applied EGF + TRF formulation downregulated the expression levels of IL-6 (interluekin-6), TNF-α (tumor necrosis factor-α) and iNOS (inducible nitric oxide synthase) throughout the whole healing process. TGF-β1 (transforming growth factor-β) and VEGF-A (vascular endothelial growth factor-A) were reduced on day 14 postburn. On the contrary, increased expression of Collagen-1 in the early stage of wound healing was observed with no effects on epidemal growth factor receptor (EGFR). The results showed beneficial application of EGF + TRF cream in the treatment of burn wound since it accelerated wound healing by relieving oxidative stress, decreasing inflammation, and promoting proper tissue modelling in the burn wound.

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Analysis of expression of vitamin E-binding proteins in H2O2 induced SK-N-SH neuronal cells supplemented with α-tocopherol and tocotrienol-rich fraction

Aishatu Ali Chiroma, Huzwah Khaza'ai, Roslida Abd Hamid, Sui Kiat Chang, Zainul Amiruddin Zakaria, Zaida Zainal

PLoS One . 2020 Nov 24;15(11):e0241112. doi: 10.1371/journal.pone.0241112. eCollection 2020.

Abstract

Natural α-tocopherol (α-TCP), but not tocotrienol, is preferentially retained in the human body. α-Tocopherol transfer protein (α-TTP) is responsible for binding α-TCP for cellular uptake and has high affinity and specificity for α-TCP but not α-tocotrienol. The purpose of this study was to examine the modification of α-TTP together with other related vitamin E-binding genes (i.e., TTPA, SEC14L2, and PI-TPNA) in regulating vitamin E uptake in neuronal cells at rest and under oxidative stress. Oxidative stress was induced with H2O2 for an hour which was followed by supplementation with different ratios of α-TCP and tocotrienol-rich fraction (TRF) for four hours. The cellular levels of vitamin E were quantified to determine bioavailability at cellular levels. The expression levels of TTPA, SEC14L2, and PI-TPNA genes in 0% α-TCP were found to be positively correlated with the levels of vitamin E in resting neuronal cells. In addition, the regulation of all the above-mentioned genes affect the distribution of vitamin E in the neuronal cells. It was observed that, increased levels of α-TCP secretion occur under oxidative stress. Thus, our results showed that in conclusion vitamin E-binding proteins may be modified in the absence of α-TCP to produce tocotrienols (TCT), as a source of vitamin E. The current study suggests that the expression levels of vitamin E transport proteins may influence the cellular concentrations of vitamin E levels in the neuronal cells.

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