Formulation and evaluation of a α-linolenic acid and vitamin E succinate microemulsion with low surfactant content and free of co-surfactant for use as a nutritional supplement

Dan Ye, Liyan Shen, Ying Sun, Di Zhang, Xiao Tan, Panpan Jing, Min Zhang, Qingping Tian

Food Chem . 2021 Dec 1;364:130433. doi: 10.1016/j.foodchem.2021.130433. Epub 2021 Jun 23.

Abstract

Herein, we have designed an alcohol-free and low-surfactant microemulsion to safely and effectively supply α-linolenic acid (ALA) and vitamin E (VE). Ternary phase diagrams show that the use of medium- or short-chain alcohols as the co-surfactant (CoS) was unfavorable for the formation of the ALA microemulsion due to the competitive hydrogen bonding effect and vitamin E succinate (VES) significantly increased the ALA microemulsion region by improving the hydrophilicity of the oil phase. The optimal microemulsion formulation (M_av) was 6.86% ALA, 1.14% VES, 12% surfactant and 80% water, with uniformly dispersed spherical particles with diameters of ~ 25.41 nm and viscosity of 35.17 mPa·s. The M_av was stable to high temperature, ionic strength and pH, and exhibited good physical and anti-oxidation stability. The M_av facilitated the release and hydrolysis of VES, indicating that the CoS-free microemulsion with low surfactant content is promising for the safe and effective supply of ALA and VE.

Ashley S Nemec-Bakk, Vijayalakshmi Sridharan, Reid D Landes, Preeti Singh, Maohua Cao, John W Seawright, Xingui Liu, Guangrong Zheng, Paari Dominic, Rupak Pathak, Marjan Boerma

Life Sci Space Res (Amst) . 2021 Nov;31:43-50. doi: 10.1016/j.lssr.2021.07.006. Epub 2021 Aug 3.

Abstract

Purpose: While there is concern about degenerative tissue effects of exposure to space radiation during deep-space missions, there are no pharmacological countermeasures against these adverse effects. γ-Tocotrienol (GT3) is a natural form of vitamin E that has anti-oxidant properties, modifies cholesterol metabolism, and has anti-inflammatory and endothelial cell protective properties. The purpose of this study was to test whether GT3 could mitigate cardiovascular effects of oxygen ion (¹⁶O) irradiation in a mouse model.

Materials and methods: Male C57BL/6 J mice were exposed to whole-body ¹⁶O (600 MeV/n) irradiation (0.26-0.33 Gy/min) at doses of 0 or 0.25 Gy at 6 months of age and were followed up to 9 months after irradiation. Animals were administered GT3 (50 mg/kg/day s.c.) or vehicle, on Monday – Friday starting on day 3 after irradiation for a total of 16 administrations. Ultrasonography was used to measure in vivo cardiac function and blood flow parameters. Cardiac tissue remodeling and inflammatory infiltration were assessed with histology and immunoblot analysis at 2 weeks, 3 and 9 months after radiation.

Results: GT3 mitigated the effects of ¹⁶O radiation on cardiac function, the expression of a collagen type III peptide, and markers of mast cells, T-cells and monocytes/macrophages in the left ventricle.

Conclusions: GT3 may be a potential countermeasure against late degenerative tissue effects of high-linear energy transfer radiation in the heart.

Vidya P Kumar, Sasha Stone, Shukla Biswas, Neel Sharma, Sanchita P Ghosh

Front Pharmacol . 2021 Nov 29;12:785165. doi: 10.3389/fphar.2021.785165. eCollection 2021.

In the original article, we neglected to include the funder “US Department of Defense Threat Reduction Agency grant H.10016_09_AR_R to SG, administered by The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.”

In the original article, we missed mentioning that we also used GT3 from American River Nutrition (Hadley, MA, United States). A correction has been made to Materials and Methods, GT3 Formulation:

“Pure GT3 was obtained from Yasoo Health Inc. (Johnson City, TN, United States) (Ghosh et al., 2009) and American River Nutrition (Hadley, MA, United States). GT3 and Tween80® (final concentration 5%) were dissolved separately in small volume of ethanol (to enable uniform mixing) and mixed together and then spin-dried under vacuum. Required volume of saline was added to the tube to achieve a final concentration of either 100 or 200 mg GT3 in 0.1 ml.”

Vikas Manjunath, Ravindra V Badhe, Maureen McCoy, Josiah Rynne, Aisha Bhatti, Abhijith Segu, Ebru Oral, Joshua J Jacobs, Paul Chastain, Divya Bijukumar, Mathew T Mathew

J Mech Behav Biomed Mater . 2021 Nov;123:104769. doi: 10.1016/j.jmbbm.2021.104769. Epub 2021 Aug 11.

Abstract

In orthopedic healthcare, Total Hip Replacement (THR) is a common and effective solution to hip-related bone and joint diseases/fracture; however, corrosion of the hip implant and the release of degradation metal ions/particles can lead to early implant failure and pose potential toxicity risk for the surrounding tissues. The main objective of this work was to investigate the potential role of Vitamin E to minimize corrosion-related concerns from CoCrMo hip implants. The study focused on two questions (i) Can Vitamin E inhibit CoCrMo corrosion? and (ii) Does Vitamin E moderate the toxicity associated with the CoCrMo implant particles? In the study (i) the electrochemical experiments (ASTM G61) with different concentrations of Vitamin E (1, 2, 3 mg/ml against the control) were performed using normal saline and simulated synovial fluid (Bovine calf serum-BCS, 30 g/L protein, pH 7.4) as electrolytes. The polished CoCrMo disc (Ra 50 nm) was the working electrode. The findings suggested that both Vitamin E-Saline (45 ± 0.9%) and Vitamin E-BCS (91 ± 3%) solutions protected against implant corrosion at a Vitamin E concentration of 3 mg/ml, but Vitamin E-BCS showed protection at all Vitamin E (1-3 mg/ml) concentration levels. These results suggested that the Vitamin E and the protein present in the BCS imparted additive effects towards the electrochemical inhibition. In the study (ii) the role of Vitamin E in cytotoxicity inhibition was studied using a mouse neuroblastoma cell line (N2a) for CoCrMo particles and Cr ions separately. The CoCrMo particles were generated from a custom-built hip simulator. The alamarBlue assay results suggested that Vitamin E provides significant protection (85% and 75% proliferation) to N2a cells against CoCrMo particles and Cr ions, respectively at 1 μg/ml concentration, as compared to the control group. However, the results obtained from ROS expression and DNA fiber staining suggest that Vitamin E is only effective against CoCrMo degradation particles and not against Cr ions. In summary, the findings show that Vitamin E can minimize the corrosion processes and play a role in minimizing the potential toxicity associated with implants.

Francesco Violi, Cristina Nocella, Lorenzo Loffredo, Roberto Carnevale, Pasquale Pignatelli

Free Radic Biol Med . 2021 Nov 25;S0891-5849(21)00825-X. doi: 10.1016/j.freeradbiomed.2021.11.027. Online ahead of print.

Abstract

Cardiovascular disease (CVD) is one of the major causes of morbidity and mortality and atherosclerosis is the common root to most of the CVD. Oxidative stress is one of the most important factors driving atherosclerosis and its complications. Thus, strategies for the prevention and treatment of cardiovascular events had oxidative changes as a potential target. Natural vitamin E consists of a family of eight different compounds, four tocopherols and four tocotrienols. All tocopherols and tocotrienols are potent antioxidants with lipoperoxyl radical-scavenging activities. In addition, α-tocopherol possesses also anti-inflammatory as well as anti-atherothrombotic effects by modulating platelet and clotting system. Experimental and in vitro studies described molecular and cellular signalling pathways regulated by vitamin E antithrombotic and antioxidant properties. While observational studies demonstrated an inverse association between vitamin E serum levels and CVD, interventional trials with vitamin supplements provided negative results. This review focus on the impact of vitamin E in the atherothrombotic process and describes the results of experimental and clinical studies with the caveats related to the interventional trials with vitamin E to prevent CVD.

Sakda Arj-Ong Vallibhakara, Katanyuta Nakpalat, Areepan Sophonsritsuk, Chananya Tantitham, Orawin Vallibhakara

Nutrients . 2021 Nov 25;13(12):4226. doi: 10.3390/nu13124226.

Abstract

Vitamin E is a strong anti-oxidative stress agent that affects the bone remodeling process. This study evaluates the effect of mixed-tocopherol supplements on bone remodeling in postmenopausal osteopenic women. A double-blinded, randomized, placebo-controlled trial study was designed to measure the effect of mixed-tocopherol on the bone turnover marker after 12 weeks of supplementation. All 52 osteopenic postmenopausal women were enrolled and allocated into two groups. The intervention group received mixed-tocopherol 400 IU/day, while the control group received placebo tablets. Fifty-two participants completed 12 weeks of follow-up. Under an intention-to-treat analysis, vitamin E produced a significant difference in the mean bone resorption marker (serum C-terminal telopeptide of type I collagen (CTX)) compared with the placebo group (-0.003 ± 0.09 and 0.121 ± 0.15, respectively (p < 0.001)). In the placebo group, the CTX had increased by 35.3% at 12 weeks of supplementation versus baseline (p < 0.001), while, in the vitamin E group, there was no significant change of bone resorption marker (p < 0.898). In conclusion, vitamin E (mixed-tocopherol) supplementation in postmenopausal osteopenic women may have a preventive effect on bone loss through anti-resorptive activity.

Ahmad Farouk Musa, Jeswant Dillon, Mohamed Ezani Md Taib, Alwi Mohamed Yunus, Abdul Rais Sanusi, Mohd Nazeri Nordin, Julian A Smith

J Cardiothorac Surg . 2021 Nov 24;16(1):340. doi: 10.1186/s13019-021-01721-6.

Abstract

Introduction: Post-operative atrial fibrillation (POAF) is associated with poorer outcomes, increased resource utilisation, morbidity and mortality. Its pathogenesis is initiated by systemic inflammation and oxidative stress. It is hypothesised that a potent antioxidant and anti-inflammatory agent such as tocotrienol, an isomer of Vitamin E, could reduce or prevent POAF.

Aims: The aim of this study is to determine whether a potent antioxidative and anti-inflammatory agent, Tocovid, a tocotrienol-rich capsule, could reduce the incidence of POAF and affect the mortality and morbidity as well as the duration of ICU, HDU and hospital stay.

Methods: This study was planned as a prospective, randomised, controlled trial with parallel groups. The control group received placebo containing palm superolein while the treatment group received Tocovid capsules. We investigated the incidence of POAF, the length of hospital stay after surgery and the health-related quality of life.

Results: Recruitment commenced in January 2019 but the preliminary results were unblinded as the study is still ongoing. Two-hundred and two patients have been recruited out of a target sample size of 250 as of January 2021. About 75% have completed the study and 6.4% were either lost during follow-up or withdrew; 4% of participants died. The mean age group was 61.44 ± 7.30 years with no statistical difference between the groups, with males having a preponderance for AF. The incidence of POAF was 24.36% and the mean time for developing POAF was 55.38 ± 29.9 h post-CABG. Obesity was not a predictive factor. No statistically significant difference was observed when comparing left atrial size, NYHA class, ejection fraction and the premorbid history. The mean cross-clamp time was 71 ± 34 min and the mean bypass time was 95 ± 46 min, with no difference between groups. There was a threefold increase in death among patients with POAF (p = 0.008) and an increase in the duration of ICU stay (p = 0.01), the total duration of hospital stay (p = 0.04) and reintubation (p = 0.045).

Conclusion: A relatively low incidence rate of POAF was noted although the study is still ongoing. It remains to be seen if our prophylactic intervention using Tocovid would effectively reduce the incidence of POAF.

Yugo Kato, Hayami Uchiumi, Ryo Usami, Hirokatsu Takatsu, Yoshinori Aoki, Shuichi Yanai, Shogo Endo, Koji Fukui

J Clin Biochem Nutr . 2021 Nov;69(3):256-264. doi: 10.3164/jcbn.21-10. Epub 2021 Jun 11.

Abstract

Obesity induces severe disorders such as type 2 diabetes and cardiovascular events, and the number of people with obesity is increasing all over the world. Furthermore, it is possible that obesity increases the risk of cognitive dysfunction via the acceleration of oxidative damage. Tocotrienols, which are part of the vitamin E family, have antioxidant and anti-obesity effects. However, the effects of tocotrienols on high-fat diet-treated mice have not been completely elucidated. In this study, we assessed changes in body weight, spatial reference memory acquisition, liver lipid droplet size, blood brain barrier-related protein expressions and antioxidative defense systems in high-fat diet-treated mice in the presence or absence of tocotrienols. The results showed that tocotrienols significantly inhibited body weight gain and lipid droplet synthesis. Although the amount was very small, it was confirmed that tocotrienols surely reached the brain in the perfused brain. Treatment with tocotrienols was tended to improve cognitive function in the control mice. However, tocotrienols did not modulate blood brain barrier-related protein expressions or antioxidative defense systems. These results indicate that treatment with tocotrienols could be effective for the prevention of obesity and cognitive dysfunction. Further extended research is needed to elucidate the relationship between anti-obesity and antioxidant effects of tocotrienols, especially in the brain.

Aslina Pahrudin Arrozi, Wan Zurinah Wan Ngah, Hanafi Ahmad Damanhuri, Suzana Makpol

Front Pharmacol . 2021 Nov 22;12:698833. doi: 10.3389/fphar.2021.698833. eCollection 2021.

Abstract

Increased amyloid-beta (Aβ) and amyloid precursor protein (APP) in the brains of Alzheimer’s disease (AD) patients are common pathological hallmarks mediating the disease progression. Growing evidence also suggests that mitochondrial abnormalities are an early feature in the pathogenesis of AD. Intervention with antioxidants has received great interest as a molecular strategy for the manipulation of mitochondrial function. Our previous preliminary study using in vitro cell models expressing different types of APP demonstrated that treatment with alpha-tocopherol (ATF) or gamma-tocopherol (GTF) modulates mitochondrial function by reducing mitochondrial reactive oxygen species (ROS), increasing the production of ATP and preventing apoptosis events, especially in cells expressing the mutant APP form. Thus, we hypothesized that ATF or GTF treatment might also alter mitochondrial metabolic pathways such as oxidative phosphorylation. The present study aimed to investigate the role of ATF and GTF in modulating mitochondrial oxidative metabolism using high-resolution respirometry. Our results showed that both ATF and GTF increased the respiratory capacity and membrane potential in the ROUTINE and OXPHOS_CI-LINKED states as well as complex IV enzyme activity in wild-type and mutant APP-overexpressing SH-SY5Y cells. Although preliminary, these findings indicate that ATF and GTF modulate mitochondrial oxidative metabolism in APP-overexpressing cells and, in part, may contribute to the planning of strategies for utilizing vitamin E isomers against mitochondrial-related diseases such as AD.

Shonia Subramaniam, Jeya Seela Anandha Rao, Premdass Ramdas, Mei Han Ng, Methil Kannan Kutty, Kanga Rani Selvaduray, Ammu Kutty Radhakrishnan

Clin Exp Immunol . 2021 Nov;206(2):161-172. doi: 10.1111/cei.13650. Epub 2021 Aug 18.

Abstract

Gamma-tocotrienol (γT3) is an analogue of vitamin E with beneficial effects on the immune system, including immune-modulatory properties. This study reports the immune-modulatory effects of daily supplementation of γT3 on host T helper (Th) and T regulatory cell (T_reg ) populations in a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with either γT3 or vehicle (soy oil) for 2 weeks via oral gavage before they were inoculated with syngeneic 4T1 mouse mammary cancer cells (4T1 cells). Supplementation continued until the mice were euthanized. Mice (n = 6) were euthanized at specified time-points for various analysis (blood leucocyte, cytokine production and immunohistochemistry). Tumour volume was measured once every 7 days. Gene expression studies were carried out on tumour-specific T lymphocytes isolated from splenic cultures. Supplementation with γT3 increased CD4⁺ (p < 0.05), CD8⁺ (p < 0.05) T-cells and natural killer cells (p < 0.05) but suppressed T_reg cells (p < 0.05) in peripheral blood when compared to animals fed with the vehicle. Higher interferon (IFN)-γ and lower transforming growth factor (TGF)-ꞵ levels were noted in the γT3 fed mice. Immunohistochemistry findings revealed higher infiltration of CD4⁺ cells, increased expression of interleukin-12 receptor-beta-2 (IL-12ꞵ2R), interleukin (IL)-24 and reduced expression of cells that express the forkhead box P3 (FoxP3) in tumours from the γT3-fed animals. Gene expression studies showed the down-regulation of seven prominent genes in splenic CD4⁺ T cells isolated from γT3-fed mice. Supplementation with γT3 from palm oil-induced T cell-dependent cell-mediated immune responses and suppressed T cells in the tumour microenvironment in a syngeneic mouse model of breast cancer.