Perspective: Should Vitamin E Recommendations for Older Adults Be Increased?

Meydani SN, Lewis ED, Wu D

Adv Nutr. 2018 Aug 11. doi: 10.1093/advances/nmy035. [Epub ahead of print]

Abstract

Current vitamin E requirements are uniformly applied across the population for those >14 y of age. However, aging is associated with alterations in cellular and physiologic functions, which are affected by vitamin E. Therefore, it is questionable whether vitamin E requirements can be uniformly applied to all adult age categories. With aging, there is dysregulation of the immune system in which there are decreased cell-mediated and pathogen defense responses coupled with an overactive, prolonged inflammatory state. Both animal and human studies in the aged suggest that intake above currently recommended levels of vitamin E may improve immune and inflammatory responses and be associated with a reduced risk of infectious disease. We review the evidence that was considered in establishing the current requirements for vitamin E and highlight data that should be considered in determining the vitamin E requirements in older adults, particularly focusing on the evidence suggesting a benefit of increased vitamin E intake on immune function and inflammatory processes and resistance to infection. The main objective of this Perspective is to initiate the discussion of whether the current Dietary Reference Intake for vitamin E should be increased for the older population. We make this suggestion on the basis of mechanistic studies showing biological plausibility, correction of a major cellular dysfunction in older adults, and strong evidence from several animal and a few human studies indicating a reduction in risk and morbidity from infections.

Montagnani Marelli M, Marzagalli M, Fontana F, Raimondi M, Moretti RM, Limonta P

J Cell Physiol. 2018 Aug 1. doi: 10.1002/jcp.27075. [Epub ahead of print]

Abstract

Vitamin E is composed of two groups of compounds: α-, β-, γ-, and δ-tocopherols (TPs), and the corresponding unsaturated tocotrienols(TTs). TTs are found in natural sources such as red palm oil, annatto seeds, and rice bran. In the last decades, TTs (specifically, γ-TT and δ-TT) have gained interest due to their health benefits in chronic diseases, based on their antioxidant, neuroprotective, cholesterol-lowering, anti-inflammatory activities. Several in vitro and in vivo studies pointed out that TTs also exert a significant antitumor activity in a wide range of cancer cells. Specifically, TTs were shown to exert antiproliferative/proapoptotic effects and to reduce the metastatic or angiogenic properties of different cancer cells; moreover, these compounds were reported to specifically target the subpopulation of cancer stem cells, known to be deeply involved in the development of resistance to standard therapies. Interestingly, recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents (i.e., chemotherapeutics, statins, “targeted” therapies) or natural compounds with anticancer activity (i.e., sesamin, epigallocatechin gallate (EGCG), resveratrol, ferulic acid). Based on these observations, different TT synthetic derivatives and formulations were recently developed and demonstrated to improve TT water solubility and to reduce TT metabolism in cancer cells, thus increasing their biological activity. These promising results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment (i.e., in combination with standard therapies) strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed.

Kumar A, Sharma R, Rana D, Sharma N

Endocr Metab Immune Disord Drug Targets. 2018 Aug 1. doi: 10.2174/1871530318666180801144822. [Epub ahead of print]

Abstract

BACKGROUND AND OBJECTIVE:

α-Tocopherol is the active form of vitamin E which have various biological functions. However, the exact molecular mechanism of its action is not fully understood. Thus, the main objective of the current study is to determine the contribution of α-tocopherol in counteraction of the apoptogenic signaling pathways induced by deltamethrin in murine thymocytes and splenocytes.

METHODS AND RESULTS:

Deltamethrin (25 µM) induces apoptosis at 18 h through activation of reactive oxygen species, caspases and depletion of glutathione in thymocytes and splenocytes. MTT assay results have shown that α-tocopherol (10 and 50 µg/ml) when added along with Deltamethrin (25µM), increases the viability of thymocytes and splenocytes in a concentration-dependent manner. The α-tocopherol treatment reduces the early markers of cell death (ROS and caspase3 activation) significantly. Further, the depleted GSH by deltamethrin, has been also restored by α-tocopherol. At 18 h, α-tocopherol (50 µg/ml) significantly reduced the Deltamethrin induced cell death. In additional, phenotyping and cytokines assay have demonstrated that alpha-tocopherol significantly ameliorated the altered immune functions.

CONCLUSION:

These findings indicate that α-tocopherol shows immunoprotective effects in Deltamethrin induced splenic and thymic apoptosis by inhibiting oxidative stress and caspase-dependent apoptogenic pathways.

Chou CC, Sung YC, Davison G, Chen CY, Liao YH

Int J Med Sci. 2018 Jul 30;15(11):1217-1226. doi: 10.7150/ijms.26340. eCollection 2018.

Abstract

Background: Exercise-induced muscle damage during intensive sport events is a very common issue in sport medicine. Therefore, the purpose is to investigate the effects of short-term high-dose vitamin C and E supplementation on muscle damage, hemolysis, and inflammatory responses to simulated competitive Olympic Taekwondo (TKD) matches in elite athletes. Methods: Using a randomized placebo-controlled and double-blind study design, eighteen elite male TKD athletes were weight-matched and randomly assigned into either a vitamin C and E group (Vit C+E; N = 9) or placebo group (PLA; N = 9). Vit C+E or PLA supplements were taken daily (Vit C+E: 2000 mg/d vitamin C; 1400 U/d vitamin E) for 4 days (3 days before and on competition day) before taking part in 4 consecutive TKD matches on a single day. Plasma samples were obtained before each match and 24-hours after the first match for determination of markers of muscle damage, hemolysis, and systemic inflammatory state. Results: Myoglobin was lower in the Vit C+E group, compared to PLA, during the match day (area under curve, AUC -47.0% vs. PLA, p = 0.021). Plasma creatine kinase was lower in the Vit C+E group (AUC -57.5% vs. PLA, p = 0.017) and hemolysis was lower in the Vit C+E group (AUC -40.5% vs. PLA, p = 0.034). Conclusions: We demonstrated that short-term (4-days) vitamin C and E supplementation effectively attenuated exercise-induced tissue damage and inflammatory response during and after successive TKD matches.

Shen CL, Kaur G, Wanders D, Sharma S, Tomison MD, Ramalingam L, Chung E, Moustaid-Moussa N, Mo H, Dufour JM

Sci Rep. 2018 Jul 27;8(1):11377. doi: 10.1038/s41598-018-29063-9.

Abstract

Diabetes is a risk factor for osteoporosis. Annatto-extracted tocotrienols (TT) have proven benefits in preserving bone matrix. Here, we evaluated the effects of dietary TT on glucose homeostasis, bone properties, and liver pro-inflammatory mRNA expression in high-fat diet (HFD)-induced type 2 diabetic (T2DM) mice. 58 male C57BL/6 J mice were divided into 5 groups: low-fat diet (LFD), HFD, HFD + 400 mgTT/kg diet (T400), HFD + 1600 mgTT/kg diet (T1600), and HFD + 200 mg metformin/kg (Met) for 14 weeks. Relative to the HFD group, both TT-supplemented groups (1) improved glucose homeostasis by lowering the area under the curve for both glucose tolerance and insulin tolerance tests, (2) increased serum procollagen I intact N-terminal propeptide (bone formation) level, trabecular bone volume/total volume, trabecular number, connectivity density, and cortical thickness, (3) decreased collagen type 1 cross-linked C-telopeptide (bone resorption) levels, trabecular separation, and structure model index, and (4) suppressed liver mRNA levels of inflammation markers including IL-2, IL-23, IFN-γ, MCP-1, TNF-α, ITGAX and F4/80. There were no differences in glucose homeostasis and liver mRNA expression among T400, T1600, and Met. The order of osteo-protective effects was LFD ≥T1600 ≥T400 = Met >HFD. Collectively, these data suggest that TT exerts osteo-protective effects in T2DM mice by regulating glucose homeostasis and suppressing inflammation.

Bhatti FUR, Kim SJ, Yi AK, Hasty KA, Cho H

Cell Tissue Res. 2018 Jun 27. doi: 10.1007/s00441-018-2857-3. [Epub ahead of print]

Abstract

Survival of mesenchymal stem cells (MSCs) against oxidative stress and inflammation is vital for effective stem cell therapy. The reactive oxygen species (ROS) result in apoptosis and release of inflammatory mediators. Adipose-derived stem cells (ASCs) have shown promise for stem cell therapy owing to their anti-inflammatory and anti-oxidant activity. Previously, we showed the benefits of vitamin E against hydrogen peroxide (H₂O₂)-induced oxidative stress in rat bone marrow-derived MSCs. In this study, we aim to evaluate the effect of vitamin E treatment on porcine adipose-derived mesenchymal stem cells (pASCs) against H₂O₂-induced oxidative stress. The oxidative stress was induced by treating pASCs with 500 μM H₂O₂ with or without vitamin E. Viability of pASCs is enhanced after vitamin E treatment. In addition, reduced cellular toxicity, total NO level, PGE₂ production and caspase-3 activity were observed after vitamin E treatment. Gene expression analysis of vitamin E-treated pASCs showed down-regulated expression for the genes associated with oxidative stress and apoptosis, viz., NOS2, Casp3, p53, BAX, MDM2, NFκB, HIF1α and VEGF-A genes. On the other hand, expression of anti-apoptotic and survival genes was up-regulated, viz., BCL2, BCL2L1 and MCL1. Furthermore, phosphorylation of Akt was attenuated following vitamin E treatment. The findings of this study may help in developing effective stem cell therapy for the diseases characterized by the oxidative stress and inflammation.

Kim Y, Gromovsky AD, Brown JM, Chung S

J Nutr Biochem. 2018 Jun 4;58:169-177. doi: 10.1016/j.jnutbio.2018.05.007. [Epub ahead of print]

Abstract

The activation of NLRP3 inflammasome in innate immune cells is associated with enhanced production of pro-inflammatory lipid mediator eicosanoids that play a crucial role in propagating inflammation. Gamma-tocotrienol (γT3) is an unsaturated vitamin E that has been demonstrated to attenuate NLRP3-inflammasome. However, the role of γT3 in regulating eicosanoid formation is unknown. We hypothesized that γT3 abolishes the eicosanoid production by modulating the macrophage lipidome. LPS-primed bone marrow-derived macrophages (BMDM) were stimulated with saturated fatty acids (SFA) along with γT3, and the effects of γT3 in modulating macrophage lipidome were quantified by using mass spectrometry based-shotgun lipidomic approaches. The SFA-mediated inflammasome activation induced robust changes in lipid species of glycerolipids (GL), glycerophospholipids (GPL), and sphingolipids in BMDM, which were distinctly different in the γT3-treated BMDM. The γT3 treatment caused substantial decreases of lysophospholipids (LysoPL), diacylglycerol (DAG), and free arachidonic acid (AA, C20:4), indicating that γT3 limits the availability of AA, the precursor for eicosanoids. This was confirmed by the pulse-chase experiment using [³H]-AA, and by diminished prostaglandin E₂ (PGE₂) secretion by ELISA. Concurrently, γT3 inhibited LPS-induced cyclooxygenases 2 (COX2) induction, further suppressing prostaglandin synthesis. In addition, γT3 attenuated ceramide synthesis by transcriptional downregulation of key enzymes for de novo synthesis. The altered lipid metabolism during inflammation is linked to reduced ATP production, which was partly rescued by γT3. Taken together, our work revealed that γT3 induces distinct modification of the macrophage lipidome to reduce AA release and corresponding lipid mediator synthesis, leading to attenuated cellular lipotoxicity.

Dixon P, Ghosh T, Mondal K, Konar A, Chauhan A, Hazra S

Drug Deliv Transl Res. 2018 Jun 1. doi: 10.1007/s13346-018-0541-5. [Epub ahead of print]

Abstract

Chemical injury by alkali burn is a major cause of corneal blindness in the clinical setting. Current management advocates multiple therapies aimed to prevent inflammation, initiate quick re-epithelialization, arrest the fibrosis, and avoid dry eye and pain by using bandage contact lenses. We hypothesized sustained delivery of the anti-inflammatory, antifibrotic drug pirfenidone through vitamin E-loaded contact lenses as a logical single approach to counter the pathology involved. Vitamin E particles were created in situ in commercial silicon hydrogel contact lenses by soaking the lenses in a vitamin E-ethanol solution. The vitamin E-laden lenses were then placed into pirfenidone-saline solution to load the drug into the lens. The contact lenses were evaluated by both in vitro and in vivo means. For in vitro, lenses were placed into 3 mL of saline solution. The concentration of pirfenidone released was measured by UV-vis spectrophotometry. The contact lenses were implanted in rabbit eyes following the alkali burn; the drug availability in the aqueous humor was evaluated by HPLC at various time points 10 min, 30 min, 2 h, and 3 h; and gene expression of inflammatory cytokines IL-1β, TNF-α, and TGF-β1 was evaluated in the cornea at the end of the study period. In another group of rabbits inflicted with alkali injury, the corneas were graded after 7 days of contact lens implantation with and without pirfenidone. A mathematical model was developed for delivery of the drug to the cornea and aqueous humor after a contact lens is inserted in the eye. The model was validated with experimental data and used to determine the bioavailability both for contact lenses and eye drops. In vitro release of unmodified commercial contact lenses saw a release time of approximately 20 min, with a partition coefficient of 2.68 ± 0.06. The release of pirfenidone from 20% vitamin E-loaded lenses saw a release time of approximately 80 min, with a partition coefficient of 4.20 ± 0.04. In vivo, the drug was available in the aqueous humor for up to 3 h. Gene expression of inflammatory cytokine IL-β1 and profibrotic growth factor TGF-β1 was significantly suppressed in corneas treated with pirfenidone contact lenses. A week after the alkali burn, the eyes with pirfenidone contact lenses showed significant improvement in corneal haze in comparison to the control eyes. About 50% of the drug loaded in the lens reached the aqueous humor compared to 1.3% with eye drops. Vitamin E-loaded contact lenses serve as a suitable platform for delivery of pirfenidone following alkali burn in rabbit eyes; positive pre-clinical outcome identifies it as promising therapy for addressing corneal inflammation and fibrosis. The bioavailability is about 40-fold higher for contact lenses compared to that for eye drops.

Qureshi AA, Zuvanich EG, Khan DA, Mushtaq S, Silswal N, Qureshi N

Lipids Health Dis. 2018 Apr 2;17(1):62. doi: 10.1186/s12944-018-0697-5.

Abstract

BACKGROUND:

Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs.

METHODS:

The anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of δ-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-α using total RNAs derived from plasmas of hepatitis C patients was investigated.

RESULTS:

Our data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% – 87%) with doses of 2.5-20 μM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, δ-tocotrienol, and quercetin were 70% – 92%. However, thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, and quinine sulphate were effective in pancreatic, prostate, breast, lungs, melanoma, Β-lymphocytes, and T-cells (Jurkat: 40% to 95%) compared to respective controls. In lung cancer cells, these compounds were effective between 5 and 40 μM. The IC₅₀ values of anti-proliferation properties of thiostrepton in most of these cell lines were between doses of 2.5-5 μM, dexamethasone 2.5-20 μM, 2-methoxyestradiol 2.5-10 μM, δ-tocotrienol 2.5-20 μM, quercetin 10-40 μM, and (-) Corey lactone 40-80 μM. In hepatitis C patients, δ-tocotrienol treatment resulted in significant decrease in the expression of pro-inflammatory cytokines.

CONCLUSIONS:

These data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, Β-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.

KEYWORDS:

B-lymphocytes; Breast; Inflammatory biomarkers; Liver; Lung; Melanoma; Pancreas; Potent anticancer compounds; Prostate; Several cancer cell lines (Hela; T-cells)

Jamilian M, Shojaei A, Samimi M, Afshar Ebrahimi F, Aghadavod E, Karamali M, Taghizadeh M, Jamilian H, Alaeinasab S, Jafarnejad S, Asemi Z

J Affect Disord. 2018 Mar 15;229:41-47. doi: 10.1016/j.jad.2017.12.049. Epub 2017 Dec 28.

Abstract

OBJECTIVE:

The aim of this study was to evaluate the effects of omega-3 and vitamin E co-supplementation on parameters of mental health and gene expression related to insulin and inflammation in subjects with polycystic ovary syndrome (PCOS).

METHODS:

Forty PCOS women were allocated into two groups and treated with 1000mg omega-3 fatty acids plus 400 IU vitamin Esupplements (n = 20) or placebo (n = 20) per day for 12 weeks. Parameters of mental health were recorded at baseline and after the 12-week intervention. Gene expression related to insulin and inflammation were measured in blood samples of PCOS women.

RESULTS:

After the 12-week intervention, compared with the placebo, omega-3 and vitamin E co-supplementation led to significant improvements in beck depression inventory total score (- 2.2 ± 2.0 vs. – 0.2 ± 1.3, P = 0.001), general health questionnaire scores (- 5.5 ± 4.6 vs. – 1.0 ± 2.3, P < 0.001) and depression anxiety and stress scale scores (- 7.2 ± 5.2 vs. – 1.3 ± 1.3, P < 0.001). Compared with the placebo, omega-3 and vitamin E co-supplementation could up-regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) expression (P = 0.04) in peripheral blood mononuclear cells (PBMC) of PCOS women. In addition, compared with the placebo, omega-3 and vitamin E co-supplementation down-regulated interleukin-8 (IL-8) (P = 0.003) and tumor necrosis factor alpha (TNF-α) expression (P = 0.001) in PBMC of PCOS women. There were no significant difference between-group changes in glucose transporter 1 (GLUT-1), IL-6 and transforming growth factor beta (TGF-β) in PBMC of PCOS women.

CONCLUSION:

Omega-3 and vitamin E co-supplementation was effective in improving parameters of mental health, and gene expression of PPAR-γ, IL-8 and TNF-α of women with PCOS.