Vitamin E and selenium improve mesenchymal stem cell conditioned media immunomodulatory effects

Fereshteh Ghasemi, Majid Khoshmirsafa, Elahe Safari, Marzieh Asgari, Mehdi Alemrajabi, Shahrzad Nojehdehi, Samane Khorrami

Stem Cell Investig . 2021 May 7;8:9. doi: 10.21037/sci-2020-008. eCollection 2021.

Abstract

Background: Mesenchymal stem cells (MSCs) with immunoregulatory properties affect immune systems. Many studies showed that antioxidants such as vitamin E (Vit E) and selenium (Se) could improve stem cells survival. This study aims to investigate the effects of MSC conditioned media (CM) treated with Vit E and Se on immune cells.

Methods: MSCs were isolated and cultured with Vit E and Se. Immature dendritic cells (DCs) and peripheral blood mononuclear cells (PBMCs) were cultured with MSC CM treated with Vit E and Se. The expression of HLA-DR, CD86, CD40, and CD83 on mature DC were evaluated. DC supernatant and PBMCs supernatant was collected for the study of TGF-β, IL-10, and IL-12. PBMCs evaluated for the expression of T-bet, GATA3, RORγt, and FOXP3.

Results: MSC CM increased CD40 on myeloid DC (mDC). CD40 has been decreased in DC treated with MSC (Vit E) and MSC (Se) CM. HLA-DR expression on DCs and IL-12 level were significantly reduced in MSC (Vit E) CM. IL-10 concentration increased in DCs treated with MSC (Vit E) and MSC (Se) CM. Treatment of PBMCs with MSC CM decreased IL-10 level, FOXP3, and RORγt expression. On the other hand, the MSC (Vit E) CM and MSC (Se) CM decreased the IL-10 level and increased IL-12, T-bet, and RORγt.

Conclusions: According to the results, the treatment of MSC with Vit E and Se enhanced the ability of MSCs to inhibit DCs and improved immunomodulatory effects. Concerning the effect of MSC on PBMC, it seems that it increased RORγt expression through monocytes.

Matthew J Kuchan, Stephen J DeMichele, Karen J Schimpf, Xinhua Chen

Curr Dev Nutr . 2021 May 3;5(6):nzab073. doi: 10.1093/cdn/nzab073. eCollection 2021 Jun.

Abstract

Background: α-Tocopherol (αT) is essential for fetal development. One study has shown that the human placenta preferentially transfers the natural stereoisomer, RRR-αT. But prenatal supplements generally contain synthetic αT (S-αT).

Objectives: We aimed to determine if umbilical cord plasma is enriched for RRR-αT in racially diverse neonates from both uncomplicated and complicated pregnancies and if cord RRR-αT enrichment is impacted by maternal αT stereoisomer profile.

Methods: We measured αT and αT stereoisomers in plasma from a randomly selected subset of 66 predominantly black and Hispanic maternal-fetal pairs from the Camden Study involving control (n = 28) and complicated pregnancies (n = 38). We collected maternal plasma at study entry (week 16 gestation; w16) and week 28 gestation (w28) and cord plasma at birth.

Results: RRR-αT was the predominant stereoisomer in all maternal and cord plasma samples, but S-αT stereoisomers were found in most samples and comprised a high percentage of αT in some maternal-neonate pairs. Cord plasma had a higher percentage RRR-αT (P < 0.05) and lower percentage S-αT (P < 0.0001) than w28 plasma. Pregnancy status did not impact maternal or cord plasma concentrations of αT, RRR-αT, or S-αT; except plasma from complicated pregnancies was higher in S-αT at w28 than at w16 (P < 0.05). Maternal w28 αT did not correlate with cord αT. However, both maternal w28 αT and S-αT positively correlated with both cord S-αT (r = 0.340, P = 0.0049; r = 0.538, P < 0.00001) and percentage S-αT (r = 0.399, P = 0.001; r = 0.786, P < 0.00001) but negatively correlated with cord percentage RRR-αT (r = -0.399, P = 0.0009; r = -0.786, P < 0.00001).

Conclusions: The proportion of RRR-αT was higher in cord compared with maternal plasma in both uncomplicated and complicated pregnancies. Our data suggest that maternal S-αT raises cord S-αT and decreases the proportion of RRR-αT in the neonatal circulation. Because the bioactivities of RRR-αT and S-αT differ, this warrants future research to determine the importance of our observations to neonatal αT status.

Shima Tavakol, Alexander M Seifalian

Biotechnol Appl Biochem . 2021 May 2. doi: 10.1002/bab.2176. Online ahead of print.

Abstract

Even though the neurodegeneration upon vitamin Edeficiency is related to the ferroptosis. Maybe the neu-ral damages in COVID-19 patients are inhibited in partusing vitamin E consumption through an anti-ferroptosismechanism. In conclusion, it might be said that RBCcharacteristics such as RDW-CV% have vital importancein the prognosis of COVID-19 patients, while the ironserum level affects RDW-CV% and RBC volume and needsmore attention to be monitored in patients. Therefore, thetoxic mechanisms behind iron serum levels such as fer-roptosis should be prevented by vitamin E consumptionthroughinhibitinglipoxygenaseandperoxylradicals.Vita-min E supplement at a high dose of 500 mg/kg may alsoact as a treatment drug to inhibit ferroptosis in COVID-19 patients and decline ferroptosis damages to multipleorgans, including lung, kidney, liver, gut, heart, and ner-vous system. Based on some reports, it is leading to viralclearance and inflammation ablation through the T cells modulation.

Giou-Teng Yiang, Tsu-Yi Chen, Cian Chen, Yu-Ting Hung, Kuan-Chun Hsueh, Tsai-Kun Wu, Ying-Ru Pan, Yi-Chung Chien, Chao-Hsuan Chen, Yung-Lung Yu, Chyou-Wei Wei

Food Sci Nutr . 2021 May 1;9(6):3308-3316. doi: 10.1002/fsn3.2298. eCollection 2021 Jun.

Abstract

Vitamin C and vitamin E are well-known antioxidant vitamins, both of which are also applied as adjunct treatments for cancer therapy. Methotrexate (MTX) is a clinical drug that is used widely for rheumatoid arthritis and cancer treatment. Human glioblastoma multiforme (GBM) is an aggressive malignant brain tumor; the mean survival time for GBM patients is <2 years with traditional therapies. Developing and investigating novel treatments are important for clinical GBM therapy. Therefore, the aim of this study was to investigate whether combined treatment with vitamin C/E and MTX can display anticancer activities on GBM. Our studies showed that MTX displays anticancer effects on GBM in a dose-dependent manner, while vitamins C and E are not cytotoxic to glioblastoma. Importantly, this study showed that vitamins C and E can promote anticancer effects on low-concentration methotrexate-treated glioblastoma. Additionally, this study suggested that MTX alone or combined with vitamins C/E inhibits GBM cell growth via the caspase-3 death pathway.

Wajiha Mahjabeen, Dilshad Ahmed Khan, Shakeel Ahmed Mirza, Muhammad Amjad Pervez

Phytother Res . 2021 Apr 25. doi: 10.1002/ptr.7113. Online ahead of print.

Abstract

The study aimed to ascertain the effects of delta-tocotrienol (δT3) supplementation on glycemic control, oxidative stress, inflammation and related micro-ribonucleic acid (miRNA) expression in patients with type 2 diabetes mellitus (T2DM). Total 110 patients of T2DM on oral hypoglycemic agents, were randomly divided into tocotrienol and placebo groups and given 250 mg δT3 or cellulose soft gel capsule once daily respectively for 24 weeks. Glycemic control, oxidative stress, inflammatory biomarkers, and miRNAs expression were measured in serum at baseline and end of the intervention by using standard laboratory methods. Compared to the placebo, δT3 supplementation resulted in a significant (p ≤ .05) reduction [mean difference (95% confidence interval)] in plasma glucose [-0.48 (-0.65, -0.30)], insulin [-1.19 (-1.51, -0.87)], homeostatic model assessment of insulin resistance [-0.67 (-0.86, -0.49)], glycosylated hemoglobin [-0.53 (-0.79, -0.28)], malondialdehyde [-0.34 (-0.45, -0.22)], high sensitive-C-reactive protein[-0.35 (-0.54, -0.16)], tumor necrosis factor-alpha [-1.22 (-1.62, -0.83)], and interleukin-6[-2.30 (-2.91, -1.68)]. More than twofold downregulation in miRNA-375, miRNA-34a, miRNA-21, and upregulation in miRNA-126, miRNA-132 expression was observed in the δT3 group compared to the placebo. The study demonstrated that δT3 supplementation in addition to oral hypoglycemic agents, improved glycemic control, inflammation, oxidative stress, and miRNA expression in T2DM without any adverse effect. Thus, δT3 might be considered as an effective dietary supplement to prevent long-term diabetic complications.

A M Shamseldeen, M Hamzawy, N A Mahmoud, L Rashed, S S Kamar, L A Harb, N Sharawy

J Biol Regul Homeost Agents . Mar-Apr 2021;35(2):457-471. doi: 10.23812/20-693-A.

Abstract

Diet pattern is an emerging risk factor for renal disease. The mechanism by which high-fat high fructose (western) diet mediates renal injury is not yet fully understood. The objective of the present study was to investigate the relationship between endoplasmic reticulum (ER) stress and autophagy in the development of renal impairment and aggravation of the inflammatory response. Eighty male rats were randomly divided into four groups as follows: a standard diet-fed (ConD), a high-fat high fructose diet fed (HFHF-V), ConD fed and orally supplemented with vitamin E (ConD-E), and HFHF fed and orally supplemented vitamin E (HFHF-E). After 12 weeks, either lipopolysaccharide (LPS) or saline was injected. We found that upregulation of endoplasmic reticulum stress-related proteins rendered the cells susceptible to injury induced by dysbiosis and microbiota-derived metabolites. A downregulation of autophagy and upregulation of caspase-12 resulted in the loss of intestinal integrity and renal tubular injury. Maintained ER stress also increased the inflammatory response to LPS. In contrast, vitamin E effectively ameliorated ER stress and promoted autophagy to protect intestinal and renal tissues. Our results provide insight into the influences of sustained ER stress activation and autophagy inhibition on the development of renal injury, which may contribute also to the enhanced inflammatory response.

Anca Ungurianu, Anca Zanfirescu, Georgiana Nițulescu, Denisa Margină

Antioxidants (Basel) . 2021 Apr 21;10(5):634. doi: 10.3390/antiox10050634.

Abstract

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component.

Chwan-Li Shen, Sivapriya Ramamoorthy, Gurvinder Kaur, Jannette M Dufour, Rui Wang, Huanbiao Mo, Bruce A Watkins

Nutrients . 2021 Apr 13;13(4):1267. doi: 10.3390/nu13041267.

Abstract

Obesity and its related complications are a world-wide health problem. Dietary tocotrienols (TT) have been shown to improve obesity-associated metabolic disorders, such as hypercholesterolemia, hyperglycemia, and gut dysbiosis. This study examined the hypothesis that the antioxidant capacity of TT alters metabolites of oxidative stress and improves systemic metabolism. C57BL/6J mice were fed either a high-fat diet (HFD control) or HFD supplemented with 800 mg annatto-extracted TT/kg (HFD+TT800) for 14 weeks. Sera from obese mice were examined by non-targeted metabolite analysis using UHPLC/MS. Compared to the HFD group, the HFD+TT800 group had higher levels of serum metabolites, essential amino acids (lysine and methionine), sphingomyelins, phosphatidylcholine, lysophospholipids, and vitamins (pantothenate, pyridoxamine, pyridoxal, and retinol). TT-treated mice had lowered levels of serum metabolites, dicarboxylic fatty acids, and inflammatory/oxidative stress markers (trimethylamine N-oxide, kynurenate, 12,13-DiHOME, and 13-HODE + 9-HODE) compared to the control. The results suggest that TT supplementation lowered inflammation and oxidative stress (oxidized glutathione and GSH/GSSH) and improved macronutrient metabolism (carbohydrates) in obese mice. Thus, TT actions on metabolites were beneficial in reducing obesity-associated hypercholesterolemia/hyperglycemia. The effects of a non-toxic dose of TT in mice support the potential for clinical applications in obesity and metabolic disease.

Laura Rodriguez, Pascale Duchez, Nicolas Touya, Christelle Debeissat, Amélie V Guitart, Jean-Max Pasquet, Marija Vlaski-Lafarge, Philippe Brunet de la Grange, Zoran Ivanovic

Biomolecules . 2021 Apr 10;11(4):558. doi: 10.3390/biom11040558.

Abstract

Alpha tocopherol acetate (αTOA) is an analogue of alpha tocopherol (αTOC) that exists in the form of an injectable drug. In the context of the metabolic hypothesis of stem cells, we studied the impact of αTOA on the metabolic energetic profile and functional properties of hematopoietic stem and progenitor cells. In ex vivo experiments performed on cord blood CD34⁺ cells, we found that αTOA effectively attenuates oxidative phosphorylation without affecting the glycolysis rate. This effect concerns complex I and complex II of the mitochondrial respiratory chain and is related to the relatively late increase (3 days) in ROS (Reactive Oxygen Species). The most interesting effect was the inhibition of Hypoxia-Inducible Factor (HIF)-2α (Hexpression, which is a determinant of the most pronounced biological effect-the accumulation of CD34⁺ cells in the G0 phase of the cell cycle. In parallel, better maintenance of the primitive stem cell activity was revealed by the expansion seen in secondary cultures (higher production of colony forming cells (CFC) and Severe Combined Immunodeficiency-mice (scid)-repopulating cells (SRC)). While the presence of αTOA enhanced the maintenance of Hematopoietic Stem Cells (HSC) and contained their proliferation ex vivo, whether it could play the same role in vivo remained unknown. Creating αTOC deficiency via a vitamin E-free diet in mice, we found an accelerated proliferation of CFC and an expanded compartment of LSK (lineage^negative Sca-1⁺cKit⁺) and SLAM (cells expressing Signaling Lymphocytic Activation Molecule family receptors) bone marrow cell populations whose in vivo repopulating capacity was decreased. These in vivo data are in favor of our hypothesis that αTOC may have a physiological role in the maintenance of stem cells. Taking into account that αTOC also exhibits an effect on proliferative capacity, it may also be relevant for the ex vivo manipulation of hematopoietic stem cells. For this purpose, low non-toxic doses of αTOA should be used.

Peter Bergin, Aoife Leggett, Chris R Cardwell, Jayne V Woodside, Ammarin Thakkinstian, Alexander P Maxwell, Gareth J McKay

BMC Nephrol . 2021 Apr 9;22(1):126. doi: 10.1186/s12882-021-02328-8.

Abstract

Background: Haemodialysis (HD) patients tend to have higher levels of oxidative stress (OS), associated with increased morbidity and premature mortality, compared to the general population. Levels of malondialdehyde (MDA), a biomarker of OS, are reduced by the antioxidant properties of vitamin E (VE) but outcomes from randomised control trials of VE supplementation on MDA in HD patients have been inconsistent.

Methods: We undertook a systematic review and meta-analysis of adult HD patients from VE supplementation studies with measures of MDA. The following search criteria of MEDLINE and EMBASE were considered from inception to January 2020: ‘dialysis’ AND ‘Vitamin E OR tocopherol’ AND ‘malondialdehyde OR MDA’. Two reviewers independently extracted study data and assessed risk of bias. Mean MDA levels and standard deviation were determined before and after VE supplementation. Standardised mean difference (SMD) and standard error were calculated as the within person difference and units of measure were not consistently recorded across all studies. The SMD were pooled using random effects meta-analysis.

Results: The SMD of MDA levels from 18 comparisons was significantly lower in HD patients following VE supplementation (- 1.55; confidence interval: – 2.17 to – 0.94, P < 0.00001). There were significant levels of heterogeneity between studies (I² value = 91%; P < 0.00001) with evidence of potential publication bias toward smaller studies.

Conclusions: Our findings support the use of VE to reduce the effects of OS in HD patients although high levels of heterogeneity and variation in the methodological approaches used by some studies highlight the need for further investigation.