Effects of tocotrienols supplementation on markers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials

Ban-Hock Khor, Hui-Ci Tiong, Shing Cheng Tan, Sok Kuan Wong, Kok-Yong Chin, Tilakavati Karupaiah, Soelaiman Ima-Nirwana, Abdul Halim Abdul Gafor

PLoS One . 2021 Jul 23;16(7):e0255205. doi: 10.1371/journal.pone.0255205. eCollection 2021.

Abstract

Studies investigating the effects of tocotrienols on inflammation and oxidative stress have yielded inconsistent results. This systematic review and meta-analysis aimed to evaluate the effects of tocotrienols supplementation on inflammatory and oxidative stress biomarkers. We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials from inception until 13 July 2020 to identify randomized controlled trials supplementing tocotrienols and reporting circulating inflammatory or oxidative stress outcomes. Weighted mean difference (WMD) and corresponding 95% confidence interval (CI) were determined by pooling eligible studies. Nineteen studies were included for qualitative analysis, and 13 studies were included for the meta-analyses. A significant reduction in C-reactive protein levels (WMD: -0.52 mg/L, 95% CI: -0.73, -0.32, p < 0.001) following tocotrienols supplementation was observed, but this finding was attributed to a single study using δ-tocotrienols, not mixed tocotrienols. There were no effects on interleukin-6 (WMD: 0.03 pg/mL, 95% CI: -1.51, 1.58, p = 0.966), tumor necrosis factor-alpha (WMD: -0.28 pg/mL, 95% CI: -1.24, 0.68, p = 0.571), and malondialdehyde (WMD: -0.42 μmol/L, 95% CI: -1.05, 0.21, p = 0.189). A subgroup analysis suggested that tocotrienols at 400 mg/day might reduce malondialdehyde levels (WMD: -0.90 μmol/L, 95% CI: -1.20, -0.59, p < 0.001). Future well-designed studies are warranted to confirm the effects of tocotrienols on inflammatory and oxidative stress biomarkers, particularly on different types and dosages of supplementation. PROSPERO registration number: CRD42020198241.

Hala M Helal, Wael M Samy, Elbadawy A Kamoun, Esmail M El-Fakharany, Doaa A Abdelmonsif, Rania G Aly, Sana M Mortada, Marwa A Sallam

Int J Nanomedicine . 2021 Jul 14;16:4781-4803. doi: 10.2147/IJN.S317409. eCollection 2021.

Abstract

Background: Tacrolimus (TAC) is a powerful immunosuppressive agent whose therapeutic applicability is confined owing to its systemic side effects.

Objective: Herein, we harnessed a natural polymer based bioconjugate composed of maltodextrin and α-tocopherol (MD-α-TOC) to encapsulate TAC as an attempt to overcome its biological limitations while enhancing its therapeutic anti-rheumatic efficacy.

Methods: The designed TAC loaded maltodextrin-α-tocopherol nano-micelles (TAC@MD-α-TOC) were assessed for their physical properties, safety, toxicological behavior, their ability to combat arthritis and assist bone/cartilage formation.

Results: In vitro cell viability assay revealed enhanced safety profile of optimized TAC@MD-α-TOC with 1.6- to 2-fold increase in Vero cells viability compared with free TAC. Subacute toxicity study demonstrated a diminished nephro- and hepato-toxicity accompanied with optimized TAC@MD-α-TOC. TAC@MD-α-TOC also showed significantly enhanced anti-arthritic activity compared with free TAC, as reflected by improved clinical scores and decreased IL-6 and TNF-α levels in serum and synovial fluids. Unique bone formation criteria were proved with TAC@MD-α-TOC by elevated serum and synovial fluid levels of osteocalcin and osteopontin mRNA and proteins expression. Chondrogenic differentiation abilities of TAC@MD-α-TOC were proved by increased serum and synovial fluid levels of SOX9 mRNA and protein expression.

Conclusion: Overall, our designed bioconjugate micelles offered an excellent approach for improved TAC safety profile with enhanced anti-arthritic activity and unique bone formation characteristics.

Sara Mohamed Naguib Abdel Hafez, Eman Elbassuoni, Walaa Yehia Abdelzaher, Nermeen N Welson, Gaber El-Saber Batiha, Khalid J Alzahrani, Fatma Alzhraa Fouad Abdelbaky

Biomed Pharmacother . 2021 Jul;139:111637. doi: 10.1016/j.biopha.2021.111637. Epub 2021 May 6.

Abstract

Methotrexate (MXT) is a chemotherapeutic drug that has been used in a wide range of clinical practices. Unfortunately, the administration of MXT during pregnancy may induce abortion, fetal deformities, and intrauterine growth retardation. Vitamin E is an antioxidant agent that can ameliorate free radical damage. The current work aimed to shed more light on the possible protective effect of vitamin E against MXT induced placental toxicity and to determine the possible mechanisms; biochemically, histologically, and immunohistochemically. Four groups were used: control pregnant, Vitamin E (VIT E) pregnant, Methotrexate (MXT) pregnant, and Vitamin E Methotrexate (VIT E-MXT) pregnant. The placental tissues were processed for light, immunohistochemical, and electron microscopic study. Other samples were obtained for biochemical study; the placental oxidant/antioxidant status was evaluated. The results showed that MXT caused various placental morphological changes in the form of distorted chorionic projection with an accumulation of hemosiderin granules in the trophoblastic cells. Maternal blood vessels showed a homogenous acidophilic material Edema of the extra-embryonic fetal membranes was noticed. A significant decreased in placental weight as well as increase in the oxidative and inflammatory markers were detected. Increased COX2 and decreased eNOS expressions were observed in the MXT group if compared to the control group. VIT E significantly restored the normal histological and immunohistochemical appearance, placental weight, and oxidant/antioxidant balance. It could be concluded the biochemical, morphological, and morphometric findings suggested that vitamin E coadministration is promising in attenuating the placental toxic effect of methotrexate. In this study, VIT E decreased the inflammatory and oxidative stress effect of methotrexate on the placental tissue by enhancing the level of eNOS.

Saminathan Shadisvaaran, Kok-Yong Chin, Mohd-Said Shahida, Soelaiman Ima-Nirwana, Xin-Fang Leong

J Oral Biosci . 2021 Jun;63(2):97-103. doi: 10.1016/j.job.2021.04.001. Epub 2021 Apr 20.

Abstract

Background: Periodontitis is a noncommunicable inflammatory disease of the soft tissue and bone surrounding the teeth in the jaw, which affects susceptible individuals with poor oral hygiene. A growing interest has been seen in the use of dietary supplements and natural products for the treatment and prevention of periodontitis. Vitamin E consists of two major groups, namely tocopherols and tocotrienols, which are botanical lipophilic compounds with excellent anti-inflammatory and antioxidant properties.

Highlight: This review aimed to summarize the preclinical and clinical findings on the effects of vitamin E on periodontitis. The current literature suggests that vitamin E could improve the periodontal status by correcting redox status imbalance, reducing inflammatory responses, and promoting wound healing, thus highlighting the potential of vitamin E in the management of periodontitis.

Conclusion: Direct evidence for the use of vitamin E supplementation or treatment of periodontitis in humans is still limited. More well-designed and controlled studies are required to ascertain its effectiveness.

Hongxing Dang, Jing Li, Chengjun Liu, Feng Xu

Front Nutr . 2021 Jun 16;8:648442. doi: 10.3389/fnut.2021.648442. eCollection 2021.

Abstract

Background: Literature is scarce on the assessment of vitamin E status in septic children. We aim to investigate the prevalence of vitamin E deficiency in critically ill children with sepsis and septic shock and its association with clinical features and outcomes. Methods: We compared serum vitamin E status between the confirmed or suspected infection and no infection groups, the sepsis shock and no sepsis shock groups upon pediatric intensive care unit admission. Clinical characteristics were compared in subgroup patients with and without vitamin E deficiency. The association between vitamin E deficiency and septic shock were evaluated using univariate and multivariable methods. Results: 182 critically ill children with confirmed or suspected infection and 114 without infection were enrolled. The incidence of vitamin E deficiency was 30.2% in the infection group and 61.9% in the septic shock subgroup (P < 0.001). Thirty-days mortality in critically ill children with vitamin E deficiency was significantly higher than that without vitamin E deficiency (27.3 vs. 14.2%, P < 0.05). Vitamin E levels were inversely associated with higher pediatric risk of mortality (r = – 0.238, P = 0.001) and cardiovascular sequential organ failure assessment (r = -0.249, p < 0.001) scores in critically ill children with infection. In multivariable logistic regression, vitamin E deficiency showed an independent effect on septic shock (adjusted OR: 6.749, 95%CI: 2.449-18.60, P < 0.001). Conclusion: Vitamin E deficiency is highly prevalent in critically ill children with sepsis and contributed to the septic shock.

Erdem Danyer, Tanay Bilal, Ayşen Altiner, İsmail Aytekin, Hasan Atalay

J Anim Physiol Anim Nutr (Berl) . 2021 Jun 11. doi: 10.1111/jpn.13560. Online ahead of print.

Abstract

The study aimed to investigate the effects of vitamin E injection for the prevention of transport stress on ewes. Kivircik ewes (2-3 years old, n = 24) were randomly separated into three groups; G1 (Control) and G2 treated with 14 ml. saline as the placebo, G3 treated with 2100 IU/ind. DL-alpha-tocopherol acetate prior to transport. G2 and G3 were transported at 80 km/h for 4 h on a truck. Serum samples were obtained before (T0) and after (T1) transport. Serum cortisol, catalase, IgG, ceruloplasmin, C-reactive protein, complement component 4, interleukin-1 beta, tumour necrosis factor-alpha, glutathione peroxidase (GPx), superoxide dismutase, malondialdehyde analyses performed by ELISA, and serum alpha-tocopherol concentrations were evaluated by HPLC-UV. Wilcoxon and Kruskal-Wallis tests were used for statistical assessments (p < 0.05). Alpha-tocopherol concentrations were founded 1.22 ± 0.82, 0.27 ± 0.14 and 0.14 ± 0.07 µmol/L, respectively, in G1, G2 and G3 at T1. Alpha-tocopherol concentration decreased significantly in G2 between T0 and T1. GPx concentrations were increased twofold in G2 and G3 between T0 and T1 (p < 0.01). As a result, G2 alpha-tocopherol concentrations decreased but, the stress and oxidative parameters tested in this study were not affected by treating 2100 IU/ind. DL-alpha-tocopherol acetate before transport.

Xiangming Ji, Hongwei Yao, Maureen Meister, Douglas S Gardenhire, Huanbiao Mo

Antioxidants (Basel) . 2021 May 31;10(6):883. doi: 10.3390/antiox10060883.

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Emphysema and chronic bronchitis are the two major phenotypes of COPD, which have many symptoms, such as dyspnea, chronic cough, and mucus overproduction. Emphysema is characterized by the destruction of the alveolar wall, while chronic bronchitis is characterized by limitations in expiratory airflow. Cigarette smoking is the most significant risk factor for the pathogenesis of COPD in the developed world. Chronic inflammation contributes to the onset and progression of the disease and furthers the risk of comorbidities. Current treatment options and prevention strategies for COPD are very limited. Tocotrienols are a group of vitamin E molecules with antioxidant and anti-inflammatory properties. Individual tocotrienols (α, γ, and δ) have shown their ability to attenuate inflammation specifically via suppressing nuclear factor-κB-mediated cytokine production. The δ- and γ-forms of tocotrienols have been indicated as the most effective in the prevention of macrophage infiltration, production of reactive oxygen species, and cytokine secretion. This review briefly discusses the pathogenesis of COPD and the role of inflammation therein. Furthermore, we summarize the in vitro and in vivo evidence for the anti-inflammatory activity of tocotrienols and their potential application to COPD management. Coupled with the bioavailability and safety profile of tocotrienols, the ability of these compounds to modulate COPD progression by targeting the inflammation pathways renders them potential candidates for novel therapeutic approaches in the treatment of COPD patients.

Tugce Demirel-Yalciner, Erdi Sozen, Esra Ozaltin, Ali Sahin, Nesrin Kartal Ozer

Biofactors . 2021 May;47(3):403-413. doi: 10.1002/biof.1700. Epub 2021 Jun 8.

Abstract

Inflammation and apoptosis signaling are crucial steps in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Alpha-tocopherol, the most active form of vitamin E, is an important modulator of signaling mechanisms, but its involvement to cholesterol-induced NASH pathogenesis remains poorly defined. Herein we have reported a novel effect of α-tocopherol in the transition from hepatic steatosis to NASH. High cholesterol diet alone (without α-tocopherol) in rabbits elevated NASH development as indicated by increased inflammatory response, apoptotic activity and liver fibrosis. Such elevation results from induction of signaling mechanisms since the expressions of IL1β, phospho c-Jun/c-Jun ratio, JNK, caspase 9, CHOP and Bax were increased, and recruitment of macrophage, α-smooth muscle actin (α-SMA) and COL1A1 into the liver tissue were induced. Alpha-tocopherol supplementation inhibited inflammatory response, apoptosis and fibrosis development without affecting lipid accumulation in high cholesterol-induced NASH. Specifically, α-tocopherol lowered the inflammatory level as observed by reduced macrophage infiltration and JNK/c-Jun signaling. Lower inflammatory status co-occurred with the reduction of CHOP and Bax expressions as well as fibrosis-related COL1A1 and α-SMA levels. Taken together, α-tocopherol supplementation inhibits cholesterol-induced NASH development by lowering JNK/c-Jun/inflammation axis in addition to JNK/CHOP/apoptosis signaling, which might contribute to resistance against NAFLD/NASH transition.

Meimei Wang, Yan Li, Yanxia Gao, Qiufeng Li, Yufeng Cao, Yizhao Shen, Panliang Chen, Jinling Yan, Jianguo Li

Reprod Domest Anim . 2021 May 12. doi: 10.1111/rda.13950. Online ahead of print.

Abstract

High-yield dairy cows are usually subject to high-intensive cell metabolism and produce excessive reactive oxygen species (ROS). Once ROS is beyond the threshold of scavenging ability, it can induce oxidative stress, imperilling the reproductive performance of cows. The study was to investigate the effects of vitamin E (VE) on H₂ O₂ -induced proliferation and apoptosis of bovine granulosa cells and the underlying molecular mechanism. Granulosa cells were pretreated with VE for 24 hr and then treated with H₂ O₂ for 6 hr. The results showed that VE treatment decreased the intracellular ROS levels, increased the MDA content, and improved the antioxidant enzyme activity in a dose-dependent manner. Furthermore, VE treatment promoted the proliferation and inhibited apoptosis in granulosa cells by up-regulation of CCND1 and BCL2 levels and down-regulation of P21, BAX, and CASP3 levels. The cytoprotective effects of VE were attributed to the activation of the NRF2 signalling pathway. Knockdown of the NRF2 impaired the cytoprotective effects of VE on granulosa cells. Besides, the PI3K/AKT and ERK1/2, but not the p38 signalling pathway is involved in the regulation of VE-mediated cell proliferation and apoptosis. The PI3K/AKT inhibitor LY294002 and ERK1/2 inhibitor SCH772984 inhibited the VE-induced granulosa cell proliferation and promoted apoptosis, whereas the p38 inhibitor SB203580 had the opposite effects. These results were confirmed by proliferation and apoptosis-related gene expression at mRNA and protein levels. The results also showed that the PI3K/AKT inhibitor LY294002 and ERK1/2 inhibitor SCH772984 inhibited VE-induced NRF2, GCLC, GCLM, and HO-1 expression, whereas the p38 inhibitor SB203580 not. Overall, the results demonstrated that VE-regulated granulosa cell proliferation and apoptosis via NRF2-mediated defence system by activating the PI3K/AKT and ERK1/2 signalling pathway.

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.