Modulation of NFκB signalling pathway by tocotrienol: A systematic review

Nurul Alimah Abdul Nasir, Muhammad Zulfiqah Sadikan, Renu Agarwal

Asia Pac J Clin Nutr . 2021 Sep;30(3):537-555. doi: 10.6133/apjcn.202109_30(3).0020.


Tocotrienols have been reported to exert anticancer, anti-inflammatory, antioxidant, cardio-protective and boneprotective effects through modulation of NFκB signalling pathway. The objective of this systematic review is to evaluate available literature showing the effect of tocotrienols on NFκB signalling pathway and identify the potential mechanisms involved. A comprehensive search was conducted using PubMed and SCOPUS databases using the keywords “tocotrienol” and “NFκB” or “nuclear factor kappa b”. Main inclusion criteria were English language original articles showing the effect of tocotrienol on NFκB signalling pathway. Fifty-nine articles were selected from the total of 117 articles initially retrieved from the literature search. Modulation of regulatory proteins and genes such as inhibition of farnesyl prenyl transferase were found to be the mechanisms underlying the tocotrienol-induced suppression of NFκB activation.

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Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

Konstantin Neukirch, Khaled Alsabil, Chau-Phi Dinh, Rossella Bilancia, Martin Raasch, Alexia Ville, Ida Cerqua, Guillaume Viault, Dimitri Bréard, Simona Pace, Veronika Temml, Elena Brunner, Paul M Jordan, Marta C Marques, Konstantin Loeser, André Gollowitzer 1 2, Stephan Permann, Jana Gerstmeier, Stefan Lorkowski, Hermann Stuppner, Ulrike Garscha, Tiago Rodrigues, Gonçalo J L Bernardes, Daniela Schuster, Denis Séraphin, Pascal Richomme, Antonietta Rossi, Alexander S Mosig, Fiorentina Roviezzo, Oliver Werz, Jean-Jacques Helesbeux, Andreas Koeberle

J Med Chem . 2021 Aug 12;64(15):11496-11526. doi: 10.1021/acs.jmedchem.1c00806. Epub 2021 Jul 19.


Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.

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Effect of δ-Tocopherol on Mice Adipose Tissues and Mice Adipocytes Induced Inflammation

Chikako Kiyose, Haruka Takeuchi, Yoshimi Yabe, Tomoki Nojima, Mana Nagase, Chie Takahashi-Muto, Rieko Tanaka-Yachi

J Oleo Sci . 2021 Aug 6. doi: 10.5650/jos.ess21124. Online ahead of print.


The study aim was to evaluate the potential anti-inflammatory effects of vitamin E analogs, especially α-tocopherol and δ-tocopherol. We used male C57BL/6JJcl mice, which were divided into four groups: the control (C), high-fat and high-sucrose diet (H), high-fat and high-sucrose diet+α-tocopherol (Ha) and high-fat and high-sucrose diet+δ-tocopherol (Hd) groups. The mice were fed for 16 weeks. To the high-fat and high-sucrose diet, 800 mg/kg of α-tocopherol or δ-tocopherol was added more. The final body weight was significantly higher in the H group than in the C group. On the other hand, the final body weight was drastically lower in the Ha group and Hd group than in the H group. However, the energy intake was not significantly different among all groups. Therefore, we assumed that α-tocopherol and δ-tocopherol have potential anti-obesity effect. Besides, inflammatory cytokine gene expression was significantly higher in the epididymal fat of the H group than in the C group. These results showed that inflammation was induced by epididymal fat of mice fed a high-fat and high-sucrose diet for 16 weeks. Unfortunately, addition of α-tocopherol or δ-tocopherol to the diet did not restrain inflammation of epididymal fat. Investigation of the anti-inflammatory effects of α-tocopherol or δ-tocopherol in co-cultured 3T3-L1 cells and RAW264.7 cells showed that δ-tocopherol inhibited increased gene expression of the inflammatory cytokines, IL-1β, IL-6, and iNOS. These results suggest that an anti-inflammatory effect in the δ-tocopherol is stronger than that in the α-tocopherol in vitro. We intend to perform an experiment by in vivo sequentially in the future.

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Effects of Co-administration of Vitamin E and Lithium Chloride on Chronic Constriction Injury-induced Neuropathy in Male Wistar Rats: Focus on antioxidant and anti-inflammatory mechanisms

Kingsley Dominic Esu, Ahmed Olalekan Bakare, Bamidele Victor Owoyele

Pain Pract . 2021 Aug 5. doi: 10.1111/papr.13064. Online ahead of print.


Objectives: This study investigated the antinociceptive effects of co-administration of lithium chloride (LiCl) and vitamin E (Vit. E) on chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. It further explored the anti-inflammatory and neuroprotective properties of LiCl and Vit. E which may be complementary to the antinociceptive effects of the two substances.

Methods: Thirty-six male Wistar rats, 190.00 ± 10.00 g of body weight (b.w) were randomly assigned to six experimental groups and administered with either normal saline, Vit. E, LiCl, or their combination, once daily for twenty-one (21) days. CCI was used to induce NP and mechanical allodynia was assessed using von Frey filaments and pinprick test. Open field maze (OFM) was used to assess the exploratory behaviour. Biochemical parameters were assessed in the dorsal root ganglion (DRG) after twenty-one days of treatment.

Results: Mechanical allodynia was developed in rats following CCI. Co-administration of LiCl and Vit.E. synergistically reduced mechanical hyperalgesia in rats which were significantly different compared with the single administration of either Vit.E. or LiCl. Combined doses of Vit.E. and LiCl significantly increases the explorative behaviour in the OFM. CCI increased malondialdehyde (MDA), tumour necrotic factor-alpha (TNF-α), calcitonin gene-related polypeptide (CGRP), calcium ion (Ca2+ ), and reduced superoxide dismutase (SOD) activities. Co-administration of LiCl and Vit.E. significantly reduced MDA, TNF-α, but increased SOD compared with ligated control.

Discussion: The findings revealed that the synergistic effects of the co-administration of Vit. E and LiCl in ameliorating neuropathic pain are mediated by their anti-inflammatory and antioxidant properties.

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Controlled Release of the α-Tocopherol-Derived Metabolite α-13′-Carboxychromanol from Bacterial Nanocellulose Wound Cover Improves Wound Healing

Jessica Hoff, Berit Karl, Jana Gerstmeier, Uwe Beekmann, Lisa Schmölz, Friedemann Börner, Dana Kralisch, Michael Bauer, Oliver Werz, Dagmar Fischer, Stefan Lorkowski, Adrian T Press

Nanomaterials (Basel) . 2021 Jul 28;11(8):1939. doi: 10.3390/nano11081939.


Inflammation is a hallmark of tissue remodeling during wound healing. The inflammatory response to wounds is tightly controlled and well-coordinated; dysregulation compromises wound healing and causes persistent inflammation. Topical application of natural anti-inflammatory products may improve wound healing, in particular under chronic pathological conditions. The long-chain metabolites of vitamin E (LCM) are bioactive molecules that mediate cellular effects via oxidative stress signaling as well as anti-inflammatory pathways. However, the effect of LCM on wound healing has not been investigated. We administered the α-tocopherol-derived LCMs α-13′-hydroxychromanol (α-13′-OH) and α-13′-carboxychromanol (α-13′-COOH) as well as the natural product garcinoic acid, a δ-tocotrienol derivative, in different pharmaceutical formulations directly to wounds using a splinted wound mouse model to investigate their effects on the wounds’ proinflammatory microenvironment and wound healing. Garcinoic acid and, in particular, α-13′-COOH accelerated wound healing and quality of the newly formed tissue. We next loaded bacterial nanocellulose (BNC), a valuable nanomaterial used as a wound dressing with high potential for drug delivery, with α-13′-COOH. The controlled release of α-13′-COOH using BNC promoted wound healing and wound closure, mainly when a diabetic condition was induced before the injury. This study highlights the potential of α-13′-COOH combined with BNC as a potential active wound dressing for the advanced therapy of skin injuries.

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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.


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.

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Potential Privilege of Maltodextrin-α-Tocopherol Nano-Micelles in Seizing Tacrolimus Renal Toxicity, Managing Rheumatoid Arthritis and Accelerating Bone Regeneration

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.


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.

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Efficacy of vitamin E in protection against methotrexate induced placental injury in albino rats

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.


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.

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Effect of vitamin E on periodontitis: Evidence and proposed mechanisms of action

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.


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.

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The Association Between Vitamin E Deficiency and Critically Ill Children With Sepsis and Septic Shock

Hongxing Dang, Jing Li, Chengjun Liu, Feng Xu

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


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.

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