The α-tocopherol-derived long-chain metabolite α-13′-COOH mediates endotoxin tolerance and modulates the inflammatory response via MAPK and NFκB pathways

Martin Schubert, Stefan Kluge, Elena Brunner, Simona Pace, Marc Birringer, Oliver Werz, Stefan Lorkowski

Free Radic Biol Med . 2022 Jan;178:83-96. doi: 10.1016/j.freeradbiomed.2021.11.032. Epub 2021 Nov 27.

Abstract

Scope: The long-chain metabolites of (LCM) vitamin E are proposed as the active regulatory metabolites of vitamin E providing, with their anti-inflammatory properties, an explanatory approach for the inconsistent effects of vitamin E on inflammatory-driven diseases. We examined the modulation of cytokine expression and release from macrophages, a fundamental process in many diseases, to gain insights into the anti-inflammatory mechanisms of the α-tocopherol-derived LCM α-13′-COOH.

Methods and results: Suppressed gene expression of C-C motif chemokine ligand 2 (Ccl2), tumor necrosis factor (Tnf), and interleukin (Il) 6 in response to lipopolysaccharides by 24 h pre-treatment with α-13′-COOH in RAW264.7 macrophages was revealed using quantitative reverse transcription PCR. Further, reduced secretion of IL1β and CCL2 was found in this setup using flow cytometry. In contrast, 1 h pre-treatment suppressed only CCL2. Consequent gene expression analysis within 24 h of α-13′-COOH treatment revealed the induction of mitogen-activated protein kinases (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) negative feedback regulators including the ‘master regulators’ dual-specificity phosphatase 1 (Dusp1/Mkp1) and tumor necrosis factor induced protein 3 (Tnfaip3/A20). Approaches with immunoblots and chemical antagonists suggest a feedback induction via activation of extracellular-signal regulated kinase (ERK), p38 MAPK and NFκB pathways.

Conclusions: CCL2 is suppressed in murine macrophages by α-13′-COOH and the indirect suppression of MAPK and NFκB pathways is likely a relevant process contributing to anti-inflammatory actions of α-13′-COOH. These results improve the understanding of the effects of α-13′-COOH and provide a basis for new research strategies in the context of inflammatory diseases.

Read More

Tocotrienol Supplementation Led to Higher Serum Levels of Lysophospholipids but Lower Acylcarnitines in Postmenopausal Women: A Randomized Double-Blinded Placebo-Controlled Clinical Trial

Chwan-Li Shen, Huanbiao Mo, Dale M Dunn, Bruce A Watkins

Front Nutr . 2021 Dec 24;8:766711. doi: 10.3389/fnut.2021.766711. eCollection 2021.

Abstract

Osteoporosis is a major health problem in postmenopausal women. Herein we evaluated the effects of 12-week tocotrienols (TT) supplementation on serum metabolites in postmenopausal, osteopenic women. Eighty-nine participants (59.7 ± 6.8 yr, BMI 28.7 ± 5.7 kg/m2) were assigned to 3 treatments: placebo (860 mg olive oil/day), 300mg TT (300 mg TT/day), and 600mg TT (600 mg TT/day) for 12 weeks. TT consisted of 90% δ-TT and 10% γ-TT. In this metabolomic study, we evaluated the placebo and 600mgTT at baseline and 12 weeks. As expected, TT and its metabolite levels were higher in the supplemented group after 12 weeks. At baseline, there were no differences in demographic parameters or comprehensive metabolic panels (CMP). Metabolomics analysis of serum samples revealed that 48 biochemicals were higher and 65 were lower in the 600mg TT group at 12 weeks, compared to baseline. The results confirmed higher serum levels of tocotrienols and lysophospholipids, but lower acylcarnitines and catabolites of tryptophan and steroids in subjects given 600mg TT. In summary, 12-week TT supplementation altered many serum metabolite levels in postmenopausal women. The present study supports our previous findings that TT supplementation helps reduce bone loss in postmenopausal osteopenic women by suppressing inflammation and oxidative stress. Furthermore, the body incorporates TT which restructures biomembranes and modifies phospholipid metabolism, a response potentially linked to reduced inflammation and oxidative stress.

Read More

Serum vitamin E levels and chronic inflammatory skin diseases: A systematic review and meta-analysis

Xiaofang Liu, Guang Yang, Mengxin Luo, Qi Lan, Xiaoxia Shi, Haoyuan Deng, Ningning Wang, Xuezhu Xu, Cong Zhang

PLoS One . 2021 Dec 14;16(12):e0261259. doi: 10.1371/journal.pone.0261259. eCollection 2021.

Abstract

Background: Vitamin E has long been linked to skin health, including all of its possible functions in cosmetic products, to its roles in membrane integrity and even the aging process. However, reports on the relationship between serum vitamin E levels and the risk of chronic inflammatory skin diseases have been inconsistent. We performed a systematic review and meta-analysis to evaluate the association between serum vitamin E levels and chronic inflammatory skin diseases.

Methods: We searched the PubMed, Web of Science and Scopus databases, with no time limit up to 30.06.2021. Studies examining serum vitamin E levels in patients with chronic inflammatory skin diseases were selected.

Results: Twenty articles met the inclusion criteria. Compared with controls, a lower vitamin E level was found in patients with vitiligo (SMD: -0.70, 95% CI: -1.21 to -0.19), psoriasis (SMD: -2.73, 95% CI: -3.57 to -1.18), atopic dermatitis (SMD: -1.08, 95% CI: -1.80 to -0.36) and acne (SMD: -0.67, 95% CI: -1.05 to -0.30).

Conclusions: Our meta-analysis showed that serum vitamin E levels were lower in patients suffering from vitiligo, psoriasis, atopic dermatitis and acne. This study highlights the need to evaluate vitamin E status to improve its level in patients with skin diseases.

Read More

A double-blind randomised controlled trial on the effect of Tocovid, a tocotrienol-rich capsule on postoperative atrial fibrillation at the National Heart Institute, Kuala Lumpur: an interim blinded analysis

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.

Read More

Metabolism of natural forms of vitamin E and biological actions of vitamin E metabolites

Qing Jiang

Free Radic Biol Med . 2021 Nov 14;S0891-5849(21)00806-6. doi: 10.1016/j.freeradbiomed.2021.11.012. Online ahead of print.

Abstract

Natural forms of vitamin E comprise four tocopherols and four tocotrienols. During the last twenty years, there have been breakthroughs in our understanding of vitamin E metabolism and biological activities of vitamin E metabolites. Research has established that tocopherols and tocotrienols are metabolized via ω-hydroxylase (CYP4F2)-initiated side chain oxidation to form 13′-hydroxychromanol and 13′-carobyxychromanol (13′-COOH). 13′-COOHs are further metabolized via β-oxidation and sulfation to intermediate carboxychromanols, terminal metabolite carboxyethyl-hydroxychroman (CEHC), and sulfated analogs. Animal and human studies show that γ-, δ-tocopherol and tocotrienols are more extensively metabolized than α-tocopherol (αT), as indicated by higher formation of CEHCs and 13′-COOHs from non-αT forms than those from αT. 13′-COOHs are shown to be inhibitors of cyclooxygenase-1/-2 and 5-lipoxygenase and much stronger than CEHCs for these activities. 13′-COOHs inhibit cancer cell growth, modulate cellular lipids and activate peroxisome proliferator-activated receptor-γ and pregnane X receptor. Consistent with mechanistic findings, αT-13′-COOH or δTE-13′-COOH, respective metabolites of αT or δ-tocotrienol, show anti-inflammatory and cancer-preventive effects, modulates the gut microbiota and prevents β-amyloid formation in mice. Therefore, 13′-COOHs are a new class of bioactive compounds with anti-inflammatory and anti-cancer activities and potentially capable of modulating lipid and drug metabolism. Based on the existing evidence, this author proposes that metabolites may contribute to disease-preventing effects of γ-, δ-tocopherol and tocotrienols. The role of metabolites in αT’s actions may be somewhat limited considering controlled metabolism of αT because of its association with tocopherol-transport protein and less catabolism by CYP4F2 than other vitamin E forms.

Read More

Effect of alpha-tocopherol and dose sensitivity on pancreatitis formation in rats with experimental pancreatitis

Deniz Tazeoğlu, Cüneyt Akyüz, Mehmet Gökçeimam, Gülçin Harman Kamalı, Ayhan Özsoy, Servet Rüştü Karahan

Ulus Travma Acil Cerrahi Derg . 2021 Nov;27(6):605-612. doi: 10.14744/tjtes.2020.89054.

Abstract

Background: Acute pancreatitis is an inflammatory disease accompanied by pancreatic inflammation characterized by acinar cell damage and leukocyte infiltration in the tissue. At present, mortality and morbidity rates are high despite the current treatment of pancreatitis; therefore, new studies and treatment studies are needed. In this study, the effects of alpha-tocopherol on different doses of L-arginine-induced experimental acute pancreatitis model were investigated.

Methods: Thirty adult male Sprague-Dawley albino rats were randomly divided into four groups; control (sham) group (n=6), acute pancreatitis group (n=8), low-dose alpha-tocopherol (200 mg/kg once intraperitoneal [IP]) group (n=8), and high dose alpha-tocopherol (400 mg/kg once ip) group (n=8). Experimental acute pancreatitis model was created by a single IP dose of 5 g/kg of L-arginine. Alpha-tocopherol was administered in a single dose intraperitoneally, 30 min before the creation of the experimental model of acute pancreatitis induced by L-arginine induction in Groups 3 and 4. Tissue and blood samples were taken under anesthesia 72 h after L-arginine injection; then the rats were sacrificed by decapitation. Serum amylase, lipase, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP) levels were examined. Pancreatic tissue samples were examined under a light microscope for histopathological examination.

Results: When the acute pancreatitis group (Group 2) was compared to the control group (Group 1), serum amylase, lipase, IL-1β, IL-6, TNF-alpha, and CRP levels were all significantly increased (p<0.05 for all). Histopathological examination showed significant difference in edema (p<0.001) and inflammation (p=0.007) scores. When the low (Group 3) and high (Group 4) dose alpha-tocopherol groups were compared to Group 2, amylase, lipase, IL-1β, IL-6, TNF-alpha, and CRP parameters were statistically significantly lower (p<0.05 for all). In the histopathological comparison of Groups 2, 3, and 4, edema and inflammation scores were decreased in Groups 3 and 4 compared to Group 2. Comparing Group 4 to Group 3, lipase (p<0.01), IL-6 (p=0.038), and TNF-alpha (p=0.002) levels were significantly decreased; no significant difference was observed in the histopathological evaluation.

Conclusion: Alpha-tocopherol was found to reduce inflammation and pancreatic damage in acute pancreatitis and was more effective in high doses.

Read More

Different forms of vitamin E and metabolite 13′-carboxychromanols inhibit cyclooxygenase-1-catalyzed thromboxane in platelets, and tocotrienols and 13′-carboxychromanols are competitive inhibitors of 5-lipoxygenase

Na-Young Park, Suji Im, Qing Jiang

J Nutr Biochem . 2021 Oct 25;108884. doi: 10.1016/j.jnutbio.2021.108884. Online ahead of print.

Abstract

Cyclooxygenase (COX-1 and COX-2)- and 5-lipoxygenase (5-LOX)-catalyzed biosynthesis of eicosanoids play important roles in inflammation and chronic diseases. The vitamin E family has four tocopherols and tocotrienols. We have shown that the metabolites of δ-tocopherol (δT) and δ-tocotrienol (δTE), i.e., δT-13′-carboxychromanol (COOH) and δTE-13′-COOH, respectively, inhibit COX-1/-2 and 5-LOX activity, but the nature of how they inhibit 5-LOX is not clear. Further, the impact of tocopherols and tocotrienols on COX-1/-2 or 5-LOX activity has not been fully delineated. In this study, we found that tocopherols and tocotrienols inhibited human recombinant COX-1 with IC50s of 1-12 µM, and suppressed COX-1-mediated formation of thromboxane in collagen-stimulated rat’s platelets with IC50s of 8-50 µM. None of the vitamin E forms directly inhibited COX-2 activity. 13′-COOHs inhibited COX-1 and COX-2 enzyme activity with IC50s of 3-4 and 4-10 µM, respectively, blocked thromboxane formation in collagen- and ionophore-stimulated rats’ platelets with IC50s of 1.5-2.5 µM, and also inhibited COX-2-mediated prostaglandins in stimulated cells. Using enzyme kinetics, we observed that δT-13′-COOH, δTE-13′-COOH and δTE competitively inhibited 5-LOX activity with Ki of 1.6, 0.8 and 2.2 µM, respectively. These compounds decreased leukotriene B4 from stimulated neutrophil-like cells without affecting translocation of 5-LOX from cytosol to the nucleus. Our study reveals inhibitory effects of vitamin E forms and 13′-COOHs on COX-1 activity and thromboxane formation in platelets, and elucidates mechanisms underlying their inhibition of 5-LOX. These observations are useful for understanding the role of these compounds in disease prevention and therapy.

Read More

Untargeted serum metabolites profiling in high-fat diet mice supplemented with enhanced palm tocotrienol-rich fraction using UHPLC-MS

Danial Efendy Goon, Sharaniza Ab-Rahim, Amir Hakimi Mohd Sakri, Musalmah Mazlan, Jen Kit Tan, Mardiana Abdul Aziz, Norizal Mohd Noor, Effendi Ibrahim, Siti Hamimah Sheikh Abdul Kadir

Sci Rep . 2021 Oct 25;11(1):21001. doi: 10.1038/s41598-021-00454-9.

Abstract

Excessive high fat dietary intake promotes risk of developing non-alcoholic fatty liver disease (NAFLD) and predisposed with oxidative stress. Palm based tocotrienol-rich fraction (TRF) has been reported able to ameliorate oxidative stress but exhibited poor bioavailability. Thus, we investigated whether an enhanced formulation of TRF in combination with palm kernel oil (medium-chain triglycerides) (ETRF) could ameliorate the effect of high-fat diet (HFD) on leptin-deficient male mice. All the animals were divided into HFD only (HFD group), HFD supplemented with ETRF (ETRF group) and HFD supplemented with TRF (TRF group) and HFD supplemented with PKO (PKO group). After 6 weeks, sera were collected for untargeted metabolite profiling using UHPLC-Orbitrap MS. Univariate analysis unveiled alternation in metabolites for bile acids, amino acids, fatty acids, sphingolipids, and alkaloids. Bile acids, lysine, arachidonic acid, and sphingolipids were downregulated while xanthine and hypoxanthine were upregulated in TRF and ETRF group. The regulation of these metabolites suggests that ETRF may promote better fatty acid oxidation, reduce oxidative stress and pro-inflammatory metabolites and acts as anti-inflammatory in fatty liver compared to TRF. Metabolites regulated by ETRF also provide insight of its role in fatty liver. However, further investigation is warranted to identify the mechanisms involved.

Read More

Different forms of vitamin E and metabolite 13′-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13′-carboxychromanols are competitive inhibitors of 5-lipoxygenase

Na-Young Park, Suji Im, Qing Jiang

J Nutr Biochem . 2021 Oct 25;100:108884. doi: 10.1016/j.jnutbio.2021.108884. Online ahead of print.

Abstract

Cyclooxygenase (COX-1 and COX-2)- and 5-lipoxygenase (5-LOX)-catalyzed biosynthesis of eicosanoids play important roles in inflammation and chronic diseases. The vitamin E family has four tocopherols and tocotrienols. We have shown that the metabolites of δ-tocopherol (δT) and δ-tocotrienol (δTE), i.e., δT-13′-carboxychromanol (COOH) and δTE-13′-COOH, respectively, inhibit COX-1/-2 and 5-LOX activity, but the nature of how they inhibit 5-LOX is not clear. Further, the impact of tocopherols and tocotrienols on COX-1/-2 or 5-LOX activity has not been fully delineated. In this study, we found that tocopherols and tocotrienols inhibited human recombinant COX-1 with IC50s of 1-12 µM, and suppressed COX-1-mediated formation of thromboxane in collagen-stimulated rat’s platelets with IC50s of 8-50 µM. None of the vitamin E forms directly inhibited COX-2 activity. 13′-COOHs inhibited COX-1 and COX-2 enzyme activity with IC50s of 3-4 and 4-10 µM, respectively, blocked thromboxane formation in collagen- and ionophore-stimulated rats’ platelets with IC50s of 1.5-2.5 µM, and also inhibited COX-2-mediated prostaglandins in stimulated cells. Using enzyme kinetics, we observed that δT-13′-COOH, δTE-13′-COOH and δTE competitively inhibited 5-LOX activity with Ki of 1.6, 0.8 and 2.2 µM, respectively. These compounds decreased leukotriene B4 from stimulated neutrophil-like cells without affecting translocation of 5-LOX from cytosol to the nucleus. Our study reveals inhibitory effects of vitamin E forms and 13′-COOHs on COX-1 activity and thromboxane formation in platelets, and elucidates mechanisms underlying their inhibition of 5-LOX. These observations are useful for understanding the role of these compounds in disease prevention and therapy.

Read More

Vitamin E supplementation in inflammatory skin diseases

Enzo Berardesca, Norma Cameli

Dermatol Ther . 2021 Oct 16;e15160. doi: 10.1111/dth.15160. Online ahead of print.

Abstract

Vitamin E is a powerful lipophilic antioxidant that protects membranes from lipid peroxidation, and consequently, oxidative damage. Oxidative stress plays a role in the development of neurodegenerative diseases. Vitamin E supplementation is recommended in patients with vitamin E deficiency due to fat malabsorption. The addition of vitamin E to the diet slows Alzheimer’s disease progression and protects older patients against respiratory infections. Recent studies also point to the involvement of oxidative stress in the pathology of immune-mediated skin diseases, such as atopic dermatitis and psoriasis. We reviewed the available clinical trials that investigated the role of vitamin E supplementation in preventing and treating atopic dermatitis and psoriasis. Data from these studies point to a positive role of vitamin E supplementation in these diseases. Still, due to limitations in study design, further evidence is needed to reach a definite conclusion.

Read More