Determination of tissue-specific interaction between vitamin C and vitamin E in vivo using senescence marker protein-30 knockout mice as a vitamin C synthesis deficiency model

Ayami Sato, Yuka Takino, Tomohiro Yano, Koji Fukui, Akihito Ishigami

SaveEmailSend to Display options full text links full text provider logo actions Cite Favorites share page navigation Title & authors Abstract Related information LinkOut - more resources Br J Nutr . 2021 Nov 2;1-33. doi: 10.1017/S0007114521004384. Online ahead of print.

Abstract

Vitamin E (α-tocopherol; VE) is known to be regenerated from VE radicals by vitamin C (L-ascorbic acid; VC) in vitro. However, their in vivo interaction in various tissues is still unclear. Therefore, we alternatively examined the in vivo interaction of VC and VE by measurement of their concentrations in various tissues of senescence marker protein-30 (SMP30) knockout (KO) mice as a VC synthesis deficiency model. Male SMP30-KO mice were divided into four groups (VC+/VE+, VC+/VE-, VC-/VE+, and VC-/VE-), fed diets with or without 500 mg/kg VE and given water with or without 1.5 g/L VC ad libitum. Then, VC and VE concentrations in the plasma and various tissues were determined. Further, gene expression levels of transporters associated with VC and VE, such as α-tocopherol transfer protein (α-TTP) and sodium-dependent vitamin C transporters (SVCTs), were examined. These results showed that the VE levels in the VC-depleted (VC-/VE+) group were significantly lower than those in the VC+/VE+ group in the liver and heart; the VC levels in the VE-depleted (VC+/VE-) group were significantly lower than those in the VC+/VE+ group in the kidneys. The α-TTP gene expression in the liver and kidneys were decreased by VC and/or VE depletion. Moreover, SVCT1 gene expression in the liver was decreased by both VC and VE depletion. In conclusion, these results indicate that VC spares VE mainly in the liver and heart, and that VE spares VC in the kidneys of SMP30-KO mice. Thus, interaction between VC and VE is likely to be tissue specific.

Mototada Shichiri, Noriko Ishida, Yoshinori Aoki, Taisuke Koike, Yoshihisa Hagihara

Free Radic Biol Med . 2021 Nov 1;175:171-183. doi: 10.1016/j.freeradbiomed.2021.08.236. Epub 2021 Aug 30.

Abstract

Stress induces emotional arousal causing anxiety, irritability, exaggerated startle behaviour, and hypervigilance observed in patients with trauma and stress-related mental disorders, including acute stress disorder and post-traumatic stress disorder. Central norepinephrine release promotes stress-induced emotional arousal. However, the regulator of emotional arousal remains unknown. Here, we show that the arachidonate-derived metabolite produced by stress-activated leukocyte 12/15-lipoxygenase is remarkably elevated in the plasma and upregulates the central norepinephrine release, resulting in the enhancement of the struggle behaviour (= escape behaviour) in the tail suspension test. Struggle behaviour is mimicking a symptom of emotional arousal. This stress-induced struggle behaviour was absent in 12/15-lipoxygenase deficient mice; however, intravenous administration of a 12/15-lipoxygenase metabolite to these mice after stress exposure rekindled the struggle behaviour. Furthermore, tocotrienols and geranylgeraniol reduced stress-induced 12/15-lipoxygenase metabolite production and suppressed the struggle behaviour. Our findings indicate that arachidonate-derived 12/15-lipoxygenase metabolite is involved in the regulation of stress-enhanced central norepinephrine release and struggle behaviour. In addition, we propose 12/15-lipoxygenase as a potential therapeutic target for the treatment of emotional arousal observed in stress-related mental disorders.

Angelo Azzi

Free Radic Biol Med . 2021 Nov 1;175:155-160. doi: 10.1016/j.freeradbiomed.2021.07.042. Epub 2021 Sep 1.

Abstract

The name vitamin E, was given by Barnett and Sure who suggested that the factor proposed by Evans and Bishop as substance “X,” be termed vitamin “E” as the next vitamin after the A, B, C and D vitamins had been already described. The identification of vitamin E with a-tocopherol was made in 1936 by Evans’ group. One year later β-tocopherol and 11 years later δ-tocopherol were isolated. Tocotrienol (named zetatocopherol) was first described in 1957 and later isolated in 1961. The antioxidant property of tocopherols was reported by Olcott and Emerson in 1937. Inherited vitamin E deficiency, AVED, characterized by a form of neuromyopathy was first described in 1981. The disease, was localized to chromosome 8q and found to be caused by a mutation of the a-TTP gene. The subsequent paragraphs are not a comprehensive review but only critical reflections on some important aspects of vitamin E research.

Yoshiro Saito

Free Radic Biol Med . 2021 Nov 1;175:121-129. doi: 10.1016/j.freeradbiomed.2021.08.234. Epub 2021 Sep 2.

Abstract

Vitamin E, a generic term for tocopherol (T) and tocotrienol (T3), is one of the most potent lipid-soluble antioxidants in the body. It is classified into T and T3 based on the difference in the side chain structure. T and T3 have four isoforms: α-, β-, γ-, and δ, which have different chroman rings. Both T and T3 exhibit a similar ability to scavenge free radicals, and the extent of this ability depends on the difference in the chroman structure. However, they display unique cytoprotective activities in cultured cells depending on the difference in the side chain structure. The cytoprotective effects of vitamin E have received much attention in the prevention of ferroptosis, which is a distinct form of cell death involving iron-dependent lipid peroxidation. This review focuses on the cytoprotective actions of vitamin E isoforms against oxidative stress, particularly the difference between T and T3 and its relation to cellular uptake and distribution. Moreover, the molecular mechanism for cytoprotection of vitamin E oxidation products is explained, and the complementary role of vitamin E and selenoproteins to prevent lipid peroxidation and ferroptosis is described. Furthermore, the evaluation of vitamin E’s radical scavenging activity in vivo using oxidative stress markers is discussed, particularly based on kinetic data and the physiological molar ratio of vitamin E to substrates, and the limited role of vitamin E as a peroxyl radical scavenger is described. The future directions and unresolved issues related to vitamin E and lipid peroxidation are also discussed.

Xiao-Dong Zang, Qing-Hui Hu, Xiao-Xu Liu, Min Da, Zhao-Cong Yang, Ji-Rong Qi, Xu-Ming Mo

World J Pediatr . 2021 Oct;17(5):517-526. doi: 10.1007/s12519-021-00454-9. Epub 2021 Sep 1.

Abstract

Background: Vitamin E is the most abundant lipid-soluble antioxidants present in plasma; however, the relationship between serum vitamin E and change in body mass index (BMI)-for-age Z scores in adolescents has not been well described.

Methods: This study is a cross-sectional study. Data were analyzed from 4014 adolescents who participated in the National Health and Nutrition Examination Survey. The nutritional status was calculated by BMI Z scores and was classified into normal weight, overweight, and obese. Multivariable-adjusted logistic regression was used to examine the association between serum vitamin E levels with overweight/obesity. Besides, the interaction effects between potential confounders and vitamin E on obesity were further evaluated.

Results: After adjusting potential confounders, serum vitamin E levels were negatively associated with overweight/obesity in girls but not in boys. Per standard deviation increment in vitamin E concentrations was associated with a 92% decreased risk of obesity in females. Besides, lower quartiles of serum vitamin E were associated with a higher risk of overweight/obesity in girls. Moreover, the inverse association between serum vitamin E levels and obesity was also found in most subgroups through subgroup analysis.

Conclusions: Our study supports the negative association between serum vitamin E levels and overweight/obesity in adolescents. A higher serum vitamin E level may be associated with a reduced probability of obesity in girls, but not in boys.

Yoshio Sumida, Masato Yoneda, Yuya Seko, Hirokazu Takahashi, Nagisa Hara, Hideki Fujii, Yoshito Itoh, Masashi Yoneda, Atsushi Nakajima, Takeshi Okanoue , Japan Study Group of NAFLD (JSG-NAFLD)

Free Radic Biol Med . 2021 Oct 26;S0891-5849(21)00767-X. doi: 10.1016/j.freeradbiomed.2021.10.017. Online ahead of print.

Abstract

Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies.

Erin M Warshaw, Jenna L Ruggiero, Joel G DeKoven, Jonathan I Silverberg, Howard I Maibach, James S Taylor, Amber R Atwater, Kathryn A Zug, Denis Sasseville, Joseph F Fowler Jr, Anthony F Fransway, Melanie D Pratt, Donald V Belsito, Vincent A DeLeo, Margo J Reeder

Dermatitis . 2021 Sep-Oct 01;32(5):308-318. doi: 10.1097/DER.0000000000000706.

Abstract

Background: Vitamin E (tocopherol) a naturally occurring mixture of antioxidants commonly used in topical skin care products, may cause allergic contact dermatitis.

Objective: The aim of this study was to characterize positive patch test reactions to tocopherol and tocopherol acetate.

Methods: This is a retrospective analysis of North American Contact Dermatitis Group patch test data to tocopherols (dl-α-tocopherol 100% and/or dl-α-tocopherol acetate 100%) from 2001 to 2016.

Results: Of the 38,699 patients patch tested to tocopherol and/or tocopherol acetate, 349 (0.9%) had positive reactions; of these, 87.6% were currently relevant. Most (51.4%) were weak (+) and/or not related to occupation (99.1%). Compared with tocopherol-negative patients, tocopherol-positive individuals were more likely to be female (72.5% vs 67.2%, P = 0.0355), have a final primary diagnosis of allergic contact dermatitis (74.2% vs 52.6%, P < 0.0001), and have dermatitis in a scattered generalized distribution (23.8% vs 18.2%, P = 0.0072); they were also less likely to have hand involvement (16.6% vs 22.3%, P = 0.0064). The most common source of tocopherol was personal care products, especially moisturizers.

Conclusions: Positive patch test reactions to tocopherols were relatively rare given their widespread use. When positive, current clinical relevance was high. Tocopherol-positive patients were more likely to be female and presented with dermatitis on the face or in a scattered generalized pattern.

Ruth Naomi, Nurul Husna Shafie, Priyatharisni Kaniappan, Hasnah Bahari

Front Nutr . 2021 Oct 26;8:754086. doi: 10.3389/fnut.2021.754086. eCollection 2021.

Abstract

Neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease, are claimed to be of major concern causing a significant disease burden worldwide. Oxidative stress, mitochondrial dysfunction and nerve damage are the main reasons for the emergence of these diseases. The formation of reactive oxygen species (ROS) is the common chemical molecule that is formed from all these three interdependent mechanisms which is highly reactive toward the neuronal cells. For these reasons, the administration of tocotrienols (T3s), which is a potent antioxidant, is proven to cater to this problem, through in vitro and in vivo investigations. Interestingly, their therapeutic potentials are not only limited to antioxidant property but also to being able to reverse the neuronal damage and act as a shield for mitochondria dysfunction. Thereby, T3s prevents the damage to the neurons. In regards to this statement, in this review, we focused on summarizing and discussing the potential therapeutic role of T3s on Alzheimer’s and Parkinson’s diseases, and their protective mechanisms based on evidence from the in vitro and in vivo studies. However, there is no clinical trial conducted to prove the efficacy of T3s for Alzheimer’s and Parkinson’s subjects. As such, the therapeutic role of T3s for these neurodegenerative disorders is still under debate.

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.

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.