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Tocotrienols Influence Body Weight Gain and Brain Protein Expression in Long-Term High-Fat Diet-Treated Mice

Yugo Kato, Yoshinori Aoki, Koji Fukui

Int J Mol Sci . 2020 Jun 25;21(12):4533. doi: 10.3390/ijms21124533.

Abstract

Obesity induces serious diseases such as diabetes and cardiovascular disease. It has been reported that obesity increases the risk of cognitive dysfunction. Cognitive dysfunction is a characteristic symptom of Alzheimer’s and Parkinson’s diseases. However, the detailed mechanisms of obesity-induced cognitive dysfunction have not yet been elucidated. The onset and progression of obesity-induced severe secondary diseases such as diabetes, cardiovascular events, and hypertension are deeply connected to oxidative stress. We hypothesized that obesity induces cognitive dysfunction via acceleration of reactive oxygen species (ROS) production. Vitamin E, which is a lipophilic vitamin, has strong antioxidative effects and consists of two groups: tocopherols and tocotrienols. Recently, it has been demonstrated that tocotrienols have strong neuroprotective and anti-obesity effects. In this study, we fed mice a high-fat diet (HFD) from 9 to 14 months of age and assessed the effect of tocotrienols treatment on body weight, brain oxidation levels, and cognitive function. The results revealed that treatment with tocotrienols inhibited body weight gain; further, tocotrienols reached the brain and attenuated oxidation in HFD-treated mice. These results indicate that tocotrienols have anti-obesity effects and inhibit obesity-induced brain oxidation.

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Culprit or Correlate? An Application of the Bradford Hill Criteria to Vitamin E Acetate

Ryan Feldman, Jonathan Meiman, Matthew Stanton, David D Gummin

Arch Toxicol . 2020 Jun;94(6):2249-2254. doi: 10.1007/s00204-020-02770-x. Epub 2020 May 25.

Abstract

Vitamin E acetate (VEA) has come under significant scrutiny due to its association with e-cigarette, or vaping, product use-associated lung injury (EVALI). In 1965, Sir Austin Bradford Hill proposed a set of criteria used to critically assess an association for causality. In this article, we apply the Bradford Hill causation criteria to VEA and the EVALI outbreak to clarify what further areas of study are needed to strengthen the causal argument. Additionally, we highlight the need for systematized approaches to rapidly identify the cause of mass poisoning events of unknown etiology.

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Deuteration of the Farnesyl Terminal Methyl Groups of δ-Tocotrienol and Its Effects on the Metabolic Stability and Ability of Inducing G-CSF Production

Xingui Liu, Zhengya Gao, Qiang Fu, Lin Song, Peiyi Zhang, Xuan Zhang, Howard Hendrickson, Peter A Crooks, Daohong Zhou, Guangrong Zheng

Bioorg Med Chem . 2020 Jun 1;28(11):115498. doi: 10.1016/j.bmc.2020.115498. Epub 2020 Apr 8.

Abstract

δ-tocotrienol (DT3), a member of vitamin E family, has been shown to have a potent radio-protective effect. However, its application as a radioprotectant is limited, at least in part, by its short plasma elimination half-life and low bioavailability. In an effort to increase the metabolic stability of DT3, a deuterium substituted DT3 derivative, d6-DT3, was designed and synthesized. d6-DT3 showed improved in vitro and in vivo metabolic stability compared to DT3. The unexpected lower potency of d6-DT3 in inducing granulocyte-colony stimulating factor (G-CSF) production in mouse revealed that the metabolite(s) of DT3 might play a major role in inducing G-CSF induction.

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Effects of Selenium and Vitamin E on Enzymatic, Biochemical, and Immunological Biomarkers in Galleria Mellonella L

Mustafa Coskun, Tamer Kayis, Emre Gulsu, Emel Alp

Sci Rep . 2020 Jun 19;10(1):9953. doi: 10.1038/s41598-020-67072-9.

Abstract

To understand the effects of micronutrients have particular biological functions that are involved mainly in the antioxidant system, which has essential implications for the development of diseases, this study investigated how vitamin E, selenium, and their combination affect lipid, protein, carbohydrate, and malondialdehyde (MDA) content; antioxidant enzyme (catalase [CAT], superoxide dismutase [SOD], glutathione-S-transferase [GST]) activity; and the total hemocyte count (THC) in larvae of Galleria mellonella L. fed different diets. Diet 1 (100 µg of selenium) significantly decreased carbohydrate and lipid content. Diets 2 (100 µg of vitamin E), 3 (100 µg of selenium and vitamin E each), and 5 (Tween 80) did not significantly affect protein and carbohydrate content. Diet 2 significantly increased the lipid content compared to diet 4 (control). Diet 1 increased CAT, SOD, and GST activity and MDA content (highest at 27.64 nmol/mg protein). Diet 2 significantly decreased SOD activity and MDA content compared to other diets. Diet 1 significantly decreased the THC compared to other diets. These results suggested that selenium changes oxidative stress parameters, energy reserves, and THC in G. mellonella. These changes could be a physiological adaptation against selenium-induced oxidative stress. Vitamin E could play a protective role in selenium toxicity.

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Tocotrienol Regulates Osteoclastogenesis in Rheumatoid Arthritis

Kyoung-Woon Kim, Bo-Mi Kim, Ji-Yeon Won, Hong Ki Min, Seoung Joon Lee, Sang-Heon Lee, Hae-Rim Kim

Korean J Intern Med . 2020 Jun 19. doi: 10.3904/kjim.2019.372. Online ahead of print.

Abstract

Background/aims: The present study aimed to investigate whether tocotrienol regulates interleukin 17 (IL-17)-induced osteoclastogenesis in rheumatoid arthritis (RA).

Methods: We evaluated the effect of tocotrienol on IL-17-induced receptor activator of nuclear factor kappa B ligand (RANKL) production using RA fibroblast-like synoviocyte (FLS), together with real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Osteoclast differentiation was confirmed after culturing IL-17-treated RA FLS and Th17 cells with tocotrienol and monocytes. We analyzed the suppressive effect of tocotrienol on Th17 cells percentage or Th17-cytokine levels among peripheral blood mononuclear cells using flow cytometry.

Results: We found that IL-17 stimulated FLS to produce RANKL and tocotrienol decreased this IL-17-induced RANKL production. Tocotrienol decreased the IL-17-induced activation of mammalian target of rapamycin, extracellular signal-regulated kinase, and inhibitor of kappa B-alpha. When monocytes were incubated with IL-17, RANKL, IL-17-treated FLS or Th17 cells, osteoclasts were differentiated and tocotrienol decreased this osteoclast differentiation. Tocotrienol reduced Th17 cell differentiation and the production of IL-17 and sRANKL; however, tocotrienol did not affect Treg cell differentiation.

Conclusions: Tocotrienol inhibited IL-17- activated RANKL production in RA FLS and IL-17-activated osteoclast formation. In addition, tocotrienol reduced Th17 differentiation. Therefore, tocotrienol could be a new therapeutic choice to treat bone destructive processes in RA.

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Relationship Between Serum Vitamin E Concentration in First Trimester and the Risk of Developing Hypertension Disorders Complicating Pregnancy

W Y Meng, W T Huang, J Zhang, M Y Jiao, L Jin, L Jin

Beijing Da Xue Xue Bao Yi Xue Ban . 2020 Jun 18;52(3):470-478.

Abstract

Objective: To investigate the incidence of hypertension disorders complicating pregnancy (HDCP) and vitamin E (VE) nutritional status among pregnant women in Beijing, and to determine the relationship between serum VE concentration in the first trimester of pregnancy and the risk of developing HDCP.

Methods: A retrospective cohort study was performed including 22 283 cases of pregnant women who underwent singleton deliveries in Tongzhou Maternal & Child Health Hospital of Beijing from January 2016 through December 2018 and received tests of serum VE concentrations in the first trimester of pregnancy. Nonconditional Logistic regression model was used to analyze the association between serum VE concentration levels and the risk of developing HDCP.

Results: The total incidence of HDCP was 5.4%, with the incidence of gestational hypertension around 2.1% and the incidence of preeclampsia-eclampsia around 3.3%. The median concentration of serum VE in early pregnancy was 10.1 (8.8-11.6) mg/L, and 99.7% of the participants had normal serum VE concentrations. The incidence of gestational hypertension and that of preeclampsia-eclampsia had been annually increasing in three years; a linear-by-linear association had also been observed between the serum VE concentrations and the years of delivery. According to the results of the univariable and the multivariable Logistic regression analyses, higher risks of developing HDCP had been observed among women with higher serum VE concentrations. Compared to those with serum VE concentrations in interquartile range (P25–P75) of all the participants, the women whose serum VE concentrations above P75 were at higher risks to be attacked by HDCP (OR = 1.34, P < 0.001), gestational hypertension (OR = 1.39, P = 0.002), or preeclampsia-eclampsia (OR = 1.34, P = 0.001), as suggested by the results of the multivariable Logistic regression model analyses. In addition, the women with serum VE concentrations of 11.2 mg/L or above had a significantly higher risk of developing HDCP than those whose serum VE concentrations of P40–P60 of all the participants, and this risk grew higher as serum VE concentrations in the first trimester of pregnancy increased.

Conclusion: Women in Beijing are at good nutritional status. From January 2016 to December 2018, the incidence of HDCP increased with serum VE concentration level, and serum VE concentration of 11.2 mg/L is an indicator of an increased risk of developing HDCP, suggesting that pregnant women should take nutritional supplements containing VE carefully.

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Vitamin E Blocks Connexin Hemichannels and Prevents Deleterious Effects of Glucocorticoid Treatment on Skeletal Muscles

Elisa Balboa, Fujiko Saavedra, Luis A Cea, Valeria Ramírez, Rosalba Escamilla, Aníbal A Vargas, Tomás Regueira, Juan C Sáez

Int J Mol Sci . 2020 Jun 8;21(11):E4094. doi: 10.3390/ijms21114094.

Abstract

Glucocorticoids are frequently used as anti-inflammatory and immunosuppressive agents. However, high doses and/or prolonged use induce undesired secondary effects such as muscular atrophy. Recently, de novo expression of connexin43 and connexin45 hemichannels (Cx43 HCs and Cx45 HCs, respectively) has been proposed to play a critical role in the mechanism underlying myofiber atrophy induced by dexamethasone (Dex: a synthetic glucocorticoid), but their involvement in specific muscle changes promoted by Dex remains poorly understood. Moreover, treatments that could prevent the undesired effects of glucocorticoids on skeletal muscles remain unknown. In the present work, a 7-day Dex treatment in adult mice was found to induce weight loss and skeletal muscle changes including expression of functional Cx43/Cx45 HCs, elevated atrogin immunoreactivity, atrophy, oxidative stress and mitochondrial dysfunction. All these undesired effects were absent in muscles of mice simultaneously treated with Dex and vitamin E (VitE). Moreover, VitE was found to rapidly inhibit the activity of Cx HCs in freshly isolated myofibers of Dex treated mice. Exposure to alkaline pH induced free radical generation only in HeLa cells expressing Cx43 or Cx45 where Ca2+ was present in the extracellular milieu, response that was prevented by VitE. Besides, VitE and two other anti-oxidant compounds, Tempol and Resveratrol, were found to inhibit Cx43 HCs in HeLa cells transfectants. Thus, we propose that in addition to their intrinsic anti-oxidant potency, some antioxidants could be used to reduce expression and/or opening of Cx HCs and consequently reduce the undesired effect of glucocorticoids on skeletal muscles.

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Effects of Vitamin A and Vitamin E on Attenuation of Amphotericin B-induced Side Effects on Kidney and Liver of Male Wistar Rats

Aref Salehzadeh, Alireza Salehzadeh, Amir-Hossein Maghsood, Shirin Heidarisasan, Masoumeh Taheri-Azandaryan, Abolfazl Ghafourikhosroshahi, Roghayeh Abbasalipourkabir

Environ Sci Pollut Res Int . 2020 Jun 8. doi: 10.1007/s11356-020-09547-w. Online ahead of print.

Abstract

Despite the fact that amphotericin B (AmB) is currently considered as the first choice for treatment of visceral leishmaniasis, it is associated with some side effects. This study was designed to investigate the protective effects of vitamins A and E against amphotericin B-induced adverse effects in the kidney and liver of rat. Thirty male Wistar rats aged 7-8 weeks and weighing around 200 g were randomly divided into five groups, each one containing six rats. The first to fifth groups received olive oil as the control groups, AmB, AmB + vitamin A, AmB + vitamin E, and AmB + vitamins A + E, respectively. Rats received vitamins by gavage (vitamin A, 1000 IU/kg and vitamin E, 100 IU/kg) and amphotericin B by injections (5.5 mg/kg body weight). The treatment was constantly continued for 5 days and days 7 and 21. At the end of the study, serum level of TAC, TOS, MDA, liver enzyme activity (ALT, AST, ALP, LDH), renal factors (urea, uric acid, and creatinine), lipid profile as well as histopathological changes of the liver and kidney were investigated. AmB significantly increased serum level of creatinine, urea, uric acid, ALP, TOS, MDA, and kidney and renal tissue damage (p < 0.05). Supplementation AmB with vitamins A and E alone or combination improved oxidative stress status, liver and renal tissue structure, and functional parameters and serum lipid profile. This study highlighted the effects of vitamin A and vitamin E on attenuation of amphotericin B-induced side effects on the kidney and liver of male Wistar rats. Combination of the two vitamins is more effective than either alone improving the oxidative stress status, serum lipid profile, or liver and renal tissue structure and functional parameters.

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