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.


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.


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 (P25P75) 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 P40P60 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.


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.


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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Sulforaphane and Vitamin E Protect From Glucotoxic Neurodegeneration and Lifespan Reduction In C. Elegans

Andrea Schlotterer, Benan Masri, M Humpert, Bernhard Karl Krämer, Hans-Peter Hammes, Michael Morcos

Exp Clin Endocrinol Diabetes . 2020 Jun 5. doi: 10.1055/a-1158-9248. Online ahead of print.


Caenorhabditis elegans is an established model organism in neurodegeneration and aging research. Oxidative stress and formation of advanced glycation endproducts (AGEs), as they occur under hyperglycemic conditions in diabetes mellitus, contribute to neuronal damage and lifespan reduction. Sulforaphane (SFN) is an indirect antioxidant, alpha-tocopherol (vitamin E) is a direct antioxidant that acts as a free radical scavenger. Aim of this study is to investigate the protective effects of SFN and vitamin E against glucotoxic damages to the neuronal system and lifespan in C. elegans. Culture conditions that mimic clinical hyperglycemia increased the formation of reactive oxygen species (ROS) (p<0.001) and the accumulation of methylglyoxal-derived advanced glycation endproducts (MG-derived AGEs) (p<0.01) with subsequent neuronal damage and neuronal dysfunction, ultimately leading to a significant shortening of lifespan (p<0.01). Treatment with both, 20 µmol/l SFN and 200 µg/ml vitamin E, completely prevented the increase in ROS and MG-derived AGEs, abolished the glucotoxic effects on neuronal structure and function, and preserved lifespan, resulting in a life expectancy similar to untreated controls. These data emphasize the relevance of indirect and direct antioxidants as potential therapeutic options for the prevention of glucotoxic pathologies.

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Comparative Effects of Alpha- And Gamma-Tocopherol on Mitochondrial Functions in Alzheimer’s Disease In Vitro Model

Aslina Pahrudin Arrozi, Siti Nur Syazwani Shukri, Wan Zurinah Wan Ngah, Yasmin Anum Mohd Yusof, Mohd Hanafi Ahmad Damanhuri, Faizul Jaafar, Suzana Makpol

Sci Rep . 2020 Jun 2;10(1):8962. doi: 10.1038/s41598-020-65570-4.


Vitamin E acts as an antioxidant and reduces the level of reactive oxygen species (ROS) in Alzheimer’s disease (AD). Alpha-tocopherol (ATF) is the most widely studied form of vitamin E besides gamma-tocopherol (GTF) which also shows beneficial effects in AD. The levels of amyloid-beta (Aβ) and amyloid precursor protein (APP) increased in the brains of AD patients, and mutations in the APP gene are known to enhance the production of Aβ. Mitochondrial function was shown to be affected by the increased level of Aβ and may induce cell death. Here, we aimed to compare the effects of ATF and GTF on their ability to reduce Aβ level, modulate mitochondrial function and reduce the apoptosis marker in SH-SY5Y cells stably transfected with the wild-type or mutant form of the APP gene. The Aβ level was measured by ELISA, the mitochondrial ROS and ATP level were quantified by fluorescence and luciferase assay respectively whereas the complex V enzyme activity was measured by spectrophotometry. The expressions of genes involved in the regulation of mitochondrial membrane permeability such as voltage dependent anion channel (VDAC1), adenine nucleotide translocase (ANT), and cyclophilin D (CYPD) were determined by quantitative real-time polymerase chain reaction (qRT-PCR), while the expressions of cyclophilin D (CypD), cytochrome c, Bcl2 associated X (BAX), B cell lymphoma-2 (Bcl-2), and pro-caspase-3 were determined by western blot. Our results showed that mitochondrial ROS level was elevated accompanied by decreased ATP level and complex V enzyme activity in SH-SY5Y cells expressing the mutant APP gene (p < 0.05). Treatment with both ATF and GTF reduced the mitochondrial ROS level with maximum reduction was observed in the cells treated with high concentrations of ATF and GTF (p < 0.05). However, only GTF at 80 µM significantly increase the ATP level and complex V enzyme activity (p < 0.05). VDAC1 and CYPD were downregulated and CypD protein was significantly overexpressed in cells transfected with the wild-type (WT) and mutant APP gene (p < 0.05). Cytochrome c release, the ratio of BAX/Bcl-2, and pro-caspase-3 expression increased in cells expressing mutated APP gene (p < 0.05). The expression of CypD and pro-caspase 3 protein, and the ratio of BAX/Bcl-2 were increased in the following order; SH-SY5Y-APP-WT < SH-SY5Y-APP Swe <SH-SY5Y-APP Swe/Ind. Treatment with both ATF and GTF reduced the release of cytochrome c and the ratio of BAX/Bcl-2. However, only GTF significantly reduced the expression of CypD and pro-caspase-3, suggestive of its unique role in AD. In conclusion, GTF has an effect that was not shown by ATF and thus suggest its potential role in the development of therapeutic agents for AD.

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Suppression of Menthyl Anthranilate (UV-A Sunscreen)-Sensitized Singlet Oxygen Generation by Trolox and α-tocopherol

Shogo Kitasaka, Mikio Yagi, Azusa Kikuchi

Photochem Photobiol Sci . 2020 Jun 2. doi: 10.1039/d0pp00023j. Online ahead of print.


Menthyl anthranilate (MA, tradename meradimate) is a UV-A absorber. The interactions of ground-state molecular oxygen with the long-lived triplet state of MA produce singlet oxygen through energy transfer. The quantum yield of singlet oxygen generation is 0.12 in air-saturated ethanol. Kinetic traces of the near-IR phosphorescence of singlet oxygen generated by MA-photosensitization have been measured in the absence and presence of Trolox (a water-soluble analogue of vitamin E and a quencher of singlet oxygen) and α-tocopherol (vitamin E, a natural antioxidant) in ethanol. Fluorescence and transient absorption measurements suggest that Trolox and α-tocopherol quench the lowest excited singlet and triplet states of MA. As a result, Trolox and α-tocopherol suppress MA-photosensitized singlet oxygen generation. Not only the quenching of singlet oxygen but also the suppression of singlet oxygen generation is the mechanism of antioxidant properties of Trolox and α-tocopherol for MA. The ability of α-tocopherol to suppress the MA-photosensitized singlet oxygen generation in isododecane, used as a solvent for an oil-soluble UV absorber, is close to that in ethanol. Suppression of sunscreen-photosensitized singlet oxygen generation is an important method for the formulation of safe cosmetic sunscreens.

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Consolidation of vitamin A and E methods onto a multiplexing liquid chromatography tandem mass spectrometry platform simplifies laboratory workflow

Zha L, Law T, MacDonald C, Kodgis I, Kellogg MD, Peake RWA

Clin Chim Acta. 2020 Jun;505:31-33. doi: 10.1016/j.cca.2020.02.020. Epub 2020 Feb 19.



Vitamin A and E are routinely monitored to assess nutritional status. The most commonly used approach for their measurement involves laborious liquid-liquid extraction followed by high-performance liquid chromatography (HPLC) analysis on dedicated instrumentation. We describe a simple, rapid protocol for measurement of vitamin A and E and their integration into an existing online sample preparation liquid chromatography tandem mass spectrometry (SPLC-MS/MS) workflow.


We performed a method comparison between the SPLC-MS/MS and HPLC methods for vitamin A and E by measuring patient specimens across the concentration range 11-81 µg/dL for vitamin A and 1-18 mg/L for vitamin E. The analysis times on each platform were also compared.


SPLC-MS/MS and HPLC methods were comparable with regards to analytical performance; mean bias across the measured range was 2.54% (95% CL: -11.56-16.64%) for vitamin A and -2.04% (95% CL: -18.20-14.12%) for vitamin E. Total analysis times were 7 min and 15 min for SPLC-MS/MS and HPLC respectively.


The development of a simplified sample preparation protocol and the use of multiplexing SPLC-MS/MS have reduced sample analysis times for vitamin A and E. This method has also optimized clinical workflow through consolidation of previously independent benches.

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Feasibility of Using Vitamin E-Loaded Poly(ε-caprolactone)/Gelatin Nanofibrous Mat to Prevent Oxidative Stress in Skin

Kalantary S, Golbabaei F, Latifi M, Shokrgozar MA, Yaseri M

J Nanosci Nanotechnol. 2020 Jun 1;20(6):3554-3562. doi: 10.1166/jnn.2020.17486.


Some occupational skin exposures lead to the formation of reactive oxygen species (ROS). The occupational exposure of workers to ROS has been found to be associated with an increased risk of developing skin injuries; therefore, it is essential to protect skin against ROS formation. Recently, some studies have been conducted on introducing better alternatives for skin protection. Nanofibers are good candidates for this purpose. The current study was carried out to assess vitamin E-loaded hybrid Poly(ε-caprolactone) (PCL)/gelatin (Gt) nanofibres mats as protective layers of skin exposed to occupational exposures. Vitamin E (VE) was successfully incorporated into PCL/Gt nanofibers while they were formed by electrospinning method. Nanofibers mats were characterized using scanning electron microscopy (SEM) and fourier transform infrared spectroscopy (FTIR). Their degradation behavior, in vitro release, biocompatibility, and antioxidant activity were studied. The diameters of the PCL/Gt/VE nanofibers decreased with the addition of vitamin E. The degradation rate of nanofibers was equal to 42.98 and 50.69% during 7 and 14 days, respectively. Nanofibers containing vitamin E showed an initial burst followed by a sustained release. The PCL/Gt/VE nanofibers exhibited good free radical scavenging activities despite being exposed to a high electrical potential during electrospinning. PCL/Gt/VE nanofibers supported a higher level of viability compared to PCL/Gt ones and significantly assisted human skin cells against tert-Butyl hydroperoxide (t-BHP) induced oxidative stress. Overall, PCL/Gt/VE nanofibers can potentially be used to protect skin against oxidative stress as a novel approach for worker’s healthcare.

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Reduction of Senescence-Associated Beta-Galactosidase Activity by Vitamin E in Human Fibroblasts Depends on Subjects’ Age and Cell Passage Number

Roberta Ricciarelli, Angelo Azzi, Jean-Marc Zingg

Biofactors . 2020 Jun 1. doi: 10.1002/biof.1636. Online ahead of print.


Cell senescence is due to the permanent cell cycle arrest that occurs as a result of the inherent limited replicative capacity toward the Hayflick limit (replicative senescence), or in response to various stressors (stress-induced premature senescence, SIPS). With the acquisition of the senescence-associated secretory phenotype (SASP), cells release several molecules (cytokines, proteases, lipids), and express the senescence-associated beta-galactosidase (SA-β-Gal). Here we tested whether vitamin E affects SA-β-Gal in an in vitro model of cell ageing. Skin fibroblasts from human subjects of different age (1, 13, 29, 59, and 88 years old) were cultured until they reached replicative senescence. At different passages (Passages 2, 9, 13, and 16), these cells were treated with vitamin E for 24 hr. Vitamin E reduced SA-β-Gal in all cells at passage 16, but at earlier passage numbers it reduced SA-β-Gal only in cells isolated from the oldest subjects. Therefore, short time treatment with vitamin E decreases SA-β-Gal in cells both from young and old subjects when reaching replicative senescence; but in cells isolated from older subjects, a decrease in SA-β-Gal by vitamin E occurs also at earlier passage numbers. The possible role of downregulation of CD36 by vitamin E, a scavenger receptor essential for initiation of senescence and SASP, is discussed.

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