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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Metabolic Benefits of Annatto-Extracted Tocotrienol on Glucose Homeostasis, Inflammation, and Gut Microbiome

Eunhee Chung, Moamen M Elmassry, Pratibha Kottapalli, Kameswara Rao Kottapalli, Gurvinder Kaur, Jannette M Dufour, Kandis Wright, Latha Ramalingam, Naima Moustaid-Moussa, Rui Wang, Abdul N Hamood, Chwan-Li Shen

Nutr Res . 2020 May;77:97-107. doi: 10.1016/j.nutres.2020.04.001. Epub 2020 Apr 17.


Emerging evidence suggests that the gut microbiome plays an important role in the pathophysiology of both obesity and type 2 diabetes mellitus. We previously reported that dietary annatto-extracted tocotrienol exerts beneficial effects by modulating inflammatory responses in mice fed a high-fat diet (HFD). The purpose of this study was to test the hypothesis that tocotrienol supplementation when combined with an HFD would result in an altered gut microbiota composition. For 14 weeks, forty-eight male C57BL/6J mice were assigned to 4 groups-low-fat diet, HFD, HFD supplemented with annatto-extracted tocotrienol at 800 mg/kg diet (AT), and HFD supplemented with metformin at 200 mg/kg diet. Glucose homeostasis was assessed by glucose and insulin tolerance tests, serum and pancreas insulin levels, and histological assessments of insulin and glucagon in pancreatic tissue. The concentrations of adipokines were measured in white adipose tissues. For the gut microbiome analysis, cecal content was collected, DNA was extracted, and 16S rRNA gene sequencing was performed. AT supplementation improved glucose homeostasis and lowered resistin, leptin, and interleukin-6 levels in white adipose tissue. Relative to the HFD group, AT-supplemented mice showed a decrease in the Firmicutes to Bacteroidetes ratio and had a lower abundance of Ruminococcus lactaris, Dorea longicatena, and Lachnospiraceae family. The relative abundance of Akkermansia muciniphila was increased in the AT group compared to the low-fat diet group. The association between the metabolic improvements and the identified bacterial taxa suggests a potential metabolic modulation caused by AT supplementation through the gut microbiota composition in mice fed an HFD.

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Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients With Homozygous Glutathione Transferase M1 Gene Deletion

Petar Djuric, Sonja Suvakov, Tatjana Simic, Dragana Markovic, Djurdja Jerotic, Aleksandar Jankovic 1, Ana Bulatovic, Jelena Tosic Dragovic, Tatjana Damjanovic, Jelena Marinkovic, Radomir Naumovic, Nada Dimkovic

Toxins (Basel) . 2020 May 27;12(6):E352. doi: 10.3390/toxins12060352.


Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygous GSTM1 gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygous GSTM1 gene deletion.

Methods: GSTM1 genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined.

Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups.

Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity.

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Anti-Inflammatory Effects of Vitamin E in Response to Candida albicans

Silvana Barros, Ana Paula D Ribeiro, Steven Offenbacher, Zvi G Loewy

Microorganisms . 2020 May 26;8(6):E804. doi: 10.3390/microorganisms8060804.


Oral mucositis, inflammation, and ulceration that occur in the oral cavity can manifest in significant pain. A formulation was designed to investigate the potential of vitamin E to ameliorate inflammation resulting from Candida albicans in cell-based systems. Human gingival fibroblasts and THP1 cells were stimulated with heat killed C. albicans and Porphyromonas gingivalis LPS (agonists). Unstimulated cells were included as controls. Cells were also simultaneously treated with a novel denture adhesive formulation that contains vitamin E (antagonist). The experimental conditions included cells exposed to the experimental formulation or the vehicle for 2 h for mRNA extraction and analysis, and cells left for 24 h under those experimental conditions for analysis of protein expression by ELISA. ssAffymetrix expression microarray pathway analyses demonstrated that the tested formulation exhibited a statistically significant (p < 0.05) inhibition of the following key inflammatory pathways: TLR 6, IL-1 signaling (IRAK, A20), NF-kappaB, IL-6 signaling (gp130, JK2 and GRB2), TNF signaling (TNF receptor) and Arachidonic acid metabolism (PLA2). Quantitative PCR array analysis confirmed the downregulation of key inflammatory genes when cells under adhesive treatment were challenged with heat killed C. albicans. PGE2 secretion was inhibited by the tested formulation only on THP1 cells after 24 h stimulation with C. albicans. These results suggest that the active formulation containing vitamin E acetate can modulate inflammatory responses, through anti-inflammatory actions as indicated by in vitro experimental conditions.

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The Role of Oral Vitamin E Supplementation in Reducing Nitrosative Stress in Adult Treated Patients With Celiac Disease: A Pilot Study

Agnieszka Piątek-Guziewicz, Agnieszka Dąbek, Magdalena Przybylska-Feluś, Paweł Zagrodzki, Tomasz Mach, Małgorzata Zwolińska-Wcisło

Pol Arch Intern Med . 2020 May 19. doi: 10.20452/pamw.15369. Online ahead of print.


The pathogenesis of celiac disease (CD) is complex and has not been fully elucidated. It has been postulated that oxidative stress, because of an increase in the concentration of reactive oxygen species and antioxidant capacity reduction, is one of the processes possibly involved in gliadin toxicity. Oxidative imbalance induced by gliadin peptides in enterocytes leads to the activation of the transcription of proinflammatory cytokines and enzymes, such as inducible nitric oxide synthase (iNOS), which in turn causes an increased production of nitric oxide (NO) metabolites favoring oxidative stress. Based on the our previous study, we hypothesized that persistent nitrosative stress despite gluten-free diet (GFD) may be responsible for persistent histopathologic changes and that GFD is only partially able to improve oxidative imbalance. Hence, serum NO levels seem to be useful as a marker of treatment efficacy, and alterations in these levels could indicate CD activity. It is possible that oral antioxidant supplementation may decrease the toxic effects of peptides. In the current study, we aimed to evaluate the effect of treatment with oral vitamin E on oxidative imbalance in adult patients with CD on GFD. For that purpose, we assessed the fasting plasma levels of nitrate as a marker of endogenous NO production and oxidative stress. Moreover, we monitored the individual components of antioxidant capacity. To the best of our knowledge, this is the first study evaluating the effects of oral vitamin E supplementation on oxidative imbalance in patients with CD.

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Maternal endotoxemia induces renal collagen deposition in adult offspring: Role of NADPH oxidase/TGF-β1/MMP-2 signaling pathway

Farias JS, Santos KM, Lima NKS, Cabral EV, Aires RS, Veras AC, Paixão AD, Vieira LD

Arch Biochem Biophys. 2020 May 15;684:108306. doi: 10.1016/ Epub 2020 Feb 17.


Maternal endotoxemia has been shown to increase renal collagen deposition in the offspring. Renal fibrosis is a hallmark of progressive chronic kidney disease. It was investigated whether maternal reactive oxygen species (ROS) leads to renal fibrosis or exacerbates unilateral ureteral obstruction (UUO)-induced renal fibrosis in the offspring of dams treated with lipopolysaccharide (LPS). Furthermore, it was studied the role of matrix metalloproteinases (MMPs) in these changes. Adults Wistar rats were obtained from dams submitted to LPS administration through the third part of gestation. To evaluate the role of maternal ROS, part of the dams received α-tocopherol simultaneously with LPS. Part of the offspring in each group was submitted to UUO at adulthood when sub-groups were treated with NADPH oxidase inhibitor, apocynin. Maternal LPS administration increased proteinuria, systolic arterial pressure and renal collagen deposition in adult offspring. LPS offspring rats also presented higher MMP-2 activity in parallel to a decreased renal cortical TIMP-2 content. These changes were correlated to increased amounts of TGF-β1 and NOX2. Maternal α-tocopherol treatment prevented collagen deposition and reduced arterial pressure in adult offspring. α-Tocopherol also inhibited maternal endotoxemia-induced changes in TGF-β1/NOX2/MMP-2 signaling. UUO led to increased collagen deposition in the contralateral kidneys of LPS offspring, which was correlated to increased NADPH oxidase activity and prevented by NADPH oxidase inhibition. In summary, maternal endotoxemia led to alterations in the TGF-β1/NOX2/MMP-2 signaling pathway in renal tissue concomitant with collagen deposition, therefore contributing to hypertension in adult offspring.

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Metabolism and Biological Activity of α-Tocopherol Derived From Vitamin E-enriched Transgenic Maize in Broilers

Zhan Tengfei, Han Yunsheng, Tang Chaohua, Zhao Qingyu, Sun Dandan, Li Ying, Jia Xueting, Zhou Lingyun, Zhang Junmin

J Sci Food Agric . 2020 May 9. doi: 10.1002/jsfa.10480


Background: The aim of this study was to investigate the metabolism of α-tocopherol derived from vitamin E-enriched transgenic maize (VER) and its effects on antioxidant and immune functions in broilers aged 1 to 42 days. A total of 360 1-day-old male broilers were randomly divided into three groups containing six replicates with 20 broilers per replicate. The negative control (NC) group and the positive control (PC) group were given non-GM maize and non-GM maize plus exogenous vitamin E (VE), respectively, and the VER group was given VER replacing the non-GM maize given to the NC group. Between days 1 and 21 and days 22 and 42, VE levels were 4.38 and 4.63 mg kg-1 in the NC group, and 14.11 and 14.91 mg kg-1 in the PC and VER group, respectively.

Results: The results showed that α-tocopherol from both VER and additives increased α-tocopherol transfer protein and cytochrome P450 concentrations. Additionally, serum α-tocopherol and α-tocopherylquinone levels of broilers in the PC and VER groups were significantly higher than those in the NC group (P < 0.05). Compared with the NC group, broilers in both groups that received α-tocopherol had reduced NF-κB p65 concentrations, significantly decreased serum prostaglandin E2 , IL-6, malondialdehyde, and hydrogen peroxide levels (P < 0.05), and significantly increased glutathione, glutathione peroxidase, and total antioxidant capacity (P < 0.05).

Conclusion: In summary, both VER and non-GM maize fortified with exogenous VE showed similar effects on broilers, indicating that the α-tocopherol in VER has sufficient biological activity.

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Efficacy of Vitamin E in Methotrexate-Induced Hepatotoxicity in Rheumatoid Arthritis: An Open-Label Case-Control Study

Binit Vaidya, Manisha Bhochhibhoya, Shweta Nakarmi

Int J Rheumatol . 2020 May 1;2020:5723485. doi: 10.1155/2020/5723485.


Objective: To examine the efficacy of vitamin E in methotrexate- (MTX-) induced transaminitis in patients with rheumatoid arthritis (RA).

Methods: A case-control study was conducted at a tertiary rheumatology center for 12 months. Patients with RA on MTX and deranged aminotransferases were included. Patients with previous liver diseases, baseline transaminitis before methotrexate initiation, alcohol intake, muscle diseases, under hepatotoxic drugs, and aminotransferases > 3 times the upper normal limit were excluded. The patients were divided into treatment (vitamin E 400 mg bid for 3 months) and control groups (no vitamin E) using a random number table. The dose of MTX was unaltered. Follow-up was done after 3 and 6 months. Independent t-test was done to compare means of two groups. Paired t-test was done to compare differences in mean.

Results: Among 230 patients, 86.5% were female with a mean BMI of 25.9 ± 4.5 kg/m2. In the treatment group, SGPT and SGOT at baseline were 73.1 ± 20.4 and 60.2 ± 24.5 IU/L, respectively; at 3-month follow-up 44.6 ± 34.2 and 38.3 ± 20.8 IU/L, respectively; and at 6-month follow-up 40.4 ± 35.7 and 34.2 ± 21.9 IU/L, respectively. In the control group, SGPT and SGOT at baseline were 63.4 ± 15.1 and 46.8 ± 13.7 IU/L, respectively, and at 3-month follow-up 55.8 ± 45.9 and 45.5 ± 30.9 IU/L, respectively. Significant decrease in the level of aminotransferases was seen in the treatment group (p value < 0.001) and not in the control group (p values 0.161 and 0.728, respectively). The change in levels of SGPT and SGOT from baseline to 3 months of follow-up was statistically significant in between two study groups (p values 0.007 and <0.001, respectively). From the control group, 29 patients were crossed over to vitamin E for the next 3 months. SGPT and SGOT decreased from 97.6 ± 44.1 to 46.1 ± 40.9 and 69.3 ± 34.9 to 29.1 ± 11.6 IU/L, respectively (p values 0.031 and 0.017, respectively).

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Microemulsion co-delivering vitamin A and vitamin E as a new platform for topical treatment of acute skin inflammation

Praça FG, Viegas JSR, Peh HY, Garbin TN, Medina WSG, Bentley MVLB

Mater Sci Eng C Mater Biol Appl. 2020 May;110:110639. doi: 10.1016/j.msec.2020.110639. Epub 2020 Jan 7.


In this study, we developed a water-in-oil microemulsion containing vitamin A (retinol) and vitamin E (α-tocopherol), which serves as a multifunctional nanosystem that co-delivers antioxidants and displayed additive effect against acute skin inflammation. Microemulsion (ME) was prepared by mixing a surfactant blend (Tween 80 and propylene glycol, 5:1) with isopropyl myristate and water (ratio of 50:40:10, respectively). Vitamin A (0.05% w/w concentration) and/or vitamin E (0.1% w/w concentration) were incorporated into the surfactant mixture of ME by stirring with a magnetic stirrer for 30 min. This multifunctional ME displayed physical stability, with low cytotoxicity in 3T3 cell line, as well as cellular internalization into the cytosol. In vivo treatments using ME delivering α-tocopherol reduced dermal expression of TNF-α by 1.3-fold (p < 0.01), when compared to unloaded ME treatment group. When retinol was added into the ME containing α-tocopherol, it further reduced TNF-α expression by 2-fold (p < 0.001), suggesting the additive effect of vitamin E and vitamin A in the treatment against skin inflammation. In conclusion, we successfully developed the use of water-in-oil ME to pack both vitamin E and vitamin A, and demonstrated for the first time its anti-inflammatory potential when applied topically to TPA-induced inflamed skin.

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Do Antioxidant Vitamins Prevent Exercise-Induced Muscle Damage? A Systematic Review

María Martinez-Ferran, Fabian Sanchis-Gomar, Carl J Lavie, Giuseppe Lippi, Helios Pareja-Galeano

Antioxidants (Basel) . 2020 Apr 29;9(5):E372. doi: 10.3390/antiox9050372.


Free radicals produced during exercise play a role in modulating cell signaling pathways. High doses of antioxidants may hamper adaptations to exercise training. However, their benefits are unclear. This review aims to examine whether vitamin C (VitC) and/or vitamin E (VitE) supplementation (SUP) prevents exercise-induced muscle damage. The PubMed, Web of Science, Medline, CINAHL, and SPORTDiscus databases were searched, and 21 articles were included. Four studies examined the effects of acute VitC SUP given pre-exercise: in one study, lower CK levels post-exercise was observed; in three, no difference was recorded. In one study, acute VitE SUP reduced CK activity 1 h post-exercise in conditions of hypoxia. In three studies, chronic VitE SUP did not reduce CK activity after an exercise session. Chronic VitE SUP did not reduce creatine kinase (CK) concentrations after three strength training sessions, but it was effective after 6 days of endurance training in another study. Chronic SUP with VitC + E reduced CK activity post-exercise in two studies, but there was no such effect in four studies. Finally, three studies described the effects of chronic VitC + E SUP and long-term exercise, reporting dissimilar results. To conclude, although there is some evidence of a protective effect of VitC and/or VitE against exercise-induced muscle damage, the available data are not conclusive.

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