Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice.

Shin J, Yang SJ, Lim Y.

Exp Biol Med (Maywood). 2017 Mar;242(5):505-515. doi: 10.1177/1535370216683836. Epub 2016 Dec 13.

Abstract

Delayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1- α, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1.

Fusi E, Giromini C, Rebucci R, Pinotti L, Caprarulo V, Cheli F, Vitari F, Domeneghini C, Baldi A.

J Anim Physiol Anim Nutr (Berl). 2017 Mar 1. doi: 10.1111/jpn.12682. [Epub ahead of print]

Abstract

Ochratoxin A (OTA) is a potent nephrotoxic fungi metabolite that affects animal and human health. At the cellular level, OTA is able to alter functions and viability by several mechanisms of action. Several strategies to counteract its toxicity have been studied. We investigated the role of α-tocopherol in counteracting OTA oxidative damage in Madin-Darby canine kidney (MDCK) cells by pre-incubating the cells for 3 hr with the antioxidant (1 nm, 10 μm) and then adding OTA (0-1.2 μg/ml) for the following 24 hr. Cell viability, lactate dehydrogenase (LDH) release, TUNEL staining and occludin and Zo1 localization by immunofluorescence were determined. Here, 1 nm α-tocopherol was shown to significantly reduce (p < .05) the cytotoxicity, LDH release and apoptotic rate induced by OTA. The presence of the antioxidant at the same concentration maintained the localization of occludin and Zo1 in the rim of the MDCK cells after the 24-hr OTA exposure. These results indicate that a low concentration of α-tocopherol could block OTA toxicity, supporting its defensive role in the cellular membrane.

Jain S, Garg T, Kushwah V, Thanki K, Agrawal AK, Dora CP.

J Drug Target. 2017 Mar 8:1-12. doi: 10.1080/1061186X.2017.1298603. [Epub ahead of print]

Abstract

The present study evaluates the prophylactic efficacy of α-tocopherol (α-TOH), resveratrol (RES), and coenzyme Q10 (CoQ10) co-loaded self-nanoemulsifying drug delivery system (α-TOH-RES-CoQ10 SNEDDS) in 7,12-Dimethylbenz[a]anthracene (DMBA) induced breast cancer model. SNEDDS formulation components were rationally selected and optimized for maximum drug loading by applying the design of experiments and further evaluated for stability in simulated gastrointestinal fluids, functional stability of antioxidants, in vitro release, Caco-2 cell uptake, oral bioavailability and prophylactic anticancer activity. The SNEDDS demonstrated excellent stability in stimulated gastrointestinal fluids. The functional activity of antioxidants was confirmed by 2,2-diphenylpicrylhydrazyl (DPPH) scavenging assay wherein significantly (p > .05) higher antioxidant activity was observed in case of SNEDDS as compared with free antioxidants. Coumarin 6 (C-6)-loaded SNEDDS formulation demonstrated remarkably higher Caco-2 cell uptake in comparison with free C-6, indicative of efficient internalization of sub-micron SNEDDS droplets by Caco-2 cells. In line with Caco-2 cell uptake observations, α-TOH-RES-CoQ10-SNEDDS showed ∼2.30- and ∼3.64-fold increase in the AUC_0-∞ values of RES and CoQ10 in comparison with free antioxidants. Significantly lower (p < .001) tumor volume (∼327 mm³) was found in case of animals treated with α-TOH-RES-CoQ10-SNEDDS in comparison with free antioxidant combination (∼1070 mm³) and DMBA control (∼1540 mm³) groups. Conclusively, the proposed strategy posed great potential in improving the prophylactic activity of antioxidants and hold promise for further exploration.

Rajeh NA, Al-Dhaheri NM.

Saudi Med J. 2017 Feb;38(2):132-137. doi: 10.15537/smj.2017.2.16049.

Abstract

OBJECTIVES:

To explore renal toxicity caused by sub-acute exposure of acrylamide and to study the protective effect of 5-Aminosalicylic acid (5-ASA) and Vitamin E (vit-E)on Acrylamide (ACR) induced renal toxicity. Methods: This study was conducted at King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, between August and November 2015. A total of 49 adult Wistar rats (250 ± 20g) aged 60 days were kept in a controlled environment and used in the present study. The rats were divided into 7 groups (control, ACR alone, ACR+5-ASA, ACR+vit-E, ACR+ASA+vit-E, vit-E alone, and ASA alone). After 5 days of ACR oral gavage treatment, the rats were observed for 24 hours then killed. Histopathology for the kidney and lactate dehydrogenase assay were carried out. Results: Acrylamide produced significant pathological changes in the kidney with acute tubular necrosis in the distal tubules that could be reversed by concomitant injection of rat with 5-ASA. Together with vitamin E, 5-ASA, showed maximum renal protection. No statistically significant difference was observed in either body weights or lactate dehydrogenase activity of ACR treated rats. Conclusion: Acrylamide exposure leads to adverse clinical pathologies of renal tubules, which were reversed by a concomitant treatment with 5-ASA and vitamin-E.

Zainuddin A, Chua KH, Tan JK, Jaafar F, Makpol S.

J Physiol Biochem. 2017 Feb;73(1):59-65. doi: 10.1007/s13105-016-0524-2. Epub 2016 Oct 14.

Abstract

Human diploid fibroblasts (HDFs) proliferation in culture has been used as a model of aging at the cellular level. Growth arrest is one of the most important mechanisms responsible for replicative senescence. Recent researches have been focusing on the function of vitamin E in modulating cellular signaling and gene expression. Therefore, the aim of this study was to elucidate the effect of palm γ-tocotrienol (vitamin E) in modulating cellular aging through p16^INK4a pathway in HDF cells. Primary culture of senescent HDFs was incubated with 70 μM of palm γ-tocotrienol for 24 hours. Silencing of p16^INK4a was carried out by siRNA transfection. RNA was extracted from the different treatment groups and gene expression analysis was carried out by real-time reverse transcription polymerase chain reaction. Proteins that were regulated by p16^INK4a were determined by western blot technique. The finding of this study showed that p16^INK4a mRNA was overexpressed in senescent HDFs, and hypophosphorylated-pRb and cyclin D1 protein expressions were increased (p < 0.05). However, downregulation of p16^INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (p < 0.05) by γ-tocotrienol led to modulation of the cell cycle regulation during cellular aging. In conclusion, senescent HDFs showed change in biological process specifically in cell cycle regulation with elevated expression of genes and proteins which may contribute to cell cycle arrest. Palm γ-tocotrienol may delay cellular senescence of HDFs by regulating cell cycle through downregulation of p16^INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions.

Ye J, Zhong X, Du Y, Cai C, Pan T.

J Endocrinol Invest. 2017 Feb 17. doi: 10.1007/s40618-017-0624-z. [Epub ahead of print]

Abstract

OBJECTIVE:

To explore the underlying mechanism and treatment of myocardial injury caused by hypothyroidism, we evaluated oxidative stress in serum and myocardial tissue of hypothyroid rats. The effect of levothyroxine (LT4) replacement therapy and vitamin E (VitE) supplementation on oxidative stress-induced injury and apoptosis of myocardial tissue is examined.

METHODS:

Male Sprague-Dawley rats were divided into five groups: normal control group, propylthiouracil group (PTU group), LT4 treatment group (PTU + LT4 group), vitamin E treatment group (PTU + VitE group), and combined treatment group (PTU + LT4 + VitE group). Superoxide dismutase (SOD) activity and malondialdehyde (MDA) expression in serum and myocardium were determined. Myocardial apoptosis index (AI) in each group was determined by TUNEL assay.

RESULTS:

SOD levels in serum were significantly increased in PTU + VitE and PTU + LT4 + Vit E groups, as compared to that in PTU and PTU + LT4 groups (P < 0.05). MDA levels in serum and myocardial tissue were significantly lower in PTU + LT4, PTU + VitE, and PTU + LT4 + VitE groups, as compared to that in the PTU group (P < 0.05). Myocardial apoptosis was significantly increased in PTU and PTU + VitE groups as compared to that in the normal control group (P < 0.05), while it was significantly lower in PTU + LT4 and PTU + LT4 + VitE groups, as compared to that in the PTU group (P < 0.05).

CONCLUSION:

In this study, levothyroxine replacement therapy and vitamin E supplementation appeared to ameliorate myocardial apoptosis in hypothyroid rats, the mechanism of which appears to be related to improved thyroid function and reduced oxidative stress.

Muzhingi T, Palacios-Rojas N, Miranda A, Cabrera ML, Yeum KJ, Tang G.

J Sci Food Agric. 2017 Feb;97(3):793-801. doi: 10.1002/jsfa.7798. Epub 2016 Jun 7.

Abstract

Biofortified maize is not only a good vehicle for provitamin A carotenoids for vitamin A deficient populations in developing countries but also a source of vitamin E, tocochromanols and phenolic compounds, which have antioxidant properties. Using high-performance liquid chromatography and a total antioxidant performance assay, the present study analyzed the antioxidant variation and antioxidant activity of 36 provitamin A improved maize hybrids and one common yellow maize hybrid. The ranges of major carotenoids in provitamin A carotenoids biofortified maize were zeaxanthin [1.2-13.2 µg g^-1 dry weight (DW)], β-cryptoxanthin (1.3-8.8 µg g^-1 DW) and β-carotene (1.3-8.0 µg g^-1 DW). The ranges of vitamin E compounds identified in provitamin A carotenoids biofortified maize were α-tocopherol (3.4-34.3 µg g^-1 DW), γ-tocopherol (5.9-54.4 µg g^-1 DW), α-tocotrienol (2.6-19.5 µg g^-1 DW) and γ-tocotrienol (45.4 µg g^-1 DW). The ranges of phenolic compounds were γ-oryzanol (0.0-0.8 mg g^-1 DW), ferulic acid (0.4-3.6 mg g^-1 DW) and p-coumaric acid (0.1-0.45 mg g^-1 DW). There was significant correlation between α-tocopherol and cis isomers of β-carotene (P < 0.01). Tocotrienols were correlated with α-tocopherol and γ-oryzanol (P < 0.01). Conclusion, genotype was significant in determining the variation in β-cryptoxanthin, β-carotene, α-tocopherol and γ-tocopherol contents (P < 0.01). A genotype × environment interaction was observed for γ-tocopherol content (P < 0.01).

Xu C, Bentinger M, Savu O, Moshfegh A, Sunkari V, Dallner G, Swiezewska E, Catrina SB, Brismar K, Tekle M.

J Diabetes Complications. 2017 Jan;31(1):4-12. doi: 10.1016/j.jdiacomp.2016.10.010. Epub 2016 Oct 18.

Abstract

Diabetes mellitus is characterized by hyperglycemia and capillary hypoxia that causes excessive production of free radicals and impaired antioxidant defense, resulting in oxidative stress and diabetes complications such as impaired wound healing. We have previously shown that modified forms of tocotrienols possess beneficial effects on the biosynthesis of the mevalonate pathway lipids including increase in mitochondrial CoQ. The aim of this study is to investigate the effects of mono-epoxy-tocotrienol-α on in vitro and in vivo wound healing models as well as its effects on mitochondrial function. Gene profiling analysis and gene expression studies on HepG2 cells and human dermal fibroblasts were performed by microarray and qPCR, respectively. In vitro wound healing using human fibroblasts was studied by scratch assay and in vitro angiogenesis using human dermal microvascular endothelial cells was studied by the tube formation assay. In vivo wound healing was performed in the diabetic db/db mouse model. For the study of mitochondrial functions and oxygen consumption rate Seahorse XF-24 was employed. In vitro, significant increase in wound closure and cell migration (p<0.05) both in normal and high glucose and in endothelial tube formation (angiogenesis) (p<0.005) were observed. Microarray profiling analysis showed a 20-fold increase of KIF26A gene expression and 11-fold decrease of lanosterol synthase expression. Expression analysis by qPCR showed significant increase of the growth factors VEGFA and PDGFB. The epoxidated compound induced a significantly higher basal and reserve mitochondrial capacity in both HDF and HepG2 cells. Additionally, in vivo wound healing in db/db mice, demonstrated a small but significant enhancement on wound healing upon local application of the compound compared to treatment with vehicle alone. Mono-epoxy-tocotrienol-α seems to possess beneficial effects on wound healing by increasing the expression of genes involved in cell growth, motility and angiogenes as well as on mitochondrial function.

Zakharova IO, Sokolova TV, Vlasova YA, Bayunova LV, Rychkova MP, Avrova NF.

Int J Mol Sci. 2017 Jan 21;18(1). pii: E216. doi: 10.3390/ijms18010216.

Abstract

The aim of the present work is to study the mechanism of the α-tocopherol (α-T) protective action at nanomolar and micromolar concentrations against H₂O₂-induced brain cortical neuron death. The mechanism of α-T action on neurons at its nanomolar concentrations characteristic for brain extracellular space has not been practically studied yet. Preincubation with nanomolar and micromolar α-T for 18 h was found to increase the viability of cortical neurons exposed to H₂O₂; α-T effect was concentration-dependent in the nanomolar range. However, preincubation with nanomolar α-T for 30 min was not effective. Nanomolar and micromolar α-T decreased the reactive oxygen species accumulation induced in cortical neurons by the prooxidant. Using immunoblotting it was shown that preincubation with α-T at nanomolar and micromolar concentrations for 18 h prevented Akt inactivation and decreased PKCδ activation induced in cortical neurons by H₂O₂. α-T prevented the ERK1/2 sustained activation during 24 h caused by H₂O₂. α-T at nanomolar and micromolar concentrations prevented a great increase of the proapoptotic to antiapoptotic proteins (Bax/Bcl-2) ratio, elicited by neuron exposure to H₂O₂. The similar neuron protection mechanism by nanomolar and micromolar α-T suggests that a “more is better” approach to patients’ supplementation with vitamin E or α-T is not reasonable.

Narayanankutty A, Kottekkat A, Mathew SE, Illam SP, Suseela IM, Raghavamenon AC.

Toxicol Mech Methods. 2017 Jan 8:1-8. doi: 10.1080/15376516.2016.1273431. [Epub ahead of print]

Abstract

Omega-3 fatty acids are well-known class of nutraceuticals with established health benefits. Recently, the oxidation products of these fatty acids are gaining attention, as they are likely to disturb body redox balance. Therefore, the efficacy of omega-3 fats under conditions of diminished antioxidant status, such as aging, is always a concern. Present study assessed the effects of omega-3 fats (DHA and EPA) together with or without vitamin-E in naturally aged rats. It was found that in omega-3 fats alone consumed rats the lipid profile was improved, while in omega-3 fat with vitamin-E-consumed group (OMVE), the hepato protective and antioxidant properties were pronounced, especially the redox status of brain tissue. It is possible that vitamin-E might have reduced the peroxidation of omega-3 fats, thereby allowing their synergistic effects. Hence, the use of vitamin-E along with omega-3 fat may be beneficial under aged conditions.