Comparing Palm Oil, Tocotrienol-Rich Fraction and α-Tocopherol Supplementation on the Antioxidant Levels of Older Adults.

Nor Azman NHE, Goon JA, Abdul Ghani SM, Hamid Z, Wan Ngah WZ

Antioxidants (Basel). 2018 May 28;7(6). pii: E74. doi: 10.3390/antiox7060074.

Abstract

BACKGROUND:

Tocotrienol and tocopherol are known to prevent numerous degenerative diseases. The aim of this study is to compare the effects of tocotrienol-rich fraction (TRF) with α-tocopherol (α-TF) on the antioxidant status of healthy individuals aged between 50 and 55 years.

METHODS:

Volunteers were divided into groups receiving placebo (n = 23), α-TF (n = 24) and TRF (n = 24). Fasting venous blood samples were taken at baseline (0 month), 3 months and 6 months of supplementation for the determination of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities as well as for reduced glutathione (GSH) and oxidized glutathione (GSSG) concentrations.

RESULTS:

CAT and GPx were unaffected by TRF and α-TF supplementations. SOD activity increased significantly after six months of TRF supplementation. Analysis by gender showed that only female subjects had significant increases in SOD and GPx activities after six months of TRF supplementation. GPx activity was also significantly higher in females compared to males after six months of TRF supplementation. The GSH/GSSG ratio increased significantly after six months of TRF and α-TF supplementation in only the female subjects.

CONCLUSION:

TRF and α-TF supplementation exhibited similar effects to the antioxidant levels of older adults with TRF having more significant effects in females.

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Proteome-wide changes in primary skin keratinocytes exposed to diesel particulate extract-A role for antioxidants in skin health

Rajagopalan P, Jain AP, Nanjappa V, Patel K, Mangalaparthi KK, Babu N, Cavusoglu N, Roy N, Soeur J, Breton L, Pandey A, Gowda H, Chatterjee A, Misra N

J Dermatol Sci. 2018 May 21. pii: S0923-1811(18)30215-9. doi: 10.1016/j.jdermsci.2018.05.003. [Epub ahead of print]

Abstract

BACKGROUND:

Skin acts as a protective barrier against direct contact with pollutants but inhalation and systemic exposure have indirect effect on keratinocytes. Exposure to diesel exhaust has been linked to increased oxidative stress.

OBJECTIVE:

To investigate global proteomic alterations in diesel particulate extract (DPE)/its vapor exposed skin keratinocytes.

METHODS:

We employed Tandem Mass Tag (TMT)-based proteomics to study effect of DPE/DPE vapor on primary skin keratinocytes.

RESULTS:

We observed an increased expression of oxidative stress response protein NRF2, upon chronic exposure of primary keratinocytes to DPE/its vapor which includes volatile components such as polycyclic aromatic hydrocarbons (PAHs). Mass spectrometry-based quantitative proteomics led to identification 4490 proteins of which 201 and 374 proteins were significantly dysregulated (≥1.5 fold, p ≤ 0.05) in each condition, respectively. Proteins involved in cellular processes such as cornification (cornifin A), wound healing (antileukoproteinase) and differentiation (suprabasin) were significantly downregulated in primary keratinocytes exposed to DPE/DPE vapor. These results were corroborated in 3D skin models chronically exposed to DPE/DPE vapor. Bioinformatics analyses indicate that DPE and its vapor affect distinct molecular processes in skin keratinocytes. Components of mitochondrial oxidative phosphorylation machinery were seen to be exclusively overexpressed upon chronic DPE vapor exposure. In addition, treatment with an antioxidant like vitamin E partially restores expression of proteins altered upon exposure to DPE/DPE vapor.

CONCLUSIONS:

Our study highlights distinct adverse effects of chronic exposure to DPE/DPE vapor on skin keratinocytes and the potential role of vitamin E in alleviating adverse effects of environmental pollution.

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Effects of High-dose Vitamin E Supplementation on Markers of Cardiometabolic Risk and Oxidative Stress in Patients with Diabetic Nephropathy: a Randomized Double-blinded Controlled Trial

Aghadavod E, Soleimani A, Hamidi G, Keneshlou F, Heidari A, Asemi Z

Iran J Kidney Dis. 2018 May;12(3):156-162.

Abstract

INTRODUCTION:

Patients with diabetic nephropathy (DN) may benefit from vitamin E‘s antilipid and antioxidant activities. This study aimed to evaluate the effects of high-dose vitamin E supplementation on markers of cardiometabolic risk and oxidative stress in patients with DN.

MATERIALS AND METHODS:

This randomized controlled trial was carried out on 54 patients with DN that were randomly divided into 2 groups to receive vitamin E supplement (800 IU/d) or placebo for 12 weeks. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine markers of cardiometabolic risk and oxidative stress.

RESULTS:

Vitamin E supplementation, compared with the placebo, resulted in a significant reduction in serum total cholesterol (-14.3 ± 29.9 mg/dL versus -0.8 ± 13.1 mg/L, P = .03), low-density lipoprotein cholesterol (-16.4 ± 28.5 mg/dL versus 0.1 ± 17.2 mg/L, P = .01), and ratio of total cholesterol to high-density lipoprotein cholesterol ratio (-0.5 ± 0.7 versus 0.1 ± 0.5, P = .001), and a significant elevation in vitamin Elevels (39.7 ± 12.4 nmol/mL versus -0.5 ± 1.3 nmol/mL, P < .001) and high-density lipoprotein cholesterol levels (1.4 ± 3.7 versus -2.1 ± 5.1 mg/L, P = .006). It also resulted in a significant elevation in plasma glutathione levels.

CONCLUSIONS:

Our study demonstrated that high-dose vitamin E supplementation for 12 weeks had favorable effects on lipid profile and glutathione levels of patients with DN, except for triglycerides, very low-density lipoprotein cholesterol, nitric oxide, and total antioxidant capacity levels.

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Vitamin E and its anticancer effects

Abraham A, Kattoor AJ, Saldeen T, Mehta JL.

Crit Rev Food Sci Nutr. 2018 May 10:1-23. doi: 10.1080/10408398.2018.1474169. [Epub ahead of print]

Abstract

Vitamin E is a lipid soluble vitamin comprising of eight natural isoforms, namely, α, β, δ, γ isoforms of tocopherol and α, β, δ, γ isoforms of tocotrienol. Many studies have been performed to elucidate its role in cancer. Until last decade, major focus was on alpha tocopherol and its anticancer effects. However, major clinical trials using alpha-tocopherol like SELECT trial and ATBC trial did not yield meaningful results. Hence there was a shift of focus to gamma-tocopherol, delta-tocopherol and tocotrienol. Unlike alpha-tocopherol, gamma-tocopherol and delta-tocopherol can scavenge reactive nitrogen species in addition to reactive oxygen species. Antiangiogenic effect, inhibition of HMG CoA reductase enzyme and inhibition of NF-κB pathway make the anti-cancer effects of tocotrienols unique compared to other vitamin E isoforms. Preclinical research on non-alpha tocopherol isoforms of vitamin E showed promising data on their anticancer effects. In this review, we deal with the current understanding on the potential mechanisms involved in the anticancer effects of vitamin E and the controversies in this field over last three decades. We also highlight the need to conduct further research on the anticancer effects of non-alpha-tocopherol isoforms in larger population and clinical setting.

KEYWORDS:

Vitamin E and cancer; anticancer mechanisms; tocopherol; tocopherol and cancer; tocotrienol

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Effects of Carnosine and Vitamin E on Nucleobindin 2 (NUCB2)/nesfatin-1, Ghrelin, Adropin, and Irisin in Experimentally Induced Ovarian Torsion

Sarac M, Bakal U, Kuloglu T, Tartar T, Aydin S, Yardim M, Artas G, Kazez A

Ann Clin Lab Sci. 2018 May;48(3):345-354.

Abstract

INTRODUCTION:

Delay in the diagnosis of ovarian torsion leads to serious histopathological changes and many problems, including infertility. Various agents have been investigated to minimize detorsion-associated potential injury. This study was performed to study the effects of carnosine and vitamin E on tissue and serum expression of Nucleobindin 2 (NUCB2)/nesfatin-1, ghrelin, adropin, and irisin to determine whether they have protective effects in cases of ovarian torsion.

MATERIAL AND METHOD:

Seventy-eight rats were allocated evenly into 13 groups. All rats, excluding those in the control and sham groups and Groups (G) III, IV, and V, were subjected to ovarian torsion for 12 hours. The groups were designated as follows: G-I (control), G-II (sham), G-III (vitamin E), G-IV (carnosine), G-V (carnosine + vitamin E), G-VI (torsion), G-VII (torsion + detorsion), G-VIII (torsion + vitamin E), G-IX (torsion + carnosine), G-X (torsion + carnosine + vitamin E), G-XI (torsion + detorsion + vitamin E), G-XII (torsion + detorsion + carnosine), and G-XIII (torsion + detorsion + carnosine + vitamin E). Serum levels of NUCB2/nesfatin-1, ghrelin, adropin, and irisin were measured by ELISA. Immunohistochemical methods were used to measure the expression of these hormones in ovarian tissue.

RESULTS:

The levels of NUCB2/nesfatin-1 immunoreactivity were increased in G-VII, G-XI, and G-XII (p<0.05). The immunoreactivity of ghrelin was significantly decreased in G-VI, G-IX, G-XI, and G-XII. However, adropin immunoreactivity did not differ significantly between the groups (p>0.05). The level of irisin immunoreactivity was decreased in G-VI, G-VII, and G-VIII (p<0.05). The serum levels of NUCB2/nesfatin-1, ghrelin, adropin, and irisin paralleled the tissue immunohistochemical results.

CONCLUSION:

Carnosine and vitamin E protected the ovaries from ischemia-reperfusion injury in ovarian torsion. These antioxidants, especially carnosine, may be useful for the treatment of ovarian torsion.

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Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism

Wan Hasan WN, Chin KY, Jolly JJ, Abd Ghafar N, Soelaiman IN.

Endocr Metab Immune Disord Drug Targets. 2018 Apr 23. doi: 10.2174/1871530318666180423122409. [Epub ahead of print]

Abstract

BACKGROUND:

Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling.

OBJECTIVE:

This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.

DISCUSSION:

Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.

CONCLUSION:

mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

KEYWORDS:

bone; bone metabolism; mevalonate pathway; tocotrienol; vitamin E.

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Effects of tocotrienol from Bixa orellana (annatto) on bone histomorphometry in a male osteoporosis model induced by buserelin

Mohamad NV, Soelaiman IN, Chin KY.

Biomed Pharmacother. 2018 Apr 16;103:453-462. doi: 10.1016/j.biopha.2018.04.083. [Epub ahead of print]

Abstract

INTRODUCTION:

Osteoporosis is a debilitating skeletal side effect of androgen deprivation therapy based on gonadotropin-releasing hormone (GnRH) agonist in men. Tocotrienol from Bixa orellana (annatto) has been demonstrated to offer protection against osteoporosis by exerting anabolic effects on bone. Thus, it may prevent osteoporosis among GnRH agonist users.

OBJECTIVE:

This study aimed to determine the effectiveness of annatto-tocotrienol on the bone turnover markers and bone histomorphometry in a model of male osteoporosis induced by buserelin (a GnRH agonist).

METHODS:

Forty-six three-months-old male Sprague-Dawley rats (three months old; 300-350 g) were randomly divided into six groups. The baseline control group (n = 6) was sacrificed at the onset of the study. The normal control group (n = 8) received corn oil (the vehicle of tocotrienol) orally daily and normal saline (the vehicle of buserelin) subcutaneously daily. The buserelin control (n = 8) received corn oil orally daily and subcutaneous buserelin injection 75 μg/kg/day daily. The calcium control (n = 8) received 1% calcium in drinking water and subcutaneous buserelin injection 75 μg/kg/day. The remaining rats were treated with two different treatments, i.e., (1) oral annatto tocotrienol at 60 mg/kg/day plus subcutaneous buserelin injection 75 μg/kg/day (n = 8); (2) oral annatto tocotrienol at 100 mg/kg/day plus subcutaneous buserelin injection 75 μg/kg/day (n = 8). The rats were injected with calcein twice before being sacrificed to label the bones. The rats were euthanized, and their blood and right femur were harvested at the end of the treatment for bone turnover markers and bone histomorphometry examination.

RESULTS:

Both serum osteocalcin and C-telopeptide of type 1 collagen were not significantly different between treated groups and buserelin control (P > 0.05). The buserelin control group had a significantly lower bone volume and higher eroded surface compared with the normal control group (P < 0.05). Both groups treated with annatto tocotrienol (60 mg/kg/day and 100 mg/kg/day) had significantly higher bone volume, trabecular thickness and osteoblast number, as well as a significantly lower single-labelled surface compared with the buserelin control (P < 0.05). Only rats treated with annatto tocotrienol 60 mg/kg/day had a significantly higher double-labelled surface compared with buserelin control (P < 0.05).

CONCLUSION:

Annatto tocotrienol can prevent trabecular bone loss by increasing the mineralising surface and osteoblasts number. Thus, it has a potential role in preventing bone loss in men using GnRH agonist

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A major component of vitamin E, α-tocopherol inhibits the anti-tumor activity of crizotinib against cells transformed by EML4-ALK

Uchihara Y, Kidokoro T, Tago K, Mashino T, Tamura H, Funakoshi-Tago M

Eur J Pharmacol. 2018 Apr 15;825:1-9. doi: 10.1016/j.ejphar.2018.02.012. Epub 2018 Feb 11.

Abstract

Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK) and is of significant therapeutic benefit to patients with non-small cell lung cancer (NSCLC) harboring the EML4-ALK fusion gene. In the present study, we demonstrated that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. α-Tocopherol significantly inhibited crizotinib-induced apoptosis in cells transformed by EML4-ALK. It also effectively attenuated the crizotinib-induced inhibition of EML4-ALK and its downstream molecules, STAT3 and ERK, and suppressed the inhibitory effects of crizotinib on EML4-ALK-mediated transformation in the focus formation assay. On the other hand, other members of the vitamin E family, namely, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, and a water-soluble analog of vitamin E, Trolox had no effects on the anti-tumor activity of crizotinib in cells transformed by EML4-ALK. Collectively, these results revealed the risk of the anti-tumor activity of crizotinib being attenuated when it is administrated in combination with vitamin Esupplements containing α-tocopherol as a major component.

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Cebpd Is Essential for Gamma-Tocotrienol Mediated Protection against Radiation-Induced Hematopoietic and Intestinal Injury

Banerjee S, Shah SK, Melnyk SB, Pathak R, Hauer-Jensen M, Pawar SA.

Antioxidants (Basel). 2018 Apr 6;7(4). pii: E55. doi: 10.3390/antiox7040055.

Abstract

Gamma-tocotrienol (GT3) confers protection against ionizing radiation (IR)-induced injury. However, the molecular targets that underlie the protective functions of GT3 are not yet known. We have reported that mice lacking CCAAT enhancer binding protein delta (Cebpd-/-) display increased mortality to IR due to injury to the hematopoietic and intestinal tissues and that Cebpd protects from IR-induced oxidative stress and cell death. The purpose of this study was to investigate whether Cebpd mediates the radio protective functions of GT3. We found that GT3-treated Cebpd-/- mice showed partial recovery of white blood cells compared to GT3-treated Cebpd⁺/+ mice at 2 weeks post-IR. GT3-treated Cebpd-/- mice showed an increased loss of intestinal crypt colonies, which correlated with increased expression of inflammatory cytokines and chemokines, increased levels of oxidized glutathione (GSSG), S-nitrosoglutathione (GSNO) and 3-nitrotyrosine (3-NT) after exposure to IR compared to GT3-treated Cebpd+/+ mice. Cebpd is induced by IR as well as a combination of IR and GT3 in the intestine. Studies have shown that granulocyte-colony stimulating factor (G-CSF), mediates the radioprotective functions of GT3. Interestingly, we found that IR alone as well as the combination of IR and GT3 caused robust augmentation of plasma G-CSF in both Cebpd⁺/+ and Cebpd-/- mice. These results identify a novel role for Cebpd in GT3-mediated protection against IR-induced injury, in part via modulation of IR-induced inflammation and oxidative/nitrosative stress, which is independent of G-CSF.

KEYWORDS:

Cebpd; GSH; GSNO; gamma tocotrienol; granulocyte-colony stimulating factor; hematopoietic injury; intestinal injury; ionizing radiation

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Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs

Qureshi AA, Zuvanich EG, Khan DA, Mushtaq S, Silswal N, Qureshi N

Lipids Health Dis. 2018 Apr 2;17(1):62. doi: 10.1186/s12944-018-0697-5.

Abstract

BACKGROUND:

Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs.

METHODS:

The anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of δ-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-α using total RNAs derived from plasmas of hepatitis C patients was investigated.

RESULTS:

Our data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% – 87%) with doses of 2.5-20 μM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, δ-tocotrienol, and quercetin were 70% – 92%. However, thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, and quinine sulphate were effective in pancreatic, prostate, breast, lungs, melanoma, Β-lymphocytes, and T-cells (Jurkat: 40% to 95%) compared to respective controls. In lung cancer cells, these compounds were effective between 5 and 40 μM. The IC50 values of anti-proliferation properties of thiostrepton in most of these cell lines were between doses of 2.5-5 μM, dexamethasone 2.5-20 μM, 2-methoxyestradiol 2.5-10 μM, δ-tocotrienol 2.5-20 μM, quercetin 10-40 μM, and (-) Corey lactone 40-80 μM. In hepatitis C patients, δ-tocotrienol treatment resulted in significant decrease in the expression of pro-inflammatory cytokines.

CONCLUSIONS:

These data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, Β-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.

KEYWORDS:

B-lymphocytes; Breast; Inflammatory biomarkers; Liver; Lung; Melanoma; Pancreas; Potent anticancer compounds; Prostate; Several cancer cell lines (Hela; T-cells)

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