Emerging evidences highlight the implication of microRNAs as a posttranscriptional regulator in aging. Several senescence-associated microRNAs (SA-miRNAs) are found to be differentially expressed during cellular senescence. However, the role of dietary compounds on SA-miRNAs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF) on SA-miRNAs (miR-20a, miR-24, miR-34a, miR-106a, and miR-449a) and established target genes of miR-34a (CCND1, CDK4, and SIRT1) during replicative senescence of human diploid fibroblasts (HDFs). Primary cultures of HDFs at young and senescent were incubated with TRF at 0.5 mg/mL. Taqman microRNA assay showed significant upregulation of miR-24 and miR-34a and downregulation of miR-20a and miR-449a in senescent HDFs (P < 0.05). TRF reduced miR-34a expression in senescent HDFs and increased miR-20a expression in young HDFs and increased miR-449a expression in both young and senescent HDFs. Our results also demonstrated that ectopic expression of miR-34a reduced the expression of CDK4 significantly (P < 0.05). TRF inhibited miR-34a expression thus relieved its inhibition on CDK4 gene expression. No significant change was observed on the expression of CCND1, SIRT1, and miR-34a upstream transcriptional regulator, TP53. In conclusion tocotrienol-rich fraction prevented cellular senescence of human diploid fibroblasts via modulation of SA-miRNAs and target genes expression.
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Polysaccharopeptide enhanced the anti-cancer effect of gamma-tocotrienol through activation of AMPK.
Liu J, Lau EY, Chen J, Yong J, Tang KD, Lo J, Ng IO, Lee TK, Ling MT.
BACKGROUND:
Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy.
METHOD:
We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (gamma-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining gamma-T3 and PSP in the treatment of prostate cancer.Result: We showed that in the presence of PSP, gamma-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward gamma-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and gamma-T3 treaments significantly reduced the growth of prostate tumor in vivo.
CONCLUSION:
Our results indicate that PSP and gamma-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.
Therapeutic Efficacy of Vitamin E δ-Tocotrienol in Collagen-Induced Rat Model of Arthritis.
Haleagrahara N, Swaminathan M, Chakravarthi S, Radhakrishnan A.
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease primarily involving inflammation of the joints. Although the management of the disease has advanced significantly in the past three decades, there is still no cure for RA. The aim of this study was to determine the therapeutic efficacy of δ-tocotrienol, in the rat model of collagen-induced arthritis (CIA). Arthritis was induced by intradermal injection of collagen type II emulsified in complete Freund’s adjuvant. CIA rats were orally treated with δ-tocotrienol (10 mg/kg) or glucosamine hydrochloride (300 mg/kg) from day 25 to 50. Efficacy was assessed based on the ability to reduce paw edema, histopathological changes, suppression of collagen-specific T-cells, and a reduction in C-reactive protein (CRP) levels. It was established that δ-tocotrienol had the most significant impact in lowering paw edema when compared to glucosamine treatment. Paw edema changes correlated well with histopathological analysis where there was a significant reversal of changes in groups treated with δ-tocotrienol. The results suggest that δ-tocotrienol is efficient in amelioration of collagen-induced arthritis. Vitamin E delta-tocotrienol may be of therapeutic value against rheumatoid arthritis.
Effects of annatto-derived tocotrienol supplementation on osteoporosis induced by testosterone deficiency in rats.
Chin KY, Ima-Nirwana S.
BACKGROUND:
Previous animal models have demonstrated that tocotrienol is a potential treatment for postmenopausal osteoporosis. This study evaluated the antiosteoporotic effects of annatto-derived tocotrienol (AnTT) using a testosterone-deficient osteoporotic rat model.
METHODS:
Forty rats were divided randomly into baseline, sham, orchidectomized, AnTT, and testosterone groups. The baseline group was euthanized without undergoing any surgical treatment or intervention. The remaining groups underwent orchidectomy, with the exception of the sham group. AnTT 60 mg/kg/day was given orally to the AnTT group, while the testosterone group received testosterone enanthate 7 mg/kg per week intramuscularly for 8 weeks. Structural changes in trabecular bone at the proximal tibia were examined using microcomputed tomography. Structural and dynamic changes at the distal femur were examined using histomorphometric methods. Serum osteocalcin and C-terminal of type 1 collagen crosslinks were measured. Bone-related gene expression in the distal femur was examined.
RESULTS:
There were significant degenerative changes in structural indices in the orchidectomized group (P<0.05), but no significant changes in dynamic indices, bone remodeling markers, or gene expression (P>0.05) when compared with the sham group. The AnTT group showed significant improvement in structural indices at the femur (P<0.05) and significantly increased expression of bone formation genes (P<0.05). Testosterone was more effective than AnTT in preventing degeneration of bone structural indices in the femur and tibia (P<0.05).
CONCLUSION:
AnTT supplementation improves bone health in testosterone-deficient rats by enhancing bone formation. Its potential should be evaluated further by varying the dosage and treatment duration.
Rice Bran Extract Compensates Mitochondrial Dysfunction in a Cellular Model of Early Alzheimer’s Disease.
Hagl S, Grewal R, Ciobanu I, Helal A, Khayyal MT, Muller WE, Eckert GP.
Mitochondrial dysfunction plays an important role in brain aging and has emerged to be an early event in Alzheimer’s disease (AD), contributing to neurodegeneration and the loss of physical abilities seen in patients suffering from this disease. We examined mitochondrial dysfunction in a cell culture model of AD (PC12APPsw cells) releasing very low amyloid-β (Aβ40) levels and thus mimicking early AD stages. Our data show that these cells have impaired energy metabolism, low ATP levels, and decreased endogenous mitochondrial respiration. Furthermore, protein levels of PGC1α as well as of Mitofusin 1 were decreased. PC12APPsw cells also showed an increased mitochondrial content, probably due to an attempt to compensate the impaired mitochondrial function. Recent data showed that stabilized rice bran extract (RBE) protects from mitochondrial dysfunction in vivo [24]. To assess the effect of a RBE on mitochondrial function, we treated PC12APPsw cells for 24 h with RBE. Key components of RBE are oryzanols, tocopherols, and tocotrienols, all substances that have been found to exert beneficial effects on mitochondrial function. RBE incubation elevated ATP production and respiratory rates as well as PGC1α protein levels in PC12APPsw cells, thus improving the impaired mitochondrial function assessed in our cell culture AD model. Therefore, RBE represents to be a promising nutraceutical for the prevention of AD.
The Little-Known Benefits Of Tocotrienols
By Thomas Rosenthal
If your vitamin E supplement contains only tocopherol forms, you may not be getting all of the benefits this nutrient has to offer. While tocopherols are very important, they lack many of the synergistic benefits offered by their cousins, the tocotrienols.
Few people realize that vitamin E is composed of eight different compounds. Half of these are called tocopherols, which is the most common form of vitamin E. The other half are known as tocotrienols.
Scientists are discovering that tocotrienols provide valuable therapeutic and preventive options for the diseases of aging that tocopherols alone may not provide.
Tocotrienols in action by The Star
Tocotrienols are fast overtaking their better-known vitamin E sibling, tocopherols, when it comes to customer satisfaction.
Researchers have long concentrated on the tocopherol members of the vitamin E family, which were discovered first. It was only in the last couple of decades that researchers have started to focus on tocotrienols.
Studies have indicated that tocotrienols are stronger antioxidants than tocopherols. In the market, tocotrienols are viewed as better, stronger form of vitamin E with positive customer feedbacks as they offer beneficial effects to the skin. Besides, the pharmacists recommend tocotrienols for heart protection, cholesterol-lowering and stroke-prevention. The recommended dose vary based on individual responses.
Gamma-tocotrienol attenuates high fat diet-induced obesity and insulin resistance by inhibiting adipose inflammation and M1 macrophage recruitment.
Zhao L, Kang I, Fang X, Wang W, Lee MA, Hollins RR, Marshall MR, Chung S.
Background and Objective:We have previously demonstrated that gamma tocotrienol (γT3) potently inhibits adipocyte hyperplasia in human adipose-derived stem cells (hASCs). In this study, our objective was to investigate the γT3 effects on early onset obesity, inflammation, and insulin resistance in vivo.Methods:Young C57BL/6 J mice were fed a high fat (HF) diet supplemented with 0.05% γT3 for 4 weeks. The concentrations of γT3 in plasma and adipose tissue were measured by HPLC. Effects of γT3 on body weight gain, adipose volume, plasma levels of fasting glucose, insulin (ELISA), pro-inflammatory cytokines (mouse cytokine array), insulin signaling (western blotting), and gene expression (quantitative real-time PCR, qPCR) in liver and adipose tissue were examined. Influences of γT3 on [3H]-2-deoxyglucose uptake and LPS-mediated NFκB signaling (western blotting) were assessed in hASCs. Effects of γT3 on macrophage M1/M2 activation were investigated by qPCR in mouse bone marrow-derived macrophages.Results:After a 4 week treatment, γT3 accumulated in adipose tissue and reduced HF diet-induced weight gain in epididymal fat, mesenteric fat, and liver. Compared to HF diet-fed mice, HF+γT3-fed mice were associated with 1) decreased plasma levels of fasting glucose, insulin, and proinflammatory cytokines, 2) improved glucose tolerance, and 3) enhanced insulin signaling in adipose tissue. There were substantial decreases in macrophage specific markers, and MCP1 indicating that γT3 reduced recruitment of adipose tissue macrophages (ATMs). Additionally, γT3 treatment in human adipocytes resulted in 1) activation of insulin-stimulated glucose uptake and 2) a significant suppression of MAP kinase and NFκB activation. In parallel, γT3 treatment led to a reduction of LPS-mediated M1 macrophage polarization.Conclusion:Our results demonstrated that γT3 ameliorates HF diet-mediated obesity and insulin resistance by inhibiting systemic and adipose inflammation, as well as ATM recruitment.
Tocotrienol modulates crucial lipid metabolism-related genes in differentiated 3T3-L1 preadipocytes.
Burdeos GC, Nakagawa K, Abe T, Kimura F, Miyazawa T.
Obesity and other lipid metabolism-related diseases have become more prevalent in recent years due to drastic lifestyle changes and dietary patterns. Unsaturated vitamin E, tocotrienol (T3), represents one of the most fascinating naturally occurring compounds that has the potential to influence a broad range of mechanisms underlying abnormal lipid metabolism processes. However, its efficacy and mechanism have been uncertain due to scarcity of data concerning the effect of T3 on lipid metabolism. In this study, we report a series of fascinating experimental findings on how T3 affects lipid metabolism in differentiated 3T3-L1 preadipocytes. Treatment with T3 (25 μM), especially δ and γ isomers, inhibited the accumulation of triglyceride and lipid droplets in differentiated 3T3-L1 cells. This manifestation was supported by mRNA and protein expression of crucial lipid metabolism-related genes. The present study provides a novel set of data pertaining to the possibility of T3 as an anti-metabolic disorder agent.
Tocotrienol Rich Fraction Reverses Age-Related Deficits in Spatial Learning and Memory in Aged Rats.
Taridi NM, Abd Rani N, Abd Latiff A, Wan Ngah WZ, Mazlan M.
Little is known about the effect of vitamin E on brain function. Therefore, in this study we evaluated the effect of tocotrienol rich fraction (TRF) on behavioral impairment and oxidative stress in aged rats. Thirty-six male Wistar rats (young: 3-months-old; aged: 21-months-old) were treated with either the control (olive oil) or TRF (200 mg/kg) for 3 months. Behavioral studies were performed using the open field test and Morris water maze (MWM) task. Blood was taken for assessment of DNA damage, plasma malondialdehyde (MDA) and vitamin E, and erythrocyte antioxidant enzyme activity. Brains were also collected to measure vitamin E levels. Results showed that aged rats exhibited reduced exploratory activity, enhanced anxiety and decreased spatial learning and memory compared with young rats. DNA damage and plasma MDA were increased, and vitamin E levels in plasma and brain were reduced in aged rats. Aged rats supplemented with TRF showed a markedly reduced level of anxiety, improved spatial learning and memory, reduced amount and severity of DNA damage, a reduced level of MDA, and increased levels of antioxidant enzyme activity and plasma/brain vitamin E compared with age-matched controls. In conclusion, TRF supplementation reverses spatial learning and memory decline and decreases oxidative stress in aged rats.