Proteomic profiling of senescent human diploid fibroblasts treated with gamma-tocotrienol

Tan JK, Jaafar F, Makpol S

BMC Complement Altern Med. 2018 Nov 29;18(1):314. doi: 10.1186/s12906-018-2383-6.



Replicative senescence of human diploid fibroblasts (HDFs) has been used as a model to study mechanisms of cellular aging. Gamma-tocotrienol (γT3) is one of the members of vitamin E family which has been shown to increase proliferation of senescent HDFs. However, the modulation of protein expressions by γT3 in senescent HDFs remains to be elucidated. Therefore, this study aimed to determine the differentially expressed proteins (DEPs) in young and senescent HDFs; and in vehicle- and γT3-treated senescent HDFs using label-free quantitative proteomics.


Whole proteins were extracted and digested in-gel with trypsin. Peptides were detected by Orbitrap liquid chromatography mass spectrometry. Mass spectra were identified and quantitated by MaxQuant software. The data were further filtered and analyzed statistically using Perseus software to identify DEPs. Functional annotations of DEPs were performed using Panther Classification System.


A total of 1217 proteins were identified in young and senescent cells, while 1218 proteins in vehicle- and γT3-treated senescent cells. 11 DEPs were found in young and senescent cells which included downregulation of platelet-derived growth factor (PDGF) receptor beta and upregulation of tubulin beta-2A chain protein expressions in senescent cells. 51 DEPs were identified in vehicle- and γT3-treated senescent cells which included upregulation of 70 kDa heat shock protein, triosephosphate isomerase and malate dehydrogenase protein expressions in γT3-treated senescent cells.


PDGF signaling and cytoskeletal structure may be dysregulated in senescent HDFs. The pro-proliferative effect of γT3 on senescent HDFs may be mediated through the stimulation of cellular response to stress and carbohydrate metabolism. The expressions and roles of these proteins in relation to cellular senescence are worth further investigations. Data are available via ProteomeXchange with identifier PXD009933.

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Tocotrienol Rich Fraction Supplementation Modulate Brain Hippocampal Gene Expression in APPswe/PS1dE9 Alzheimer’s Disease Mouse Model

Wan Nasri WN, Makpol S, Mazlan M, Tooyama I, Wan Zurinah Wan Ngah WZ, Damanhuri HA

J Alzheimers Dis. 2018 Nov 28. doi: 10.3233/JAD-180496. [Epub ahead of print]


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive abilities. AD is associated with aggregation of amyloid-β (Aβ) deposited in the hippocampal brain region. Our previous work has shown that tocotrienol rich fraction (TRF) supplementation was able to attenuate the blood oxidative status, improve behavior, and reduce fibrillary-type Aβ deposition in the hippocampus of an AD mouse model. In the present study, we investigate the effect of 6 months of TRF supplementation on transcriptome profile in the hippocampus of APPswe/PS1dE9 double transgenic mice. TRF supplementation can alleviate AD conditions by modulating several important genes in AD. Moreover, TRF supplementation attenuated the affected biological process and pathways that were upregulated in the AD mouse model. Our findings indicate that TRF supplementation can modulate hippocampal gene expression as well as biological processes that can potentially delay the progression of AD.

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Challenges and Opportunities of Nanotechnology as Delivery Platform for Tocotrienols in Cancer Therapy

Maniam G, Mai CW, Zulkefeli M, Dufès C, Tan DM, Fu JY

Front Pharmacol. 2018 Nov 26;9:1358. doi: 10.3389/fphar.2018.01358. eCollection 2018.


Plant-derived phytonutrients have emerged as health enhancers. Tocotrienols from the vitamin E family gained high attention in recent years due to their multi-targeted biological properties, including lipid-lowering, neuroprotection, anti-inflammatory, antioxidant, and anticancer effects. Despite well-defined mechanism of action as an anti-cancer agent, their clinical use is hampered by poor pharmacokinetic profile and low oral bioavailability. Delivery systems based on nanotechnology were proven to be advantageous in elevating the delivery of tocotrienolsto tumor sites for enhanced efficacy. To date, preclinical development of nanocarriers for tocotrienols include niosomes, lipid nanoemulsions, nanostructured lipid carriers (NLCs) and polymeric nanoparticles. Active targeting was explored via the use of transferrin as targeting ligand in niosomes. In vitro, nanocarriers were shown to enhance the anti-proliferative efficacy and cellular uptake of tocotrienols in cancer cells. In vivo, improved bioavailability of tocotrienols were reported with NLCs while marked tumor regression was observed with transferrin-targeted niosomes. In this review, the advantages and limitations of each nanocarriers were critically analyzed. Furthermore, a number of key challenges were identified including scale-up production, biological barriers, and toxicity profiles. To overcome these challenges, three research opportunities were highlighted based on rapid advancements in the field of nanomedicine. This review aims to provide a wholesome perspective for tocotrienol nanoformulations in cancer therapy directed toward effective clinical translation.

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Vitamin E supplementation and caloric restriction promotes regulation of insulin secretion and glycemic homeostasis by different mechanisms in rats

Venturini PR, Thomazini BF, Oliveira CA, Alves AA, Camargo TF, Domingues CEC, Barbosa-Sampaio HCL, do Amaral MEC

Biochem Cell Biol. 2018 Nov 27:1-9. doi: 10.1139/bcb-2018-0066. [Epub ahead of print]


Vitamin E and caloric restriction have antioxidant effects in mammals. The aim of this study was to evaluate effects of vitamin E supplementation and caloric restriction upon insulin secretion and glucose homeostasis in rats. Male Wistar rats were distributed among the following groups: C, control group fed ad libitum; R, food quantity reduction of 40%; CV, control group supplemented with vitamin E [30 mg·kg-1·day-1]; and RV, food-restricted group supplemented with vitamin E. The experiments ran for 21 days. Glucose tolerance and insulin sensitivity was higher in the CV, R, and RV groups. Insulin secretion stimulated with different glucose concentrations was lower in the R and RV groups, compared with C and CV. In the presence of glucose and secretagogues, insulin secretion was higher in the CV group and was lower in the R and RV groups. An increase in insulin receptor occurred in the fat pad and muscle tissue of groups CV, R, and RV. Levels of hepatic insulin receptor and phospho-Akt protein were higher in groups R and RV, compared with C and CV, while muscle phospho-Akt was increased in the CV group. There was a reduction in hepatic RNA levels of the hepatocyte growth factor gene and insulin degrading enzyme in the R group, and increased levels of insulin degrading enzyme in the CV and RV groups. Thus, vitamin E supplementation and caloric restriction modulate insulin secretion by different mechanisms to maintain glucose homeostasis.

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Tocotrienol-rich fraction supplementation prevents foetal loss in females mated with corticosterone-treated male Sprague-Dawley rats.

Abd Aziz NAA, Chatterjee A, Chatterjee R, Durairajanayagam D

Andrologia. 2018 Nov 20:e13199. doi: 10.1111/and.13199. [Epub ahead of print]


This study examined whether tocotrienol supplementation to corticosterone-treated male rats could prevent foetal loss in females upon their mating. Epididymides of adult male Sprague-Dawley (SD) rats with proven fertility were surgically separated at the testis-caput junction. Twenty-four hours post-surgery, these animals received for 7 days either: tocopherol-stripped corn oil (Control), corticosterone 25 mg/kg s.c. (CORT), CORT 25 mg/kg s.c. and tocotrienol-rich fraction (TRF) 100 mg/kg orally (CORT + TRF) or TRF 100 mg/kg orally (TRF). On day 8, males were cohabited with proestrus females. A spermatozoa-positive vaginal smear indicated pregnancy. Males were euthanised for analysis of testosterone and antioxidant activities. Reproductive organs were weighed. On day 8 of pregnancy, females were laparotomised to count the number of implantation sites. Pregnancy was continued until term. Number of pups delivered and their weights were determined. Data were analysed using ANOVA. Malondialdehyde levels were significantly lower in CORT + TRF group compared with CORT group. Enzymatic antioxidant activities, testosterone level and reproductive organ weights were significantly higher in CORT + TRF group compared with CORT group. Number of implantation sites and live pups delivered, and their birth weights from females mated with CORT + TRF males were significantly higher compared to CORT group. Therefore, TRF prevents foetal loss in females mated with CORT + TRF-treated males.

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Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence

Malavolta M, Pierpaoli E, Giacconi R, Basso A, Cardelli M, Piacenza F, Provinciali M

Biol Proced Online. 2018 Nov 20;20:22. doi: 10.1186/s12575-018-0087-4. eCollection 2018.


Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family since they have opened new opportunities to prevent or treat a multitude of age-related chronic diseases. The beneficial effects of T3 include the amelioration of lipid profile, the promotion of Nrf2 mediated cytoprotective activity and the suppression of inflammation. All these effects may be the consequence of the ability of T3 to target multiple pathways. We here propose that these effects may be the result of a single target of T3, namely senescent cells. Indeed, T3 may act by a direct suppression of the senescence-associated secretory phenotype (SASP) produced by senescent cells, mediated by inhibition of NF-kB and mTOR, or may potentially remove the origin of the SASP trough senolysis (selective death of senescent cells). Further studies addressed to investigate the impact of T3 on cellular senescence “in vitro” as well as in experimental models of age-related diseases “in vivo” are clearly encouraged.

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δ-Tocopherol promotes thermogenic gene expression via PGC-1α upregulation in 3T3-L1 cells

Tanaka-Yachi R, Shirasaki M, Otsu R, Takahashi-Muto C, Inoue H, Aoki Y, Koike T, Kiyose C

Biochem Biophys Res Commun. 2018 Nov 17;506(1):53-59. doi: 10.1016/j.bbrc.2018.10.021. Epub 2018 Oct 15


Activation of thermogenic adipocytes (brown and beige) has been considered an attractive target for weight loss and treatment of metabolic disease. Peroxisome proliferator-activated receptor γ co-activator-1 α (PGC1-α) is a master regulator of thermogenic gene expression in thermogenic adipocytes. We previously reported that α-tocopherol upregulated PGC-1α gene expression and promoted thermogenic adipocyte differentiation in mammalian adipocytes. In this study, we investigated the effects of the vitamin E analogs (α-, γ- and δ-tocopherol) on PGC-1α and uncoupling protein 1 (UCP1) gene expression in 3T3-L1 cells. The expression of PGC-1α and UCP1 increased significantly with the addition of δ-tocopherol. In δ-tocopherol-treated cells, nuclear translocation of PGC-1α increased, as did p38 mitogen-activated protein kinase (MAPK) expression and phosphorylation. Our results suggest that p38 MAPK activation by δ-tocopherol contributes to PGC-1α activation and UCP1 induction.

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Does α-Tocopherol Flip-Flop Help to Protect Membranes Against Oxidation?

Boonnoy P, Karttunen M, Wong-Ekkabut J

J Phys Chem B. 2018 Nov 15;122(45):10362-10370. doi: 10.1021/acs.jpcb.8b09064. Epub 2018 Nov 6.


α-Tocopherols (α-toc) are crucial in protecting biological membranes against oxidation by free radicals. We investigate the behavior of α-toc molecules in lipid bilayers containing oxidized lipids by molecular dynamics (MD) simulations. To verify the approach, the location and orientation of α-toc are first shown to be in agreement with previous experimental results. The simulations further show that α-toc molecules stay inside the lipid bilayer with their hydroxyl groups in contact with the bilayer surface. Interestingly, interbilayer α-toc flip-flop was observed in both oxidized and nonoxidized bilayers with significantly higher frequency in aldehyde lipid bilayer. Free-energy calculations were performed, and estimates of the flip-flop rates across the bilayers were determined. As the main finding, our results show that the presence of oxidized lipids leads to a significant decrease of free-energy barriers and that the flip-flop rates depend on the type of oxidized lipid present. Our results suggest that α-toc molecules could potentially act as high-efficacy scavengers of free radicals to protect membranes from oxidative attack and help stabilize them under oxidative stress.

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Alpha-tocopherol potentiates the cervical resistance decreasing effects of COX-inhibitors in pregnant rats: the putative role of cyclooxygenase-2 inhibition

Kothencz A, Hajagos-Toth J, Szucs KF, Schaffer A, Gaspar R

J Pharmacol Exp Ther. 2018 Nov 15. pii: jpet.118.251850. doi: 10.1124/jpet.118.251850. [Epub ahead of print]


Vitamin E and their analogues as antioxidant and lipid soluble compounds can have diverse effects on the physiological processes. By binding to receptors and enzymes, they may modify the action of drugs. It has been proved that alpha-tocopherol succinate modifies the effects of β2 agonist terbutaline and cyclooxygenase (COX) inhibitors on rat trachea and myometrium. Our aim was to investigate how alpha-tocopherol and COX inhibitors may influence cervical resistance in rats. The cervical resistance of non-pregnant and 22-day-pregnant Sprague-Dawley rats was determined in an isolated organ bath in vitro. Alpha-tocopherol-succinate (10-7 M) was used, while the COX non-selective diclofenac (10-6 M), the COX-2 selective rofecoxib (10-6 M) and the COX-1 selective SC-560 (10-6 M) were applied as inhibitors. The COX activities of the cervices were measured by enzyme-immunoassay. The modifying effect of single doses of COX-inhibitors and tocopherol on the onset of labor was investigated in vivo. The cervical resistance of non-pregnant samples was not changed by either alpha-tocopherol or COX inhibitors. On pregnant cervices, tocopherol, diclofenac or rofecoxib pretreatment decreased cervical resistance that was further reduced by COX-inhibitors after pretreatment with tocopherol. Alpha-tocopherol elicited a significant COX-2 enzyme inhibition in pregnant cervical samples. By co-administration of tocopherol and rofecoxib, the parturition was initiated earlier than in the other groups. It is supposed that COXs play a significant role not only in cervical ripening, but also in the contraction of the cervical smooth muscle a few hours before parturition. This latter action may be developed by COX-2 liberated prostaglandins.

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Vitamin E intake and risk of stroke: a meta-analysis

Cheng P, Wang L, Ning S, Liu Z, Lin H, Chen S, Zhu J

Br J Nutr. 2018 Nov;120(10):1181-1188. doi: 10.1017/S0007114518002647.


Findings from observational studies on the associations between vitamin E intake and stroke risk remain controversial, and the dose-response relationship between vitamin E intake and risk of stroke remains to be determined. We conducted a meta-analysis of prospective studies aiming to clarify the relationships between vitamin E intake and risk of stroke. Relevant studies were identified by searching online databases through to June 2018. We computed summary relative risks (RR) with corresponding 95 % CI. Among 3156 articles retrieved from online databases and relevant bibliographies, nine studies involving 3284 events and 220 371 participants were included in the final analyses. High dietary vitamin E intake was inversely associated with the risk of overall stroke (RR=0·83, 95 % CI 0·73, 0·94), and with the risk of stroke for individuals who were followed-up for <10 (RR=0·84, 95 % CI 0·72, 0·91). There was a non-linear association between dietary vitamin E intake and stroke risk (P=0·0249). Omission of any single study did not alter the summary result. In conclusion, this meta-analysis suggests that there is a significant inverse relationship between dietary vitamin E intake and stroke risk. This meta-analysis provides evidence that a higher dietary vitamin E intake is associated with a lower stroke risk.

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