Tocotrienols for bone health: a translational approach.

Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, Chyu MC, Ima-Nirwana S

Ann N Y Acad Sci. 2017 Aug;1401(1):150-165. doi: 10.1111/nyas.13449.

Abstract

Osteoporosis, a degenerative bone disease, is characterized by low bone mass and microstructural deterioration of bone tissue resulting in aggravated bone fragility and susceptibility to fractures. The trend of extended life expectancy is accompanied by a rise in the prevalence of osteoporosis and concomitant complications in the elderly population. Epidemiological evidence has shown an association between vitamin E consumption and the prevention of age-related bone loss in elderly women and men. Animal studies show that ingestion of vitamin E, especially tocotrienols, may benefit bone health in terms of maintaining higher bone mineral density and improving bone microstructure and quality. The beneficial effects of tocotrienols on bone health appear to be mediated via antioxidant/anti-inflammatory pathways and/or 3-hydroxy-3-methylglutaryl coenzyme A mechanisms. We discuss (1) an overview of the prevalence and etiology of osteoporosis, (2) types of vitamin E (tocopherols versus tocotrienols), (3) findings of tocotrienols and bone health from published in vitro and animal studies, (4) possible mechanisms involved in bone protection, and (5) challenges and future direction for research.

Ikegami H, Kawawa R, Ichi I, Ishikawa T, Koike T, Aoki Y, Fujiwara Y

J Nutr. 2017 Aug 23. pii: jn248575. doi: 10.3945/jn.117.248575. [Epub ahead of print]

Abstract

Background: Animal studies on the effects of vitamin E on bone health have yielded conflicting and inconclusive results, and to our knowledge, no studies have addressed the effect of vitamin E on bone in animals consuming a high-fat diet (HFD).Objective: This study aimed to evaluate the effect of excessive vitamin E on bone metabolism in normal male mice and ovariectomized female mice fed a normal diet (ND) or HFD.Methods: In the first 2 experiments, 7-wk-old male mice were fed an ND (16% energy from fat) containing 75 (control), 0 (vitamin E-free), or 1000 (high vitamin E) mg vitamin E/kg (experiment 1) or an HFD (46% energy from fat) containing 0, 200, 500, or 1000 mg vitamin E/kg (experiment 2) for 18 wk. In the third experiment, 7-wk-old sham-operated or ovariectomized female mice were fed the ND (75 mg vitamin E/kg) or HFD containing 0 or 1000 mg vitamin E/kg for 8 wk. At the end of the feeding period, blood and femurs were collected to measure bone turnover markers and analyze histology and microcomputed tomography.Results: In experiments 1 and 2, vitamin E intake had no effect on plasma alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) activity, or bone formation, resorption, or volume in femurs in mice fed the ND or HFDs. In experiment 3, bone volume was significantly reduced (85%) in ovariectomized mice compared with that in sham-operated mice (P < 0.05), but it did not differ among mice fed the 3 diets. Plasma ALP and TRAP activities and bone formation and resorption in femur were similar among ovariectomized mice fed the HFD containing 0 or 1000 mg vitamin E/kg.Conclusions: The results suggest that excess vitamin E intake does not cause bone loss in normal male mice or in ovariectomized or sham-operated female mice, regardless of dietary fat content.

Dong Y, Chen X, Liu Y, Shu Y, Chen T, Xu L, Li M, Guan X

Int J Geriatr Psychiatry. 2017 Aug 23. doi: 10.1002/gps.4780. [Epub ahead of print]

Abstract

OBJECTIVE:

Whether low-serum vitamin E increases the risk of Alzheimer disease (AD) in older people remains inconclusive. This meta-analysis aims to synthesize evidence-based case-control studies to evaluate the association between serum vitamin E and the risk of AD.

METHODS:

Potentially relevant studies were selected through PubMed, Embase, Wanfang, Chongqing VIP, and China National Knowledge Infrastructure databases by using the core terms Vitamin E/alpha-tocopherol and Alzheime’s disease/senile dementia/AD in the titles, abstracts, and keywords of the articles. The association between serum vitamin E levels and AD was estimated by using the weighted mean difference (WMD) and 95% confidence interval by adopting a random effects model. Heterogeneity was assessed by using Cochran Q test and I² statistic. Forest plot was used to present the results graphically from meta-analysis. Publication bias was evaluated by using funnel plots and Egger test.

RESULTS:

We identified 17 studies that met the eligibility criteria. The studies included 2057 subjects with 904 AD patients and 1153 controls. The results indicated that AD patients had a lower concentration of serum vitamin E compared with healthy controls among older people (WMD = -6.811 μmol/L, 95% confidence interval -8.998 to -4.625; Z = -6.105, P < .001). Publication bias was not detected and sensitivity analysis performed by omitting each study, and calculating the pooled WMD again for the remaining studies indicated the results stable.

CONCLUSIONS:

Alzheimer disease is associated with a low concentration of serum vitamin E in older people. However, necessary prospective cohort studies should be conducted to determine the risk of serum vitamin E for AD in the future.

Uchihara Y, Ueda F, Tago K, Nakazawa Y, Ohe T, Mashino T, Yokota S, Kasahara T, Tamura H, Funakoshi-Tago M

PLoS One. 2017 Aug 14;12(8):e0183003. doi: 10.1371/journal.pone.0183003. eCollection 2017.

Abstract

Anaplastic large cell lymphomas (ALCL) are mainly characterized by harboring the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The ALK inhibitor, crizotinib specifically induced apoptosis in Ba/F3 cells expressing NPM-ALK by inhibiting the activation of NPM-ALK and its downstream molecule, signal transducer and activator of transcription factor 3 (STAT3). We found that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although α-tocopherolsuppressed the inhibitory effects of crizotinib on the signaling axis including NPM-ALK and STAT3, it had no influence on the intake of crizotinib into cells. Crizotinib also directly inhibited the kinase activity of NPM-ALK; however, this inhibitory effect was not altered by the co-treatment with α-tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with α-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of α-tocopherolattenuated the anti-tumor activity of crizotinib against NPM-ALK-provoked tumorigenesis in vivo. Furthermore, the α-tocopherol-induced inhibition of crizotinib-caused apoptosis was also observed in NPM-ALK-positive cells derived from ALCL patients, namely, SUDHL-1 and Ki-JK. Collectively, these results not only revealed the novel mechanism underlying crizotinib-induced apoptosis in NPM-ALK-positive cells, but also suggest that the anti-tumor effects of crizotinib are attenuated when it is taken in combination with vitamin E.

Chia LL, Jantan I, Chua KH

Curr Pharm Biotechnol. 2017 Aug 8. doi: 10.2174/1389201018666170808144703. [Epub ahead of print]

Abstract

BACKGROUND:

Tocotrienols (T3) are the natural occurring vitamin E derivatives that possess antioxidant properties and therapeutic potential in diabetic complications. The bioactivities of the derivatives are determined by the number and arrangement of methyl substitution on the structure.

OBJECTIVE:

The objective of this study was to determine the effects of T3 derivatives, δ-T3, γ-T3 and α-T3 on insulin secretion of rat pancreatic islets in a dynamic culture.

METHOD:

Pancreatic islets isolated from male Wistar rats were treated with T3 for 1 h at 37 oC in a microfluidic system with continuous operation that provided a stable cell culture environment. Glucose (2.8 mM and 16.7 mM, as basal and stimulant, respectively) and potassium chloride (KCl) (30 mM) were added to the treatment in calcium free medium. The supernatant were collected for insulin measurements.

RESULTS:

Short-term exposure (1 h) of δ-T3 to β cells in the stimulant glucose condition significantly potentiated insulin secretion in a dose-dependent manner. γ-T3 and α-T3 also displayed dose-dependent effect but less effective in the activation of insulin secretion. Essentially, KCl, a pancreatic β cell membrane depolarizing agent, added into the treatment further enhanced the insulin secretion of δ-T3, γ-T3 and α-T3 with ED50 values of 504, 511 and 588 µM, respectively.

CONCLUSION:

The findings suggest the potential of δ-T3 in regulating glucose-stimulated insulin secretion (GSIS) in response to the intracellular calcium especially in the presence of KCl.

Abu-Fayyad A, Nazzal S

Int J Pharm. 2017 Aug 7;528(1-2):463-470. doi: 10.1016/j.ijpharm.2017.06.031. Epub 2017 Jun 13.

Abstract

Gemcitabine is the first line therapy for pancreatic cancer. It is, however, extensively metabolized to the inactive form by deamination enzymatic reaction. Conjugation of gemcitabine with fatty acids on its 4-amino group was found to protect it from deamination deactivation reaction. The objective of the present study was to test the in-vitro anticancer activity of gemcitabine conjugated to the γ-tocotrienol isomer of vitamin E against pancreatic tumor cells. This objective was based on reported studies in which it was demonstrated that free tocotrienolisomers of vitamin E can potentiate the anticancer activity of gemcitabine. To accomplish this objective, a full synthesis scheme for gemcitabine conjugation to fatty acids (stearic and linoleic) and the tocopherol and tocotrienol isomers of vitamin E (α-T and γ-T3) was presented. The conjugates were characterized by ¹H NMR and mass spectrometry analysis and tested for their susceptibility to deamination. Also discussed is the impact of entrapping the conjugates into nanoemulsions on the physiochemical properties of the delivery system and the in vitro anticancer activity of gemcitabine against Bx-PC-3 and PNAC-1 pancreatic cancer cells. In-vitro enzymatic deamination study showed that the γ-T3 conjugate of gemcitabine was least affected by deamination deactivation reaction when compared with the free and conjugated gemcitabine in solution. Furthermore, in-vitro cytotoxicity study demonstrated that entrapment of gemcitabine-lipid conjugates into nanoemulsions significantly enhanced their anticancer activity when compared to the free drug. It was concluded that conjugation to the γ-T3 isomer is a viable option for gemcitabine delivery and is worthy of further investigation.

Kanchi MM, Shanmugam MK, Rane G, Sethi G, Kumar AP

Drug Discov Today. 2017 Aug 5. pii: S1359-6446(17)30137-X. doi: 10.1016/j.drudis.2017.08.001. [Epub ahead of print]

Abstract

Vitamin E family members: tocotrienols and tocopherols are widely known for their health benefits. Decades of research on tocotrienols have shown they have diverse biological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective and skin protection benefits, as well as improved cognition, bone health, longevity and reduction of cholesterol levels in plasma. Tocotrienols also modulate several intracellular molecular targets and, most importantly, have been shown to improve lipid profiles, reduce total cholesterol and reduce the volume of white matter lesions in human clinical trials. This review provides a comprehensive update on the little-known therapeutic potentials of tocotrienols, which tocopherols lack in a variety of inflammation-driven diseases.

Xu W, Mi Y, He P, He S, Niu L

Molecules. 2017 Aug 4;22(8). pii: E1299. doi: 10.3390/molecules22081299.

Abstract

γ-Tocotrienol, a kind of isoprenoid phytochemical, has antitumor activity. However, there is limited evidence that it has an effect on cervical cancer. In this study, the capacity to inhibit proliferation and induce apoptosis in human cervical cancer HeLa cells and the mechanism underlying these effects were examined. The results indicated that a γ-tocotrienol concentration over 30 μM inhibited the growth of HeLa cells with a 50% inhibitory concentration (IC₅₀) of 46.90 ± 3.50 μM at 24 h, and significantly down-regulated the expression of proliferative cell nuclear antigen (PCNA) and Ki-67. DNA flow cytometric analysis indicated that γ-tocotrienol arrested the cell cycle at G0/G1 phase and reduced the S phase in HeLa cells. γ-tocotrienol induced apoptosis of HeLa cells in a time- and dose-dependent manner. γ-tocotrienol-induced apoptosis in HeLa cells was accompanied by down-regulation of Bcl-2, up-regulation of Bax, release of cytochrome from mitochondria, activation of caspase-9 and caspase-3, and subsequent poly (ADP-ribose) polymerase (PARP) cleavage. These results suggested that γ-tocotrienol could significantly inhibit cell proliferation through G0/G1 cell cycle arrest, and induce apoptosis via the mitochondrial apoptotic pathway in human cervical cancer HeLa cells. Thus, our findings revealed that γ-tocotrienol may be considered as a potential agent for cervical cancer therapy.