The worldwide cardiovascular disease (CVD) burden has resulted in an intense interest in pharmaceutical approaches to combat this multifactorial disease. Vitamins are high-flying among natural or endogenous compounds, considered to be beneficial to human health and have become attractive targets for research. Of all the vitamins, tocopherols and tocotrienols, parent congeners in the vitamin E family, are found to be effective in decreasing mortality due to CVD. As understanding of the antioxidant effect of this vitamin evolved, tocotrienols gained eminence in recent years and researchers begun to further study the biological effects of it. Tocotrienols have several cardioprotective effects; including antagonizing the oxidation of low density lipoproteins, anti atherosclerotic, inhibiting platelet aggregation and monocyte adhesion, preventing smooth muscle proliferation and various other cardiovascular disorders. Recent studies have also revealed the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes and neurological diseases at both preclinical and clinical levels. The multitargeted role of tocotrienols in most degenerative diseases proves it to be an ideal candidate as a nutraceutical/pharmaceutical agent for useful exploitation.

Inhibitory effects of palm α-, γ- and δ-tocotrienol on lipopolysaccharide-induced nitric oxide production in BV2 microglia

Tan SW, Ramasamy R, Abdullah M, Vidyadaran S

Cell Immunol. 2011;271(2):205-9. Epub 2011 Jul 23

Anti-inflammatory actions of the vitamin E fragment tocotrienol have not been described for microglia. Here, we screened palm alpha-, gamma- and delta-tocotrienol isoforms and Tocomin(R) 50% (contains spectrum of tocotrienols and tocopherols) for their ability to limit nitric oxide (NO) production by BV2 microglia. Microglia were treated with varying doses of tocotrienols for 24h and stimulated with 1 mug/ml lipopolysaccharide (LPS). All tocotrienol isoforms reduced NO release by LPS-stimulated microglia, with 50 muM being the most potent tocotrienol dose. Of the isoforms tested, delta-tocotrienol lowered NO levels the most, reducing NO by approximately 50% at 48 h post-LPS treatment (p<.05). None of the tocotrienol doses tested affected microglia viability.

Vitamin E forms inhibit IL-13/STAT6-induced eotaxin-3 secretion by up-regulation of PAR4, an endogenous inhibitor of atypical PKC in human lung epithelial cells

Wang Y, Moreland M, Wagner JG, Ames BN, Illek B, Peden DB, Jiang Q.

J Nutr Biochem. 2011 Jul 15.

Eotaxin-3 (CCL-26), a potent chemokine for eosinophil recruitment and contributing significantly to the pathogenesis of asthma, is secreted by lung epithelial cells in response to T helper 2 cytokines including interleukin 13 (IL-13). Here we showed that vitamin E forms, but not their metabolites, differentially inhibited IL-13-stimulated generation of eotaxin-3 in human lung epithelial A549 cells. The relative inhibitory potency was γ-tocotrienol (γ-TE) (IC50 ∼15 μM)>γ-tocopherol, δ-tocopherol (IC50 ∼25-50 μM)>α-tocopherol. Consistent with suppression of eotaxin, γ-TE treatment impaired IL-13-induced phosphorylation of STAT6, the key transcription factor for activation of eotaxin expression, and consequently blocked IL-13-stimulated DNA-binding activity of STAT6. In search of the upstream target of γTE by using inhibitor and siRNA approaches, we discovered that the atypical protein kinase C (aPKC) signaling, instead of classical PKC, p38 MAPK, JNK or ERK, played a critical role in IL-13-stimulated eotaxin generation and STAT6 activation. While showing no obvious effect on aPKC expression or phosphorylation, γ-TE treatment resulted in increased expression of prostate-apoptosis-response 4 (PAR4), an endogenous negative regulator of aPKCs. Importantly, γ-TE treatment led to enhanced formation of aPKC/PAR4 complex that is known to reduce aPKC activity via protein-protein crosstalk. Our study demonstrated that γ-TE inhibited IL-13/STAT6-activated eotaxin secretion via up-regulation of PAR4 expression and enhancement of aPKC-PAR4 complex formation. These results support the notion that specific vitamin E forms may be useful anti-asthmatic agents.

Tocotrienols: Inflammation and cancer

Nesaretnam K, Meganathan P.

Ann N Y Acad Sci. 2011 Jul;1229:18-22.

Inflammation is an organism’s response to environmental assaults. It can be classified as acute inflammation that leads to therapeutic recovery or chronic inflammation, which may lead to the development of cancer and other ailments. Genetic changes that occur within cancer cells themselves are responsible for many aspects of cancer development but are dependent on ancillary processes for tumor promotion and progression. Inflammation has long been associated with the development of cancer. The distinct characteristics of cancer cells to proliferate, metastasize, evade apoptotic signals, and develop chemoresistance have been linked to the inflammatory response. Due to the involvement of multiple genes and various pathways, current drugs that target single genes have not been effective in providing a therapeutic cure. On the other hand, natural products target multiple genes and therefore have better success compared to drugs. Tocotrienols, the potent isoforms of vitamin E, are such a natural product. This review will discuss the relationship between cancer and inflammation with particular focus on the roles played by NF-κB, STAT3, and COX-2.

Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study

Chin, S. F.,Ibahim, J.,Makpol, S.,Abdul Hamid, N. A.,Abdul Latiff, A.,Zakaria, Z.,Mazlan, M.,Mohd Yusof, Y. A.,Abdul Karim, A.,Wan Ngah, W. Z.

Nutr Metab (Lond) 2011;8(1):42

Abstract

Background: Vitamin E supplements containing tocotrienols are now being recommended for optimum health but its effects are scarcely known. The objective was to determine the effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months.

Methods: Sixty-two subjects were recruited from two age groups: 35-49 years (n = 31) and above 50 years (n = 31), and randomly assigned to receive either TRF or placebo capsules for six months. Blood samples were obtained at 0, 3rd and 6th months.

Results: HDL-cholesterol in the TRF-supplemented group was elevated after 6 months (p < 0.01). Protein carbonyl contents were markedly decreased (p < 0.001), whereas AGE levels were lowered in the > 50 year-old group (p < 0.05). Plasma levels of total vitamin E particularly tocopherols were significantly increased in the TRF-supplemented group after 3 months (p < 0.01). Plasma total tocotrienols were only increased in the > 50 year-old group after receiving 6 months of TRF supplementation. Changes in enzyme activities were only observed in the > 50 year-old group. SOD activity was decreased after 3 (p < 0.05) and 6 (p < 0.05) months of TRF supplementation whereas CAT activity was decreased after 3 (p < 0.01) and 6 (p < 0.05) months in the placebo group. GPx activity was increased at 6 months for both treatment and placebo groups (p < 0.05).

Conclusion: The observed improvement of plasma cholesterol, AGE and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age.

BACKGROUND: The bran part of red rice grain is concentrated with many phytochemicals, including proanthocyanidins, oryzanol and vitamin E, that exert beneficial effects on human health, but it contains low levels of essential minerals such as Fe and Zn. In the present study, the protein, lipid, phytochemicals and mineral contents in bran samples were compared among red rice SA-586 and its NaN₃-induced mutants.

RESULTS: The plant heights of NaN₃-induced mutants were decreased. The contents of protein, lipid, total phenolics, total flavonoids, total anthocyanins, total proanthocyanidins, total γ-oryzanol, total tocopherols and total tocotrienols also varied among the tested mutants. The brans of mutants M-18, M-56 and M-50 contained more proanthocyanidins, γ-oryzanol, vitamin E than that of SA-586, respectively. M-54 accumulated more Fe content (588.7 mg kg⁻¹ bran dry weight) than SA-586 (100.1 mg kg⁻¹ bran dry weight).

CONCLUSIONS: The brans of M-18, M-50 and M-56 are good sources of proanthocyanidins, vitamin E and γ-oryzanol, respectively, while the bran of M-54 is rich in Fe. Thus these mutants could be used to produce high-value phytochemicals or Fe byproducts from bran during rice grain milling or as genetic resources for rice improvement programs.

Induction of apoptosis by γ-tocotrienol in human cancer cell lines and leukemic blasts from patients: Dependency on Bid, cytochrome c, and caspase pathway

Inoue A, Takitani K, Koh M, Kawakami C, Kuno T, Tamai H.

Nutr Cancer. 2011;63(5):763-70. Epub 2011 Jun 9.

Tocotrienols (Toc3) have been suggested to possess anticancer effects besides antioxidant and antiinflammatory effects. Previous studies have demonstrated that Toc3 induce apoptosis in epithelial carcinoma. However, the effects of Toc3 on malignant hematopoietic cells have not yet been thoroughly investigated. We investigated Toc3-induced apoptosis in human hematological cancer cell lines. α-, δ-, and γ-Toc3 induced concentration-dependent apoptosis, and γ-Toc3 demonstrated more effective induction than the other Toc3 derivatives in HL-60 cells. γ-Toc3 may have induced apoptosis by activation of the caspase cascade, cytochrome c (Cyt.c) release, Bid cleavage, and mitochondorial membrane depolarization in HL-60, NB-4, Raji, and SY-5Y cells. Furthermore, 10-30 μM γ-Toc3 showed cytotoxicity for leukemic cells from various patients regardless of lymphoblastic, myeloblastic, or relapsed leukemia, but the cytotoxic effect was weak in normal mononuclear cells, interestingly. γ-Toc3 may have a role in cancer prevention and potential for treating hematological malignancies.

Blog Archives