X-Message-Number: 32320 Date: Sun, 17 Jan 2010 21:10:07 -0800 (PST) From: Subject: synergism between tocotrienol and resveratrol [Clinical trials with alpha tocopherol show that this form of vitamin E offers no mortality benefit in humans. I'd wager that the results would be different with tocotrienol, particularly in combination with resveratrol.] J Cell Mol Med. 2009 Oct 3. [Epub ahead of print] Co-ordinated autophagy with resveratrol and gamma-tocotrienol confers synergetic cardioprotection. Lekli I, Ray D, Mukherjee S, Gurusamy N, Ahsan MK, Juhasz B, Bak I, Tosaki A, Gherghiceanu M, Popescu LM, Das DK. Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, USA. ABSTRACT This study compared two dietary phytochemicals, grape-derived resveratrol and palm oil-derived gamma-tocotrienol, either alone or in combination, on the contribution of autophagy in cardioprotection during ischemia and reperfusion. Sprague Dawley rats weighing between 250-300 gm were randomly assigned to one of the following groups: vehicle, ischemia/reperfusion (I/R), resveratrol+I/R, gamma-tocotrienol+I/R, resveratrol+gamma-tocotrienol+I/R. For resveratrol treatments, the rats were gavaged with resveratrol [2.5 mg/kg] for 15 days while for gamma-tocotrienol experiments the rats were gavaged with gamma-tocotrienol [0.3 mg/kg] for 30 days. For the combined resveratrol +gamma-tocotrienol experiments, the rats were gavaged with gamma-tocotrienol for 15 days, and then gavaging continued with resveratrol along with gamma-tocotrienol for a further period of 15 days. After 30, days, isolated perfused hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. Our results showed for the first time that at least in part, the cardioprotection (evidenced from the ventricular performance, myocardial infarct size and cardiomyocyte apoptosis) with resveratrol and gamma-toctrienol was achieved by their abilities to induce autophagy. Most importantly, resveratrol and gamma-tocotrienol acted synergistically providing greater degree of cardioprotection simultaneously generating greater amount of survival signal through the activation of Akt-Bcl-2 survival pathway. Autophagy was accompanied by the activation of Beclin and LC3-II as well as mTOR signaling, which were inhibited by either 3-methyl adenine (3-MA) or Wortmannin. The autophagy was confirmed from the results of transmission electron microscopy and light microscopy as well as with confocal microscopy. It is tempting to speculate that during ischemia and reperfusion autophagy along with enhanced survival signals helps to recover the cells from injury. PMID: 19799646 [Here synergism was again noted between tocotrienol and resveratrol.] Int J Oncol. 2008 Oct;33(4):851-9. Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Hsieh TC, Wu JM. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA. Numerous dietary phytochemicals have shown anti-breast carcinogenic activities when tested in vitro; however, in most cases, the demonstrated efficacy of individual phytochemicals requires doses not readily achievable in vivo. Therefore, whether diets might exert translational promises and benefits in clinical settings and prevention of breast cancer remain unclear. Since cancer cells are endowed with complex, redundant, converging and diverging pathways spanning both the genetic and metabolic networks that are not merely replicates of those in normal cells, it is of interest to test whether a multicomponent approach involving lower, physiologically relevant doses of natural dietary agents may be developed as a chemopreventive strategy for breast cancer. Herein, we investigated, using the estrogen receptor-positive MCF-7 breast cancer cells as a model, whether the combination of epigallocatechin gallate (EGCG), resveratrol and gamma-tocotrienol at suboptimal doses elicits synergism in suppressing cell proliferation, modulating gene expression, and increasing antioxidant activity, as compared to each of the three phytochemicals added alone. The results showed that there was a approximately 33, 50 and 58% inhibition of cell proliferation by > or =50 microM EGCG, > or =25 microM resveratrol and > or =10 microM gamma-tocotrienol, respectively, added as a single agent. When a suboptimal dose (10 microM) of each phytochemical was used, a significant additive effect in suppression of cell proliferation was observed with the combination of resveratrol and gamma-tocotrienol whereas the three phytochemicals added together did not produce more pronounced inhibition of cell proliferation. A significant additive effect in reducing cyclin D1 and bcl-2 expression was found when gamma-tocotrienol was added with either EGCG or resveratrol. Functional synergism among the three phytochemicals was only observed in the induction of quinone reductase NQO1. These results suggest that diet-based protection against breast cancer may partly derive from synergy amongst dietary phytochemicals directed against specific molecular targets in responsive breast cancer cells, and provide support for the feasibility of the development of a diet-based combinatorial approach in the prevention and treatment of breast cancer. PMID: 18813800 J Neurochem. 2009 Dec 17. [Epub ahead of print] Nanomolar vitamin E alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A(2) and causes neuroprotection. Khanna S, Parinandi NL, Kotha SR, Roy S, Rink C, Bibus D, Sen CK. Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210. ABSTRACT Our previous works have elucidated that the 12-lipoxygenase (12-Lox) pathway is directly implicated in glutamate-induced neural cell death, and that such that toxicity is prevented by nM concentrations of the natural vitamin E alpha-tocotrienol (TCT). In the current study we tested the hypothesis that phospholipase A(2) (PLA(2)) activity is sensitive to glutamate and mobilizes arachidonic acid (AA), a substrate for 12-Lox. Furthermore, we examined whether TCT regulates glutamate-inducible PLA(2) activity in neural cells. Glutamate challenge induced the release of [(3)H]AA from HT4 neural cells. Such response was attenuated by calcium chelators (EGTA and BAPTA), cPLA(2)-specific inhibitor (AACOCF(3)) as well as TCT at 250 nM. Glutamate also caused the elevation of free polyunsaturated fatty acid (AA and docosahexaenoic acid) levels and disappearance of PL-esterified AA in neural cells. Furthermore, glutamate induced a time-dependent translocation and enhanced serine phosphorylation of cPLA(2) in the cells. These effects of glutamate on fatty acid levels and on cPLA(2) were significantly attenuated by nM TCT. The observations that AACOCF(3), transient knock-down of cPLA(2) as well as TCT significantly protected against the glutamate-induced death of neural cells implicate cPLA(2) as a TCT-sensitive mediator of glutamate induced neural cell death. This work presents first evidence recognizing glutamate-induced changes in cPLA(2) as a novel mechanism responsible for neuroprotection observed in response to nanomolar concentrations of TCT. PMID: 20028458 [Below tocotreinols, but not alpha tocopherol suppress tissue damage.] Drug Chem Toxicol. 2009;32(4):319-25. Effect of tocotrienols on iron-induced renal dysfunction and oxidative stress in rats. Gupta A, Chopra K. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Ferric nitrilotriacetate (Fe-NTA) is a well-established nephrotoxic agent. This study was designed to investigate the modulatory effect of the subacute administration of tocotrienol-rich fraction (T3), a product from palm oil, and alpha-tocopherol (T) on Fe-NTA-induced renal injury and oxidative stress. Fe-NTA administration markedly increased blood urea nitrogen (BUN) and serum creatinine level, which was coupled with a marked lipid peroxidation, reduced activity of glutathione levels, and morphological alterations in rat kidney. Pretreatment with T3 (50 mg/kg/day) and T (50 mg/kg/day) for 7 days before Fe-NTA administration significantly reduced the serum creatinine and BUN levels, reduced lipid peroxidation in a significant manner, and restored levels of reduced glutathione and superoxide dismutase. T3 pretreatment also attenuated the serum tumor necrosis factor-alpha levels, as compared to pretreatment with T, and restored normal renal morphology. These findings suggest a strong correlation between iron-induced oxidative stress and renal dysfunction and point toward the protective effects of T3 in Fe-NTA-induced renal injury. PMID: 19793023 Eur J Appl Physiol. 2009 Nov;107(5):587-95. Epub 2009 Aug 25. Effects of tocotrienol-rich fraction on exercise endurance capacity and oxidative stress in forced swimming rats. Lee SP, Mar GY, Ng LT. Ping Tin Enterprise Co., Ltd., Kaohsiung, Taiwan. The present study aimed to examine the effects of tocotrienol-rich fraction (TRF) on exercise endurance and oxidative stress in forced swimming rats. Rats fed on isocaloric diet were orally given 25 (TRF-25) and 50 (TRF-50) mg/kg of TRF, or 25 mg/kg D-alpha-tocopherol (T-25) whilst the control group received only the vehicle for 28 days, followed by being forced to undergo swimming endurance tests, with measurements taken of various biochemical parameters, including blood glucose, lactate and urea nitrogen, glycogen, total antioxidant capacity, antioxidant enzymes, thiobarbituric acid-reactive substances (TBARS), and protein carbonyl. Results showed that the TRF-treated animals (268.0 +/- 24.1 min for TRF-25 and 332.5 +/- 24.3 min for TRF-50) swam significantly longer than the control (135.5 +/- 32.9 min) and T-25-treated (154.1 +/- 36.4 min) animals, whereas there was no difference in the performance between the T-25 and control groups. The TRF-treated rats also showed significantly higher concentrations of liver glycogen, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as of muscle glycogen and SOD than the control and the T-25-treated animals, but lower levels in blood lactate, plasma and liver TBARS, and liver and muscle protein carbonyl. Taken together, these results suggest that TRF is able to improve the physiological condition and reduce the exercise-induced oxidative stress in forced swimming rats. PMID: 19705143 Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=32320