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