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Is resveratrol's toxicity fully understood?

resveratrol inflammation david sinclair topical resveratrol stem cells

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#1 pleiotropic

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Posted 13 September 2015 - 06:03 AM


Resveratrol induces long-lasting IL-8 expression and peculiar EGFR activation/distribution in human keratinocytes: mechanisms and implications for skin administration

 

Abstract

Anti-inflammatory and skin tumour preventing effects of resveratrol have been extensively studied pre-clinically and resveratrol has been proposed for clinical investigations. To provide a basis or/and limitations for topical administration to human skin, molecular mechanisms underlying resveratrol effects towards normal human epidermal keratinocytes (NHEK) were evaluated. NHEK were challenged by either resveratrol alone or by its combination with TNFalpha or TGFalpha, and time-dependent molecular events were monitored. Interleukin 8 (IL-8) expression and its mRNA stability, ERK1/2, p65/RelA, and EGFR phosphorylation were determined. Intracellular distribution of EGFR/P-EGFR was measured in the membrane, cytoplasmic, and nuclear fractions. Specific DNA binding activity of NFκB (p65/RelA) and AP-1(c-Fos), NHEK proliferation, and molecular markers of apoptosis/cell cycle were detected. Resveratrol induced delayed, long-lasting and steadily growing IL-8 gene and protein over-expression as well as enhanced EGFR phosphorylation, both abrogated by the EGFR kinase inhibitor PD168393. However, resveratrol did not act as a phosphatase inhibitor. ERK phosphorylation was transiently inhibited at early time-points and activated at 6-24 h. Accordingly, c-Fos-specific DNA binding was increased by resveratrol. Cellular distribution of EGFR/P-EGFR was shifted to membrane and nucleus while cytosolic levels were reduced concomitant with enhanced degradation. Notwithstanding high nuclear levels of EGFR/P-EGFR, spontaneous and TGFalpha-triggered cell proliferation was strongly suppressed by resveratrol mainly through cell cycle arrest.

CONCLUSIONS/SIGNIFICANCE:

Resveratrol synergized with TNFα in the induction of delayed, long-lasting IL-8 expression through sustained EGFR-ERK axis activation. The time course indicates that resveratrol metabolites could be implicated. Topical administration of Resv to psoriatic patients over-expressing TNFα, IL-8 and EGFR-ERK in the skin should be cautiously considered. Since high nuclear levels of EGFR correspond to increased risk of tumorigenesis, chronic resveratrol application to the skin may be potentially dangerous. Wound healing acceleration by resveratrol could not be envisaged due to its anti-proliferative effects towards normal keratinocytes.

 

 

Resveratrol exerts dosage and duration dependent effect on human mesenchymal stem cell development.

 

Studies in the past have illuminated the potential benefit of resveratrol as an anticancer (pro-apoptosis) and life-extending (pro-survival) compound. However, these two different effects were observed at different concentration ranges. Studies of resveratrol in a wide range of concentrations on the same cell type are lacking, which is necessary to comprehend its diverse and sometimes contradictory cellular effects. In this study, we examined the effects of resveratrol on cell self-renewal and differentiation of human mesenchymal stem cells (hMSCs), a type of adult stem cells that reside in a number of tissues, at concentrations ranging from 0.1 to 10 µM after both short- and long-term exposure. Our results reveal that at 0.1 µM, resveratrol promotes cell self-renewal by inhibiting cellular senescence, whereas at 5 µM or above, resveratrol inhibits cell self-renewal by increasing senescence rate, cell doubling time and S-phase cell cycle arrest. At 1 µM, its effect on cell self-renewal is minimal but after long-term exposure it exerts an inhibitory effect, accompanied with increased senescence rate. At all concentrations, resveratrol promotes osteogenic differentiation in a dosage dependent manner, which is offset by its inhibitory effect on cell self-renewal at high concentrations. On the contrary, resveratrol suppresses adipogenic differentiation during short-term exposure but promotes this process after long-term exposure. Our study implicates that resveratrol is the most beneficial to stem cell development at 0.1 µM and caution should be taken in applying resveratrol as an anticancer therapeutic agent or nutraceutical supplement due to its dosage dependent effect on hMSCs.

 

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These are just two studies I've seen so far that would suggest resveratrol is not completely benign.  One might also question whether related molecules have the same issues but are under-researched.  Can we reconcile these with 1g doses taken by those such as David Sinclair?   Thanks in advance for your thoughts.


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#2 niner

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Posted 14 September 2015 - 04:41 AM

Ignore any in vitro (test tube) results at concentrations greater than about 1 micromolar (µM) as you are unlikely to see such levels in vivo.  Resveratrol does in fact have a lot of effects.  It's a very promiscuous compound.



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#3 2tender

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Posted 23 October 2015 - 11:26 AM

I just wanted to mention I used the highest quality liquified resveratrol capsules available, daily for over a year, I did'nt catch any colds or flu even though I was in close contact with the general public, daily, I lost quite a bit of fat as well. However, as a weightlifter, endeavoring to gain and maintain enlarged muscle appearance, it did'nt enhance that at all. I did'nt experience any toxicity, even though I was using other supps. I stopped using it because it was too expensive, weight loss, and it's effects were contrary to my weight training goals. I hope that is helpful to someone here.


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