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Silymarin activates SIRT1 3-5 fold in vitro


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#1 Fredrik

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Posted 19 June 2007 - 12:49 PM


This was posted on the calorie restriction mailing list:

Li LH, Wu LJ, Tashiro SI, Onodera S, Uchiumi F, Ikejima T.

Activation of the SIRT1 pathway and modulation of the cell cycle were
involved in silymarin's protection against UV-induced A375-S2 cell
apoptosis.

J Asian Nat Prod Res. 2007 Apr-May;9(3):245-52.
PMID: 17566917

Abstract

Silymarin, derived from the milk thistle plant, Silybum marianum, has been
traditionally used in the treatment of liver disease. Our previous study
demonstrated that silymarin has an anti-apoptotic effect against UV
irradiation.

In this study, SIRT1, a human deacetylase that was reported to promote cell
survival, was activated by silymarin (5 × 10^-4 mol/L) in UV-irradiated
human malignant melanoma, A375-S2 cells, followed by down-regulated
expression of Bax and decreased release of cytochrome c. Cleavage of
procaspase-3 and digestion of its substrates, the inhibitor of
caspase-activated DNase (ICAD) and poly(ADP-ribose) polymerase (PARP), were
also reduced. Consistent with its protective effect on UV-induced apoptosis,
silymarin (5 × 10^-4 mol/L) also increased G2/M phase arrest, possibly
providing a prolonged time for efficient DNA repair.

Consequently, that silymarin protected A375-S2 cell against UV-induced
apoptosis was partially through SIRT1 pathway and modulation of the cell
cycle distribution.

Keywords: Silymarin; A375-S2 cell; UV irradiation; Anti-apoptosis; SIRT1;
Cell cycle arrest

... Here, we found that silymarin's inhibitory mechanism on UV-induced
A375-S2 cell apoptosis has a relationship with SIRT1, a member of the
conserved sirtuin family of nicotinamide adenine dinucleotide
(NAD+)-dependent deacetylases, which is a key regulator of cell defences and
survival in response to a variety of stresses 4-6 ...

2. Results and discussion

2.1 Silymarin protected A375-S2 cells against UV-induced cell death

Table 1 shows the viability ratio of A375-S2 cells, which were treated with
various concentrations of silymarin for 1 h and then further incubated for
12 h after UV irradiation. It was found that silymarin protected
UV-irradiated A375-S2 cells from death in a dose-dependent manner (cell
viability ratio was increased to 92.5% at the concentration of 5 × 10^-4
mol/L) and that it had no cytotoxic effect on the cells.

Table 1. Protective effect of silymarin on cell viability in
UV-irradiated A375-S2 cells (%).
===================================
Silymarin (mol/L)---Cell viability (%)
----UV irradiation Without UV irradiation
===================================
0 18.2±3.4 100.0±2.8
1 × 10^-5 17.8±2.6 100.3±2.4
5 × 10^-5 18.9±4.3 98.5±3.7
1 × 10^-4 28.3±2.5 103.1±1.6
2 × 10^-4 34.7±4.2 105.7±4.9
3 × 10^-4 45.6±1.6 105.4±4.1
4 × 10^-4 69.7±3.8 107.3±6.2
5 × 10^-4 92.5±5.6** 103.5±3.1
===================================
Mean±SD, n = 3.
**P < 0.01 vs 0 mol/L.

2.2 Silymarin reversed UV irradiation-induced morphologic changes in A375-S2
cells

In response to cellular insults, cells attempt to repair and defend
themselves, but if unsuccessful, they often undergo programmed cell death,
or apoptosis. Therefore, in order to determine whether silymarin protected
A375-S2 cells against UV-induced cell death through anti-apoptotic pathway,
the morphologic changes were observed. When A375-S2 cells were cultured for
12 h after UV irradiation, marked morphologic changes were observed as
compared with the untreated control (figure 2a,c). The majority of cells
became round, and some of these cells showed membrane blebbing (figure 2c),
which were hallmarks of apoptosis, while silymarin pre-treatment (5 × 10^-4
mol/L) reversed these morphologic changes (figure 2d).

2.3 The expression of SIRT1 was up-regulated in UV-irradiated A375-S2 cells
after silymarin pre-treatment

SIRT1 play an important role in cell defences and survival in response to
stress 4-6. To investigate whether SIRT1 might be responsible for the
ability of silymarin to protect A375-S2 cells from UV-induced apoptosis, the
expression of SIRT1 was examined by Western blot analysis, which was found
to be markedly up-regulated by silymarin (5 × 10^-4 mol/L) in UV-irradiated
A375-S2 cells as compared to that of silymarin-untreated cells (figure 3),
suggesting that silymarin's protection against UV irradiation might be
through SIRT1 pathway.

2.4 The protein expressions involved in SIRT1 pathway

Since up-regulated SIRT1 activity [6] could deacetylate the DNA repair
factor Ku70, causing it to sequester the proapoptotic factor Bax away from
the outer mitochondrial membrane to the cytoplasm, forming a complex with
Ku70, the subsequent release of cytochrome c was inhibited as the result of
Bax protein relocalisation. Downstream events including caspase activation
and cleavage of ICAD and PARP were attenuated, thereby inhibiting
stress-induced apoptotic cell death. In our study, it was found that the
expression of Bax and release of cytochrome c from mitochondria were
attenuated in UV-irradiated A375-S2 cells after silymarin pre-treatment
(figure 3). Cleavage of procaspase-3 to caspase-3 (figure 4) and digestion
of its substrates, ICAD and PARP, were also inhibited subsequently (figure
5).

2.5 The effect of silymarin on UV-induced cell cycle modulation

Cell cycle progression is important for maintaining homeostasis, especially
when there is an insult to DNA [12,13]. Physiological stress or an insult to
DNA could cause arrest in different stages of the cell cycle. Since UV
irradiation is known to damage DNA directly, the effect of UV irradiation
and silymarin pre-treatment on cell cycle progression was assessed. It was
found that UV exposure caused a S arrest (29.62 versus 16.00% in control) at
the expense of a decrease in G2/M phase cells (0 versus 7.86% in control)
(figure 6a,c, table 2). Pre-treatment with silymarin (5 × 10^-4 mol/L),
however, reversed the UV-induced S arrest, resulting in an increase in G2/M
phase cells (7.45% in silymarin+UV versus 0 in UV alone) (figure 6c,d, table
2). In general, an arrest in G2/M phase of the cell cycle allows cells more
time to repair damaged DNA before mitosis (M phase), until the damage of the
genome is repaired. Since silymarin treatment resulted in an accumulation of
UV-irradiated cells at G2/M phase, part of the protective effect of
silymarin against UV-induced apoptosis might be due to its effect on cell
cycle distribution. However, detailed studies remain to be conducted to
delineate the molecular mechanism involved in this action of silymarin. In
addition, apoptotic sub-G0/G1 phase peak, caused by UV irradiation, was
reduced obviously by silymarin pre-treatment (figure 6c,d).

Table 2. Effects of silymarin on cell cycle distribution (%).
==============================================
Group---Cell phage (%)
---G0/G1 S G2/M
==============================================
Medium control 76.14 16.00 7.86
Silymarin (5 × 10^-4 mol/L) 75.60 16.45 7.95
UV irradiation (52.1 J/m2) 70.38 29.62 0
Silymarin (5 × 10^-4 mol/L)+UV irradiation (52.1 J/m2) 76.39 16.16 7.45

In conclusion, silymarin promoted UV-irradiated A375-S2 cell survival partly
through SIRT1 pathway. It also modulated the distribution of the cell cycle
to allow more time for the damaged cells to repair. Present results may
broaden silymarin's potential therapy use for many diseases in the future.
[B]

Edited by fredrik, 19 June 2007 - 01:49 PM.


#2 lucid

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Posted 19 June 2007 - 01:12 PM

If this is capable of achieving CR effects that would be awesome where as Silymarin is much cheaper than tresv.
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#3 maxwatt

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Posted 19 June 2007 - 02:37 PM

If this is capable of achieving CR effects that would be awesome where as Silymarin is much cheaper than tresv.


It's less well studied. Silymarin composes about 80% of a good grade of commercial milk thistle extract. Silimarin is composed of three substances, about 60% of Silymarin constists of Silibin; this is the ingredient thought to activate SIRT1; it is similar to fisetin in structure. Fisetin is half as effective by weight at activating SIRT1 as resveratrol (one of the Sinclair studies if you want to search for it.) The other substances in Silymarin have not been tested for SIRT1 activation.

My wife gets diarrhea from even the 98% resveratrol I import (and test), and to the synthetic Paul Wakfer helped obtain. It is the resveratrol itself, not the emodin or other impurities that cause this, but she has no problem with Silymarin.

You can buy capsules containing 175 mg of 80% Silymarin extract (140 mg of actual Silymarin.) This in turn is about 60% Silibin, or 84 mg of Silibin. It is perhaps equivalent to 42 mg of resveratrol. Lets be optimistic, and assume the other substances also activate SIRT1 to some degree, or the activation is slightly better than the 50% equivalent of resveratrol. That would make one capsule equivalent to about 50 mg of resveratrol. My wife takes 6 capsules a day. for an equivalent to about 300 mg of resveratrol.

The cost is $17 for 100 capsules (lower cost than most) which works out to approximately (click click click) $3.40 a gram. This is not so inexpensive as some of the high strength resveratrol products on the market, but it may be easier on some people's guts. If you have this problem, try a 98% resveratrol extract. If you still have a problem, maybe Silimarin is your best option. If my wife could "stomach" resveratrol, I'd prefer she use it.

Caveat: there are seven sirtuin genes, including SIRT1. The are activated to different degrees by the various known sirtuin agonists, including resveratrol. Silymarin has not been shown to increase lifespan in eukarotes, much less in vertebrates, as resveratrol has been shown to do. Silymarin is the only proven antidote to amanita muchroom poisoning. (Intravenous transfusion.) It prevents the damage to the liver from the amatoxins, which causes death or the need for a liver transplant. It is thought to work by reducing apoptosis, and its action on p53 de-acetylase, effects also shown by resveratrol in vitro in numerous studies.

(spelling corrections)

Edited by maxwatt, 20 June 2007 - 02:23 AM.


#4 bixbyte

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Posted 19 June 2007 - 09:53 PM

If this is capable of achieving CR effects that would be awesome where as Silymarin is much cheaper than tresv.


It's less well studied. Silymarin composes about 80% of a good grade of commercial milk thistle extract. Silimarin is composed of three substances, about 60% of Silymarin constists of Silibin; this is the ingredient thought to activate SIRT1; it is similar to fisetin in structure. Fisetin is half as effective by weight at activating SIRT1 as resveratrol (one of the Sinclair studies if you want to search for it.) The other substances in Silymarin have not been tested for SIRT1 activation.

My wife gets diarrhea from even the 98% resveratrol I import (and test), and to the synthetic Paul Wakfer helped obtain. It is the resveratrol itself, not the emodin or other impurities that cause this, but she has no problem with Silymarin.

You can buy capsules containing 175 mg of 80% Silymarin extract (140 mg of actual Silymarin. This in turn is about 60% Silibin, or 84 mg of Silibin. It is perhaps equivalent to 42 mg of resveratrol. Lets be optimistic, and assume the other substances also activate SIRT1 to some degree, or the activation is slightly better than the 50% equivalent of resveratrol. That would make one capsule equivalent to about 50 mg of resveratrol. My wife takes 6 capsules a day. for an equivalent to about 300 mg of resveratrol.

The cost is $17 for 100 capsules (lower cost than most) which works out to approximately (click click click) $3.40 a gram. This is not so inexpensive as some of the high strength resveratrol products on the market, but it may be easier on some people's guts. If you have this problem, try a 98% resveratrol extract. If you still have a problem, maybe Silimarin is your best option. If my wife could "stomach" resveratrol, I'd prefer she use it.

Caveat: there are seven sirtuin genes, including SIRT1. The are activated to different degrees by the various known sirtuin agonists, including resveratrol. Silymarin has not been shown to increase lifespan in eukarotes, much less in vertebrates, as resveratrol has been shown to do. Silymarin is the only proven antidote to amanita muchroom poisoning. (Intravenous transfusion.) It prevents the damage to the liver frin the amatoxins, which causes death or the need for a liver transplant. It is thought to work by reducing apoptosis, and its action on p53 de-acetylase, effects a;sp shown by resveratrol in vitro in numerous studies.



Hi Max,

Can one take RSV in combination with Silymarin?
What would be the optimal dosages?

Alex

#5 health_nutty

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Posted 19 June 2007 - 10:24 PM

Thanks for the post, good stuff as always...

#6 maxwatt

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Posted 19 June 2007 - 11:47 PM

Hi Max,

Can one take RSV in combination with Silymarin?
What would be the optimal dosages?

Alex


(I see you enjoy playing with html....)

I do not know the answer to your question; no one does. I took Silymarin for it's SIRT1 activating properties before I had a reliable supply of 98% resveratrol, (which I can get much more cheaply than Silymarin capsules) and noted it produced some of the same effects I noted with both resveratrol and Fo Ti (which contains a resveratrol analogue.) The first effect was reduced sensitivity to cold. The second effect ws a feeling of well being and increased energy, which became less pronounced over time; not because the supplement lost effectiveness, but because I became used to the feeling and took it for granted.

My estimates of relative dose effectiveness of resveratrol vs. silymarin are guess work. I believe they are accurate within 50%.

For a while I took resveratrol in the morning, and silymarin in the evening. I noticed no particular benefit or ill effect with the combination. I stopped when I increased my dose of resveratrol, and did not wish to take a higher concomitant dose of silymarin. I was taking enough capsules as it was.

Bulk Silimarin would be less espensive than bulk resveratrol, but there are problems obtaining proper purity-- testing is needed -- and we are only speculating it has life-extending properties; resveratrol is much better researched.

As for resveratrol becoming much cheaper, the cost is limited by the cost of energy and chemicals needed to extract it, which is done by HPLC. I think the peasants who harvest knotweed in China get 25 cents for 1000 kilos. The cost of the refined product will not drop by more than 50%, if that much. When it does, I don't expect the bottlers to pass on the savings. They have other costs: bottles, pills, distribution and advertising.

#7 bixbyte

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Posted 20 June 2007 - 01:43 AM


Hi Max,

Can one take RSV in combination with Silymarin?
What would be the optimal dosages?

Alex


(I see you enjoy playing with html....)

I do not know the answer to your question; no one does. I took Silymarin for it's SIRT1 activating properties before I had a reliable supply of 98% resveratrol, (which I can get much more cheaply than Silymarin capsules) and noted it produced some of the same effects I noted with both resveratrol and Fo Ti (which contains a resveratrol analogue.) The first effect was reduced sensitivity to cold. The second effect ws a feeling of well being and increased energy, which became less pronounced over time; not because the supplement lost effectiveness, but because I became used to the feeling and took it for granted.

My estimates of relative dose effectiveness of resveratrol vs. silymarin are guess work. I believe they are accurate within 50%.

For a while I took resveratrol in the morning, and silymarin in the evening. I noticed no particular benefit or ill effect with the combination. I stopped when I increased my dose of resveratrol, and did not wish to take a higher concomitant dose of silymarin. I was taking enough capsules as it was.

Bulk Silimarin would be less espensive than bulk resveratrol, but there are problems obtaining proper purity-- testing is needed -- and we are only speculating it has life-extending properties; resveratrol is much better researched.

As for resveratrol becoming much cheaper, the cost is limited by the cost of energy and chemicals needed to extract it, which is done by HPLC. I think the peasants who harvest knotweed in China get 25 cents for 1000 kilos. The cost of the refined product will not drop by more than 50%, if that much. When it does, I don't expect the bottlers to pass on the savings. They have other costs: bottles, pills, distribution and advertising.


MAX,

Two molecules with the ability to stop P53; adds the SIRT 1
More of the same, with the UV shielding effect?
Maybe a little silymarin would be synergistic.
If you can take it at night losing the Congestion and Serotonin uptake from RSV.

I'll go order a 100 caps for testing purposes.
Just my own thoughts.

Alex
(purple is cool)

#8 maxwatt

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Posted 20 June 2007 - 02:40 AM

MAX,

Two molecules with the ability to stop P53; adds the SIRT 1
More of the same, with the UV shielding effect?
Maybe a little silymarin would be synergistic.
If you can take it at night losing the Congestion and Serotonin uptake from RSV.

I'll go order a 100 caps for testing purposes.
Just my own thoughts.

Alex
(purple is cool)


It is possible they are synergistic, perhaps from differentially activating different kinds of Sirtuin genes; one might be more effective in the mitochondria, the other in the nucleus.... not that they are necessarily, just how they might be more beneficial in combination than either one alone. But we are only guessing.

I can get you bulk silymarin for $60 a kilogram. Dirt cheap compared to resveratrol. I'd need to order 100 kilos unless I could get sample quantities.

Edited by maxwatt, 20 June 2007 - 11:23 AM.


#9 edward

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Posted 20 June 2007 - 12:21 PM

Very very interesting. I have been taking large doses of Silymarin for a long time, simply because it has some great effects as a general antioxidant, great support for the liver and liver enzymes. This makes it even more attractive, very cool, thanks for the info.

#10 edward

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Posted 20 June 2007 - 12:24 PM

I'd love to find some in vivo studies with dosages.

Maxwatt, how did you arrive at your dosage rationale i.e. 50% of the activity of T-Resveratrol per milligram of actual Silibin?

#11 maxwatt

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Posted 20 June 2007 - 01:53 PM

I'd love to find some in vivo studies with dosages.

Maxwatt, how did you arrive at your dosage rationale i.e. 50% of the activity of T-Resveratrol per milligram of actual Silibin?


I thought I explained it in my post; it's based on the approximate amount of silibin in the silymarin extract, and the fact silibin is very similar to fisetin, and fisetin is about half as effective as resveratrol byweight at activating SIRT1 (from ome of Sinclair's papers.) Not a sloid chain of inverences, but the best I could come up with in the absence of any direct studies. I believe it's correct within an order of magnitude ;)

#12 lucid

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Posted 20 June 2007 - 02:19 PM

Well another thing we know is that resveratrol has horrible bioavailabilty and an extremely short halflife (especially initially, halflife slows down as resv builds up in the liver). So if there was another way to mimic cr it could be ideal. Lots of studies are needed...

#13 bixbyte

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Posted 20 June 2007 - 02:46 PM


MAX,

Two molecules with the ability to stop P53; adds the SIRT 1
More of the same, with the UV shielding effect?
Maybe a little silymarin would be synergistic.
If you can take it at night losing the Congestion and Serotonin uptake from RSV.

I'll go order a 100 caps for testing purposes.
Just my own thoughts.

Alex
(purple is cool)


It is possible they are synergistic, perhaps from differentially activating different kinds of Sirtuin genes; one might be more effective in the mitochondria, the other in the nucleus.... not that they are necessarily, just how they might be more beneficial in combination than either one alone. But we are only guessing.

I can get you bulk silymarin for $60 a kilogram. Dirt cheap compared to resveratrol. I'd need to order 100 kilos unless I could get sample quantities.



Max,

Could I cap them together?
Make a cap with 98% and Sily as a longevity formula.

(I am into colors today)


Alex

#14 health_nutty

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Posted 20 June 2007 - 08:39 PM

Very very interesting. I have been taking large doses of Silymarin for a long time, simply because it has some great effects as a general antioxidant, great support for the liver and liver enzymes. This makes it even more attractive, very cool, thanks for the info.


What dosage do you take?

#15 maxwatt

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Posted 20 June 2007 - 10:23 PM

Silymarin and resveratrol differ in their effects on fasting blood glucose. Silymarin reduces fasting glucose:

Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M.

The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial.
Phytother Res. 2006 Dec;20(12):1036-9.
PMID: 17072885

".....The results showed a significant decrease in HbA(1)c, FBS [Fasting Blood Glucose], total cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients compared with placebo as well as with values at the beginning of the study in each group. In conclusion, silymarin treatment in type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile.


Resveratrol has shown a positive effect on lipid profiles, but not on fasting blood glucose, though it may improve insulin sensitivity.

I think Bixbyte's plan to combine resveratrol and silymarin is feasible, though I don't think it need be in the same capsule. Serum levels of resveratrol fall to nil about four hours after administration. One could take resveratrol in the morning, and silymarin in the evening on the off chance this will eliminate any unfavorable interaction between them. And one could take them at the same time to see if any interference is noticed, or if a synergistic effect seems to appear. Of course, it will be difficult to tease out any effects with a sample size of one.

#16 lucid

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Posted 20 June 2007 - 10:33 PM

Resveratrol has shown a positive effect on lipid profiles, but not on fasting blood glucose, though it may improve insulin sensitivity.

Sirtris' srt-501 advertises that it decreases blood glucose levels and increases insulin levels.

#17 maxwatt

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Posted 20 June 2007 - 11:02 PM

Sirtris' srt-501 advertises that it decreases blood glucose levels and increases insulin levels.


What, besides resveratrol, is in the formulation?

There are no human studies in pub med showing an effect on fasting glucose. There arei n vitro studies showing increased glucose uptake in cells, but nothing published so far that shows a reduction if fasting glucose. As I noted no such decrease in my own glucose levels, I suspect there won't be a simple relationship.

#18 lucid

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Posted 20 June 2007 - 11:46 PM

Well the roadshow is taken down, so I can't review it and I can't find their trial results @ their website, but:
http://findarticles...._1/ai_n16852623

Activation of SIRT1 is believed to be a key pathway by which resveratrol regulates such processes as glucose and insulin production, fat metabolism, and cell survival.

In their presentation, they do say patients in one of their phase II trial had decreased blood glucose levels, I would be interesting to see the source, but as I said I can't find it, Ill check it later.

#19 inawe

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Posted 21 June 2007 - 12:06 AM

Taking 800 mgr/day of resveratrol I haven't seen a decrease in my blood glucose. But I read that Sirtris is running clinical trials on diabetics (or pre-diabetics?) using 2.5-5 gr/day. Also in combination with metformin. So they must have a hint that at high dosage it does have an effect on glucose. Unless they are planning to adjudicate the effect of metformin on their product.

#20 bixbyte

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Posted 21 June 2007 - 02:53 AM

Well the roadshow is taken down, so I can't review it and I can't find their trial results @ their website, but:
http://findarticles...._1/ai_n16852623

In their presentation, they do say patients in one of their phase II trial had decreased blood glucose levels, I would be interesting to see the source, but as I said I can't find it, Ill check it later.


Lucid,

What trial results?
I would be careful buying stock of any biotech company.
The tests are designed for phase 1 and then go up the ladder if the success of the pharmaceutical products warrant more studies.
At each phase 95% of the meds fail and 5% move up the ladder to the next phase.
So far Sirtris has had a $38 million burn rate and sold ~6 million shares for (-+)10 bucks so I am guessing their burn rate would require another tender offer for paying for many more additional tests at two more future dates going forward.
In my opinion you have to spend more than $100 million to pass Phase III.
I have been invested in biotechs for at least 30 years.
I generally buy biotechs when they are around a buck or two.
Chinese medicine is over 2,000 years old and anyone can buy some RSV at a health food store.


Invest at your own risk.

Alex


#21 mirian

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Posted 21 June 2007 - 03:00 AM

I'm anxious for that NCE-1 Sirtris made. It's 2 to 3 times more effective than resveratrol at activating SIRT1.

Even, if it's $5 a pill daily that would be worth it. Only of course they show it's safe.

Edited by mirian, 21 June 2007 - 05:37 AM.


#22 bixbyte

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Posted 21 June 2007 - 03:10 AM

I'm anxious for that NCE-1 Sirtris made. It's 2 to 3 times more efffective than resveratrol at activating SIRT1.

Even if it's $5 a pill daily that would be worth it. Only of course they show it's safe.



Mirian,

In order for Sirtris to pass FDA phase III drug trials you might have to wait 10 years.
This is for a Pill that is 2 to 3 X more effective than standard RSV I can purchase at a health Food store?



Alex

#23 mirian

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Posted 21 June 2007 - 05:39 AM

No, it's 2 to 3 times more effective than the SRT501 resveratrol Sirtris is using which is a proprietary trans resveratrol with that Sirtris developed to increase blood levels far better than any dietary supplements containing resveratrol.

But, even then their resveratrol being SRT501 only activated SIRT1 by 200+%. Sirtris New Chemical Entities-1 (NCE-1) activates by 707% no comparison:

Read the 15th one down:

http://www.revgenetics.com/sirtis.htm

Edited by mirian, 21 June 2007 - 05:54 AM.


#24 curious_sle

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Posted 21 June 2007 - 09:44 PM

Resveratrol has shown a positive effect on lipid profiles, but not on fasting blood glucose, though it may improve insulin sensitivity.


You might be interested in this:

Eur J Pharmacol. 2007 May 22; [Epub ahead of print]

Resveratrol enhances insulin secretion by blocking K(ATP) and K(V)
channels of beta cells.

Chen WP, Chi TC, Chuang LM, Su MJ.

Institute of Pharmacology, National Taiwan University Medical College,
Taipei, Taiwan.

The present study investigated the effect of resveratrol on the
electrophysiology and insulin secretion of pancreatic beta cells, and
examined resveratrol-induced alterations in insulin levels and plasma
glucose of normal and streptozotocin-induced diabetic rats. Whole-cell
voltage clamp study in the MIN6 cell, a mouse beta cell line, revealed
that resveratrol significantly inhibited ATP-sensitive K(+) current at
3 mumol/l, and voltage-gated K(+) currents at 30 mumol/l. Ca(2+)-
activated K(+) current was activated by resveratrol at 100 mumol/l. In
MIN6 cells stained with membrane potential dye DiBAC(4)(5),
resveratrol markedly depolarized membrane potential at the
concentrations of 3-100 mumol/l. Insulin secretion was increased in
the presence of resveratrol in MIN6, Hit-T15, and RIN-m5F cells.
Resveratrol (3 mg/kg, i.p.) increased insulin secretion associated
with a lowering in plasma glucose in normal rats, but not in
streptozotocin-diabetic rats within the initial 60 min. In conclusion,
resveratrol can act as an insulin-secretagogue through I(KATP) and
I(KV) inhibition which can contribute to plasma glucose lowering
effect in normal rats.

PMID: 17573071 [PubMed - as supplied by publisher]

#25 maxwatt

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Posted 21 June 2007 - 10:36 PM

Resveratrol has shown a positive effect on lipid profiles, but not on fasting blood glucose, though it may improve insulin sensitivity.


You might be interested in this:

Eur J Pharmacol. 2007 May 22; [Epub ahead of print]

Resveratrol enhances insulin secretion by blocking K(ATP) and K(V)
channels of beta cells.

Chen WP, Chi TC, Chuang LM, Su MJ.

Institute of Pharmacology, National Taiwan University Medical College,
Taipei, Taiwan.
....[snip]....
In conclusion,
resveratrol can act as an insulin-secretagogue through I(KATP) and
I(KV) inhibition which can contribute to plasma glucose lowering
effect in normal rats.

PMID: 17573071 [PubMed - as supplied by publisher]


I saw this. It shows improved insulin sensitivity, but not an effect on fasting blood glucose. :(

#26 maxwatt

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Posted 21 June 2007 - 10:51 PM

No, it's 2 to 3 times more effective than the SRT501 resveratrol Sirtris is using which is a proprietary trans resveratrol with that Sirtris developed to increase blood levels far better than any dietary supplements containing resveratrol.

But, even then their resveratrol being SRT501 only activated SIRT1 by 200+%. Sirtris New Chemical Entities-1 (NCE-1) activates by 707% no comparison:

Read the 15th one down:

http://www.revgenetics.com/sirtis.htm


In another thread, by analysis of Sirtris' patent applications., several members concluded that:

1. SRT501 is micronized resveratrol combined with an excipient, specifically Tween, or polysorbate 80
2. PEG 3325 is equally effective as an excipient, is sold over-thecounter as Miralax, a laxative, but the laxative dose at 17 grams is much higher than the amount needed to solublize the resveratrol; also PEG3325 tastes better than polysorbate 80. **
3. Sirtris' lead NCE is most probably acetylated trans-resveratrol.

Now, back to Silymarin: It can be purchased in bulk for under $100/kg, 80% standardized extract. It compares favorably with 50% resveratrol in price. It probably has some favorable effects on fasting glucose that resveratrol does not have. My conclusion is that it is a good idea to take both substances. I also think metformin added to the regimen will have additional CR mimetic effects.


* Directions for making your own resveratrol formulation with improved bioavailability using PEG3325 are available on request. Email or PM me.

#27 inawe

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Posted 21 June 2007 - 10:57 PM

Actually, according to PMID: 17573071, instead of having an effect on insulin sensitivity, resveratrol acts as a insulin secretagogue (which is not as good).

On the other hand, this is contradicted by "Resveratrol-induced inhibition of insulin secretion from rat pancreatic islets: evidence for pivotal role of metabolic disturbances" (PMID: 17578889 [PubMed - as supplied by publisher]).

The situation of resveratrol vs. insulin/glucose is rather confusing. Let's hope the Sirtris trials clear this up.

#28 edward

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Posted 22 June 2007 - 02:59 PM

Very very interesting. I have been taking large doses of Silymarin for a long time, simply because it has some great effects as a general antioxidant, great support for the liver and liver enzymes. This makes it even more attractive, very cool, thanks for the info.


What dosage do you take?


Up until reading this thread and considering higher dosages I have been taking 800 mg of Milk Thistle (standardized for 80% silymarin). 400 mg in the AM and 400 mg in the afternoon. I'm considering upping this due to the SIRT activation.

#29 pycnogenol

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Posted 22 June 2007 - 03:35 PM

Question: Is Silybin Phytosome (one part silymarin bound to two parts
phosphatidylcholine) the one to take or will plain silymarin extract work
just as well?

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#30 bixbyte

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Posted 23 June 2007 - 12:54 AM

No, it's 2 to 3 times more effective than the SRT501 resveratrol Sirtris is using which is a proprietary trans resveratrol with that Sirtris developed to increase blood levels far better than any dietary supplements containing resveratrol.

But, even then their resveratrol being SRT501 only activated SIRT1 by 200+%. Sirtris New Chemical Entities-1 (NCE-1) activates by 707% no comparison:

Read the 15th one down:

http://www.revgenetics.com/sirtis.htm


In another thread, by analysis of Sirtris' patent applications., several members concluded that:

1. SRT501 is micronized resveratrol combined with an excipient, specifically Tween, or polysorbate 80
2. PEG 3325 is equally effective as an excipient, is sold over-thecounter as Miralax, a laxative, but the laxative dose at 17 grams is much higher than the amount needed to solublize the resveratrol; also PEG3325 tastes better than polysorbate 80. **
3. Sirtris' lead NCE is most probably acetylated trans-resveratrol.

Now, back to Silymarin: It can be purchased in bulk for under $100/kg, 80% standardized extract. It compares favorably with 50% resveratrol in price. It probably has some favorable effects on fasting glucose that resveratrol does not have. My conclusion is that it is a good idea to take both substances. I also think metformin added to the regimen will have additional CR mimetic effects.


* Directions for making your own resveratrol formulation with improved bioavailability using PEG3325 are available on request. Email or PM me.



Max,


Since SRT501 might in fact be a basically better absorbable version of Knotweed.
Acetylating a RSV chain sounds like a very simple college chem reaction.
Why would Sirtris hire about 29 PhDs if your supposition is near correct?
I don't get it.


Alex




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