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Resveratrol Is a Nonselective Phosphodiesterase Inhibitor

should we be concerned?

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#1 trance

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Posted 04 February 2012 - 11:11 PM


In a recent Science Daily article outlining a new paper in Cell (Cell 148, 421–433, February 3, 2012) journal, expresses concerns about the possible toxicity of resveratrol impacting unknown protein synthesis in the body.

http://www.scienceda...20202151133.htm

"Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use."



Should we be concerned?

I have attached the actual article from Cell journal below.



#2 bixbyte

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Posted 05 February 2012 - 01:35 AM

In a recent Science Daily article outlining a new paper in Cell (Cell 148, 421–433, February 3, 2012) journal, expresses concerns about the possible toxicity of resveratrol impacting unknown protein synthesis in the body.

http://www.scienceda...20202151133.htm

"Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use."



Should we be concerned?

I have attached the actual article from Cell journal below.


_______________________________________________

NOTE: This Mice study tested the Medication Rolipram some was a Resveratrol Medication Study.


SUMMARY
Resveratrol, a polyphenol in red wine, has been reported
as a calorie restriction mimetic with potential
antiaging and antidiabetogenic properties. It is
widely consumed as a nutritional supplement, but
its mechanism of action remains a mystery. Here,
we report that the metabolic effects of resveratrol
result from competitive inhibition of cAMP-degrading
phosphodiesterases, leading to elevated cAMP
levels. The resulting activation of Epac1, a cAMP
effector protein, increases intracellular Ca2+ levels
and activates the CamKKb-AMPK pathway via phospholipase
C and the ryanodine receptor Ca2+-release
channel. As a consequence, resveratrol increases
NAD+ and the activity of Sirt1. Inhibiting PDE4 with
rolipram reproduces all of the metabolic benefits of
resveratrol, including prevention of diet-induced
obesity and an increase in mitochondrial function,
physical stamina, and glucose tolerance in mice.

Therefore, administration of PDE4 inhibitors may
also protect against and ameliorate the symptoms
of metabolic diseases associated with aging.

Edited by bixbyte, 05 February 2012 - 02:09 AM.


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#3 bixbyte

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Posted 05 February 2012 - 02:16 AM

Resveratrol Is a Nonselective Phosphodiesterase Inhibitor
The intracellular levels of cAMP are determined by the activities
of ACs, which synthesize cAMP from ATP, and cyclic nucleotide
PDEs, which hydrolyze cAMP or cGMP to AMP or GMP, respectively.
We measured the effect of resveratrol on the activities of
representatives of all three major subclasses of mammalian
ACs. As shown in Figure S3A, resveratrol had no effect on AC
activity, either in the basal state or in the activated state, suggesting
that resveratrol increases cAMP levels by inhibiting PDEs.
The PDE superfamily is comprised of 11 types of PDEs
(PDE1–11) of which multiple isoforms exist. PDEs have different
substrate specificities: PDEs 4, 7, and 8 are cAMP-selective
hydrolases, PDEs 5, 6, and 9 are cGMP-selective hydrolases,
and PDEs 1, 2, 3, 10, and 11 can hydrolyze both cAMP and
cGMP to varying degrees. Multiple members of the PDE superfamily
are usually expressed in each cell. We measured the activities
of recombinant PDEs 1, 2, 3, 4, and 5 in the presence
________

of resveratrol. We found that resveratrol inhibited PDE1
(IC50 6 mM), PDE3 (IC50 10 mM), and PDE4 (IC50 14 mM)
but did not affect the activity of PDEs 2 or 5 (Figure 4A).
To determine how resveratrol inhibits PDEs, we measured the
effect of cAMP and resveratrol on the kinetics of recombinant
PDE3 activity (Figure 4B). At high concentrations of cAMP, the
inhibitory effect of resveratrol on PDE3 disappeared, suggesting
that resveratrol is competing with cAMP, and a Lineweaver-Burk
plot is consistent with a competitive inhibition mechanism (Figure
4C). To directly demonstrate that resveratrol competes
with cAMP in its binding site, we incubated PDE3 with the
fluorescent cAMP analog 8-azido[DY547]-cAMP, which crosslinks
to its binding site when stimulated with UV, in the presence
of increasing concentrations of either resveratrol or cAMP. Both
resveratrol and cAMP competed with 8-azido[DY547]-cAMP for
the binding site in PDE3 (Figure 4D). Because the binding of
8-azido[DY547]-cAMP to PDE3 is irreversible, whereas the
binding of resveratrol or cAMP is reversible, the data shown in
Figure 4D are an underestimation of the actual competitiveness
of cAMP or resveratrol. A simulation of the docking of resveratrol
into the catalytic pocket of PDE3 suggests that resveratrol may
fit into the catalytic pocket in two orientations (Figures S3B–
S3E). Taken together, these findings support the conclusion
that resveratrol increases cAMP levels by competitively inhibiting
PDEs.
----------

Resveratrol Activates AMPK and Increases
Mitochondrial Biogenesis by Inhibiting PDEs
By treating myotubes with specific PDE3 and PDE4 inhibitors,
we determined that 76% of the total basal PDE activity was
attributable to PDE4 and 18% to PDE3 (Figures 5A and S4). To
corroborate our in vitro biochemical findings that resveratrol
inhibits PDEs, we sought genetic evidence by using a PDE4
mutation. Previously, it has been shown that the upstream
conserved regions (UCRs) of PDE4 increase the sensitivity of
PDE4 to competitive inhibitors, whereas the catalytic domain
of PDE4, which is missing the UCRs, is more resistant to the
known competitive inhibitors (Burgin et al., 2010). We found
that the UCRs of PDE4 are also important for inhibition by resveratrol
because the resveratrol IC50 of the PDE4 catalytic domain
was approximately 2.4-fold higher than that of the full-length
PDE4 (33 mM versus 14 mM) (Figure 5B). If resveratrol
activates AMPK by inhibiting PDE4, resveratrol-induced phosphorylation
of ACC and AMPK in myotubes expressing the
PDE4 catalytic domain should be reduced compared to those
expressing full-length PDE4. As shown in Figure 5C, this was
indeed the case.
If the metabolic effects of resveratrol result from inhibiting
PDEs, a known PDE inhibitor should produce metabolic effects
very similar to those produced by resveratrol. Because PDE4
makes up most of the PDE activity in myotubes, we treated
_____

myotubes with the PDE4 inhibitor rolipram and found that rolipram
increased cAMP to levels similar to those induced by resveratrol
in myotubes (Figure 5D). Like resveratrol, rolipram
stimulated the phosphorylation of AMPK and ACC in an
Epac1-dependent manner (Figure 5E). To demonstrate that rolipram
can activate AMPK in vivo, we treated mice with rolipram
and harvested skeletal muscle. As shown in Figure 5F, rolipram-
treated mice had higher levels of phosphorylated AMPK
and ACC than vehicle-treated mice. Like resveratrol, rolipram
increased NAD+ levels (Figure 5G) and increased PGC-1a deacetylation
(Figure 5H), suggesting that rolipram increased
Sirt1 activity.
To test whether rolipram can reproduce the metabolic effects
of resveratrol in vivo, we determined the effect of rolipram (2 mg/
kg/day) on C57BL6/J mice fed with an HFD. After 12–14 weeks
of treatment, we isolated skeletal muscle and measured the
mRNA levels of genes that are known to be induced by resveratrol
and AMPK, such as eNOS, PGC-1a, and others important for
mitochondrial biogenesis. We found that rolipram consistently
increased the mRNA levels of these genes (Figure 5I). In agreement
with this, treatment with resveratrol, rolipram, or cAMP
induced mitochondrial biogenesis in myotubes to comparable
levels (Figure 5J). Rolipram and resveratrol also increased mitochondrial
content to similar levels in mouse skeletal muscle (Figure
5K). To determine whether increased mitochondrial function
improved exercise tolerance, we exercised rolipram-treated
mice on a treadmill. Rolipram-treated mice ran a significantly
greater distance on a treadmill before exhaustion than control
mice (445 ± 19mversus 268 ± 50 m) (Figure 5L). Taken together,
these findings indicate that rolipram and resveratrol have very
similar effects on mitochondrial biogenesis in skeletal muscle.
PDE Inhibition Protects against Diet-Induced Obesity
and Glucose Intolerance
The similarity between the effects of rolipram and resveratrol
also extended to WAT. As was the case with resveratrol-treated
mice (Baur and Sinclair, 2006; Um et al., 2010), the phosphorylation
levels of AMPK and ACC were increased in the WAT of
rolipram-treated mice (Figure 6A). C57BL6/J mice treated with
rolipram were resistant to weight gain on an HFD (Figure 6B)
and had less fat content (Figure 6C) even though their food intake
was similar to that of control mice (Figure 6D). Decreased weight
gain despite normal food intake suggests that rolipram increased
the metabolic rate. Because rolipram, like resveratrol and 007,
increased the oxygen consumption rate (Figure 2D, right) and
fat oxidation in myotubes (Figure 2E), we measured the oxygen
consumption rate in rolipram-treated mice. The oxygen
consumption rate was increased in rolipram-treated mice (Figure
6E), but physical activity levels were not affected (Figure 6F),
indicating that rolipram increased the basal metabolic rate.
Consistent with this, both resveratrol- and rolipram-treated
mice had higher body temperatures in the fasting state than
control mice (Figure 6G). Rolipram, like resveratrol (Um et al.,
2010), increased the expression levels of thermogenic genes
such as uncoupling proteins (UCPs) and PGC-1a in the adipose
tissue (Figure 6H).
PGC-1a increases ROS scavenging capacity (St-Pierre et al.,
2003). Consistent with rolipram-treated mice expressing higher
levels of PGC-1a, rolipram-treated mice had lower ROS levels
(Figure 6I). Considering all of the metabolic changes that rolipram
produced, including the reduction of ROS and fat mass
and increased mitochondrial function, we expected that rolipram
would improve glucose tolerance. Indeed, rolipram-treated mice
were more glucose tolerant than were control mice (Figure 6J).
Glucagon-like peptide-1 (GLP-1), which is secreted from the
gut, has antidiabetogenic activities, and GLP-1 analogs, as
well as drugs that increase the endogenous GLP-1 levels, are
part of type 2 diabetes therapy. The expression of GLP-1 is positively
regulated by cAMP (Gevrey et al., 2002) and therefore may
be induced when either resveratrol and rolipram inhibits PDEs.
Supporting this idea, we found that both resveratrol and rolipram
increased serum levels of GLP-1 by almost 20% (Figure 6K).
Together, these results indicate that both resveratrol and
rolipram may protect against type 2 diabetes by diverse mechanisms
including hormonal regulation.
DISCUSSION
By demonstrating that resveratrol activates the cAMP-Epac1-
AMPK-Sirt1 pathway, this study, in conjunction with previous
studies (Beher et al., 2009; Borra et al., 2005; Kaeberlein et al.,
2005; Pacholec et al., 2010), explains how resveratrol activates
Sirt1 without directly targeting it. Although resveratrol was
initially shown to directly activate Sirt1 in an assay that utilized
a fluorophore-linked substrate (Howitz et al., 2003), our studies
show that resveratrol indirectly activates Sirt1 in vivo due to its
effect on cAMP signaling.
Our findings on the mechanism of resveratrol action have
implications for other known putative Sirt1 activators such as
SRT1720, SRT2183, and SRT1460 (Milne et al., 2007; Pacholec
et al., 2010). Like resveratrol, they were discovered as Sirt1 activators
by using the fluorophore-tagged substrate and only
exhibit Sirt1 activation in the presence of fluorophore-modified
substrate. Thus, it is likely that they may also activate Sirt1 via
an upstream target in vivo. Because the metabolic effects of
SRT1720 are nearly identical to those of resveratrol (Milne
et al., 2007; Feige et al., 2008), it is tempting to speculate that
these compounds, or at least SRT1720, act via pathways similar
to those of resveratrol.
cAMP signaling is highly complex, and its outcomes vary depending
on the effector activated by cAMP and on other factors
including the cell type, the cellular compartment of cAMP action,
and the duration and intensity of cAMP signaling. cAMP is a key
mediator of metabolic regulation, and the identification of PDEs
as resveratrol targets might explain how resveratrol mimics
some aspects of CR. Nutrient deprivation increases cAMP levels
as a consequence of increased glucagon and catecholamine
signaling and decreased insulin/IGF-1 signaling (Rondinone
et al., 2000; Selawry et al., 1973). Resveratrol, by increasing
cAMP levels and activating Epac1, may induce some of the pathways
that are normally induced during CR (Figure 7). The positive
health benefits of PDE4 inhibitors, such as improved memory
(Burgin et al., 2010) and protection against aging-related
diseases such as Alzheimer’s (Smith et al., 2009) and Parkinson’s
(Yang et al., 2008) diseases, have been demonstrated in
animal models. It is therefore possible that PDE4 inhibitors
____

may be useful for treating metabolic diseases and other aging related
diseases in humans.

______

10 nM [3H]cAMP (45000 cpm) or [3H]cGMP as substrates. Less than
10%–15% of the substrates were hydrolyzed during the PDE reaction.
Portions of solubilized cell lysates were assayed for PDE activity by incubation
with resveratrol (0–100 mM) or with specific PDE inhibitors. Recombinant
PDE1 (10 ng) activity was assayed by using 4 mg/ml calmodulin and
0.8 mM Ca2+ together with [3H]cAMP as substrate in the reaction mixture.
Recombinant PDE2 (15 ng) activity was assayed in the presence of 1 mM
cGMP, which activated it by 3 fold. Activities of recombinant PDE3
(1 ng) and PDE4 (1 ng) were assayed by incubation in a reaction mixture
containing 1 mg/ml BSA, with [3H]cAMP. Recombinant PDE5 (150 ng)
activity was assayed using [3H]cGMP as substrate. PDE activity is expressed
as pmol of cAMP or cGMP hydrolyzed/min/mg protein. The
PDE3 inhibitor cilostamide and the PDE4 inhibitor rolipram were used to
define PDE specificity. Recombinant full-length PDE4D was purchased
from Signalchem, and the recombinant PDE4D catalytic domain was
purchased from Enzo Life Sciences. To measure the activities of PDE3 or
PDE4 in C2C12 lysates, PDE activity was measured in the presence of
1 mM cilostamide or 10 mM rolipram.
_____

Animal Experiments
All experiments were approved by the NHLBI ACUC (Animal Care and Use
Committee). C57BL/6J mice were originally purchased from Jackson Laboratory.
Four- to six-week-old male mice were housed with a 12 hr light-dark cycle
(light on 6 am–6 pm) with free access to food and water. For all rolipram-related
studies, mice were dosed once daily by oral gavage with 2 mg/kg/day rolipram
(Enzo Life Sciences) or with saline and were fed a HFD (40% calories from fat,
Research Diets) for up to 14 weeks. To measure the effect of resveratrol on
cAMP production, C57BL/6J mice were injected (intraperitoneally [i.p.]) with
resveratrol (20 mg/kg body weight) or with DMSO (vehicle). For studies
involving chronic resveratrol treatment, C57BL/6J mice were fed a HFD containing
resveratrol (400 mg/kg/day) for 14 weeks.
Metabolic Measurements
Body weight and caloric intake were monitored weekly. Plasma glucose was
measured by using a glucometer (Ascensia). For the glucose tolerance test,
mice were fasted for 16 hr, and 1 mg/g glucose was injected i.p. Blood glucose was measured at 0, 15, 30, 45, 60, and 90 min after injection. Prior to the treadmill endurance tests, the mice were trained for 3 days by running on an Exer-3/6 mouse treadmill (Columbus Instruments) at 10 m/min for 5 min.

For the endurance test, the treadmill was set at a 15 incline, and the speed was
increased in a stepwise fashion (10 m/min for 10 min followed by 14 m/min
for 5 min and then the final speed of 18 m/min). The test was terminated
when mice reached exhaustion, which was defined as immobility for more
than 30 s. Locomotor activity of mice was measured by photobeam breaks
by using the Opto-Varimex-4 (Columbus Instruments). Indirect calorimetry
was performed using Oxymax chambers (Columbus Instruments). All mice
were acclimatized for 24 hr before measurements. Resting metabolic rate
was determined by calculating the average energy expenditure at each
30 min time point during a 24 hr period.

#4 maxwatt

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Posted 05 February 2012 - 03:14 AM

Luteolin too is a strong PDE4 inhibitor. It has been shown to be a stronger SIRT1 activator than resveratrol, for that matter. Many phytochemicals have overlapping or opposing activity. Resveratrol's stimulation of cAMP has been known for several years. There also surely are metabolic differences between individuals such that they will have different responses to various phytochemicals. I like the effects I get with resveratrol plus luteolin, while bixbyte has breathing problems if he uses luteolin. Dosage is also an improtant piece of the puzzle. The results of this paper are not directly applicable to humans dosing orally. C57BL/6J mice were injected intraperitoneally [i.p.]) with resveratrol (20 mg/kg body weight. That would a whopping dose for a human to inject even allowing for metabolic scaliing*, and the blood levels obtained from injection are far higher than can be obtained by taking a pill.

Usually the human equivalent dose allowing for metaboilic is given as 1/6th the amount per kg However human's have far more efficient enzymes for metabolizing phytochemicals than do mice, and the actual equivalent may be an equal amount per kg, or even several times as much.

#5 Lufega

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Posted 06 February 2012 - 07:46 PM

Did this article just make resveratrol completely worthless as a supplement, since there are other PDE4 inhibitors with better bioavailability ? Or can someone prove that this is some sort of conspiracy to discredit resveratrol, since it can't be patented ? I think maxwatt mentioned before that he had found a better alternative to Resv, which is luteolin. Guess he was right !

The authors present evidence that resveratrol does not directly activate sirtuin 1, a protein associated with aging. Rather, the authors found that resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), enzymes that help regulate cell energy.


In this study, the researchers methodically traced out the metabolic activity in cells treated with resveratrol and identified PDE4 in the skeletal muscle as the principal target for the health benefits of resveratrol. By inhibiting PDE4, resveratrol triggers a series of events in a cell, one of which indirectly activates sirtuin 1

.



Edited by Lufega, 06 February 2012 - 07:47 PM.

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#6 maxwatt

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Posted 07 February 2012 - 05:54 PM

Not completely. Resveratrol does directly activate SIRT1, as shown by another assay than those authors refer to. I've posted that study here before. They also found luteolin was a more powerful activator than resveratrol. However, resveratrol may have other properties that make it worth taking. We know it stimulates mitochondria, so as to improve exercise tolerance and perhaps combat age-related sarcopenia, which has not been demonstrated for luteolin. I currently use both, FWIW.
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#7 geo12the

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Posted 07 February 2012 - 05:55 PM

This is an interesting study but it falls into the trap of being overly reductionistic and sweeping in its conclusions.
Back when people believed the effects of resveratrol were solely due to SIRT activation I was very skeptical. Although this study could provide some insight into the mechanism of action for the health benefits of resveratrol, I am skeptical that you can ascribe all the health benefits of resveratrol to this one pathway.
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#8 trance

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Posted 07 February 2012 - 06:21 PM

Not completely. Resveratrol does directly activate SIRT1, as shown by another assay than those authors refer to. I've posted that study here before. They also found luteolin was a more powerful activator than resveratrol. However, resveratrol may have other properties that make it worth taking. We know it stimulates mitochondria, so as to improve exercise tolerance and perhaps combat age-related sarcopenia, which has not been demonstrated for luteolin. I currently use both, FWIW.


Where are you sourcing your luteolin from, and how are you taking it in relationship to your resveratrol?

#9 maxwatt

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Posted 08 February 2012 - 02:41 AM

You can get reasonable quality luteolin from Beyond-a-century.com. Or you can buy it from the factory in China. Luteolin is a strong PDE4 inhibitor.

I take the two together in the morning, putting the powders in my cheek and sipping water. 400 mg of luteolin and 125 mg resveratrol currently, though I've tried other ratios and doses. , such as 300/300, 400/100. My dog's arthritis isn't held in check with just luteolin, and some resveratrol seems necessary for that effect. (My own arthritis is similarly responsive.) I also cannot say what is the best ratio, and I suspect it is variable that depends on genetics.

Edited by maxwatt, 08 February 2012 - 02:57 PM.


#10 hmm

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Posted 09 February 2012 - 04:16 PM

OK maxwatt, I made my order from Beyond for $28 plus shipping. Thanks for the info!

#11 abelard lindsay

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Posted 14 February 2012 - 05:32 AM

I have been trying to get nootropic benefit out of PDE4 inhibitors + Forskolin with pretty decent results.

I've reference a bunch of studies on the nootropic angle over here:

http://www.longecity...ly-induced-ltp/
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#12 Lufega

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Posted 14 February 2012 - 07:10 AM

I have been trying to get nootropic benefit out of PDE4 inhibitors + Forskolin with pretty decent results.

I've reference a bunch of studies on the nootropic angle over here:

http://www.longecity...ly-induced-ltp/


Now combine that with prolyl endopeptidase inhibitor. Rosemary works well. That'll really blow you away...

#13 bixbyte

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Posted 16 February 2012 - 10:04 PM

You can get reasonable quality luteolin from Beyond-a-century.com. Or you can buy it from the factory in China. Luteolin is a strong PDE4 inhibitor.

I take the two together in the morning, putting the powders in my cheek and sipping water. 400 mg of luteolin and 125 mg resveratrol currently, though I've tried other ratios and doses. , such as 300/300, 400/100. My dog's arthritis isn't held in check with just luteolin, and some resveratrol seems necessary for that effect. (My own arthritis is similarly responsive.) I also cannot say what is the best ratio, and I suspect it is variable that depends on genetics.


Have you tried putting the powder under your tongue?
I have been applying dry 98% Resveratrol powder under my tongue.
I think this helps lower my HR by a couple beats during the treadmill.

#14 gizmobrain

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Posted 11 March 2012 - 09:23 AM

I have been trying to get nootropic benefit out of PDE4 inhibitors + Forskolin with pretty decent results.

Now combine that with prolyl endopeptidase inhibitor. Rosemary works well. That'll really blow you away...


I'm interested in this post in particular. I'm curious to know if there's been any members that have seen positive results with a stack such as Luteolin, Reservatrol, Forskolin, and Rosemary (or Berberine and Baicalin), and what sort of dosages were used.

I can't seem to find anything that directly lists Rosemary as a prolyl endopeptidase inhibitor.

I just recently set out to learn about MAO and COMT inhibitors, now I have to add Prolyl Endopeptidase and Phosphodiesterase inhibitors to my list of confusing things that I barely grasp...

Edited by zrbarnes, 11 March 2012 - 09:32 AM.


#15 Turnbuckle

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Posted 11 March 2012 - 03:52 PM

In a recent Science Daily article outlining a new paper in Cell (Cell 148, 421–433, February 3, 2012) journal, expresses concerns about the possible toxicity of resveratrol impacting unknown protein synthesis in the body.

http://www.scienceda...20202151133.htm

"Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use."



Should we be concerned?

I have attached the actual article from Cell journal below.



I took 200 mg of resveratrol for years, then a year ago began to develop all sorts of joint pains that got worse over a period of months. Since I'd read of others having such pains, I cut out the resveratrol and the pain began to diminish, and was about 80% gone after a week. It didn't go away entirely until I switched the NSAID I was taking to naproxen. I now consider resveratrol as too dangerous to fool around with.

Edited by Turnbuckle, 11 March 2012 - 03:54 PM.


#16 maxwatt

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Posted 11 March 2012 - 06:25 PM

Thow of us who have experienced joint pain with resveratrol have found it resolves if one's vitamin D intake is adequate, as measured by a hydroxy-D25 blood test. Mine was 28, clinically insufficient, but by supplementing with vitamin D3 I brought the level up to 36, and was able to take resveratrol without developing joint pain. (Currently at 4000 units daily of D3, blood levels are 46, about as high as I want them.) Others have had similar results, though one man had joint pain with a blood level that tested in the 40's. We believe this effect may be due to the anti-aromatase activity of resveratrol; anti-aromatase drugs similarly require high vitamin D level to avoid joint pain.

If you want to take resveratrol for the benefits we (in this forum) seem to have found can be had vis a vis: positive effect on osteoarthritis, increased endurance and improved cardiovascular function, and reduction in sarcopenia, test your blood evels and supplement with vitamin D if they are low.

#17 Turnbuckle

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Posted 11 March 2012 - 06:31 PM

Thow of us who have experienced joint pain with resveratrol have found it resolves if one's vitamin D intake is adequate, as measured by a hydroxy-D25 blood test. Mine was 28, clinically insufficient, but by supplementing with vitamin D3


I doubt that was my problem as I'd been taking 5000 IUs of D3 daily for years. Another suggestion was that resveratrol chelates copper and that leads to a copper deficiency, so I took copper and zinc for a few days, but I can't say that was the solution as I'd already stopped the resveratrol by then.

Edited by Turnbuckle, 11 March 2012 - 06:36 PM.


#18 maxwatt

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Posted 12 March 2012 - 01:24 AM

Resveratrol is such a weak chelator of copper, that the blood levels we can get from taking it orally,have a negligible effect . Not surprising that copper supplements had no effect.

WRT vitamn D, you could be an outlier whom vitamin D does not help, or possiby you absorb it poorly. If the D3 was a powder capsule rather than an oil capsule, this is especially likely. But without knowing your actual hydroxy D25 blood serum levels, there is no way to tell. Some people report low blood levels despite taking D3 in doses as high as yours, or higher. If your doctor won't order the test, or your insurance won't pay, LE offers the test for as little as $25 to members, perhaps $35 for non-members. It's worth doing even if you do not intend to supplement resveratrol. With D3, too high a level is as bad as too low a level. I would not wantmy levels to be over 50.

#19 bixbyte

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Posted 12 March 2012 - 10:07 PM

In a recent Science Daily article outlining a new paper in Cell (Cell 148, 421–433, February 3, 2012) journal, expresses concerns about the possible toxicity of resveratrol impacting unknown protein synthesis in the body.

http://www.scienceda...20202151133.htm

"Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use."



Should we be concerned?

I have attached the actual article from Cell journal below.



I took 200 mg of resveratrol for years, then a year ago began to develop all sorts of joint pains that got worse over a period of months. Since I'd read of others having such pains, I cut out the resveratrol and the pain began to diminish, and was about 80% gone after a week. It didn't go away entirely until I switched the NSAID I was taking to naproxen. I now consider resveratrol as too dangerous to fool around with.


__________________




Hi :) , Maybe your joint pains are a preexisting condition?

-------------
Original post link:

http://www.scienceda...20202151133.htm

(Here I cut and paste some of Resveratrol's PDE1-10 Inhibitors. Specifically PDE4)
We found
that the UCRs of PDE4 are also important for inhibition by resveratrol
because the resveratrol IC50 of the PDE4 catalytic domain
was approximately 2.4-fold higher than that of the full-length
PDE4 (33 mM versus 14 mM) (Figure 5B). If resveratrol
activates AMPK by inhibiting PDE4, resveratrol-induced phosphorylation
of ACC and AMPK in myotubes expressing the
PDE4 catalytic domain should be reduced compared to those
expressing full-length PDE4. As shown in Figure 5C, this was
indeed the case.



______

http://en.wikipedia....erase_inhibitor

PDE4 selective inhibitors

PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD, and rhinitis. They suppress the release of cytokines and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects[26] and have also recently been proposed for use as antipsychotics.[27][28]

On October 26, 2009, The University of Pennsylvania reported that researchers at their institution had discovered a link between elevated levels of PDE4 (and therefore decreased levels of cAMP) in sleep deprived mice. Treatment with a PDE4 inhibitor raised the deficient cAMP levels and restored some functionality to Hippocampus-based memory functions.[29]

Edited by bixbyte, 12 March 2012 - 10:09 PM.


#20 abelard lindsay

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Posted 13 March 2012 - 03:59 AM

I have been trying to get nootropic benefit out of PDE4 inhibitors + Forskolin with pretty decent results.

Now combine that with prolyl endopeptidase inhibitor. Rosemary works well. That'll really blow you away...


I'm interested in this post in particular. I'm curious to know if there's been any members that have seen positive results with a stack such as Luteolin, Reservatrol, Forskolin, and Rosemary (or Berberine and Baicalin), and what sort of dosages were used.

I can't seem to find anything that directly lists Rosemary as a prolyl endopeptidase inhibitor.

I just recently set out to learn about MAO and COMT inhibitors, now I have to add Prolyl Endopeptidase and Phosphodiesterase inhibitors to my list of confusing things that I barely grasp...


I have had pretty good results. I've been taking it for a couple of months with nothing extremely bad happening and I'm pretty damn sure it has had positive cognitive benefits. In fact I felt like going on an isochroma like rant about it but refrained because frick if I know if there's long term side effects, it's a bit experimental, and maybe I'm not smarter just hypomanic?

#21 X_Danny_X

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Posted 14 March 2012 - 10:25 PM

So is prolyl endopeptidase inhibitor Luteolin anti aging as well? Also I keep hearing that increasing cAMP will help you lose weight. I didnt realize that Luteolin can increase intelligence/cognitive function.

Where can I buy Luteolin from a reliable source?

I am taking Deprenyl/Seligiline, Ashwagandha, ALCAR, Spirulina (for Uridine), Eggs (for Choline), Vitamin D (10,000 IU), Vitamin E. I was taking Cats Claw and PQQ but I decided not to restock on those.


I hope Luteolin doesn't intefere with or cause issues with Deprenyl.

Edited by X_Danny_X, 14 March 2012 - 10:34 PM.


#22 gizmobrain

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Posted 14 March 2012 - 11:06 PM

I hope Luteolin doesn't intefere with or cause issues with Deprenyl.


I am wondering this as well, since Deprenyl inhibits MAO and luteolin causes increased DAT. I'm not sure I fully understand MAO's and DAT yet, and how MAO/MAT/COMT all play in together. I need to read a neuroscience textbook :)


http://www.ncbi.nlm....pubmed/19815045

Abstract

Monoamine transporters playing major roles in regulating normal and abnormal synaptic activity are associated with various neuropsychological disorders. In spite of the discovery of a series of structurally different monoamine transporter antagonists for the therapy approach, no practical pharmaceutical can act as a transporter activator. Here, we isolated luteolin and apigenin from the fruit of Perilla frutescens (L.) Britt by using an activity-guided extraction technique, and proved that the two compounds possess actions of enhancing monoamine uptake either upon monoamine-transporter transgenic Chinese hamster ovary (CHO) cells or upon wild dopaminergic cell lines, with higher specificity for dopamine (DA) uptake than for norepinephrine (NE)- and serotonin (5HT)-uptake, as well as with more potency and greater efficacy for luteolin than for apigenin. Further, in the transgenic cells, the principal NE/DA uptake activation by luteolin was significantly prevented by respective transporter inhibitor, and the transmitter-uptake-enhancing action was independent of its ligands, which is in support of the compounds as monoamine transporter activators. Furthermore, luteolin evoked a marked disinhibition of cocaine-targeted effect in CHO cells overexpressing dopamine transporter. Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity.


Edited by zrbarnes, 14 March 2012 - 11:10 PM.


#23 X_Danny_X

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Posted 15 March 2012 - 12:59 AM

MAO enzymes breaks down neutransmitters, so it is good to somehow reduce them. the body does still them since MAO enzymes are found your stomach and not only in your brain. COMT inhibitors such as Cats Claw will strengthen any MAO inhibitor substance such as Deprenyl. I was taking them together.

Im trying to understand the abstract, but i think it is saying that it does work in terms of increasing cognitive but can get you high.

#24 maxwatt

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Posted 15 March 2012 - 04:42 AM

I would drop the deprenyl, as I do not believe it has much of an upside. But the MAO effects of luteolin should be negligible in any case.

I believe BAC is selling a reasonably good powder form at a reasonable price.

#25 gizmobrain

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Posted 15 March 2012 - 10:07 AM

I would drop the deprenyl, as I do not believe it has much of an upside. But the MAO effects of luteolin should be negligible in any case.

I believe BAC is selling a reasonably good powder form at a reasonable price.


My background of why I'm on deprenyl/selegiline:

After being diagnosed with ADHD-PI (though I have never had any signs of hyperactivity, i.e. I fall in with the SCT crowd), I tried Ritalin (naseous, vomiting, space cadet), Adderall (heart palpitations, high bp, tunnel vision, etc), Strattera (somnolence, tired, ineffective), and Nuvigil (no effect?). I was briefly on d-amp, and it gave all the concentration effects of Adderall without the motivation effects, which I chalk up to that bit of l-amp in the Adderall..

After being on Deprenyl/Selegiline 10mg for a few months, I've noticed an increase in concentration, but nothing in the motivation department. I like that Selegiline is neuroprotective versus the stimulates that are neuro-trashing. I definitely noticed a decline in my memory after taking Adderall that took months to wear off.

For those keeping track, my understanding is that my serotonin system is in tip top shape, my dopamine is only slightly lacking (wears off too fast), and my norepinephrine levels seem to stay ridiculously low unless I take Adderall.

So I'm still on my quest to find something that has a similar outcome on my motivation that l-amphetamine does. Of course, I'm also always looking for ways to improve my cognitive function in general. Sometimes these two missions seem to contradict each other. My newest experiment involves PDE4 and PREP inhibition, to see if that gets me anywhere, which is how I ended up in this thread.

What's in my supplement stack - Google Doc

It's a combination of what was available at the local health store and what I could get for cheap at Walgreens on clearance.

If someone was going for PDE4 and PREP inhibition, would my artichoke/rosemary/forskolin/resveratrol stack be a half-way effective means? Or should I have gone with Celery Seed extract and berberine? Any advice on dosage?

I was thinking of taking 1 of each, on an empty stomach each morning, but honestly, I don't know.

I also have some CoQ10 and BioPQQ on their way.

#26 maxwatt

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Posted 15 March 2012 - 12:57 PM

I suspect you would have liked ephedra when it was available. citrus aurantium should be similarly effective. I would still drop the deprenyl. And most of the other things. If you don't know what it is doing, don't be taking. I can't really comment on the entire regimen, or offer other advice, than that it seems more complicated than you need.

I'm surprised Nuvigil (modafinal) was not effective for you; it's a noradrenaline reuptake inhibitor. Dosage? Or maybe the non-racemic form sold as Provigil would be efficacious? But if the synephrine in Citrus aurantium works for you, and it is cheaper, go for it.

Also consider you may be part of the 10% of the population that is folate deficient, due to a genetic quirk that renders some unable to convert folic acid into the active form of the vitamin. Half the population is affected to some degree by the MTHFR gene, and 10% are homozygous for the gene. By supplementing with methyl-tetra-hydro-folate you can correct teh deficiency, and reduce your cancer risk. But it also acts as an anti-depressant, and improves motivation in those that need it.

Edited by maxwatt, 15 March 2012 - 01:30 PM.


#27 gizmobrain

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Posted 15 March 2012 - 08:27 PM

I suspect you would have liked ephedra when it was available. citrus aurantium should be similarly effective. I would still drop the deprenyl. And most of the other things. If you don't know what it is doing, don't be taking. I can't really comment on the entire regimen, or offer other advice, than that it seems more complicated than you need.

I'm surprised Nuvigil (modafinal) was not effective for you; it's a noradrenaline reuptake inhibitor. Dosage? Or maybe the non-racemic form sold as Provigil would be efficacious? But if the synephrine in Citrus aurantium works for you, and it is cheaper, go for it.

Also consider you may be part of the 10% of the population that is folate deficient, due to a genetic quirk that renders some unable to convert folic acid into the active form of the vitamin. Half the population is affected to some degree by the MTHFR gene, and 10% are homozygous for the gene. By supplementing with methyl-tetra-hydro-folate you can correct teh deficiency, and reduce your cancer risk. But it also acts as an anti-depressant, and improves motivation in those that need it.


The regimen I posted above is based off of this thread and a few others. I just started it yesterday, more as an experiment then anything else.

Rosemary is an acetylcholinesterase and GABA transaminase inhibitor, anti-viral, anti-bacterial, anti-inflammatory, and antioxidant. (It also protects skin cells against UV-A radiation). It contains Luteolin, which as discussed in this thread, is a PDE4 inhibitor.

Artichoke can improve blood cholesterol ratios, help increase good intestinal bacteria, and it also contains Luteolin.

Coleus forskohlii is an acetylcholinesterase inhibitor, and contains Forskolin, which can stimulate adenylate cyclase activity and increase cAMP. It is a vasodilator, and can increasing lean mass, bone mass, and testosterone. In combination with a PDE4 inhibitor, it can inhibit colon cancer cell growth and cause long-term potentiation in neuronal populations.

Resveratrol, of course, has already been discussed in this thread as a PDE4 inhibitor.



Off topic:

As far as stimulants go, ephedrine and synephrine works somewhat to correct my motivation issue, but the effects are too much in the PNS, and not so much in the CNS. Pseudoephedrine gets a little closer to working in the right areas, but it takes quite a bit and gives me a dry mouth like crazy. 1,3-dimethylamylamine (DMAA) seems to work fairly well for me, though it only lasts 3-5 hours. I once took a supplement that combined ephedrine, yohimbine HCL, and 1,3-dimethylamylamine all together, and my mind was as clear as it has ever been, but this seemed dangerous (even though it felt cleaner than Adderall).

I've debated going back on the DMAA or 5 mg of Adderall, in combination with some of the inhibitors. I just think it would be awesome if I could do without stimulants at all.

Nuvigil was weird. I never felt a thing from it, no matter how much I took. I never tried Provigil because of the cost (the Nuvigil was a free trial). Strattera was the noradrenaline reuptake inhibitor. I had high hopes for it, but it made me sleep for 6 hours every time I took it. I even started taking it at night, but it never seemed to help during the day. I had a lot of side effects too, mostly with muscle issues.

My theory at the time was that my brain just doesn't release enough noradrenaline for the Strattera to even work effectively, which I felt was validated when I found that Adderall worked, but d-amp did not.

I'm actually taking sublingual methylcolobalmin in the morning, and methylfolate, p5p, magnesium l-threonate, and omega-3 at night, too.

Edited by zrbarnes, 15 March 2012 - 08:29 PM.


#28 gizmobrain

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Posted 17 March 2012 - 01:24 AM

I have been trying to get nootropic benefit out of PDE4 inhibitors + Forskolin with pretty decent results.

Now combine that with prolyl endopeptidase inhibitor. Rosemary works well. That'll really blow you away...


I'm interested in this post in particular. I'm curious to know if there's been any members that have seen positive results with a stack such as Luteolin, Reservatrol, Forskolin, and Rosemary (or Berberine and Baicalin), and what sort of dosages were used.

I can't seem to find anything that directly lists Rosemary as a prolyl endopeptidase inhibitor.

I just recently set out to learn about MAO and COMT inhibitors, now I have to add Prolyl Endopeptidase and Phosphodiesterase inhibitors to my list of confusing things that I barely grasp...


I have had pretty good results. I've been taking it for a couple of months with nothing extremely bad happening and I'm pretty damn sure it has had positive cognitive benefits. In fact I felt like going on an isochroma like rant about it but refrained because frick if I know if there's long term side effects, it's a bit experimental, and maybe I'm not smarter just hypomanic?


Did you happen to notice any tiredness at the beginning? Both days I've taken the stack, and I have gotten sleepy, though it was easily reversed with some stimulant.

Edited by zrbarnes, 17 March 2012 - 01:27 AM.


#29 abelard lindsay

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Posted 17 March 2012 - 04:15 AM

I used Now Foods Artichoke Extract for the Luteolin (at least 2). Also, it's good to stack with Caffeine, and make sure you are using at least 500mg of Resveratrol (e.g RevGenetics 500). I didn't use Rosemary, Berberine or Baicalin in my stack.

Edited by abelard lindsay, 17 March 2012 - 04:17 AM.


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#30 kenj

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Posted 17 March 2012 - 11:45 AM

I took 200 mg of resveratrol for years, then a year ago began to develop all sorts of joint pains that got worse over a period of months. Since I'd read of others having such pains, I cut out the resveratrol and the pain began to diminish, and was about 80% gone after a week. It didn't go away entirely until I switched the NSAID I was taking to naproxen. I now consider resveratrol as too dangerous to fool around with.


Turnbuckle,

I got the same weird joint pains from resveratrol a couple years back, and had to stop running and pause resv because of it.
When I began taking resv again, the joint pain seemed to have diminished (or maybe I was on a better "joint supplement program". I was also taking Vitamin D, and experimented with increasing dosages (2,000-10,000 IU's - always in D3/softgel form), granted, I never got my blood levels tested.

Although the joint pain/tendonitis symptoms was manageable and didn't bother me, in hindsight I *think* the resveratrol somehow worsened my joints when I exercised. I did get increased stamina, and what people generally report re: positive effects so I kept taking it.

A couple months back I ran out of resv, so I decided to take a break from it. And, the last couple days I've been taking it again and, voilà, experiencing the same boring and notable joint pain like when I initially started taking it, so I'm thinking I for whatever reason need to "introduce" resv to my system, slowly again.
I've been taking Vitamin D consistently for years now, FWIW.
It's still a puzzle to me.




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