1084 replies to this topic

[tintinet]

Full Member,

I don't think I have gotten hives from anything else that I have taken. Furthermore, other things may also be contributing to my hives but it is clear that when I take the resveratrol I get hives, and when I stop taking resveratrol my hives go away.

Missminni,

I'm 6'1" and weight 200 pounds. My hips are a complicated problem because I have both arthritis and bursitis. Over the past few months my hips have improved significantly. The things that I have been doing differently from the past are: 1) getting myofascial release of the hip and thigh (mostly along the IT band), 2) doing leg raises 3 times a week from various angles with ankle weights, and 3) taking resveratrol mixed with lecithin.

I have no doubt that the first two things above have helped me. I'm not yet sure how much the resveratrol has. It may have or it may not have, but I'm reluctant to change anything yet because of my improvement. (I didn't notice the immediate relief that some others here have.) I may have noticed a bigger improvement from the topical application, but honestly I'm not sure of that either.

The reason I was taking 2 grams daily is because that's where Max Watt and others have noticed relief. I only went to 4 grams orally for 1 day, because I was curious to see if I could replicate the effect of the oral and topical application on my hives by doubling my oral dose. (I could not.) Finally, I'm no longer taking resveratrol orally. I'm currently only taking it topically. It's much cheaper that way and it may be having more effect. (I estimate that the 4 grams of resveratrol I mixed in with 30 ml of DMSO should last at least 2 weeks to a month.)

And finally, even if it's not helping my arthritis (something that I am not sure about), I hopefully am receiving the other benefits of resveratrol.

Albert

What variant of resveratrol are you using? PC extract? If so, perhaps a trial of the synthetic >99% purity t-resveratrol might help determine if it's really t-resveratrol to which you have an allergy vs. some other substance in PC extracts.

[asnufu]

Full Member,

I don't think I have gotten hives from anything else that I have taken. Furthermore, other things may also be contributing to my hives but it is clear that when I take the resveratrol I get hives, and when I stop taking resveratrol my hives go away.

Missminni,

I'm 6'1" and weight 200 pounds. My hips are a complicated problem because I have both arthritis and bursitis. Over the past few months my hips have improved significantly. The things that I have been doing differently from the past are: 1) getting myofascial release of the hip and thigh (mostly along the IT band), 2) doing leg raises 3 times a week from various angles with ankle weights, and 3) taking resveratrol mixed with lecithin.

I have no doubt that the first two things above have helped me. I'm not yet sure how much the resveratrol has. It may have or it may not have, but I'm reluctant to change anything yet because of my improvement. (I didn't notice the immediate relief that some others here have.) I may have noticed a bigger improvement from the topical application, but honestly I'm not sure of that either.

The reason I was taking 2 grams daily is because that's where Max Watt and others have noticed relief. I only went to 4 grams orally for 1 day, because I was curious to see if I could replicate the effect of the oral and topical application on my hives by doubling my oral dose. (I could not.) Finally, I'm no longer taking resveratrol orally. I'm currently only taking it topically. It's much cheaper that way and it may be having more effect. (I estimate that the 4 grams of resveratrol I mixed in with 30 ml of DMSO should last at least 2 weeks to a month.)

And finally, even if it's not helping my arthritis (something that I am not sure about), I hopefully am receiving the other benefits of resveratrol.

Albert

What variant of resveratrol are you using? PC extract? If so, perhaps a trial of the synthetic >99% purity t-resveratrol might help determine if it's really t-resveratrol to which you have an allergy vs. some other substance in PC extracts.

Of course, the purity of the extract doesn't detract substantially from the validity of Albert's experiment. It may not be a strictly controlled experiment, but it adheres to scientific principle and is pretty persuasive IMO....

[tintinet]

Full Member,

I don't think I have gotten hives from anything else that I have taken. Furthermore, other things may also be contributing to my hives but it is clear that when I take the resveratrol I get hives, and when I stop taking resveratrol my hives go away.

Missminni,

I'm 6'1" and weight 200 pounds. My hips are a complicated problem because I have both arthritis and bursitis. Over the past few months my hips have improved significantly. The things that I have been doing differently from the past are: 1) getting myofascial release of the hip and thigh (mostly along the IT band), 2) doing leg raises 3 times a week from various angles with ankle weights, and 3) taking resveratrol mixed with lecithin.

I have no doubt that the first two things above have helped me. I'm not yet sure how much the resveratrol has. It may have or it may not have, but I'm reluctant to change anything yet because of my improvement. (I didn't notice the immediate relief that some others here have.) I may have noticed a bigger improvement from the topical application, but honestly I'm not sure of that either.

The reason I was taking 2 grams daily is because that's where Max Watt and others have noticed relief. I only went to 4 grams orally for 1 day, because I was curious to see if I could replicate the effect of the oral and topical application on my hives by doubling my oral dose. (I could not.) Finally, I'm no longer taking resveratrol orally. I'm currently only taking it topically. It's much cheaper that way and it may be having more effect. (I estimate that the 4 grams of resveratrol I mixed in with 30 ml of DMSO should last at least 2 weeks to a month.)

And finally, even if it's not helping my arthritis (something that I am not sure about), I hopefully am receiving the other benefits of resveratrol.

Albert

What variant of resveratrol are you using? PC extract? If so, perhaps a trial of the synthetic >99% purity t-resveratrol might help determine if it's really t-resveratrol to which you have an allergy vs. some other substance in PC extracts.

Of course, the purity of the extract doesn't detract substantially from the validity of Albert's experiment. It may not be a strictly controlled experiment, but it adheres to scientific principle and is pretty persuasive IMO....

Yes and no. Yes, his experiment is strong evidence he's allergic to some substance in the t-resveratrol containing preparation he's taking, but it doesn't absolutely prove it's the t-resveratrol in the preparation he's taking to which he is allergic, if he's taking an extract.

Edited by tintinet, 07 December 2007 - 09:51 PM.

[ilanso]

perhaps a trial of the synthetic >99% purity t-resveratrol might help determine if it's really t-resveratrol to which you have an allergy vs. some other substance in PC extracts.
...
Yes, his experiment is strong evidence he's allergic to some substance in the t-resveratrol containing preparation he's taking, but it doesn't absolutely prove it's the t-resveratrol in the preparation he's taking to which he is allergic, if he's taking an extract.

Well, access to synthetic is notoriously difficult. Albert, have you been using just one source? In the affirmative, my previous proposal sounds less and less off its rocker: let a few of us send you our mini-samples and see what happens.

[missminni]

Resveratrol in regard to working out:
Before I took it, my workouts felt harder and harder.
It was uphill. After 40 minutes, I was very done. Tired too.
When I started the Res, my same workout became easier and
I could push myself further. Now, I find that I work out twice as long as I used
to and don't even realize it until I look at the time. Instead of
getting harder it's getting easier.
I love it.
Reading back over that,
it sounds like an advertisement doesn't it.
and it's really true.
Have there been any other reports of hive break outs with Res?

[AlbertN]

perhaps a trial of the synthetic >99% purity t-resveratrol might help determine if it's really t-resveratrol to which you have an allergy vs. some other substance in PC extracts.
...
Yes, his experiment is strong evidence he's allergic to some substance in the t-resveratrol containing preparation he's taking, but it doesn't absolutely prove it's the t-resveratrol in the preparation he's taking to which he is allergic, if he's taking an extract.

Well, access to synthetic is notoriously difficult. Albert, have you been using just one source? In the affirmative, my previous proposal sounds less and less off its rocker: let a few of us send you our mini-samples and see what happens.

I'd really prefer not to test everyone's resveratrol. As far as what resveratrol I've used, the first batch was a 99% pure batch from Anthony Loerra, the second was a 98% batch that I got from Max Watt, and the third was also a 98% batch I got from Max Watt. All three batches have given me hives. Max, if you remember, did both of my batches come from the same source or did you get multiple different batches?

Albert

Edited by albertn, 08 December 2007 - 12:47 AM.

[missminni]

perhaps a trial of the synthetic >99% purity t-resveratrol might help determine if it's really t-resveratrol to which you have an allergy vs. some other substance in PC extracts.
...
Yes, his experiment is strong evidence he's allergic to some substance in the t-resveratrol containing preparation he's taking, but it doesn't absolutely prove it's the t-resveratrol in the preparation he's taking to which he is allergic, if he's taking an extract.

Well, access to synthetic is notoriously difficult. Albert, have you been using just one source? In the affirmative, my previous proposal sounds less and less off its rocker: let a few of us send you our mini-samples and see what happens.

I'd really prefer not to test everyone's resveratrol. As far as what resveratrol I've used, the first batch was a 99% pure batch from Anthony Loerra, the second was a 98% batch that I got from Max Watt, and the third was also a 98% batch I got from Max Watt. All three batches have given me hives. Max, if you remember, did both of my batches come from the same source or did you get multiple different batches?

Albert

I've used the same Res and didn't get hives. Maybe it's your personal reaction or maybe it is something else you are taking that is interacting with the res in a negative way.

[AlbertN]

I think this is going in the wrong direction. I don't think it's the source of resveratrol that's the problem since I've gotten hives from multiple different batches. To me the hives are just an indication that the resveratrol is getting in my system more topically than orally.

Albert

[asnufu]

I think this is going in the wrong direction. I don't think it's the source of resveratrol that's the problem since I've gotten hives from multiple different batches. To me the hives are just an indication that the resveratrol is getting in my system more topically than orally.

Albert

Tintinet: this is my point. I'm not saying this is a clincher argument, but Albert _is_ showing us a relationship between indication H (hives), substance R (resv) and an inhibitor C (claritin). Apparently, R(oral) in sufficient doses produces H unless inhibited by C while R(topical) produces systemic H in much lower doses.
If we could persuade Albert to do the following, we would be that much the wiser:

1) Find out if where the C / R(topical) cutoff point lies, i.e. at what doses does C start to inhibit R(topical) - the obvious way would be to reduce doses of R(topical) until C has an inhibitory effect
2) Find out if 2*C will inhibit 2*R(topical) when the cutoff point has been determined to see if the relationship is linear (an indication of this, not a proof)
3) Find out how big a dose of R(oral) it takes to break the inhibitory effect of C determined in 1

So Albert, are you willing to be our guinea pig :shifty:

[ilanso]

This would only help determine what dose of loratadine is needed to counteract the skin side effects resv. and only be of interest to Albert (or a few other allergic people).

So Albert, are you willing to be our guinea pig?

A more intriguing quest would be that for a real guinea pig (preferably a knockout pig, since they are closer to us, not only size-wise) to similarly act as a resvemeter. Our testing / calibration / administration route problems would be cheaply solved.
I am curious if anyone in Albert's family shares this sensitivity. The new deCODEme.com personal "DNA reading" service might be helpful in identifying the individual nucleotide(s) involved (wishful thinking). And it only costs $985 per relative. :thumb:

[missminni]

I think this is going in the wrong direction. I don't think it's the source of resveratrol that's the problem since I've gotten hives from multiple different batches. To me the hives are just an indication that the resveratrol is getting in my system more topically than orally.

Albert

I see your point. I definitely agree that more res gets absorbed
through cutaneous application with DMSO than taken orally. I've noticed that.

[asnufu]

This would only help determine what dose of loratadine is needed to counteract the skin side effects resv. and only be of interest to Albert (or a few other allergic people).

So Albert, are you willing to be our guinea pig?

A more intriguing quest would be that for a real guinea pig (preferably a knockout pig, since they are closer to us, not only size-wise) to similarly act as a resvemeter. Our testing / calibration / administration route problems would be cheaply solved.
I am curious if anyone in Albert's family shares this sensitivity. The new deCODEme.com personal "DNA reading" service might be helpful in identifying the individual nucleotide(s) involved (wishful thinking). And it only costs $985 per relative. :thumb:

Well, yeah, and as a side effect, it would give an indication of the R(oral)/R(topical) bioavailability ratio, if you believe the hives are caused only the R and not by the method of ingestion.

[Anthony_Loera]

Just a quick FYI for a possible new way to administer in the future:

(Thanks Steve for the email!)

FYI. -- Steve

"DNA Syringe"

December 3, 2007; (New Scientist) -- Apply an electric field to a cell,
and the permeability of the cell membrane increases significantly in a
process known as electroporation. Researchers have used this technique
for some time to inject cells with drugs and even pieces of DNA, but will
only work in a lab dish. Now Marlin Mickle and Michael Lovett, both at
the University of Pittsburgh, have come up with a device that does a similar
kind of thing for cells inside the body.

The machine is a hand-held electrical stimulator that incorporates a syringe.
The idea is that the DNA to be inserted into cells is injected into the body,
which is then zapped with an electric current, allowing the DNA to travel
across cell membranes.

Mickle and Lovett say the device can also be used to improve wound
healing and to stimulate peripheral nerves that have suffered damage.
Electrical stimulation can kill cells, though, so the machine will need careful
testing before it is proven safe to use.

-- Justin Mullins



A

Edited by Anthony_Loera, 08 December 2007 - 01:58 PM.

[missminni]

update 92 year old father and resveratrol:
Last night my dad, at my suggestion, took
400 mg of 98% res powder in addition to his R300 capsule before bed.
He said he slept through the night (this is highly unusual for him)
and had the best night sleep he's had in many years.
He also woke up pain free and did not have to take a vicadan.
That's amazing. Also his right hand which was numb and
he was unable to grasp with prior to taking Res
is now 75% improved. He will be taking the addtional
400mg powder three times a day with the R300 capsule
from now on.
He is so pleased with the results.

P.S.
I think that results with Res are more noticeable when you
actually have issues like he has.
When nothing is wrong with
you, you may not notice any difference.

[asnufu]

update 92 year old father and resveratrol:
Last night my dad, at my suggestion, took
400 mg of 98% res powder in addition to his R300 capsule before bed.
He said he slept through the night (this is highly unusual for him)
and had the best night sleep he's had in many years.
He also woke up pain free and did not have to take a vicadan.
That's amazing. Also his right hand which was numb and
he was unable to grasp with prior to taking Res
is now 75% improved. He will be taking the addtional
400mg powder three times a day with the R300 capsule
from now on.
He is so pleased with the results.

P.S.
I think that results with Res are more noticeable when you
actually have issues like he has.
When nothing is wrong with
you, you may not notice any difference.

Thanks for these updates, missminni - it's useful information, even if it is "only" anecdotal. I too think it's becoming more and more clear that you need to have some ailment - arthritis, autoimmune disease, or simply progressed aging as with your father, to experience tangible, hard-to-dismiss effects of R. However, I'm hoping that us young'uns (*coughs* I'm 34) in good health may experience retarded aging, of course, but also increased stamina and peak performance. I certainly intend to test your DMSO method with myself and a barbell - I know how much and for how long I can squat on an off-day and on a peak day; we'll see if the DMSO method makes any difference.

[missminni]

Thanks for these updates, missminni - it's useful information, even if it is "only" anecdotal. I too think it's becoming more and more clear that you need to have some ailment - arthritis, autoimmune disease, or simply progressed aging as with your father, to experience tangible, hard-to-dismiss effects of R. However, I'm hoping that us young'uns (*coughs* I'm 34) in good health may experience retarded aging, of course, but also increased stamina and peak performance. I certainly intend to test your DMSO method with myself and a barbell - I know how much and for how long I can squat on an off-day and on a peak day; we'll see if the DMSO method makes any difference.

I absolutely agree. Wish I could have started it sooner. Thanks goodness I was doing Aloe all these years. I really do attribute my good health and youthful appearance to it, since I really didn't do anything else all that different from my friends who aged
and got all sorts of ailments.

[enzyme]

I've been on a relatively heavy dose of resveratrol (Revgenetic's R500) for a couple of weeks, and I'm wondering how I can make sure that I'm getting the most out of it: to get the health/longevity benefits, and to make sure I'm not throwing all this money down the toilet.

Does anyone have any evidence for taking it one way or the other:
• One large dose vs. Several smaller doses spaced throughout the day
• On an empty stomach vs with a meal
• At the beginning of the day vs at the end
• Dissolved into alcohol (?) and drunk vs. taken with water
• Taken with quercetin or any other substance that enhances uptake & prevents metabolism or elimination by the body

I guess there's a question of whether metabolism is a good thing or not. I've read that glucuronidation/sulfation in the liver actually helps carry the molecule to its intended cell nucleus targets.

I've found it's a bit hard to separate some people's contentions & practices from what we've read with respect to other vitamins. For instance, vitamin C should be spaced out during the day, hence time-release formulas, but for gene-flipping that might not be ideal for resveratrol. (I don't know) The same for on an empty stomach vs with a meal – sometimes it seems like a philosophical discussion more than anything else.

Would be interested to hear what others have read and found out. (I realize that there are still a lot of unknowns, but maybe some have found more info than I have)

I've been taking 10mg/kg+ having joined Paul & Kitty Wakfer's purchase of resveratrol powder. 2hrs later my urine is frothy & has a characteristic odour as it all starts coming out again.

My blood work/urinalysis is fine. In fact, my previously abnormal LFT's are now normal. However, I am plagued by tendonopathy & metatarsalgia. This may be (probably is) coincidental.

Two things:

(1) I would like to be able to recover/recycle all the resveratrol sulphate & glucuronide that I am now peeing onto my Jasmine plants for my personal (re)use.

(2) I would like to see more scientific study using the sulphate/glucuronide conjugates as mediators of life extension as this is what is what is circulating in me as opposed to the aglycone which is what the worms have been getting. Does anyone even know if the conjugates have any activity?

(3) Will someone please turn the heating down because it is always far too hot in here ... in fact, everywhere.

Frothily yours,

[niner]

I've been on a relatively heavy dose of resveratrol ...(lead post)

I've been taking 10mg/kg+ having joined Paul & Kitty Wakfer's purchase of resveratrol powder. 2hrs later my urine is frothy & has a characteristic odour as it all starts coming out again.

My blood work/urinalysis is fine. In fact, my previously abnormal LFT's are now normal. However, I am plagued by tendonopathy & metatarsalgia. This may be (probably is) coincidental.

Two things:

(1) I would like to be able to recover/recycle all the resveratrol sulphate & glucuronide that I am now peeing onto my Jasmine plants for my personal (re)use.

(2) I would like to see more scientific study using the sulphate/glucuronide conjugates as mediators of life extension as this is what is what is circulating in me as opposed to the aglycone which is what the worms have been getting. Does anyone even know if the conjugates have any activity?

(3) Will someone please turn the heating down because it is always far too hot in here ... in fact, everywhere.

Frothily yours,

Welcome to Resville, enzyme! (I see you're new around here.)

The tendonopathy and metatarsalgia is probably not a coincidence. See here and the tendonitis thread within: http://www.imminst.o...&...st&p=212553

(1) Fuggedaboudit! Too expensive to do the purification and chemistry. High purity resveratrol prices (powder or even caps, if you'd like) are coming down in price. See the resveratrol price watch thread: http://www.imminst.o...&...st&p=161168

(2) So would I. I've even seen a paper in the literature where they said someone should look into the activity of resveratrol metabolites.

Edited by niner, 09 December 2007 - 05:46 AM.

[bentl]

Thanks goodness I was doing Aloe all these years. I really do attribute
my good health and youthful appearance to it, since I really didn't do anything
else all that different from my friends who aged and got all sorts of ailments.

(my apologies for going off topic)

Hi missminni,

I've been thinking of adding Aloe to my life for some time...even have a gallon in the refrigerator.

I would appreciate it if you would tell us how much aloe you take, how you take it,
how often, what kind, etc.

Thanks

Edited by bentl, 09 December 2007 - 08:21 AM.

[missminni]

Thanks goodness I was doing Aloe all these years. I really do attribute
my good health and youthful appearance to it, since I really didn't do anything
else all that different from my friends who aged and got all sorts of ailments.

(my apologies for going off topic)

Hi missminni,

I've been thinking of adding Aloe to my life for some time...even have a gallon in the refrigerator.

I would appreciate it if you would tell us how much aloe you take, how you take it,
how often, what kind, etc.

Thanks

I started a thread about it last week that met with mostly skepticism and ridicule. I guess people think if it isn't a pill or chemical it's not worthy.
The main thing for me is that I used the fresh leaf, not the already processed aloe like you have in your frig. I personally don't believe that it
holds the benefits it does unless it's fresh from the leaf. Here's the thread:
http://www.imminst.o...mp;hl=Aloe Vera
I'd be happy to answer any other questions you have about it on that thread.

Edited by missminni, 09 December 2007 - 01:58 PM.

[enzyme]

I've been on a relatively heavy dose of resveratrol ...(lead post)

I've been taking 10mg/kg+ having joined Paul & Kitty Wakfer's purchase of resveratrol powder. 2hrs later my urine is frothy & has a characteristic odour as it all starts coming out again.

My blood work/urinalysis is fine. In fact, my previously abnormal LFT's are now normal. However, I am plagued by tendonopathy & metatarsalgia. This may be (probably is) coincidental.

Two things:

(1) I would like to be able to recover/recycle all the resveratrol sulphate & glucuronide that I am now peeing onto my Jasmine plants for my personal (re)use.

(2) I would like to see more scientific study using the sulphate/glucuronide conjugates as mediators of life extension as this is what is what is circulating in me as opposed to the aglycone which is what the worms have been getting. Does anyone even know if the conjugates have any activity?

(3) Will someone please turn the heating down because it is always far too hot in here ... in fact, everywhere.

Frothily yours,

Welcome to Resville, enzyme! (I see you're new around here.)

The tendonopathy and metatarsalgia is probably not a coincidence. See here and the tendonitis thread within: http://www.imminst.o...&...st&p=212553

(1) Fuggedaboudit! Too expensive to do the purification and chemistry. High purity resveratrol prices (powder or even caps, if you'd like) are coming down in price. See the resveratrol price watch thread: http://www.imminst.o...&...st&p=161168

(2) So would I. I've even seen a paper in the literature where they said someone should look into the activity of resveratrol metabolites.

Thanks Niner,

I have some thoughts about resveratrol & tendons which I want to explore - I'll do it in that thread.

[geo12the]

(2) I would like to see more scientific study using the sulphate/glucuronide conjugates as mediators of life extension as this is what is what is circulating in me as opposed to the aglycone which is what the worms have been getting. Does anyone even know if the conjugates have any activity?


(2) So would I. I've even seen a paper in the literature where they said someone should look into the activity of resveratrol metabolites.

Here is a paper that suggests that glycosylated resveratrol is inactive:

Nutrition and Cancer
2007, Vol. 58, No. 1, Pages 66-74
Kineman‌ et al.
Department of Food Science and Human Nutrition, Iowa State University, Ames

Transgenic Alfalfa That Accumulates Piceid (Trans-Resveratrol-3-O-Beta-D-glucopyranoside) Requires the Presence of Beta -Glucosidase to Inhibit the Formation of Aberrant Crypt Foci in the Colon of CF-1 Mice

Plants have been genetically enhanced to produce a number of products for agricultural, industrial and pharmaceutical purposes. This technology could potentially be applied to providing chemoprevention strategies to the general population. Resveratrol (3,5,4'-trihydroxystilbene) is a compound that has been shown to have protective activity against a number of cancers and could be an ideal candidate for such an application. Alfalfa that was genetically modified to express resveratrol-synthase was used as a model in applying biotechnological approaches to cancer prevention. The transgenic alfalfa, which accumulates resveratrol as a glucoside (piceid = trans-resveratrol-3-O-Beta-D-glucopyranoside) (152 ± 17.5 μg piceid/g dry weight), was incorporated into a standard mouse diet at 20% of the diet by weight and fed for 5 wk to 6-wk-old, female CF-1 mice (N = 17–30) that were injected with a single dose of azoxymethane (5 mg/kg body weight). While the addition of resveratrol-aglycone (20 mg/kg diet) to the basal diet reduced the number of aberrant crypt foci/mouse, the transgenic alfalfa did not inhibit the number, size, or multiplicity of aberrant crypt foci in the colon of the CF-1 mice relative to control alfalfa which does not accumulate resveratrol-glucoside. However, diets containing transgenic alfalfa with an exogenous Beta-glucosidase (860 U/kg diet) did significantly inhibit the number of aberrant crypt foci in the distal 2 cm of the colon of the mice relative to mice fed diets containing the transgenic alfalfa without the enzyme (P < 0.05; Fisher's Combination of p-values). The Beta-glucosidase alone appeared to have no effect on the inhibition of aberrant crypt foci. These results suggest that piceid in transgenic piceid-accumulating alfalfa was not bioavailable.

[niner]

(2) I would like to see more scientific study using the sulphate/glucuronide conjugates as mediators of life extension as this is what is what is circulating in me as opposed to the aglycone which is what the worms have been getting. Does anyone even know if the conjugates have any activity?

(2) So would I. I've even seen a paper in the literature where they said someone should look into the activity of resveratrol metabolites.

Here is a paper that suggests that glycosylated resveratrol is inactive:

Nutrition and Cancer
2007, Vol. 58, No. 1, Pages 66-74
Kineman‌ et al.
Department of Food Science and Human Nutrition, Iowa State University, Ames

Transgenic Alfalfa That Accumulates Piceid (Trans-Resveratrol-3-O-Beta-D-glucopyranoside) Requires the Presence of Beta -Glucosidase to Inhibit the Formation of Aberrant Crypt Foci in the Colon of CF-1 Mice

Plants have been genetically enhanced to produce a number of products for agricultural, industrial and pharmaceutical purposes. This technology could potentially be applied to providing chemoprevention strategies to the general population. Resveratrol (3,5,4'-trihydroxystilbene) is a compound that has been shown to have protective activity against a number of cancers and could be an ideal candidate for such an application. Alfalfa that was genetically modified to express resveratrol-synthase was used as a model in applying biotechnological approaches to cancer prevention. The transgenic alfalfa, which accumulates resveratrol as a glucoside (piceid = trans-resveratrol-3-O-Beta-D-glucopyranoside) (152 ± 17.5 μg piceid/g dry weight), was incorporated into a standard mouse diet at 20% of the diet by weight and fed for 5 wk to 6-wk-old, female CF-1 mice (N = 17–30) that were injected with a single dose of azoxymethane (5 mg/kg body weight). While the addition of resveratrol-aglycone (20 mg/kg diet) to the basal diet reduced the number of aberrant crypt foci/mouse, the transgenic alfalfa did not inhibit the number, size, or multiplicity of aberrant crypt foci in the colon of the CF-1 mice relative to control alfalfa which does not accumulate resveratrol-glucoside. However, diets containing transgenic alfalfa with an exogenous Beta-glucosidase (860 U/kg diet) did significantly inhibit the number of aberrant crypt foci in the distal 2 cm of the colon of the mice relative to mice fed diets containing the transgenic alfalfa without the enzyme (P < 0.05; Fisher's Combination of p-values). The Beta-glucosidase alone appeared to have no effect on the inhibition of aberrant crypt foci. These results suggest that piceid in transgenic piceid-accumulating alfalfa was not bioavailable.

Thanks for the paper, geo12the. This tells us that an oral dose of a resveratrol glucopyranoside (piceid) is inactive, but there are two differences between this and the metabolites of resveratrol. One is that the resveratrol metabolites are already in the blood, whereas we don't know the distribution of piceid. Does it get absorbed through the gut? Its higher water solubility compared to resveratrol would argue that it not get in as easily. On the other hand, it might hitch a ride on a glucose transporter, so we'd need to know the oral pharmacokinetics of piceid to sort that out. The second difference is in the structure of the glycone, where piceid's is a neutral glucose and the glucuronic acid that is attached to resveratrol in the liver and gut is a glucose with a carboxylate on the #6 carbon. If the carboxylate were a big determinant of recognition by a glucuronidase, then maybe the neutral glucose wouldn't be cleaved. In other words, piceid is not an exact model of the glucuronide metabolite.

If oral piceid worked as well as resveratrol, that would be a good argument for active metabolites, but I'm not sure that we can infer the reverse because it doesn't work. They say in the last line of the abstract that their results indicate that piceid is not bioavailable. I don't think they can really say that though, in that it may be getting absorbed, but not having a pharmacological effect. In other words, it might not be getting into plasma, or it might not work, or both.

[enzyme]

(2) I would like to see more scientific study using the sulphate/glucuronide conjugates as mediators of life extension as this is what is what is circulating in me as opposed to the aglycone which is what the worms have been getting. Does anyone even know if the conjugates have any activity?

(2) So would I. I've even seen a paper in the literature where they said someone should look into the activity of resveratrol metabolites.

Here is a paper that suggests that glycosylated resveratrol is inactive:

Nutrition and Cancer
2007, Vol. 58, No. 1, Pages 66-74
Kineman‌ et al.
Department of Food Science and Human Nutrition, Iowa State University, Ames

Transgenic Alfalfa That Accumulates Piceid (Trans-Resveratrol-3-O-Beta-D-glucopyranoside) Requires the Presence of Beta -Glucosidase to Inhibit the Formation of Aberrant Crypt Foci in the Colon of CF-1 Mice

Plants have been genetically enhanced to produce a number of products for agricultural, industrial and pharmaceutical purposes. This technology could potentially be applied to providing chemoprevention strategies to the general population. Resveratrol (3,5,4'-trihydroxystilbene) is a compound that has been shown to have protective activity against a number of cancers and could be an ideal candidate for such an application. Alfalfa that was genetically modified to express resveratrol-synthase was used as a model in applying biotechnological approaches to cancer prevention. The transgenic alfalfa, which accumulates resveratrol as a glucoside (piceid = trans-resveratrol-3-O-Beta-D-glucopyranoside) (152 ± 17.5 μg piceid/g dry weight), was incorporated into a standard mouse diet at 20% of the diet by weight and fed for 5 wk to 6-wk-old, female CF-1 mice (N = 17–30) that were injected with a single dose of azoxymethane (5 mg/kg body weight). While the addition of resveratrol-aglycone (20 mg/kg diet) to the basal diet reduced the number of aberrant crypt foci/mouse, the transgenic alfalfa did not inhibit the number, size, or multiplicity of aberrant crypt foci in the colon of the CF-1 mice relative to control alfalfa which does not accumulate resveratrol-glucoside. However, diets containing transgenic alfalfa with an exogenous Beta-glucosidase (860 U/kg diet) did significantly inhibit the number of aberrant crypt foci in the distal 2 cm of the colon of the mice relative to mice fed diets containing the transgenic alfalfa without the enzyme (P < 0.05; Fisher's Combination of p-values). The Beta-glucosidase alone appeared to have no effect on the inhibition of aberrant crypt foci. These results suggest that piceid in transgenic piceid-accumulating alfalfa was not bioavailable.

Thanks for the paper, geo12the. This tells us that an oral dose of a resveratrol glucopyranoside (piceid) is inactive, but there are two differences between this and the metabolites of resveratrol. One is that the resveratrol metabolites are already in the blood, whereas we don't know the distribution of piceid. Does it get absorbed through the gut? Its higher water solubility compared to resveratrol would argue that it not get in as easily. On the other hand, it might hitch a ride on a glucose transporter, so we'd need to know the oral pharmacokinetics of piceid to sort that out. The second difference is in the structure of the glycone, where piceid's is a neutral glucose and the glucuronic acid that is attached to resveratrol in the liver and gut is a glucose with a carboxylate on the #6 carbon. If the carboxylate were a big determinant of recognition by a glucuronidase, then maybe the neutral glucose wouldn't be cleaved. In other words, piceid is not an exact model of the glucuronide metabolite.

If oral piceid worked as well as resveratrol, that would be a good argument for active metabolites, but I'm not sure that we can infer the reverse because it doesn't work. They say in the last line of the abstract that their results indicate that piceid is not bioavailable. I don't think they can really say that though, in that it may be getting absorbed, but not having a pharmacological effect. In other words, it might not be getting into plasma, or it might not work, or both.

Glucuronides might/may not have biological activity but they make great prodrugs in anti-cancer therapy because cancer cells overexpress beta-glucuronidase. Resveratrol is absorbed & then conjugated rapidly. Resveratrol glucuronide gets distributed everywhere. It happily latches onto tumour specific targets (e.g. breast cancer-associated antigen amongst many) where it is converted back to resveratrol because of elevated tumor b-glucuronidase activity. Then it zaps the cancer cell - even the smallest metastasis. It finds them. So, it is bioavailable - when & wear it matters. Not in the blood - on the cancer cell. If I were Sirtris I would modify it to improve its anticancer activity. They would have no trouble getting trials done & might give us chemotherapy that does not make you feel really shitty. Imagine the revenue from that ...

[bixbyte]

I've been taking 10mg/kg+ having joined Paul & Kitty Wakfer's purchase of resveratrol powder. 2hrs later my urine is frothy & has a characteristic odour as it all starts coming out again.

My blood work/urinalysis is fine. In fact, my previously abnormal LFT's are now normal. However, I am plagued by tendonopathy & metatarsalgia. This may be (probably is) coincidental.


(1) I would like to be able to recover/recycle all the resveratrol sulphate & glucuronide that I am now peeing onto my Jasmine plants for my personal (re)use.

Frothily yours,

Can you put your frothy liquid into a brandy sniffer and just enjoy it? :biggrin:

Cheers! :smile:

[niner]

Glucuronides might/may not have biological activity but they make great prodrugs in anti-cancer therapy because cancer cells overexpress beta-glucuronidase. Resveratrol is absorbed & then conjugated rapidly. Resveratrol glucuronide gets distributed everywhere. It happily latches onto tumour specific targets (e.g. breast cancer-associated antigen amongst many) where it is converted back to resveratrol because of elevated tumor b-glucuronidase activity. Then it zaps the cancer cell - even the smallest metastasis. It finds them. So, it is bioavailable - when & wear it matters. Not in the blood - on the cancer cell. If I were Sirtris I would modify it to improve its anticancer activity. They would have no trouble getting trials done & might give us chemotherapy that does not make you feel really shitty. Imagine the revenue from that ...

Resveratrol might really be useful for cancer. This is a pretty cool functionality. We don't actually know that the resveratrol glucuronide is distributed everywhere, though. It probably isn't, since the point of glucuronidation (and all xenobiotic metabolism, for that matter) is to increase the water solubility of compounds, causing them to partition away from lipid tissues and ultimately into the urine. As I recall, the res glucuronides have a pretty OK half life in blood, so they don't wash out super-rapidly, like some glucuronides do. The beta glucuronidase emitted by tumors seems to be a function of necrosis rather than being intrinsic to the cell, at least from my reading. Thus the glucuronide prodrugs work better in larger tumors. It may not work on small metastases. The glucuronide makes it harder for a compound to penetrate a cell, so glucuronides as prodrugs work best when there's an extracellular glucuronidase activity. I don't know how common that is, aside from necrotic tissue and in the intestines.

[ilanso]

enzyme: Resveratrol glucuronide gets distributed everywhere. It happily latches onto tumour specific targets (e.g. breast cancer-associated antigen amongst many) where it is converted back to resveratrol because of elevated tumor b-glucuronidase activity. Then it zaps the cancer cell

Zap? How? Has the mechanism been elucidated?

[enzyme]

Glucuronides might/may not have biological activity but they make great prodrugs in anti-cancer therapy because cancer cells overexpress beta-glucuronidase. Resveratrol is absorbed & then conjugated rapidly. Resveratrol glucuronide gets distributed everywhere. It happily latches onto tumour specific targets (e.g. breast cancer-associated antigen amongst many) where it is converted back to resveratrol because of elevated tumor b-glucuronidase activity. Then it zaps the cancer cell - even the smallest metastasis. It finds them. So, it is bioavailable - when & wear it matters. Not in the blood - on the cancer cell. If I were Sirtris I would modify it to improve its anticancer activity. They would have no trouble getting trials done & might give us chemotherapy that does not make you feel really shitty. Imagine the revenue from that ...

Resveratrol might really be useful for cancer. This is a pretty cool functionality. We don't actually know that the resveratrol glucuronide is distributed everywhere, though. It probably isn't, since the point of glucuronidation (and all xenobiotic metabolism, for that matter) is to increase the water solubility of compounds, causing them to partition away from lipid tissues and ultimately into the urine. As I recall, the res glucuronides have a pretty OK half life in blood, so they don't wash out super-rapidly, like some glucuronides do. The beta glucuronidase emitted by tumors seems to be a function of necrosis rather than being intrinsic to the cell, at least from my reading. Thus the glucuronide prodrugs work better in larger tumors. It may not work on small metastases. The glucuronide makes it harder for a compound to penetrate a cell, so glucuronides as prodrugs work best when there's an extracellular glucuronidase activity. I don't know how common that is, aside from necrotic tissue and in the intestines.

[enzyme]

Glucuronides might/may not have biological activity but they make great prodrugs in anti-cancer therapy because cancer cells overexpress beta-glucuronidase. Resveratrol is absorbed & then conjugated rapidly. Resveratrol glucuronide gets distributed everywhere. It happily latches onto tumour specific targets (e.g. breast cancer-associated antigen amongst many) where it is converted back to resveratrol because of elevated tumor b-glucuronidase activity. Then it zaps the cancer cell - even the smallest metastasis. It finds them. So, it is bioavailable - when & wear it matters. Not in the blood - on the cancer cell. If I were Sirtris I would modify it to improve its anticancer activity. They would have no trouble getting trials done & might give us chemotherapy that does not make you feel really shitty. Imagine the revenue from that ...

Resveratrol might really be useful for cancer. This is a pretty cool functionality. We don't actually know that the resveratrol glucuronide is distributed everywhere, though. It probably isn't, since the point of glucuronidation (and all xenobiotic metabolism, for that matter) is to increase the water solubility of compounds, causing them to partition away from lipid tissues and ultimately into the urine. As I recall, the res glucuronides have a pretty OK half life in blood, so they don't wash out super-rapidly, like some glucuronides do. The beta glucuronidase emitted by tumors seems to be a function of necrosis rather than being intrinsic to the cell, at least from my reading. Thus the glucuronide prodrugs work better in larger tumors. It may not work on small metastases. The glucuronide makes it harder for a compound to penetrate a cell, so glucuronides as prodrugs work best when there's an extracellular glucuronidase activity. I don't know how common that is, aside from necrotic tissue and in the intestines.

Well, when in solution the glucuronide will go everywhere the circulation goes. If it meets a glucuronidase - it releases resveratrol. Glucuronidation isn't just elimination, it can be regarded as a transport mechanism.

The beta glucuronidase emitted by tumors probably is a function of necrosis as you say - but as a lysosomal marker enzyme for phagocytic cells which one might expect to be very active in areas of necrosis. However, it is also expressed on cancer cell surface membranes. It is active in tissue matrix degradation which is necessary before the metastatic cell can break free of its immediate surrounds & get into blood/lymph wherever. Anyway, the point is that glucuronide prodrug & its cellular target end up in the same compartment.

Tissue (ECM) degredation is a problem that most metastasizing cells will meet & so beta glucuronidase markers might be on most metastatic cells. If so, that is a good target to go for wether you are mother evolution or a pharma dude. IDK if the work been done yet. Has it? Are you in a position to catagorically state that the tumour marker thing has been done & dusted & that cell membrane beta glucuronidase is not usually expressed on met cell membranes?

I suspect we don't know if the glucuronide prodrugs work best in large tumours - what we do know is that they have mainly been used against large tumours because that was how the trials were setup. You could not easily investigate mets in this way because how would you know they were there? However, I do know that it would be a non-sequitur to conclude they don't work against mets because the trials were done against solid tumours.

[enzyme]

enzyme: Resveratrol glucuronide gets distributed everywhere. It happily latches onto tumour specific targets (e.g. breast cancer-associated antigen amongst many) where it is converted back to resveratrol because of elevated tumor b-glucuronidase activity. Then it zaps the cancer cell

Zap? How? Has the mechanism been elucidated?

Well, maybe not "zap" though it does roll off the tongue easier than "exerts its chemoprotective action"

It works against cancer cells in loads of ways - wether that translates upwards to protecting me & thee remains to be proven

There are trials under way

No doubt someone will fiddle with the molecule & make it even more useful in this field shortly