Not always good to suppress NFKB?
hmm 26 May 2008
About 3 weeks after this I was disappointed to have a herpes outbreak, particularly because outbreaks usually occur once a year and I had just had an outbreak 2 months earlier. It seemed disappointing to think that the RSV was hurting in this area rather than helping. I decided to force the issue a bit and double the dosage (4 grams per day) to give the RSV twice the opportunity to have either a negative or positive effect. (The dose might actually have been effectively more than doubled because I also started mixing my RSV-vodka solution into a half glass of lecithin-dissolved-in-water to improve delivery.) Within a few days, not only did I get a small "extra" outbreak near the original herpes outbreak, but I also got a case of shingles (first time).
Herpes simplex is pretty flaky so I try not to read too much into when it comes and goes, though it does seem to coincide fairly predictably with phases of sleep deprivation and poor nutrition for me. But herpes zoster was completely unexpected and from what I am reading, usually strikes older people with zonked-out immune systems. However, it has been at least 6 months since I had even a mild cold, and that was probably a year after the previous cold.
I'm trying to sort out possible implications of my experience, but I'm a bit lost. One scenario I speculated was that the RSV is blocking an inflammatory agent of my immune system (nfkb?). Blocking nfkb response stops inflammation (and accompanying aches and pains), but perhaps the nfkb (or whatever inflammatory agent is being blocked) is responsible for triggering some other part of my immune system to fight herpes virus replication. So even as RSV blocks inflammation, it is perhaps also deterring my primary defense against herpes (both simplex and zoster) recurrence?
Right off the bat, however, I question that speculation. If the speculation is correct, I would have expected to see more folks reporting cases of shingles on this site (especially since posters on this site seem to be increasing their dosage levels, and especially because it is my understanding that a large percentage of people in general have had chickenpox in their childhood). I have read about rashes, hives and eczema on this site, but not shingles.
In weighing my future RSV options (I've stopped RSV for now), I am questioning what actual benefits I am getting from RSV. I believe that if I had taken RSV even 10 years ago, I might not have noticed any benefits. But now, in my 50's, there are lots of pains to relieve that didn't exist 10 years ago. The pain relief is fairly crucial as far as continuing my present lifestyle.
But what is the nature of this pain relief? Is it simply buying me an extra bit of time while I (painlessly) grind the last vestiges of hip and knee cartilages down to nothing? Or is RSV effecting some actual repair upon my joints? The heels feel great, but without the warning signal of the pain, am I now at an extra risk of popping a tendon?
It appears like I don't have much of a chance of ever ramping up to amounts equivalent to those used in the famous mice experiments, so those benefits seem well out of reach. Besides the apparent breakdown in herpes defenses, higher dosages of RSV also seem to cause unbelievably rancid farts (the smallest of which must be contained at all costs – related to sulfonation?) along with unpredictable bowel movements ranging from diarrhea to loose stools.
My inclination at this time is to get all healed up and then start back with a long term regimen of maybe a gram of powder per day, which should be enough to maintain the pain relief with (hopefully) minimal negative side effects. I hope my shingles experience is unique to my own personal circumstances.
Edited by hmm, 26 May 2008 - 07:34 PM.
Anthony_Loera 26 May 2008
http://scholar.googl...r...p;hl=en&lr=
Resveratrol and "varicella-zoster" herpes zoster:
http://scholar.googl...amp;btnG=Search
Resveratrol and Joints:
http://www.imminst.o...FKB-t22224.html
Just glancing at some of the studies in animals, it decreases cartilage destruction and inhibits some of the herpes replication.
(of course, we are not big rats... so human studies are needed.)
Edited by Anthony_Loera, 26 May 2008 - 09:00 PM.
hmm 26 May 2008
But I am not finding a study where this test is being done with oral application of RSV. Maybe there is some kind of threshhold amount of RSV taken orally and repeatedly that would keep every cell in the body soaked so thoroughly with RSV as to deny replication of herpes (zoster or simplex) virus. If there is, it appears I didn't hit it at 2 grams in the morning and 2 grams at night. So, if I don't ingest enough to soak every single one of my cells thoroughly enough with RSV, perhaps I end up in some inbetween-area where my normal defenses are disabled but have not been replaced with anything substantial enough to prevent viral replication in all areas of my body...
Edited by hmm, 26 May 2008 - 09:57 PM.
Anthony_Loera 26 May 2008
perhaps I end up in some inbetween-area where my normal defenses are disabled but have not been replaced with anything substantial enough to prevent viral replication in all areas of my body.
Perhaps your normal defenses are enhanced, but because resveratrol is metabolized within 16 minutes of oral intake, you may need a topical solution to work on the very specific issue that you have.
A
Edited by Anthony_Loera, 26 May 2008 - 10:38 PM.
hmm 26 May 2008
Actually, one reason I wanted to post this is for the record, so we don't end up in a situation where it winds up happening to a bunch of people who all think they are unique examples simply because none of them ever posted their experience.
Edited by hmm, 26 May 2008 - 11:13 PM.
FunkOdyssey 26 May 2008
hmm: As far as I'm concerned, it seems unlikely for your experience to have been coincidental, especially when you pressed the issue and produced a shingles outbreak with an even higher dose.
Edited by FunkOdyssey, 26 May 2008 - 11:11 PM.
hmm 26 May 2008
I don't feel as certain, Funk. I kind of always thought that just about everybody has had chickenpox. And a lot of people have been taking dosages of RSV as high and higher than mine, so there should have been more than one case of shingles so far.hmm: As far as I'm concerned, it seems unlikely for your experience to have been coincidental, especially when you pressed the issue and produced a shingles outbreak with an even higher dose.
One speculation I had is that the population on this web site might be less prone to my shingles experience because they tend to be all "buffed out" on other effective supplements.
Edited by hmm, 26 May 2008 - 11:58 PM.
Brainbox 27 May 2008
malbecman 27 May 2008
Kang SS, Cuendet M, Endringer DC, Croy VL, Pezzuto JM, Lipton MA.
Synthesis and biological evaluation of a library of resveratrol analogues as
inhibitors of COX-1, COX-2 and NF-kappaB.
Bioorg Med Chem. 2008 May 16; [Epub ahead of print]
PMID: 18487053 [PubMed - as supplied by publisher]
Because resveratrol has such a broad spectrum of effects, it will probably also have relative high dependency on the individual (with his/her own underlying pathology and/or genetics) that is taking it.
Mind 27 May 2008
Someone slap me if I am way off base here.
maxwatt 27 May 2008
J Virol. 2006 Jun;80(11):5113-24.
Inhibition of the NF-kappaB pathway by varicella-zoster virus in vitro and in human epidermal cells in vivo.Jones JO, Arvin AM.
Stanford University School of Medicine, 300 Pasteur Drive, Rm. G312, Stanford, CA 94305-5208, USA. jeremy.jones@ucsf.edu
Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella and herpes zoster. Using human cellular DNA microarrays, we found that many nuclear factor kappa B (NF-kappaB)-responsive genes were down-regulated in VZV-infected fibroblasts, suggesting that VZV infection inhibited the NF-kappaB pathway. The activation of this pathway causes a cellular antiviral response, including the production of alpha/beta interferon, cytokines, and other proteins that restrict viral infection. In these experiments, we demonstrated that VZV interferes with NF-kappaB activation in cultured fibroblasts and in differentiated epidermal cells in skin xenografts of SCIDhu mice infected in vivo. VZV infection of fibroblasts caused a transient nuclear translocation of p50 and p65, the canonical NF-kappaB family members. In a process that was dependent upon the presence of infectious VZV, these proteins rapidly became sequestered in the cytoplasm of VZV-infected cells. Exclusion of NF-kappaB proteins from nuclei was associated with the continued presence of IkappaBalpha, which binds p50 and p65 and prevents their nuclear accumulation. IkappaBalpha levels did not diminish even though the protein became phosphorylated and ubiquitinated, as determined based on detection of the characteristic high-molecular-weight form of the protein, and the 26S proteasome remained functional in VZV-infected cells. VZV infection also inhibited the characteristic degradation of IkappaBalpha that is induced by exposure of fibroblasts to tumor necrosis factor alpha. As expected, herpes simplex virus 1 caused the persistent nuclear translocation of NF-kappaB proteins, which has been shown to facilitate its replication, whereas VZV infection progressed without persistent NF-kappaB nuclear localization. We suggest that VZV has evolved a mechanism to limit host cell antiviral defenses by sequestering NF-kappaB proteins in the cytoplasm, a strategy that appears to be unique among the herpesviruses.
PMID: 16698992
The full paper is available free HERE
Mixter 27 May 2008
FULL NFKB knockout apparently produces liver cirrhosis...
http://www.nature.co...mt2004586a.html
we need most of those function encoding genes, supplementation
just down-regulates it a bit, at most it should be to the extend
to which gene expression changes with old age.
But (it's even mentioned in Ending Aging) gene expression is
a (compensatory) response to aging, not a cause, and some
of it is beneficial (while some of the response runs haywire
like inflammation/immune system in atherosclerosis)...
Good reason to limit resveratrol intake, and anything that
influences chromatin directly, to sane levels. An exception
are methylating agents like folate, TMG,B12, etc., at least
if you stay sane (below 1mg of folate/B12 etc.)... hypermethylation
is also used to kill some cancers b/c it's cytotoxic... too much
of anything is bad, but hard to get there with supplements,
but >400mg TRES may get you there...
Anthony_Loera 27 May 2008
But I do find Max's study interesting, regarding the varicella-zoster virus and how Res at 4 grams maybe too much for folks with this virus.
hmm, how much do you weigh?
A
hmm 28 May 2008
I weigh around 180 pounds currently.hmm, how much do you weigh?
A
Edited by hmm, 28 May 2008 - 04:36 AM.
niner 28 May 2008
Nice find, maxwatt. This part caught my eye... Is it possible that resveratrol could suppress an HSV1 breakout? If HSV1 likes NFKB, and RSV inhibits NFKB, it seems plausible.As expected, herpes simplex virus 1 caused the persistent nuclear translocation of NF-kappaB proteins, which has been shown to facilitate its replication, whereas VZV infection progressed without persistent NF-kappaB nuclear localization.
maxwatt 28 May 2008
Nice find, maxwatt. This part caught my eye... Is it possible that resveratrol could suppress an HSV1 breakout? If HSV1 likes NFKB, and RSV inhibits NFKB, it seems plausible.As expected, herpes simplex virus 1 caused the persistent nuclear translocation of NF-kappaB proteins, which has been shown to facilitate its replication, whereas VZV infection progressed without persistent NF-kappaB nuclear localization.
Come to think of it, I've had no cold sores since I started taking resveratrol. I did get a canker sore, and packed some of the powder on it and held it between my gum and the ore until it "dissolved". It immediately stopped hurting and was gone the next day.
zoolander 28 May 2008
Here's a little diagram that may help
One area of research that I am involved in at the moment is looking at the intracellular redox status of the cell and how to regulate the above reaction to try and minimise muscle damage in diseases such as muscular dystrophy. Keep in mind though that this pathway is a feed forward reaction that results in the adaptive response and the removal of damage/cellular stress. I spoke of this a little while back. There's a nice little bunch of research out there now that suggests that antioxidants before exercise obliterates the adaptive response by quenching the free radicals produced during the exercise that drive the inflammatory reaction.
Edited by zoolander, 28 May 2008 - 11:47 PM.
hmm 29 May 2008
Thanks for your post. Please forgive me if I am misunderstanding your words/diagram, and let me try to extrapolate from it. If the NF-KB response is something that can switch fairly quickly between active and inactive, then I should have a reasonable chance of finding an optimal dosage of RSV that I can take each day just before my morning sports event, that will be sufficient to inhibit NF-KB for the 2 or so hours of exertion, and beyond that time will have faded from the cell/blood stream enough so that for most of the rest of the day, my normal immune system defenses will be fully functional? (I will be able to have my RSV and eat it too? Pain relief and normal immune response?)
hmm 29 May 2008
Nice find, maxwatt. This part caught my eye... Is it possible that resveratrol could suppress an HSV1 breakout? If HSV1 likes NFKB, and RSV inhibits NFKB, it seems plausible.As expected, herpes simplex virus 1 caused the persistent nuclear translocation of NF-kappaB proteins, which has been shown to facilitate its replication, whereas VZV infection progressed without persistent NF-kappaB nuclear localization.
Here is another quote from the study MaxWatt referenced: "NF-B activation appears to be necessary for fully efficient HSV replication; inhibition results in lower viral yields, coincident with decreased transcription of viral genes that have NF-B response elements in their promoters (3, 21, 48, 57)."
From the way I am understanding this now, it seems like I got the worst of both worlds. So NF-KB activation actually falls right into HSV's plan? If NF-KB suppression was really a big factor in my situation, then I either should have gotten hit by one virus or the other, rather than both. Maybe my immune system is just generally shot for some other reason...
Edited by hmm, 29 May 2008 - 05:02 AM.
niner 29 May 2008
It could be that the herpes was a fluke, and the RSV had something to do with the shingles. Or maybe they were both flukes. I think that you can at least make a better case for the shingles RSV connection.From the way I am understanding this now, it seems like I got the worst of both worlds. So NF-KB activation actually falls right into HSV's plan? If NF-KB suppression was really a big factor in my situation, then I either should have gotten hit by one virus or the other, rather than both. Maybe my immune system is just generally shot for some other reason...
zoolander 29 May 2008
Zoolander,
Thanks for your post. Please forgive me if I am misunderstanding your words/diagram, and let me try to extrapolate from it. If the NF-KB response is something that can switch fairly quickly between active and inactive, then I should have a reasonable chance of finding an optimal dosage of RSV that I can take each day just before my morning sports event, that will be sufficient to inhibit NF-KB for the 2 or so hours of exertion, and beyond that time will have faded from the cell/blood stream enough so that for most of the rest of the day, my normal immune system defenses will be fully functional? (I will be able to have my RSV and eat it too? Pain relief and normal immune response?)
The short answer to that question/proposition is no.
In essence if you are taking an antioxidant to quench the free radicals (ROS) then the supplement is just quenching the free radical. That's simple. However, if you don't use antioxidants then you have an increase in free radicals and the above reaction takes place. The above reaction essentially takes place to counteract changes within the cell i.e maintain homeostasis. These events often strengthen the bodies own abilities to deal with stress. This is the adaptaive response. In healthy people the adaptive response to a stimulus/stress is good.
Guest_Kismet_* 29 May 2008
I am not sure if they achieved any kind of consensus, though, but the last page says in essence: "I don't think anti-oxidants are in any way detrimental to muscle growth. In fact, I would say it is just the opposite."
Hedgehog 29 May 2008
Resveratrol: an original mechanism on tyrosinase inhibition.
Bernard P, Berthon JY. Greentech S. A., Biopôle Clermont Limagne, 63360 Saint Beauzire Cedex, France.
This paper forms part of studies searching for new bioactive ingredients for cosmetics, for example, in the whitening agent field. The aim of our work was to present resveratrol as an original substrate for tyrosinase with very promising cosmetic perspectives. This study was based on several spectrophotometric analyses with minor adaptations. These analyses suggested that resveratrol is biotransformed by tyrosinase into an oxydated form, becoming a powerful inhibitor of tyrosinase. Furthermore, we show that resveratrol can be used as an additive compound in whitening cosmetics, particularly with a Morus alba extract. These results may help in understanding tyrosinase active site structure and mechanism.
Mixter 29 May 2008
One area of research that I am involved in at the moment is looking at the intracellular redox status of the cell and how to regulate the above reaction to try and minimise muscle damage in diseases such as muscular dystrophy.
Nice. Extremely interesting. When I read resveratrol I just thought about direct gene regulatory actions,
but redox status affecting NFKB related phosphorylation obviously plays a big role with many antioxidants.
I actually heard about all this from the perspective of neurotoxicity instead of muscle:
lots of these mechanisms, amyloid, but also including most heavy metal based neurotoxicity, work
via this pathway involving NfKB oxidation...
There's some new research about TGF-beta, modulating the phosphatidylinositol-3-kinase pathway to
reduce neurotoxicity (includind much cell-junk related), maybe you know it, but anyway (and for the rest):
http://www.ncbi.nlm....pubmed/18356065
Studying this system in depth makes a lot of sense.. and knowledge is probably transferrable to
other redox-related signaling systems, apart from NfKB/TNF-a. As I understand it, the things controlling
it are (at least): gradients of thiols in various redox states (reflecting redox state), redox-state-dependent
enzyme kinetics, but also (especially as you mention NfKB, but not limited to it) a vast range of genomic
and epigenetic redox-based interactions, which are the most interesting effects in the whole picture
(if you want to optimize the process e.g. by inhibiting kinases/tuning redox state, maybe the aftereffects
are not all relevant, but for aging these are perhaps the most interesting effects).
There's a great book about this called "Redox-Genome Interactions in Health and Disease" which almost
a must-read for people seriously interested in making SENS of redox biochemistry , includes a lot of
pathobiochemistry.
AFAIK, free book available here: http://books.google....id=sVqn2CURsUkC
Edited by mixter, 29 May 2008 - 08:01 PM.
zoolander 29 May 2008
NOTE: cellular cysteine content can be increased with dietary protein and/or N-acetyl-cysteine (NAC)
Edited by zoolander, 29 May 2008 - 11:00 PM.
hmm 03 Jun 2008
Yes maybe NFKB has something to do with the shingles, but it looks like I was trying to make NFKB into too much of a factor in these outcomes. From googling around it appears that NFKB inflammation is associated with eczema. As much RSV as MissMini was taking, she should have been suppressing NF-KB, and suppressing NF-KB appears to be a favored way to treat eczema rather than cause it. Same with me and my herpes simplex. I started taking a gram again yesterday, and like many times before, woke up at 2 or 3 in the morning and didn't sleep again until around 6AM. Experience told me that I wouldn't really be too tired the next day because of the RSV. But what kinds of various factors in my system might I be disrupting by foregoing all that sleep, that might indirectly result in some kind of unexpected viral attack?It could be that the herpes was a fluke, and the RSV had something to do with the shingles. Or maybe they were both flukes. I think that you can at least make a better case for the shingles RSV connection.From the way I am understanding this now, it seems like I got the worst of both worlds. So NF-KB activation actually falls right into HSV's plan? If NF-KB suppression was really a big factor in my situation, then I either should have gotten hit by one virus or the other, rather than both. Maybe my immune system is just generally shot for some other reason...
Edited by hmm, 03 June 2008 - 03:36 AM.
hmm 03 Jun 2008
There was a guy back in December named "Darth Hack" who seemed curious about transdermal patches. He posted here a few times and then stopped. He was a bit radical in terms of taking 8 grams RSV per day, but I thought he had really done some careful consideration and planning. His strategy seemed to be to ingest a gram every 2 hours so he could maintain a consistently high level of RSV in his blood. I think he wanted a transdermal patch so he could keep his blood levels high in RSV even while he was sleeping. It's tempting to think there might be some kind of extreme dosage level like Darth Hack's where , if you could reach it and maintain it for long enough, you could achieve that super-mouse status of 30% more strength and longer life, and also be pretty much immune from the weird side effects of the dosages that fall inbetween 1 gram and 8 grams...
Darth Hack, are you out there? Are you still doing 8 grams a day? Did you turn into a 30%-plus man, or did you OD? Or something else?
niner 03 Jun 2008
Lack of sleep is never good. I'm wondering about this resveratrol-induced insomnia that you're experiencing. It sounds like an impurity problem to me, like something you would see with a 50% product. I can take a couple grams of resveratrol at night without any sleep effects, but a cup of tea too late in the day and I'm reaching for the Ambien.Yes maybe NFKB has something to do with the shingles, but it looks like I was trying to make NFKB into too much of a factor in these outcomes. From googling around it appears that NFKB inflammation is associated with eczema. As much RSV as MissMini was taking, she should have been suppressing NF-KB, and suppressing NF-KB appears to be a favored way to treat eczema rather than cause it. Same with me and my herpes simplex. I started taking a gram again yesterday, and like many times before, woke up at 2 or 3 in the morning and didn't sleep again until around 6AM. Experience told me that I wouldn't really be too tired the next day because of the RSV. But what kinds of various factors in my system might I be disrupting by foregoing all that sleep, that might indirectly result in some kind of unexpected viral attack?It could be that the herpes was a fluke, and the RSV had something to do with the shingles. Or maybe they were both flukes. I think that you can at least make a better case for the shingles RSV connection.From the way I am understanding this now, it seems like I got the worst of both worlds. So NF-KB activation actually falls right into HSV's plan? If NF-KB suppression was really a big factor in my situation, then I either should have gotten hit by one virus or the other, rather than both. Maybe my immune system is just generally shot for some other reason...
hmm 03 Jun 2008
Unfortunately I didn't save the information sheet that came with the order from VP concerning what exact batch I am using. I got the impression there were issues around a certification document on the VP web site that shows 87% RSV for their product rather than 99%. That issue appeared to be resolved on this site, however, and multiple posters here seemed to believe that the VP quality was, in general, OK. How tough/costly is it to get a sample tested?Lack of sleep is never good. I'm wondering about this resveratrol-induced insomnia that you're experiencing. It sounds like an impurity problem to me, like something you would see with a 50% product. I can take a couple grams of resveratrol at night without any sleep effects, but a cup of tea too late in the day and I'm reaching for the Ambien.
Edited by hmm, 03 June 2008 - 03:33 PM.
mikeinnaples 03 Jun 2008
Unfortunately I didn't save the information sheet that came with the order from VP concerning what exact batch I am using. I got the impression there were issues around a certification document on the VP web site that shows 87% RSV for their product rather than 99%. That issue appeared to be resolved on this site, however, and multiple posters here seemed to believe that the VP quality was, in general, OK. How tough/costly is it to get a sample tested?Lack of sleep is never good. I'm wondering about this resveratrol-induced insomnia that you're experiencing. It sounds like an impurity problem to me, like something you would see with a 50% product. I can take a couple grams of resveratrol at night without any sleep effects, but a cup of tea too late in the day and I'm reaching for the Ambien.
I believe its been tested by hedgehog.