22 replies to this topic

[NDM]

<H3 style="MARGIN-TOP: 0px; PADDING-TOP: 0px" class=sectionHeader>

I found the following 2009 study below: TNF-alpha inhibitors may increase the risk of herpes zoster reactivation. In the last few months since I've started heavy supplementation, I've frequently felt a tingling in my lower lip, which is the prodromal symptom of a herpes eruption. I suspect some of the supplements I take are TNF-alpha inhibitors, and I opened this thread to pool together here the collective knowledge we have of which supplements are
TNF-alpha inhibitors. Please contribute. Here are some of my suspects. Is it the case that if something is a known anti-cancer agent, it likely is a TNF-a inhibitor? For some I've already detected leads through Google searches:

curcumin
"Now for the good news: An in vitro study just published in
Investigative Ophthalmology and Visual Science (IOVS) suggested that Curcumin has the ability to mediate transcription factor NF-kappa B (NFkB) production, which has the ability to block the inflammatory and apoptotic effect of TNF-a."

astragalus
echinacea
Cordyceps
Quercetin
Glucosamine
Pomegranate
Propolis
Oliveleaf
Bilberry
Resveratrol
NAD+
Ashwagandha
Rhodiola
Bacopa
Gotu Kola
EGcG/Green Tea
Grape Seed Extract
Cinnamon
Broccoli
Astaxanthin
Schizandra
Milk Thistle
Artichoke
NAC

Risk of Herpes Zoster in Patients With Rheumatoid
Arthritis Treated With Anti–TNF-alpha Agents

- Source: Journal of the American Medical Association, Feb 18, 2009by Anja Strangfeld, MD, et al.February 17, 2009

Context: The risk of bacterial infection is
increased in patients treated with drugs that inhibit tumor necrosis factor
a (TNF-alpha). Little is known about the reactivation of latent viral
infections during treatment with TNF-alpha inhibitors.

Objective: To investigate whether TNF-alpha inhibitors together as a class, or separately as either monoclonal anti–TNF-alpha antibodies (adalimumab,
infliximab) or a fusion protein (etanercept), are related to higher rates of
herpes zoster in patients with rheumatoid arthritis.

Design, Setting, and
Patients: Patients were enrolled in the German biologics register
RABBIT, a prospective cohort, between May 2001 and December 2006 at the
initiation of treatment with infliximab, etanercept, adalimumab, or
anakinra, or when they changed conventional disease-modifying antirheumatic
drug (DMARD). Treatment, clinical status, and adverse events were assessed
by rheumatologists at fixed points during follow-up. Main Outcome
Measures: Hazard ratio (HR) of herpes zoster episodes following
anti–TNF-alpha treatment. Study aims were to detect a clinically significant
difference (HR, 2.0) between TNF-alpha inhibitors as a class compared with
DMARDs and to detect an HR of at least 2.5 for each of 2 types of TNF-alpha
inhibitors, the monoclonal antibodies or the fusion protein, compared with
conventional DMARDs.


Results: Among 5,040 patients receiving TNF-alpha
inhibitors or conventional DMARDs, 86 episodes of herpes zoster occurred in
82 patients. Thirty-nine occurrences could be attributed to treatment with
anti–TNF-alpha antibodies, 23 to etanercept, and 24 to conventional
DMARDs.The crude incidence rate per 1000 patient-years was 11.1 (95%
confidence interval [CI], 7.9-15.1) for the monoclonal antibodies, 8.9 (95%
CI, 5.6-13.3) for etanercept, and 5.6 (95% CI, 3.6-8.3) for conventional
DMARDs.Adjusted for age, rheumatoid arthritis severity, and glucocorticoid
use, a significantly increased risk was observed for treatment with the
monoclonal antibodies (HR, 1.82 [95% CI, 1.05-3.15]), although this risk was
lower than the threshold for clinical significance. No significant
associations were found for etanercept use (HR, 1.36 [95% CI, 0.73-2.55]) or
for anti–TNF-alpha treatment (HR, 1.63 [95% CI, 0.97-2.74]) as a class.


Conclusion: Treatment with monoclonal anti–TNF-alpha antibodies may be
associated with increased risk of herpes zoster, but this requires further
study.


Source: Journal of the American Medical Association, Feb
18, 2009;301(7):737-744. PMID: 19132156, by Strangfeld A,
Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, Zink A. German Rheumatism Research Centre and Department of Rheumatology and Clinical
Immunology, Charite- University Medicine, Berlin.</H3>

[NDM]

fish oil is a TNF-a inhibitor! NAC also seems to be one!



Grimble, Robert F., Howell, W. Martin, O'Reilly, Gillian, Turner, Stephen J., Markovic, Olivera, Hirrell, Sharon, East, J. Malcolm and Calder, Philip C. (2002) The ability of fish oil to suppress tumor necrosis factor alpha production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor α production. American Journal of Clinical Nutrition, 76, (2), 454-459.
http://eprints.soton.ac.uk/25567/

Abstract



Background: Tumor necrosis factor {alpha} (TNF-{alpha}) mediates inflammation. High TNF-{alpha} production has adverse effects during disease. Polymorphisms in the TNF-{alpha} and lymphotoxin {alpha} genes influence TNF-{alpha} production. Fish oil suppresses TNF-{alpha} production and has variable antiinflammatory effects on disease.

Objective: We examined the relation between TNF-{alpha} and lymphotoxin {alpha} genotypes and the ability of dietary fish oil to suppress TNF-{alpha} production by peripheral blood mononuclear cells (PBMCs) in healthy men.

Design: Polymorphisms in the TNF-{alpha} (TNF*1 and TNF*2) and lymphotoxin {alpha} (TNFB*1 and TNFB*2) genes were determined in 111 healthy young men. TNF-{alpha} production by endotoxin-stimulated PBMCs was measured before and 12 wk after dietary supplementation with fish oil (6 g/d).

Results: Homozygosity for TNFB*2 was 2.5 times more frequent in the highest than in the lowest tertile of inherent TNF-{alpha} production. The percentage of subjects in whom fish oil suppressed TNF-{alpha} production was lowest (22%) in the lowest tertile and doubled with each ascending tertile. In the highest and lowest tertiles, mean TNF-{alpha} production decreased by 43% (P < 0.05) and increased by 160% (P < 0.05), respectively. In the lowest tertile of TNF-{alpha} production, only TNFB*1/TNFB*2 heterozygous subjects were responsive to the suppressive effect of fish oil. In the middle tertile, this genotype was 6 times more frequent than the other lymphotoxin {alpha} genotypes among responsive individuals. In the highest tertile, responsiveness to fish oil appeared unrelated to lymphotoxin {alpha} genotype.

Conclusion: The ability of fish oil to decrease TNF-{alpha} production is influenced by inherent TNF-{alpha} production and by polymorphisms in the TNF-{alpha} and lymphotoxin {alpha} genes.

A novel mechanism for the inhibition of NFκB activation in vascular endothelial cells by natural antioxidants

ABSTRACT

The activation of Nuclear Factor κ B (NF-κB) in vascular endothelial cells, in response to

biochemical or biomechanical stimuli, is associated with vascular pathologies such as

atherosclerosis. The present manuscript studies the ability of the natural antioxidant.

pomegranate wine (PW), to inhibit tumor necrosis factor α (TNF-α) or shear stress-mediated.

NF-κB activation in vascular endothelial cells and compares it to that of red wine (RW) and Nacetyl

cysteine (NAC). PW and RW act as potent antioxidants in vascular endothelial cells,

inhibiting the oxidation of 2.,7.-dichloroflurescin diacetate in TNF-α treated cells. PW (as well

as RW and NAC) acted as potent inhibitors of NF-κB activation (migration into the nucleus and

DNA binding activity) in vascular endothelial cells. Nevertheless, PW and NAC failed to inhibit

TNF-α induced serine 32/36 phosphorylation and IκBα degradation. Surprisingly, these

antioxidants alone induced enhanced IκB serine phosphorylation, which was not accompanied by

IκBα degradation, or NF-κB nuclear translocation. This phosphorylation did not involve serine

32/36. Furthermore, we show for the first time that NAC inhibited TNF-α mediated

phosphorylation of p65 (ser536), whereas PW had no effect on this phosphorylation. Thus,

natural antioxidants may serve as potent NF-κB inhibitors in vascular endothelial cells, yet act

through unique and divergent pathways.

................................................................................
.....................................................
here's another discussion of the study, for context. Please note that at stake are not only herpes reactivations, but also bacterial and fungal infections

TNF Inhibitors May Increase Shingles Risk


February 18, 2009 — Drugs that inhibit tumor necrosis factor-alpha (TNF-α) have already been associated with serious infectious complications, and investigators say shingles should now be added to the list.

"Based on our data, we recommend careful monitoring of patients treated with monoclonal anti-TNF-α antibodies for early signs and symptoms of herpes zoster," report the researchers, led by Anja Strangfeld, MD, from the German Rheumatism Research Center, in Berlin.

Based on our data, we recommend careful monitoring of patients.
Their work appears in the February 18 issue of the Journal of the American Medical Association.

In an accompanying editorial, Drs Richard Whitley and John Gnann, from the University of Alabama at Birmingham, suggest this study provides the best evidence to date for a positive association between treatment with TNF inhibitors and herpes zoster.

Shingles is a neurocutaneous disease that results from the reactivation of the varicella-zoster virus. It is characterized by a painful vesicular dermatomal rash.

Herpes zoster is one of the most common adverse events reported in clinical trials of TNF inhibitors. Complications include bacterial superinfection and, more frequently, postherpetic neuralgia, which can cause substantial morbidity.

Reactivation of Varicella Zoster Virus

Drugs that inhibit tumor necrosis factor are now widely used for the management of a variety of inflammatory processes such as rheumatoid arthritis.

For patients in whom the disease activity cannot be sufficiently controlled with conventional disease-modifying antirheumatic drugs (DMARDs), alternatives targeting TNF-α have become indispensable, the research team points out.

"As with many medical advances, benefit comes with a price," Drs Whitley and Gnann add, "and an important consequence of anti-TNF-α therapy is increased risk of infection — especially tuberculosis." Other studies have linked TNF inhibitors with increased risk of serious bacterial and fungal infections.

Associations between TNF inhibitors and viral infections have not been as clearly defined, the editorialists point out, although previous case reports of severe episodes of herpes zoster in patients receiving these drugs have appeared in the literature.

Dr. Strangfeld and colleagues studied a prospectively collected database from a German biologics register of patients with rheumatoid arthritis to determine whether the frequency of herpes zoster was increased and, if so, whether the increased risk was linked to therapy.

In a population of 5040 patients with rheumatoid arthritis,they identified 86 cases of herpes zoster in 82 individuals. Of these, 39 cases were temporally linked to treatment with adalimumab or infliximab, 23 to the fusion protein etanercept, and 24 to conventional DMARDs.

The herpes zoster incidence rate was 11.1 per 1000 patient-years in the group treated with the monoclonal antibodies, 8.9 per 1000 patient-years for etanercept, and 5.6 per 1000 patient-years for conventional DMARDs.

Older age and prednisone use were confirmed to be risk factors for development of herpes zoster, as previously described in other populations.

Herpes Zoster Vaccine Contraindicated

"The herpes zoster vaccine has clearly been shown to reduce the risk and severity of shingles in immunocompetent adults 60 years or older," Drs Whitley and Gnann note. "However, because it is a live-virus vaccine, vaccination of immunocompromised patients is contraindicated."

Until sufficient safety data are available, administration of the herpes zoster vaccine to patients receiving anti-TNF-α therapy is not recommended, the researchers conclude.

Dr. Strangfeld and colleagues are quick to point out that more study is needed. "Our analyses are based on a limited number of herpes zoster episodes."

JAMA. 2009;301:737-744, 774-775.

Edited by NDM, 08 April 2009 - 09:52 PM.

[NDM]

lifted from google

Natural TNF inhibitors that affect the MAPK p38 pathway include:

• Curcumin from turmeric
• Ginger
• Selenium
• Kava

• Capsaicin from hot peppers (mixed evidence)

From a book on natural anti-cancer therapy:
http://www.trafford....ts/03-0833.html
TNF INHIBITORS -

melatonin
milk thistle
cat's claw
VES
genestein
EGCG.

AND RESVERATROL...Nutrition & Metabolism 2008, 5:17doi:10.1186/1743-7075-5-17


Abstract

Background
Adipocytes express inflammatory mediators that contribute to the low-level, chronic inflammation found in obese subjects and have been linked to the onset of cardiovascular disorders and insulin resistance associated with type 2 diabetes mellitus. A reduction in inflammatory gene expression in adipocytes would be expected to reverse this low-level, inflammatory state and improve cardiovascular function and insulin sensitivity. The natural products, curcumin and resveratrol, are established anti-inflammatory compounds that mediate their effects by inhibiting activation of NF-κB signaling. In the present study, we examined if these natural products can inhibit NF-κB activation in adipocytes and in doing so reduce cytokine expression.


Methods
Cytokine (TNF-α, IL-1β, IL-6) and COX-2 gene expression in 3T3-L1-derived adipocytes was measured by quantitative real-time PCR (qRT-PCR) with or without TNFα-stimulation. Cytokine protein and prostaglandin E₂ (PGE₂) expression were measured by ELISA. Effects of curcumin and resveratrol were evaluated by treating TNFα-stimulated adipocytes with each compound and 1) assessing the activation state of the NF-κB signaling pathway and 2) measuring inflammatory gene expression by qRT-PCR and ELISA.


Results
Both preadipocytes and differentiated adipocytes express the genes for TNF-α, IL-6, and COX-2, key mediators of the inflammatory response. Preadipocytes were also found to express IL-1β; however, IL-1β expression was absent in differentiated adipocytes. TNF-α treatment activated NF-κB signaling in differentiated adipocytes by inducing IκB degradation and NF-κB translocation to the nucleus, and as a result increased IL-6 (6-fold) and COX-2 (2.5-fold) mRNA levels. TNF-α also activated IL-1β gene expression in differentiated adipocytes, but had no effect on endogenous TNF-α mRNA levels. No detectable TNFα or IL-1β was secreted by adipocytes. Curcumin and resveratrol treatment inhibited NF-κB activation and resulted in a reduction of TNF-α, IL-1β, IL-6, and COX-2 gene expression (IC₅₀ = 2 μM) and a reduction of secreted IL-6 and PGE₂ (IC₅₀ ~ 20 μM).


Conclusion
Curcumin and resveratrol are able to inhibit TNFα-activated NF-κB signaling in adipocytes and as a result significantly reduce cytokine expression. These data suggest that curcumin and resveratrol may provide a novel and safe approach to reduce or inhibit the chronic inflammatory properties of adipose tissue.

Edited by NDM, 08 April 2009 - 10:32 PM.

[david ellis]

I found the following 2009 study below: TNF-alpha inhibitors may increase the risk of herpes zoster reactivation. In the last few months since I've started heavy supplementation, I've frequently felt a tingling in my lower lip, which is the prodromal symptom of a herpes eruption.

I was trying to understand why I had cold sores on my lips after upping my Vitamin D intake. I haven't had them since I was a teenager. Your post caused me to google and see if Vitamin D was also a TNF-alpha inhibitor.

So, I found a link that reads to me like Vitamin D also does TNF-alpha inhibition.

From the study
"AIM: The aim of this study was to investigate whether KH 1060, a vitamin D analogue, could decrease tumor necrosis factor-alpha (TNF-alpha) levels in patients with inflammatory bowel disease (IBD)

CONCLUSION: This study shows that KH 1060 acts as an immunomodulator on PBMC, acting as TNF-alpha inhibitor. This finding provides strong evidence that vitamin D status could be an important regulator of immunity IBD."

[NDM]

I found the following 2009 study below: TNF-alpha inhibitors may increase the risk of herpes zoster reactivation. In the last few months since I've started heavy supplementation, I've frequently felt a tingling in my lower lip, which is the prodromal symptom of a herpes eruption.

I was trying to understand why I had cold sores on my lips after upping my Vitamin D intake. I haven't had them since I was a teenager. Your post caused me to google and see if Vitamin D was also a TNF-alpha inhibitor.

So, I found a link that reads to me like Vitamin D also does TNF-alpha inhibition.

From the study
"AIM: The aim of this study was to investigate whether KH 1060, a vitamin D analogue, could decrease tumor necrosis factor-alpha (TNF-alpha) levels in patients with inflammatory bowel disease (IBD)

CONCLUSION: This study shows that KH 1060 acts as an immunomodulator on PBMC, acting as TNF-alpha inhibitor. This finding provides strong evidence that vitamin D status could be an important regulator of immunity IBD."

That's amazing...we've been sleeping in bed with the enemy all along. Many of the products I've been taking, however superficially different, seem to have in common TNF-alpha inhibition...Now I see Andre's wisdom...Even though each of the supps might have only slightly suppressed TNF, their joint effect was soo powerful that the herpes virus reactivated DESPITE MY SYSTEMATIC ATTEMPTS TO MINIMIZE ARGININE-RICH FOODS.
The TNF suppression seems to explain the viral reactivation, whereas my avoidance of arginine and supplementation with lysine seem to explain why the reactivation was kept at a minimum level (mere tingling in my lip, with no eruption).

I knew that something is fishy and that there must be more to the story than mere arginine/lysine imbalance, but what was getting me mad was the fact that the virus was active despite me taking lysine AND LOTS OF SUPPOSEDLY IMMUNE-BENEFICIAL SUPPS (resveratrol, EGCG, curcumin, milk thisle, NAC, vitamin D, etc).

Anyway I plan to limit my taking to only those supps from which a google search does not return an inhibitory effect on TNF. If there are any left.

[NDM]

The hunt goes on:

vitamin C seems involved in TNF suppression as well...

Vitamin C Inhibits NF-kB Activation by TNF Via the

Activation of p38 Mitogen-Activated Protein Kinase1

Andrew G. Bowie2 and Luke A. J. O'Neill

The transcription factor NF-kB is a central mediator of altered gene expression during inflammation, and is implicated in a

number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the

activation of NF-kB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs.

The induction of a NF-kB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of

vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit

another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-kB. Inhibition by vitamin C was not

simply an antioxidant effect, because redox-insensitive pathways to NF-kB were also blocked. Vitamin C was shown to block IL-1-

and TNF-mediated degradation and phosphorylation of I-kBa (inhibitory protein that dissociates from NF-kB), due to inhibition

of I-kB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase,

because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580

reversed the inhibitory effect of vitamin C on IKK activity, I-kBa phosphorylation, and NF-kB activation. The results identify p38

as an intracellular target for high dose vitamin C. The Journal of Immunology, 2000, 165: 7180–7188.

................................................................................
.............................

Can someone competent in pharmacology tell us if the following quote lifted from google actually says that piracetam is a TNF-inhibitor? I do not clearly understand what they say:

"Expression of membrane-bound (mb) and soluble (s) forms of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor-α (TNF-α) has been measured by enzyme-linked immunosorbent assay in cultured human brain microvessel endothelial cells. Both the mb and the s forms of VCAM-1 and ICAM-1 were upregulated by TNF-α; however, the stimulation of the s forms was delayed in time. When piracetam, a neuroprotective drug, was added to the tissue culture medium simultaneously with TNF-α, the expression of mbVCAM-1 and ICAM-1 was lowered. Differential upregulation of mb and s forms of adhesion molecules and a novel effect of piracetam have been demonstrated in human brain microvessel endothelial cell cultures."

Edited by NDM, 08 April 2009 - 11:16 PM.

[kilgoretrout]

You know, I have seen this sort of research "result" of "inibiting TNF-kB" FOR ALMOST EVERY SUPPLEMENT THAT EXISTS!!! Seriously, it seems EVERYTHING seems to have some effect on "TNF receptors" in some way or another... they must be VERY VERY finicky receptors!!!

I bet VERY VERY few of them are actual results seen in real living humans when these supplements are used at reasonable normal doses.

I chased down this trail too myself for months a few years ago on a whole list of substances before coming to this conclusion.

Honestly, I would not worry about it. You are just freaking yourself out looking at these incredibly obscure cell-line research reports and thinking that without advanced multiple degrees in biosciences that you have ANY IDEA what they mean, just because google found a few key words in them. Yes you are smart, but believe me, you don't have ANY IDEA WHAT THESE MEAN! Get over it.

Let alone what they mean to a human taking a normal dose. Also "in vivo" as they say (LOOK FOR THAT PHRASE IN THESE RESEARCH REPORTS!!!!!!!) there are so MANY MANY competing and complicating and normalizing influences, such that I will bet my HOUSE! that taking a few grams of vitamin C a day (or whatever) has ABSOLUTE ZERO effect on your systemic or local TNF levels.

Edited by kilgoretrout, 08 April 2009 - 11:27 PM.

[NDM]

You know, I have seen this sort of research "result" of "inibiting TNF-kB" FOR ALMOST EVERY SUPPLEMENT THAT EXISTS!!!

I bet if you look at those studies, they are when they add enormous concentrations to test tubes or petrie dishes of various cell cultures. Or in mice that were given what would be equivalent to like a KILOGRAM of said supplement in a normal sized human.

I bet VERY VERY few of them are actual results seen in real living humans when these supplements are used at reasonable normal doses.

But if you take many many supps each with a small TNF inhibitory effect, the aggregate effect can be significant.

Yet, given that so many seem to have TNF inhibitory effect, I'd love to find a quantitative ranking of them to know exactly which are the major villains.

................................................................................
...................

Finally, something suspected to increase TNF: ASPIRIN...so the Hungarian doctor who proposed years ago in an obscure journal that aspirin works against herpes might have been right.


Aspirin, TNF-alpha, NFkB, and survival in multiple myeloma: the importance of measuring TNF-alpha.
Aspirin and other cyclooxygenase inhibitors can increase levels of tumor necrosis factor-alpha and engage pro-apoptosis paths and/or anti-apoptosis paths. Seemingly conflicting data are briefly reviewed. Aspirin has been shown to slightly increase survival duration in multiple myeloma. In this brief note caution is raised about use of aspirin and COX inhibitors generally in inflammatory states and specifically in myeloma. Should they increase tumor necrosis factor-alpha they could exacerbate disease. A figure is presented showing the tendency for interleukin-6 and tumor necrosis factor-alpha, both demonstrated to be growth factors in myeloma, to be counter-regulated. Since both are now easily measured by specialty labs, it would be reasonable to monitor these during myeloma treatment generally, and particularly when using aspirin, COX inhibitors, or any other drug with potential to increase these growth factors.

&



Aspirin use in myeloma: a note of caution regarding potential tumour necrosis factor-alpha elevation.
Kast RE.PMID: 16611319

Edited by NDM, 08 April 2009 - 11:37 PM.

[kilgoretrout]

But if you take many many supps each with a small TNF inhibitory effect, the aggregate effect can be significant.

It is completely incorrect for you to assume that it has any effect whatsoever. Again, these reports are NOT in humans ingesting these supplements in a pill.

Most of them are in a cell culture in a test tube.

There is NO REASON to believe that this has any relation to taking these things by mouth by a living human.

There are MANY other processes, systems, enzymes, control genes, etc etc etc that are effecting your levels of TNF at the times and places in you body where it counts.

UNLESS YOU SEE A STUDY THAT SAYS THEY STUDIED LIVE HUMANS TAKING X amount of Y and it had Z effect on levels of TNF in a way that had Q bad effect in a statistically significant percent of people (what percent is enough??? see what I mean?).... IGNORE IT!!!

Very few of us here are professional research medical biochemists are we? We have NO IDEA what these things are actually talking about, and what they mean to a human taking a supplement pill, no matter how smart we think we are.

Edited by kilgoretrout, 08 April 2009 - 11:37 PM.

[NDM]

But if you take many many supps each with a small TNF inhibitory effect, the aggregate effect can be significant.

It is completely incorrect for you to assume that it has any effect whatsoever. Again, these reports are NOT in humans ingesting these supplements in a pill.

Most of them are in a cell culture in a test tube.

There is NO REASON to believe that this has any relation to taking these things by mouth by a living human.

There are MANY other processes, systems, enzymes, control genes, etc etc etc that are effecting your levels of TNF at the times and places in you body where it counts.

UNLESS YOU SEE A STUDY THAT SAYS THEY STUDIED LIVE HUMANS TAKING X amount of Y and it had Z effect on levels of TNF in a way that had Q bad effect in a statistically significant percent of people (what percent is enough??? see what I mean?).... IGNORE IT!!!

Very few of us here are professional research medical biochemists are we? We have NO IDEA what these things are actually talking about, and what they mean to a human taking a supplement pill, no matter how smart we think we are.

May I remind you the title of the original paper that started this thread:

Risk of Herpes Zoster in Patients With Rheumatoid
Arthritis Treated With Anti–TNF-alpha Agents

humans, not cell cultures

[FunkOdyssey]

The paper that started this thread concluded that anti-TNF-alpha antibodies, but not TNF inhibitors as a class, were associated with increased risk of herpes. Huge difference between anti-TNF-a antibodies and the piddly effects of these foods and supplements you've listed, which is starting to look like a comprehensive list of everything known to be healthful that you can put in your body.

Do you have your complete regimen listed anywhere? Maybe there is a single offender we could isolate, if you are certain some aspect of your regimen is responsible for the herpes reactivation (certain it is not coincidence).

Edited by FunkOdyssey, 08 April 2009 - 11:58 PM.

[NDM]

The paper that started this thread concluded that anti-TNF-alpha antibodies, but not TNF inhibitors as a class, were associated with increased risk of herpes. Huge difference between anti-TNF-a antibodies and the piddly effects of these foods and supplements you've listed, which is starting to look like a comprehensive list of everything known to be healthful that you can put in your body.

Yes, but the study did not include natural TNF-inhibitors. Given the fact that I reasonably ruled out other normal causes of herpes reactivation, and given the fact that the authors of the study consider TNF-inhibition to be causally implicated in herpes reactivation, I have a reasonable right to provisionally infer - following a BETTER SAFE THAN SORRY STRATEGY - that ABSENCE OF EVIDENCE IS NOT EVIDENCE OF ABSENCE. By reducing my intake of natural TNF-inhibitors in the following days I want to check on my own skin if the extension of the study's results to natural TNF inhibitors is potentially warranted.

Let me put it the other way around: wouldn't it be foolish for me to continue taking all these natural TNF inhibitors and be stressed everyday by the risk of herpes, when there is prima facie evidence that these supps might be the cause of my herpes reactivation?

Using a cost/benefit analysis of the two potential courses of action, it seems to me fully rational to probe this hypothesis by temporary reducing/suspending these supps. The cost of a false alarm is small (financially, actually I save $), and the potential benefit of a correct hit is great (reduction in everyday dread that I'm about to get a herpes eruption).

---------------------------------------------------------------------------------------


Glucosamine sulfate (GS) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo, but its mechanism is unknown. We investigated whether GS could modulate the proinflammatory cytokine-induced expression of the gene for intercellular adhesion molecule (ICAM)-1, an inflammatory protein in human retinal pigment epithelial (RPE) cells. METHODS: ARPE-19 cells were used as a model to determine the effects of GS on the expression of the ICAM-1 gene upregulated by TNF-alpha or IFN-gamma, by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction (RT-PCR). The activation and nuclear translocation of the nuclear factors NF-kappaB and STAT1 were evaluated by immunocytochemistry, Western blot analysis, and electrophoretic mobility shift assay (EMSA). RESULTS: Both TNF-alpha and IFN-gamma increased the expression of ICAM-1 at the mRNA and protein levels in a time- and dose-dependent manner in ARPE-19 cells. GS effectively downregulated the TNF-alpha- or IFN-gamma-induced expression of ICAM-1 in the protein and mRNA level in a dose-dependent manner. GS further inhibited the nuclear translocation of p65 proteins in TNF-alpha and phosphorylated STAT1 in IFN-gamma-stimulated ARPE-19 cells. CONCLUSIONS: GS inhibits the expression of the ICAM-1 gene in ARPE-19 cell stimulated with TNF-alpha or IFN-gamma through blockade of NF-kappaB subunit p65 and nuclear translocation of STAT1. This study has demonstrated a potentially important property of GS in reducing ICAM-1 mediated inflammatory mechanisms in the eye.PMID: 16431966

[FunkOdyssey]

Using a cost/benefit analysis of the two potential courses of action, it seems to me fully rational to probe this hypothesis by temporary reducing/suspending these supps. The cost of a false alarm is small (financially, actually I save $), and the potential benefit of a correct hit is great (reduction in everyday dread that I'm about to get a herpes eruption).

Yes, this does sound rational -- more rational than previous posts that put things like pomegranate, green tea and broccoli on some kind of blacklist and described using them as "sleeping with the enemy".

[NDM]

Using a cost/benefit analysis of the two potential courses of action, it seems to me fully rational to probe this hypothesis by temporary reducing/suspending these supps. The cost of a false alarm is small (financially, actually I save $), and the potential benefit of a correct hit is great (reduction in everyday dread that I'm about to get a herpes eruption).

Yes, this does sound rational -- more rational than previous posts that put things like pomegranate, green tea and broccoli on some kind of blacklist and described using them as "sleeping with the enemy".

I am not writing academic papers here. I am trying to work out through a problem, and part of that working out involves a quick and dirty screening of potential suspects as a first step toward a more detailed investigation. The sleeping with the enemy metaphor came to my mind because some of the things I was taking to prevent the herpes turned out to be potential aggravating factors of it.

The supps I am taking are those listed in the initial post.
..............................

Ashwagandha also is involved in TNF activity, although the text is not that clear on its net effect:

"Ashwagandha suppressed the expression of TNF-induced NF- Bregulated

antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1ß-converting

enzyme&ndash;inhibitory protein) and metastatic (cyclooxygenase-2 and intercellular adhesion molecule-1) gene

products, enhanced the apoptosis induced by TNF and chemotherapeutic agents, and suppressed cellular TNF-induced

invasion and receptor activator of NF- B ligand-induced osteoclastogenesis. The results indicated that ashwagandha

inhibited activation of NF- B and NF- B-regulated gene expression, which may explain the ability of withanolides to

enhance apoptosis and inhibit invasion and osteoclastogenesis." [ Ichikawa et al Mol Cancer Ther

2006;5(6):1434&ndash;45]

................................................................................
.........................................

The evidence on cordyceps is ambiguous...some studies suggest TNF suppression; some induction.
http://www.shen-nong...rdyceps.html#13

Edited by NDM, 09 April 2009 - 12:37 AM.

[FunkOdyssey]

If I had to guess the single most likely culprit from your list, I'd go with quercetin.

[NDM]

If I had to guess the single most likely culprit from your list, I'd go with quercetin.

Thanks (My guess is that it's the cumulative effect of too many supps, not any single item).

The first two entries on google on quercetin point in different directions. Enough to warrant declaring it provisionally suspect:


<LI class=g><H3 class=r>Quercetin inhibits TNF-induced NF-κB transcription factor ...</H3>Quercetin inhibited TNF-induced interferon-y-inducible protein 10 (I P-10) and macrophage inflammatory protein 2 (M I P-2) gene expression in Mode-K cells ...
cat.inist.fr/?aModele=afficheN&cpsidt=18716579 - Similar pages
by PA RUIZ - 2007 - Cited by 11 - Related articles - All 3 versions<LI style="MARGIN-LEFT: 3em" class=g><H3 class=r>Quercetin, a bioflavonoid, accelerates TNF-α-induced growth ...</H3>Apoptosis assays revealed an accelerating effect of quercetin on TNF-α-induced apoptosis in MC3T3-E1 cells. In addition, Fas activation and poly (ADP ...
cat.inist.fr/?aModele=afficheN&cpsidt=17404749 - Similar pages
by YO SON - 2006

[NDM]

Enough for me for today; I'll just take my daily baby aspirin for now and wait and see for the next days if the tingling naturally subsides.

The most important thing now would be to get a quantitative grasp of the actual TNF-inhibitory effect of these natural supps, but I guess it's unlikely that anybody has ever attempted such a ranking (couldn't find any lead on google). Maybe the most powerful are the ones listed in that fighting cancer book (assuming that the author didn't include trivia on such a topic).

[StrangeAeons]

Have I overlooked something here, or are we forgetting basic medicine?
Cold sores and their prodrome are symptomatic of herpes simplex, not herpes zoster!

[NDM]

Have I overlooked something here, or are we forgetting basic medicine?
Cold sores and their prodrome are symptomatic of herpes simplex, not herpes zoster!

True, but they are part of the same viral family, so, until positive evidence comes to say that H simplex specifically is not reactivated by TNF inhibitors, it seems reasonable to assume that absence of positive evidence is not evidence of absence. Online I noticed that drugs or supps that are recommended for one type of herpes are usually also recommended for the other types, precisely because they have many things in common (family resemblance).

Last night I did not take my usual evening combo:

1mg melatonin
2 capsules ashwagandha
3 capsules gotu kola
Bacopa tincture
3 g glycine
2 capsules glucosamine
1 g pyroglutamic acid
400mg magnesium
250 mg DMAE

This morning I did not take my usual combo:

3g fish oil
10 mg lutein
4 mg astaxanthin
60 mg CoQ10
1 capsule Curcumin/sesame
4000 IU vit D
1 capsule K2
1 capsule enzogenol
1 capsule policosanol
4 capsules pomegranate
1 capsule bilberry
500mg vit C
baby aspirin
2 capsules cordyceps
100mg grape seed extract
1 capsule cinnamon
1 capsule resveratrol NOW
1 capsule quercetin
1 tablet NAD+
2 g piracetam

(I take them not at once but spread throughout the morning from 7 til 11:30).


And I don't have the tingling in my lower lip, even though I had a Starbucks Grande Americano (coffee is rich in arginine).

My problem is that I don't want to choose between being beautiful (herpes-free) and stupid versus ugly and smart. So I want to get back to supplementing...if only I were able to determine which of these supps are the main trigger. So probably next week I'll start timidly and slowly to reintroduce some of them and see how much I can stretch it.

................................................................................
.........................................

As far as I have been able to learn, and I did spend quite some time at the task, any time one has a herpes eruption, one of the following 5 hypotheses compete for the explanation:

1. immune system is overwhelmed with other infections, so Herpes profits and wakes up
2. excessive arginine and deficit of lysine in one's diet
3. digestive stress (e.g. forcing oneself to eat stuff one does not like)
4. psychological stress (induced either ex post facto by some failure/rejection or ante factum by some big challenge ahead)
5. excessive suppression of TNF-a by an array of otherwise great supplements

A favoring factor (without being itself a sufficient cause) are cracked lips.

If you are aware of other hypotheses, feel free to add to the list.

[StrangeAeons]

Hypothesis:
has your prodrome developed?
If so, consider herpes simplex.

They may be in the same "family", but they have very different presentations! Throwing up some half-cocked logic dismisses the empirical reality of the virus, just so you can go back to playing your theoretical-biology games. Mutual vulnerability to a certain agent doesn't mean identical presentation. Acne vulgaris and anthrax both respond to doxycycline, guess which one I had in my teens? Show me ANY evidence with gravity, even a case study, where shingles presents with cold sores.

[hullcrush]

Funk may be onto something. Quercetin's a helluva drug. It's not even really a supplement. If you are taking 500 mg / day it will manipulate the CYP system as well. What exactly are you taking your extensive list of supplements for?

I've also noticed as well that pretty much everything inhibits TNF-alpha. Have you had your levels tested? They can be for $100 at lef.org Make sure to wash out your supplements before this blood test.

There may be study bias indicating that researchers are looking at reducing TNF-alfa as a drug target, but not at increasing basal levels. Intentional inflammation, while useful in some situations, is largely a pathological process.

[tham]

Inflammatory cytokines, including TNF-alpha, typically go up
as we age, and inhibiting them is one of the goals of an anti-
aging protocol - thus the fact that one of the pathways by
which many life extension supplements and drugs work is vide
lowering the levels of these cytokines is not surprising.

For example, I've taken pentoxifylline (Trental) as a life
extension drug before - it inhibits IL-1beta, IL-6 and TNF-alpha.
However, it aggravated my gastritis as well as caused some
nausea (pentoxifylline is a methylxanthine), so I had to stop it.

And when you suppress a biochemical which is supposed to be
part of your immune system's weapon, there may be some
repercussions, such as reactivation of latent viruses, or
increased risk of cancer - similar to the double-edged sword
of lengthening telomerase.


TNF-alpha fights cancer, but in the process also causes cachexia.
Its upregulation as we age is also the main cause of aging cachexia.
Thus the use of its drugs or supplements which downregulate it,
such as pentoxifylline, thalidomide, fish oil.

http://www.imminst.o...showtopic=26610


The use of the TNF-alpha inhibitor drugs, ethanercept and
infliximab, in psoriasis and rheumatoid arthritis for example,
has been linked with an increased risk of cancer.

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum

http://www.ncbi.nlm....l=pubmed_docsum



Paradoxically, TNF-alpha itself is also known to promote cancer
and is thus a double-edged sword as well.

http://www.ncbi.nlm....l=pubmed_docsum

[Joe Cohen]

SUPPLEMENTS AND LIFESTYLE FACTORS THAT INHIBIT TNF-ALPHA