The first study shows that cells of CFS patient respond dieffenrtly to immune stimuli and release much more nuclear factor kappa beta



The second one, which I found in an unrealted searhc, slides into place nicely



which signalling molecules other than prostaglandins mediate the effect of TNFalpha ? as the first study shows, it may well be NFkappaB

nice.

now we just need to shut down NFkappaB. problem is that those agent that shut it down induce lethargy. I'm hypothesizing a stimulnat like nicotine, high dose NAC/ALA, behavioural changes and immunomoudlators like immunovur could be the end of CFS. I will be soon putting this theory into practice.

From more reading on NFKappaB, it seems to be activated by bacterial infections, by the Toll-lile receptors. infact, NF-κB seems to act as a "first responder" to harmful cellular stimuli and as such is activated by all kinds of surface and nuclear receptros. In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity.

NF-κB upregulates genes involved in T-cell development, maturation and proliferation.

it would seem that the immune system of CFS patients seems to be in an oevrly defensive state as a result to somekind of past stressors such as PTSD, infectiosn , toxins etc.

So, how can we reduce NF-κB or normalize its activation?

we could limit toxins by drinking purified water and eating organic foods
we could reduce ROS by taking antioxidants such as NAC, ALA
we could limit exposure to virii and bacteria, at least chronic one, i.e treat it very firmly. I'm not very sure about that one.

other thoughts?

ATB, resident infection experts (Benson) do chime in

Great great work.

That second study, regarding TNF-Alpha impacting directly on excercise is the most profoundly important confirmation of a hypothesis that infection fighting in the brain would have to lead to deactivation of impulses (i.e. excercise) which require anti-inflammatory endocrine responses, in order that glia can focus the response without having to support other neural-orientated tasks. We expected to find this but to find such a profound effect on excercise just from TNF-alpha is really important.

I've come across quite a few related studies when I have the time to find them I'll post them up. One or two of interest regarding the brain infection angle includes that microglia, when stimulated by the presence of infection (TNF-Alpha), are active in sucking up glutamate (see end of post) which could have affects in a variety of conditions of abnormal glutamate response as well as possibly on excercise. And its not just cytokines that elicit responses - it was found that glia can detect viral proteins directly and respond to them.

This suggests a possible latent infection in the CNS if CNS TNF-alpha is elevated.

The problem is, from what I gather, latent herpes virus infection in the brain may only be detectable by brain biopsy, as it may not emerge in the blood or periphery.

So we wont know yet, until better tests are developed.

It seems to me that there could be a low-level brain-viral cause of CFS.

Coxsackie-B virus may be implicated as could the herpes family, and many other viruses.

Now I've had my self tested for plasma evidence of viral infection and micoplasma - all negative, but in a high proportion of CFS there is evidence of recent fighting by the immune system against these agents.

My early CFS symptoms strongly support a viral model.

It began during exams as a stomach upset (implicating the entero-virus coxsakie and then became much worse. The symptoms of low-grade fever were constant over the next few years.

In my year, of 200 people, at least 3 were later confirmed to have developed ME / CFS from about that time, which is much above the various population averages according to various sources, indicating a cluster through a viral origin.

In CFS there seems to be underactive immune systems and in others over active inflammatory responses. Anti-inflammatories and antioxidants do seem beneficial to symptoms, as does avoidance of alcohol. I would recommend CFS sufferers look at herbs like Nigella Sativa. In CFS, membrane oxidative stress is an outcome and it appears to stimulate the immune response, which may explain the intollerence to alcohol. Many nutrients and herbs could impact on these oxidative stress and related signalling mechanisms, but to prevent down-regulation of the immune system, the Th-1 functions should be supported by DHEA, sleep regularity and melatonin, and raising antioxidant levels (esp glutathione), especially if allergic dissorders are in evidence. Antiviral herbs that support the Th-1 wing should in theory be taken at night to avoid effects during the day. Growth hormone appears to be low at night in CFS, this can be supported by amino-acids glycine and glutamine, at least in normal people. Omega 3's will damp down inflammation but not excessively impair Th-1 functions (they may actually boost them).

L-Serine looks very useful from preliminary data, but one wonders if it effects CNS cytokines like TNF-alpha?




Microglia are odd creatures in the human brain - comprising about 15% of all CNS brain cells they do not function the same in humans as in rodents - in rats, microglia release iNOS but in humans astrocytes do. Microglia and astrocytes in humans seem to have swapped some roles with microglia detecting and when initiating the response presumably in astrocytes, the microglia busy themselves then sucking up the glutamate which the astrocytes do then not absorb. These cytokines and underlying infections could explain diseases of altered glutamate / NMDA signalling such as Schizophrenia. Since evidence already links these glutaminergic conditions to infection, I would suggest that many psychotic cases are infections interfering with neural-glial signalling, and when they occur young, they induce psychosis, and when in older people, they tend to induce fatigue (but also neuro-psychiatric problems).

That being said, in many cases of CFS a sudden onset does not exist, and a long descent may be subliminally in evidence as effected by diet, stress, and genes. A number of polymorphisms were found in one study to be highly predictive of CFS versus controls, and these polymorphisms related to methylation pathways, serotonin transporter and glutathione.

Similar polymorphisms also predict autism - but, the question is, how can genetic dissorders in one cause autism and another cause CFS? The answer is that they are probably weak effects, because in autism, it is not polymorphisms but copy number abnormalities that seem to cause true autism.

In CFS the studies are so contradictory and the reason is probably that different subsets, like in autism spectrum disorder, where profoundly different levels of debilitation are lumped together in the term, are being selectively looked at at different stages of a condition and with different causes. Thus the Japanese look for low NK cells and in western studies many show no impairment of these. This sort of problem makes evaluating the solution very difficult.

I was thinking about doing the follwoing:

dose a gram or more of NAC when getting up, before workouts, afternoon (3PM). dose 0.5 gram pre bed.
dose 100mg Na-rALA when gettnig up and 200mg before going to sleep.
dose curcumin+bioperine (not sure when yet... pre workouts?)

for better abosrption of NAC I need to ake it with animal/whey proetin or with glycine/glutamiine right? how much aminos with it?

to keep NO from dropping, dose hystidine or AEE with the NAC

I'm gonna buy organic chicken breast from now on... any tips to msassively reduce the amount of toxin exposure?

regarding the ciguatoxin, it may seem to be the most likely explanation (occams razor and all that) that its comming from the diet, but I think some reseaRchers think an endogenous microbe is producing it in the CFS sufferer.

What is interesting is that we are on the verge of discovering a number of new microbes that cause diseases, and in gut conditions one recent finding is that a normal stomach bug is over-prevalent in the gut surface, and is a newly discovered variant that contains genes from various other nasty pathogens which it has obtained in situ and this is likely playing a leading role in that condition (crohns IIRC).

Bugs are mutating all the time and it is only a matter of time before they possess genes for doing really nasty things especially when they may be obtained from common microbes. Genes easily cross genera and as such, if the mutants aren't crowded out and ejected, pathogenesis evolves quickly.

So I think its quite likely that a retro virus or other gene transfer has brought in the abnormal proteins seen in CFS.

ok... but once you have it what do you do?

Or and I think this most appropriate given the signs of membrane oxidation seen in CFS, you might best raise NO by blocking superoxide anion which has the nice benefit of reducing peroxynitrate (which seems to be increased in CFS) whilst this spares NO.

Pomegranate especially its pericarp (or peel in plain English) was found to be very effective in doing this, as is higher dose Grape Seed Extract.

These can massively reduce superoxide molecule but pomegranate peel also potently blocks membrane oxidation to within normal values in chemically induced damage, and also restored several antioxidant enzymes. Combining with grape seed also and NAC but I would prefer at low dose with RALA would be an ideal combination for ensuring all antioxidant enzymes are functional.

For CFS, Sea Kelp for iodine and glutathione raising effects, NAC, nigella saitiva ((very potent inhibitor of membrane peroxidation) and all round anti-inflammatory, though, strangely, also one study showed it raised TNF-Alpha and had immune boosting effects regarding viruses and cancer, which is possibly something we want for some and not for others - this may preclude that it is used at night but I haven't experienced success with this yet), 100-200mg GSE for morning dose, maybe a top-up of another 100mg later, 50 mg N-RALA, say 200mg NAC, Pomegranate pericarp or similar, along with appropriate folic acid sources, B12 and some methyl donors, maybe Glutamine, L-Serine amino acids, a relatively simple and affordable stack for the morbing (with boosters during the day. Ashwagandha looks promising for its capacity to boost the immune system in times of stress, as would vitamin C. Bacopa for antioxidant enzyme effects.

Easy to blend in some DHEA and yes, one of my favourites, LITHIUM. Though long term low dose lithium for most is probably not advisable, it offers such neuroprotective benefits that I would consider it an important part of a CFS treatment considering ample evidence of CNS problems.

I would put the immune boosters LAG and herbs in the night time stack with glycine, glutamine and melatonin, with a lot of magnesium and reasonable amount of zinc.

If infection is present, then aloe vera, nigella sativa, red algea extract would be part of the solution, and if micoplasma is suspected, then this has a herbal agent as well which I posted in another thread.

If not, then immune overactivation is likely, and Vitamin D is desirable.

Boosting the immune response with sleep and its antioxidant defenses is a very important part I am sure. If allergies are present in CFS a shift towards Th-1 is indicated in theory. (reasonable but not excessive D3, lots of O3, vitamin E and DHEA, and raising immune cell antioxidant defenses along with sleep all key.

The benefits of L-Serine and I find for glutamine may be related to an immune boosting effect. Incidentally, L-Serine should boost brain phosphatidyl serine levels when taken with DHA, especially when also taken with glycerophosphyl choline. More PS but not ACh is indicated for the CFS with congnitive problems.


Following the stack, the ideal breakfast would be protein based since protein has markedly lower oxidative effects in the body compared with fatty foods (one hour of elevation compared to 3). Protein like whey protein is probably a great idea for the morning with some soluble fibre for the gut if implicted.

Targeting TNF-alpha in Alzheimers;

http://www.medscape.com/viewarticle/529176


Interestingly, IFN Gamma and TNF-Alpha ctually stimulate amyloid production - http://ajp.amjpathol.org/cgi/content/full/170/2/680
and TNF-Alpha and co-stimulation of NMDA induces neuronal death


and....

http://www.jimmunol.org/cgi/content/abstract/165/12/7180


The Journal of Immunology, 2000, 165: 7180-7188.
Copyright © 2000 by The American Association of Immunologists

Vitamin C Inhibits NF-B Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase1
Andrew G. Bowie2 and Luke A. J. O’Neill
Department of Biochemistry, Trinity College, Dublin, Ireland

The transcription factor NF-B 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-B by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-B-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-B. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-B were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-B (inhibitory protein that dissociates from NF-, due to inhibition of I-B 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-B phosphorylation, and NF-B activation. The results identify p38 as an intracellular target for high dose vitamin C.

<---if this pans out, actions on CNS cytokines might be a means by which ascorbic acid improves sex drive according to one study, though we dont yet know if it does lower TNF-alpha in the brain.

What is also interesting is that before bed, in the late evening, there is a natural increase in the anti-inflammatory IL-10 and I think that this might be designed to enhance mating behaviors.

From some dudes research page; http://www.bio.davidson.edu/courses/Immuno...f/tnfalpha.html

"Strategies for preventing TNF-A activity include neutralization of the cytokine via either anti-TNF antibodies, soluble receptors, or receptor fusion proteins; supression of TNF-A synthesis via drugs such as cyclosporine A, glucocorticoides, or cytokine IL-10; reduction of responsiveness to TNF-A via repeated low dose stimulation; and lastly, by inhibition of secondary mediators such as IL-1, IL-6, or nitric oxide (Tracey et al., 1993). "

Anyway, another study showed no cytokine effects from vitamin C and E in long term use.

But here's one on silymarin and NF-kappa beta.

http://www.jimmunol.org/cgi/content/full/163/12/6800


The role of free radicals in inducing NF-Kb when stimulated by TNF-Alpha - potentially very relevant to CFS where of course ROS is indicated;

http://ajplung.physiology.org/cgi/content/full/279/2/L302

This could partially explain the increased NF-Kb response in CFS.


This was very interesting regarding inhibition of TNF-a induced NF-Kb response in endothelial cells, by lipoic acid but NOT by glutathione status;

http://www.fasebj.org/cgi/content/full/15/13/2423

DING DONG!!


http://publib.upol.cz/~obd/fulltext/Biomed/2005/1/29.pdf

Milk Thystle lowers TNF-Alpha and Nuclear Factor Kappa B -

But better still.....

One study has shown that it might help the brain fifght viruses (yet lowers inflammatory cytokines - )

An interesting study aiming at neuro-immunomodula-tion mediated by silybin was accomplished by Sakai et
al.50. Major histocompatibility complex (MHC) I is usu-ally suppressed in neuronal cells and neuroblastoma cells and this may lead to persistent viral infections. Induction of MHC I molecules in neuronal cells can stimulate the immune system to be able quickly to identify intracellular pathogens by cytotoxic T cells and remove the viruses from the central nervous system. Silymarin treatment resulted in the expression of MHC I in cells. Therefore, it was proposed that silymarin may be useful in the treatment of encephalitis. More studies, both in vitro and in vivo are, however, required.

<---That is very interesting, especially if it permits lower TNF-alpha in progressive treatment.

Some more data on MHC in CNS;

http://ajp.amjpathol.org/cgi/content/full/159/4/1219

This is significant, as drugs that lower TNF-Alpha can make viral infections worse, as you'd expect, such as in the case of West Nile Virus. WNV symptoms also looks like CFS which means that lowering immunity against a brain pathogen is something we need to be cautious about. If, and this is the problem, we dont know if we have a brain infection, then we need to proceed with herbal and nutrient therapies aimed at having immune boosting effects, are anti-viral and which positively modulate chronic immune responses.

To that end, micoplasmas are unlikely to be causative as number of strains infected in an individual correlate with length of CFS suffering, indicating an opportunistic nature rather than primnary causative one.

Viruses such as retro-viruses, herpes and coxsakie are particularly implicated in CFS. Testing for these is straight forward, but only for evidence of infection fighting in the periphery.

In the CNS, it has been shown that at least one Herpes virus (HHV-2 I recall) can get in, and persist in an entirely as yet undetectible mannor, unless a biopsy of the brain is taken.

Therefore, we might assumne that low level infection in the CNS may cause lingering CFS. The infection maty also be cured, but continued dysruption result by altered signalling and residence of immune cells in the brain, which makes it contentious whether we want anti-inflammatories, as we dont know if infection is actually still present.

Epstein Barr, a herpes virus, reduces TNF-Alpha receptor as a survival strategy;

http://www.mindandmuscle.net/forum/index.p...t=0#entry419931

Lithium synnergises with TNF-Alpha in cancer cells but was indicted to lower TNF-Alpha in a low dose HIV positive subject study.

http://www.jbc.org/cgi/content/full/276/28/25939

http://grouppekurosawa.com/blog/2005/11/ca...of-tumor_28.htm

http://www.natap.org/2006/HIV/091106_04.htm

Some studies suggest that lithium might incraese TNF-alpha, others suggest it is lowered.

In the following, it lowered IL-1 and TNF-alpha but increased IL-6 in monocytes;

http://www.antenna.nl/lithium/nascholing/c...tstemmingen.htm


and, that is correlated to depression symptoms in healthy men;

http://www.psychosomaticmedicine.org/cgi/c...t/full/65/3/362

Calculations of partial correlation coefficients controlling for age, race, body mass index, and alcohol use indicated that BDI score was significantly associated with IL-1 (r = 0.27), IL-1ß (r = 0.44), TNF- (r = 0.57), MCP-1 (r = 0.52), and IL-8 (r = 0.33). In addition, relative to men with BDI scores below 10, men with BDI scores of 10 or above exhibited an overexpression of IL-1ß (p = .004), TNF- (p = .005), IL-8 (p = .002), and MCP-1 (p = .025).

CONCLUSIONS: Relative to men with no or minimal symptoms of depression, men with mild to moderate levels of depressive symptoms showed overexpression of monocyte-associated proinflammatory cytokines and chemokines.


More on CNS toxicity of cytokines;

http://www.jimmunol.org/cgi/content/full/172/11/7043 - complex stuff

Berberine might be promising;

1: J Biomed Sci. 2005 Oct;12(5):791-801. Epub 2005 Nov 9. Links
Acetaldehyde-induced interleukin-1beta and tumor necrosis factor-alpha production is inhibited by berberine through nuclear factor-kappaB signaling pathway in HepG2 cells.Hsiang CY, Wu SL, Cheng SE, Ho TY.
Graduate Institute of Medical Science, China Medical University, Taichung 404, Taiwan. cyhsiang@mail.cmu.edu.tw

Alcoholic liver disease (ALD) is one of the most common liver diseases in the world. Increased levels of proinflammatory cytokines, including interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), have been correlated with the patients affected by ALD. However, the direct effect of alcohol in the induction of IL-1beta and TNF-alpha has not been clarified. In this study, we demonstrated that acetaldehyde, the metabolic product of ethanol, was able to induce IL-1beta and TNF-alpha production in HepG2 cells. Nuclear factor-kappaB (NF-kappaB), the transcription factor involved in the regulation of cytokine production, was also activated by acetaldehyde through inhibitory kappaB-alpha (IkappaB-alpha) phosphorylation and degradation. However, the NF-kappaB inhibitors, such as aspirin, cyclosporin A and dexamethasone, inhibited both the acetaldehyde-induced NF-kappaB activity and the induced cytokine production. Therefore, these data suggested that acetaldehyde stimulated IL-1beta and TNF-alpha production via the regulation of NF-kappaB signaling pathway. By screening 297 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we found that Coptis chinensis (Huang-Lien) and Phellodendron amurense (Huang-Po) were capable of inhibiting acetaldehyde-induced NF-kappaB activity. Berberine, the major ingredient of these herbs, abolished acetaldehyde-induced NF-kappaB activity and cytokine production in a dose-dependent manner. Moreover, its inhibitory ability was through the inhibition of induced IkappaB-alpha phosphorylation and degradation. In conclusion, we first linked the acetaldehyde-induced NF-kappaB activity to the induced proinflammatory cytokine production in HepG2 cells. Our findings also suggested the potential role of berberine in the treatment of ALD.

PMID: 16132116 [PubMed - indexed for MEDLINE]

-it did this in lung and fat cells as well....

also, is an antidepressant in rodents, at least;

Our findings demonstrated that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin or dopamine) and further, the antidepressant-like effect of berberine in the forced-swim test involved an interaction with the l-arginine-NO-cGMP pathway.

PMID: 17585901 [PubMed - in process]


EDIT - another study showed it raised iNOS and IL-1 in CNS in states of existing inflammation (amyloid induced)

I'm taking hefty doses of sylmarin but am wary as like most good thigns there is a caveat - it blocks the Ar

How would I combine all of this with immunovir?

I plan to take 2 grams a day for two months.
by the way I have virii(HPV) and bacteria(Chlamydia). I'm starting to take antibiotics tomorrow for 10 days for the Chlamydia. after that its R&R for 20 days and than immunovir for 8 weeks for the HPV and CFS.

BTW any tips on what to take with the antibiotics (doxcyline) to ensure they do their job and dont fuck me up?

Well in the other CFS threaad, fatuigue syndromes and imnunity, there was a lot of potential antimicrobial agents and synnergists that could be of help. Maybe worth starting a thread on your particular questions.

hmm ATB, check it:



Bingo motherfucker!!!

futhermore, there goes the negative/positve feedback loop again. more moreadrenaline=less tnf alpha and less adrenaline = more tnf alpha...

how about taking curcumin in my morning and afernoon stack?

and ginseng! anyone still taking it? what kind of extract do you use?

can anyone get this text:

this is even more interesting

one more thing - tnf-alpha lowers Testosterone.

This is a useful thread, thankyou Liorhh. On the TNF alpha, thought I would mention a couple of pertinent findings;

TNF-a arrests cell clock progression, blocking waking phases

TNF-a also potently blocks EPO, though there are circumstances when it boosts it.

http://www.hhv-6foundation.org/febpressrelease.pdf

It appears more evidence is comming to light on brain infection in CFS. I think this explains symptoms more clearly in many cases than anything else.