Lemon peel is a rich source of nobiletin, found in this study to inhibit NF-kB. Inhibition of NF-kB was associated with a decrease in: NO production, PGE-2, and COX-2, each of which is an important mediator of pain and inflammation in arthritis.
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Tag Archive: NF-kB
Blessed milk thistle may bless those with MS
Silibinin is a mixture of flavonolignans extracted from blessed milk thistle. It has for some time been recognized for its beneficial effects in protecting the liver against toxins. More recently it has been demonstrated that silibinin inhibits NF-kB.
The researchers whose publication is briefly summarized below hypothesized that, as a natural NF-kB inhibitor, silibinin might be useful in the treatment of multiple sclerosis.
Employing the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), they looked at the effects of silibinin on spinal cord demyelination and inflammation. The results of their investigation indicated that silibinin is both immunosuppressive and immunomodulatory and that it might be useful in the treatment of MS.
Theory of inflammation
Inflammation can be good or bad – appropriate or excessive. Unless otherwise indicated, when used here the word “inflammation” means bad or excess inflammation – the kind that results in disease – not the kind that protects us from infections and assists in healing.
Good and bad inflammation are different but not unrelated. In fact all [...]
Migraine attacks can be prevented by inhibiting NF-kB
A number of different medications and medication classes have been found to be at least somewhat effective in the prevention of acute migraine attacks.
However, because upstream events triggering migraine attacks are poorly understood, identification of these agents has largely been the result of serendipitous observations combined with presumed class effects (e.g. anticonvulsants).
A better understanding of migraine would allow for a more rational approach to the discovery and development of medications to prevent migraine attacks.
On investigation, a number of existing migraine preventatives are found to inhibit NF-kB.
It is proposed that migraine results from over-activation of NF-kB (though some as yet unknown mechanism) and that effective migraine prevention can be achieved through the use of NF-kB inhibitors. Of particular value might be those natural NF-kB inhibitors which have been proven safe by extensive human use over the course of several millenia.
Triptan analog inhibits NF-kB
The triptans are an effective class of acute anti-migraine medications. Their mechanism of action has yet to be entirely determined, though they are known to be bind at 5-HT1b/d (serotonin) receptors.
In the study below, the effect of a similar molecule was investigated. m-CPP binds non-specifically to both 5-HT1 and 5-HT2 receptors. It may be that the anti-inflammatory effects of m-CPP are mediated through binding sites that are not effected by triptans. However, the triptans do exhibit certain anti-inflammatory effects that are similar to those observed for m-CPP. One possibility is that triptans also inhibit NF-kB and that some portion of their efficacy in the treatment of migraine is thereby accounted for.
Natural NF-kB inhibitors in migraine
Migraine is a disease of inflammation – and NF-kB is the Master Switch for inflammation.
Emerging consensus recognizes the importance, in migraine, of the over-production of:
* TNF – NF-kB controls it.
* iNOS (NO) – NF-kB controls it.
* CGRP – NF-kB at least affects it, perhaps critically, perhaps entirely.
Therefore, by inhibiting NF-kB, a reduction in each of the above mediators of migraine inflammation might be achieved.
Inhibition of NF-kB might be achieved most effectively, and certainly most safely, with the use of natural NF-kB inhibitors.
Feverfew inhibits NO via inhibition of NF-kB in migraine
In the study below, using the nitroglycerin induced model of migraine, it was shown that parthenolide, the purported active ingredient in feverfew, inhibited nitric oxide (NO) production in the trigeminal nucleus by inhibiting NF-kB.
Excess NO production is implicated in the pathogenesis of all headache. It is also an important mediator in other disease conditions.
Migraine mix: CGRP, TNF, NF-kB, TMJ
In both TMJ and migraine, high levels of CGRP are found in the trigeminal ganglion. CGRP is a neuropeptide and its release is associated with neuroinflammation. That inflammation is associated with an increase in other pro-inflammatory cytokines.
In the study briefly summarized below, administration of TNF led to an increase in CGRP. While the authors postulate that the MAPK pathway is of greatest importance, NF-kB was also shown to be activated. NF-kB activation both results from, and results in, higher levels of TNF. That is, TNF activates NF-kB and activated NF-kB turns on the production of more TNF.
As with most inflammation events, the interaction of the various components is complex and not completely understood. What is clear is that inflammation happens, that it’s important, and that CGRP, NF-kB, TNF and the trigeminal ganglion are each involved – both in migraine and in TMJ.
Nf-kB inhibition blocks CGRP release
CGRP may be a key mediator of inflammation in migraine. Several CGRP inhibitors are now being developed. Trials conducted to date show these to be of about equal effectiveness with triptans, but without the side effects that result from vasoconstriction by triptans.
Activation of NF-kB may lead to transcription and then release of CGRP.
Inhibiting NF-kB reduced CGRP levels.
An effective inhibitor of NF-kB might therefore perform as well, or better than, an inhibitor of CGRP.
Traditional migraine medications inhibit NF-kB
Traditional Chinese medications used in the treatment of migraine are shown to inhibit NF-kB.
The authors suggest that traditional Chinese medications are effective in the treatment of migraine because they inhibit NF-kB.
NF-kB activation in trigeminal nucleus in migraine
In those with migraine, nitroglycerin (NTG) induces severe delayed headache, resembling spontaneous migraine attacks. This has proven to be a good model for migraine.
The publication summarized below sought to explore a possible mechanism by which NTG results in migraine and found that NTG administration resulted in an increase in activated NF-kB in the trigeminal nerve.
Everything you need to know about aging
Many have argued that aging is genetically pre-programmed – in which case there is little we can do to slow it down. However, because NF-kB over-activation has now been shown to be a major cause of the physical changes associated with aging, we can slow aging by reducing the level of NF-kB activation.
Synergy of multiple NF-kB inhibitors
Turmeric (curcumin) and resveratrol found to act synergistically in the treatment of arthritis.
This is an essential publication because it demonstrates that by combining different natural inhibitors of NF-kB, a greater anti-inflammatory effect may be achieved than is possible with either agent alone. The study further suggests that this might be especially true when the different agents act to inhibit NF-kB through different mechanisms.
By implication, the observed synergy will not be limited to the specific combination studied (curcumin + resveratrol.)
Banjo combines a number of different natural NF-kB inhibitors, each of which may act through a slightly different mechanism in the inhibition of NF-kB. While many of the individual agents might provide some benefit, Banjo is expected to provide a substantially greater benefit than any single agent. That possibility is confirmed by the study briefly summarized below.
NF-kB, atherosclerosis and aging
Excess NF-kB activation underlies vascular damage associated with aging.
A number of risk factors are associated with the onset of clinically significant atherosclerosis. Among those risk factors are high blood pressure, metabolic disease and a number of lifestyle related risks such as obesity and smoking.
Aging itself has come to be seen as an independent risk factor in the development of atherosclerosis, as vascular inflammation and atherosclerosis is observed with increasing frequency at greater age, even in the absence of other risk factors. Age-related oxidative stress is believed responsible for this effect on aging vessels.
The review briefly summarized below suggests that oxidative stress is mediated through multiple pro-inflammatory pathways, all of which converge on NF-kB, resulting in excess activation of NF-kB in the aged vasculature.
The implication of this publication is that by preventing or reducing excess NF-kB activation the effects of aging on blood vessels can be countered.
Everything you need to know about osteoarthritis
NF-kB inhibition as the Holy Grail of osteoarthritis treatment
This is an essential publication because it really does tell us (nearly) everything we need to know in order to effectively treat osteoarthritis.
The publication referenced below lays it out – it’s very simple:
* Osteoarthritis is characterized by cartilage destruction and inflammation of the membrane that surrounds the joint (the synovium.)
* Cartilage destruction is the result of inflammation.
* The inflammation results from excess activation of NF-kB.
* Chondroitin sulfate works because it inhibits NF-kB.
The cause of osteoarthritis.
In chronological order:
Excess NF-kB activation => inflammation => joint destruction & pain
The root of the problem is obvious: Excess NF-kB activation.
The ideal treatment is obvious: Prevent excess NF-kB activation.
Nitric oxide & NF-kB in osteoarthritis
The role of NO as either beneficial or detrimental in the arthritic joint has long been debated. NO appears to act in a very complex manner. However, the fact that it inhibits NF-kB and therefore serves an anti-inflammatoey roles suggests that NO inhibition may have detrimental effects in osteoarthritis.
The weak NF-kB inhibitor glucosamine may be useful in IBD.
Essentially all NF-kB inhibitors, even the relatively ineffective NF-kB inhibitor glucosamine, may be of benefit in the treatment of diverse conditions associated with inflammation – including inflammatory bowel disease.
Glucosamine, which was originally combined with chondroitin sulfate in preparations for the treatment of osteoarthritis, was originally believed to act primarily by “re-building cartilage” and “providing nutrition” to the joint.
It is now recognized, however, that glucosamine is an anti-inflammatory agent – a weak NF-kB inhibitor.
As such, glucosamine will do what NF-kB inhibitors do – it will treat inflammation and may therefore find application in any number of inflammation related conditions.
In the study summarized here, the effects of glucosamine in the treatment of a rat model of inflammatory bowel disease are investigated and found to be promising.
However, it is this author’s opinion that glucosamine will never find practical application in the treatment of inflammatory bowel disease (ulcerative colitis and Crohn’s.) It is simply not a potent enough inhibitor of NF-kB and would require administration in amounts far too great to be practical.
Furthermore, there are much more effective, faster-acting NF-kB inhibitors readily available.
Nonetheless, this study serves as a useful demonstration of the safety and efficacy of NF-kB inhibitors – in this case when used for the treatment of inflammatory bowel disease.
New glucosamine derivative acts by inhibiting NF-kB
Glucosamine is a weak inhibitor of NF-kB, and thus an anti-inflammatory agent with potential therapeutic use in the treatment of inflammation, such as in osteoarthritis.
A new derivative of glucosamine was examined it was likewise found to be an inhibitor of NF-kB.
NF-kB activation pathway in fibromyalgia
This is an essential publication because it:
* Demonstrates excess NF-kB activation in muscles of fibromyalgia patients;
* Provides a possible explanation for connective tissue changes in fibromyalgia; and,
* Suggests one means by which local pain and inflammation might become self-perpetuating in fibromyalgia.
Pregabalin (Lyrica) inhibits NF-kB
Fibromyalgia is associated with increased levels of “substance P” – a neurotransmitter and neuromodulator that is found in the brain and spinal cord and that is associated with inflammatory processes and especially pain processes.
Pregabalin is used in the treatment of seizure, neuropathic pain and fibromyalgia. It is thought to act by binding to a specific receptor on nerve cells and reducing or slowing nerve transmissions in the central nervous system.
In this study it was shown to reduce the ability of substance P to activate NF-kB.
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