Discussion in 'Other Health News and Research' started by natasa778, Jun 28, 2015.
So suicidal people should try to inhibit cytokines, right?
Hip posted an amazing list of inhibitors a few months ago:
Given below are lists of supplements and drugs that inhibit microglial activation, and inhibit the pro-inflammatory cytokines released from activated microglia.
Inhibitors of Microglial Activation
All the following may have beneficial effects in lowering microglial activation and brain inflammation:
Valcyte (valganciclovir) and Cytovene (ganciclovir) potently inhibit microglial activation. 1
Low-dose naltrexone (LDN) appears to block the TLR-4 receptor on microglia, inhibiting microglial activation. 1
Hyaluronic acid (a supplement) reduces microglial activation by a TLR-4 receptor mechanism (like LDN) 1
Lithium significantly inhibits LPS-induced microglial activation, via suppression of LPS-induced TLR-4 expression. 1
Ar-turmerone (found within turmeric) 1
Vitamin E 1
Wogonin (flavonoid from skullcap herb) 1
Baicalein (flavonoid from skullcap herb) blocks LPS-induced activation of microglia. 1
Silymarin (found within milk thistle herb) significantly inhibits the LPS-induced activation of microglia. 1
Genistein (a flavonoid supplement) 1
Tetracyclines (a class of antibiotic, which includes minocycline, doxycycline and tetracycline) inhibit ischemia-induced activation of microglia. 1
Minocycline (antibiotic) 1
Sulforaphane (a supplement, obtained from cruciferous vegetables) 1
N-acetyl-glucosamine 1 (note: only the N-acetyl-glucosamine form of glucosamine can cross the blood-brain barrier)
Sesame seed oil 1
Andrographolide (from the herb Andrographis paniculata) 1
Acetate (which you can get from ordinary vinegar) inhibits microglial activation in a rat model of Lyme disease. 1
Cannabidiol (non psychoactive component of Cannabis, available as Cibdex and Dew Drops Hemp Oil). 1
Dextromethorphan (a cough mixture cough suppressant) 1
Siberian ginseng (Eleutherococcus senticosus) appears to inhibit microglial activation. 1
Ginsenoside Rg3 (from Panax ginseng) 1
Gastrodia elata (a Chinese herb, aka: Tian Ma) 1
Isodojaponin D (from the herb Isodon japonicus) 1
Tetrandrine (from the Chinese herb Stephania tetrandra, aka: Han Fang Ji) 1
Risperidone (antipsychotic drug) significantly inhibits interferon gamma-induced microglial activation in vitro. 1
Terminalia chebula (Indian herb) inhibits LPS-induced microglia activation. 1
Astrocyte-derived GDNF is a potent inhibitor of microglial activation. 1 The herb Rehmannia glutinosa induces GDNF. 1
Resveratrol may reduce microglial activation. 1
Memantine (NMDA receptor-blocking drug) reduces microglial activation. 1
Palmitoylethanolamide (PEA) reduces microglial activation induced by formalin or MPTP. 1 2
Inhibitors of Inflammatory Cytokine Release from Activated Microglia
All the following may have beneficial effects by reducing the inflammatory cytokines released by activated microglia:
Phytoestrogens lower inflammatory cytokines IL-1β, IL-6 and TNF-α. 1
Vinpocetine supplement inhibited the production of nitrite oxide and inflammatory cytokines such as IL-1β, IL-6 and TNF-α in BV-2 microglia. 1
Simvastatin (cholesterol-lowering medication) reduces IL-1β and inhibits the activation of microglial cells in traumatic brain injury. 1
Rifampicin (antibiotic) inhibits nitric oxide, iNOS, COX-2, IL-1β, TNF-α and prostaglandin E2 from LPS- stimulated microglia. 1
Propentofylline inhibits LPS-induced release of IL-1β and TNF-α from activated microglia. 1
Ceftriaxone (injectable antibiotic) reduced IL-1β released from microglia during ischemia. 1
Sulforaphane attenuates the LPS-induced increase of IL-1β, IL-6 and TNF-α expression in microglia. 1
Obovatol (from Magnolia officinalis) attenuates microglia-mediated neuroinflammation. 1
Spironolactone inhibits TNF-α release (by 50% to 60% at 10 µM) from LPS-activated microglia. 1
Ibudilast (a Japanese drug which inhibits TLR-4) suppresses the production of nitric oxide, reactive oxygen species, IL-1β, IL-6, TNF-α and enhanced the production of IL-10. 1
Inflexin significantly inhibits the release of nitric oxide from microglia. 1
Piper kadsura (Japanese pepper) inhibits IL-1β and TNF-α release from microglia. 1
Reishi (Ganoderma lucidum) inhibits nitric oxide, IL-1β and TNF-α release from microglia. 1
Magnesium sulfate inhibits the release of iNOS, nitric oxide, prostaglandin E2, IL-1β and TNF-α in LPS-activated microglia. 1
Amantadine reduces the release of pro-inflammatory factors from activated microglia. 1
SSRI antidepressants potently inhibit microglial TNF-α and nitric oxide production in microglia. 1
Curcumin (found within turmeric) blocks the production of nitric oxide, TNF-α, IL-1α and IL-6 in IFN-gamma- and LPS-stimulated microglia. 1
Icariin (from the herb Epimedium, aka: horny goat weed) significantly inhibits nitric oxide, prostaglandin E2, reactive oxygen species, IL-1β, IL-6 and TNF-α in LPS-activated microglia. 1 Note that icariin's oral bioavailability is only 12%, but rises to 40-62% if taken with a lactase inhibitor. 1
Luteolin (flavonoid supplement) inhibits LPS-induced release of nitric oxide, COX-2, TNF-α, IL-1β, IL-6 and prostaglandin E2 from microglia. 1 2
Fisetin (a flavonoid supplement, found in strawberries and mangoes) markedly suppresses nitric oxide, iNOS, TNF-α, IL-1β, COX-2, and prostaglandin E2 in LPS-stimulated microglia cells. 1
Pioglitazone (Actos) inhibits nitric oxide, iNOS, TNF-α, IL-6 and IL-1β production in LPS-stimulated microglia. 1
Oxymatrine inhibits production of nitric oxide, iNOS, PGE2, COX-2, TNF-α, IL-1β and IL-6 in LPS-stimulated BV2 microglial cells. 1 Oxymatrine also down-regulates TLR-2 and TLR-4. 1
Beta-glucans attenuates TLR-2- and TLR-4-mediated cytokine production by microglia. 1
Inhibitors of Inflammatory Cytokine Release from Astrocytes
The activities of astrocyte cells in the brain are closely tied in with the process of microglial activation. All the following may have beneficial effects by reducing the inflammatory cytokines released by astrocytes:
Rehmannia glutinosa steamed root reduces astrocyte IL-1 and TNF-a secretion. 1 This steamed (cooked) Rehmannia glutinosa root has the Chinese name Shu Di Huang. This is slightly different to raw (uncooked) Rehmannia glutinosa root, whose Chinese name is Sheng Di Huang. The latter is prone to causing strong stomach aches.
Dandilion (Taraxacum officinale) decreased TNF-α secretion from rat astrocytes. 1
Alpha lipoic acid decreased IL-1β, TNF-α, IL-6 and iNOS secretion from astrocytes. 1
Resveratrol decreased the expression of TNF-α, IL-6, iNOS and NO in astrocytes. 1 2
Dimethyl fumarate (Tecfidera, a very expensive drug) decreased the expression of IL-1β, TNF-α, IL-6 and NO in astrocytes. 1
Inhibitors of Glutamate Release from Activated Microglia
Inducers of Microglial Activation
The following substances increase microglial activation and brain inflammation, and will likely worsen ME/CFS symptoms:
Lipopolysaccharide (LPS), which derives from Gram negative bacteria, increases microglial activation.
Interferon gamma, which is secreted by the body during infection, increases microglial activation.
Homocysteine promotes proliferation and activation of microglia. 1
To counter this increase microglial activation by the above factors, note that:
• Andrographolide (from the herb Andrographis paniculata) inhibits interferon gamma. 1
• Increasing methylation (such as by the methylation protocol) reduces homocysteine, which will then reduce microglial activation. Indeed, the fact that methylation reduces homocysteine levels may help explain why the methylation protocol appears to be beneficial for ME/CFS. The most important supplements for reducing homocysteine are: folate, the vitamins B12, B6 and B2, zinc and trimethylglycine. 1 Other homocysteine-reducing supplements include: N-acetyl-cysteine reduces plasma homocysteine levels. 1 Phytic acid (aka: inositol hexakisphosphate or IP6) is a supplement that reduces plasma homocysteine. 1 Choline or betaine reduces homocysteine. 1
Inducers of Inflammatory Cytokine Release from Microglia
The following substances increase the release of pro-inflammatory cytokines from activated microglia, and will likely worsen ME/CFS symptoms:
Leptin (a hormone) induces IL-1β release from rat microglia. 1 Leptin may also increase IL-6 release from microglia. 1
Lactate induces IL-1β, IL-6 and TNF-α release from rat microglia, as well as IL-6 and TNF-α release from rat astrocytes. 1 Lactate is produced by the muscles during exercise, and can cross the blood-brain barrier quite easily.
The Two Main Types of Microglial Activation
There are actually two main modes of microglial activation:
Classical microglial activation which is neurodestructive (and involves COX-2, iNOS, IL-6, and TNF-alpha).
Alternative microglial activation which is neuroprotective (and involves FIZZ-1, YM-1, Arginase-1, and IL-4).
Classical microglial activation is the "kill" mode which destroys pathogens in the brain; alternative microglial activation is the repair mode which heals the brain. When we talk about microglial activation and is destructive effects, we are referring to classical microglial activation.
(There is also a recently discovered third mode of microglial activation called acquired deactivation, which is similar to alternative activation in that it is also an anti-inflammatory and repair mode of microglia).
Factors that Switch Off the Microglia's Neuroprotective Mode, and Switch on the Neurodestructive Mode
Oxidative stress and lack of Nrf2 may favor the neurodestructive (classical) mode of microglial activation over the neuroprotective (alternative) mode. 1 So taking Nrf2-activators may help flip to the neuroprotective microglial activation mode. Genistein, sulforaphane and artesunate activate Nrf2, and there are Nrf2-activator supplements like this one: XYMOGEN Nrf2-activator.
NADPH oxidase promotes the neurodestructive (classical) phenotype of microglial activation over the neuroprotective (alternative) phenotype. NADPH oxidase is a membrane-bound enzyme found on microglia and macrophages; this enzyme generates the free radical superoxide in order to kill pathogens. Apocynin (also called acetovanillone) from the herb Picrorhiza kurroa is a potent NADPH oxidase inhibitor, and has been shown to promote the neuroprotective microglial mode. 1 Apocynin inhibits NADPH oxidase by preventing the assembly of this enzyme.
Lipopolysaccharide (LPS) from Gram negative bacteria seems to switch microglia from their neuroprotective mode into their neurodestructive mode. Thus if any LPS was getting into the brain (perhaps from a leaky gut, from a Gram negative sinus infection, or even a Gram negative bacterial infection within the brain), then this would tend to promote the neurodestructive mode of microglia, and prevent the activation of the neuroprotective mode of microglia. Though note that very little LPS passes through an intact blood-brain barrier.1
Ochratoxin A, a mycotoxin which Dr Joseph Brewer found in 83% of ME/CFS patients, and in zero percent of healthy controls, 1 promotes the neurodestructive mode of microglial activation. 1
• Hyaluronic acid appears to inhibit microglia activation by acting on the TLR-4 receptor, just as LDN does. So hyaluronic acid, which is available as a supplement, may be a good alternative (or an adjunct) to LDN. Hyaluronic acid also has antiviral properties, and inhibits a range of viruses including coxsackievirus B5. 1 Some other TLR-4 antagonists are given here. Oxymatrine also has TLR-4 and TLR-2 effects: it down-regulates the the expression of these two receptors in the brain.
• The improvements in ME/CFS symptoms that Prof Montoya observed in his study treating ME/CFS patients with the antiviral Valcyte may have arisen from this drug's microglial activation-inhibiting effects, as well as its antiviral and Th1/Th2 immunomodulatory effects.
Inhibitors of Microglial Neurotoxicity: Focus on Natural Products
Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders
Last edited: Jun 16, 2015
Here's a little mundane excerpt which, considered together with the more technical analytic biochemistry begs the question 'what to take NOW, ie and how much, how often, is more 'x,y..n' better (and...contraindications?):
Access @ LEF.org
<<Life Extension Magazine January 2014
http://www.lifeextension.com/magazine/2014/1/turn-off-the-cytokine-switch/page-01 (link added by moderator)
Turn Off the Cytokine Switch
By Morris Eagleton
In a remarkable series of discoveries, scientists have uncovered the main biochemical “switch” that turns on many of the chronic diseases of aging.
Known as HMGB1 (for “High Mobility Group Box-1”), this intriguing protein molecule triggers the release of the cytokines—a collection of chemical signals—that generate inflammation in your body.1
And as inflammation accumulates, aging accelerates, to the point that most scientists now speak about “inflammaging” as a single entity that underlies disorders that cause premature death, including conditions ranging from diabetes and atherosclerosis to lung disease and cancer, to name just a few.2-4
In an exciting new development, the discovery of HMGB1 as the switch that turns “on” accelerated aging has led to the development of a safe and effective means of turning “off” that switch and reducing premature senescence.
Research over the past few years has demonstrated that two natural ingredients can directly control HMGB1, switching off the massive cytokine flow that generates age-related inflammation and leads to disease and premature death.
Tested in prestigious hospital research laboratories, two plant extracts, mung bean seed coat and green tea, extended life spans and increased survival rate caused by inflammation in blood poisoning (sepsis) by up to 82%.5,6
This combination of natural ingredients can reduce total body exposure to the ravages of inflammation. By doing so, maturing individuals can protect themselves from accelerated aging, guard against inflammation-induced chronic disorders, and live a longer and more productive life... .>>
My note: LEI offers 'Mitochrondial Energizer'(s) and 'Cytokine Suppressor'(s). I am intrigued by the concomitant use of these and other instigators....?
While the above may be true I wonder how many studies included a control group.
Do you have a more specific url? I get a page with many search results.
I'm somewhat skeptical, especially with the media, when it comes to studies purporting to have a solution that will slow down or reverse aging. Many of the studies are on cells in a petri dish. I think there may be some in lab animals, but I'm not sure about that.
If there is a drug or supplement that halts aging I think it won't happen until many yeats to come. Maybe not even in our lifetime.
If you go to The Life Extension site (LEF.org) you should find references to their monthly magazine with indexes to topics, wherein lies the specific source of the above.
I otherwise signed on to get their text 'Disease and Prevention,'. 5th edition for general quick references. I also have it on my iPad for ease of use (from Amazon). So, seeing and getting to a specific url is a bit of a roundabout. You can try:
I am the quintessential skeptic... . While LEF sells pricey supplements (at a discount to members) and offers a plethora of blood testing, including Cytokines, its book is a credible text with surprisingly indepth information and references on mainstream and alternative medicine, noting pretty fairly whether they be results from double blind, anecdotal, in vitro, animal studies, et al. it covers most areas of interest to a general public and many topics interrelated to CFS/ME, with plenty of science.
If you want to cross reference it with an expansive authority on even deeper related science try 'The Textbook of Natural Medicine,' 4th edn, Pizzorno, et al, Churchill Livingston, 2012 (also available as a Kindle book, Amazon.com, or same authors' earlier 2nd edition entitled ''The Clinician's Handbook of Natural Medicine,"
Churchill Livingston, 2007. (Both are as good as it gets, IMO.)
I had forgotten Life Extention is published by Dr. Mercola's company.Dr, Mercola is not someone I choose to follow as I disagree with about 99.9% of what he says. He's also been investigated numerous times by the FDA for exaggerated claims about his vitamins.
There are a lot of once credible 'authorities' around who became questionable, including former gurus such as Cheney, Teitlebaum, et al. However, like them or not, rather than ad hominem discounting 99.9% of their work, it seems more fair and reasonable to weigh the specific merits of each of the referenced ingredients which comprise one of their assertions.
At your request I simply provided a source to justify the published claim. I'm not defending the author(s) as I am not aware of the FDA claims you allege.
I just wonder if they are related to the referenced material.
The explanations in the above text, again, seems reliable and consistent enough for general interest. Reviewers have found it jives with the other referenced texts, which examine the topics down to the biochemical molecular level. Are these authors
'Quacks' as well in your eyes? If so, you're in a minority legion!
Choose your own nectar as there are otherwise detractors for every potion
ever concocted. To wit, Thomas Edison was a failure until his 3000th experiment,
so said many, media included. A. Einstein traveled with some similar ignominy.
Do you have overriding positions to offer relative to Cytokines as per the above publications? If yes, then annotations would be helpful in evaluating their credulity.
If no, then I suppose is's okay to keep using these sources as credible references?
You are right, you were providing references I had asked for. Thank you.
But just because others have failed in the eyes of the public and were later vindicated really has nothing to do with whether Dr. Mercola or anyone else for that matter is correct. The opposite has also happened. One does not necessarily lead to the other.
The study may or may not be correct. I don't know. My skepticism comes from my opinion of Dr. Mercola's medical recommendations.
Since I find Dr. Mercola's theories flawed and that's pretty much across the board, I would not use his treatments.
Others have different takes on him and base their treatment decisions on that.
I don't follow your further reasoning as it's a non sequitor to the subject of the thread and to one conclusion referenced above by author Morris Eagleton, (contained on the LEF site which DOES follow the logic of the thread:
"...This combination of natural ingredients can reduce total body exposure to the ravages of inflammation. By doing so, maturing individuals can protect themselves from accelerated aging, guard against inflammation-induced chronic disorders, and live a longer and more productive life... ."
Even without a lot of science to back it up this simple conclusion does not seem far afield of the reality of the benefits of supplements, here of those that inhibit cytokine production (especially given what IS known about cytokines). Again, you do not state nor support an opinion which would otherwise refute this statement.
'...The study may or may not be correct. I don't know. My skepticism comes from my opinion of Dr. Mercola's medical recommendations. Since I find Dr. Mercola's theories flawed and that's pretty much across the board, I would not use his treatments. Others have different takes on him and base their treatment decisions on that...' )
At your post's prompting I reviewed some of the controversy surrounding Mercola; then looked further into whether or not he's directly controlling the LEF research. I did not find it to be the case and am not aware of further leanings of Dr. Mercola. D.O. regarding the specifics of this thread - that the reduction of cytokines is beneficial as an anti-inflammatory agent. So, back to the references and the thrust of this thread, with which I happen to agree... .
I was not really addressing abstractly nor specifically increasing the lifespan reference. However,
it follows that if one reduces inflammation in the body then a priori it further follows that reducing cyctokines must extend life span, ergo that a large percentage of 'early' deaths are due to or related to inflammatory origins. (Many references known; none cited here due to general acceptance.)
IMO, the re-posting @Hip's list of cytokine reducers is of great benefit to a lot of people who subscribe to CFS/ME as autoimmunity under attack: the information can be used today to begin lowering the inflammatory conditions that lead to symptoms.
FWIW, it has been my observation that most successful innovators have been mavericks, pioneers and found answers by deviating from the maintream.
@Stretched Green tea has become a mainstay of my protocol. I began it following recommendations of Martin Pall (in my signature) for antioxidants to scavenge peroxynitrite. Once my peroxy symptoms lessened, I reduced from 3 litres/day to 1. Also green tea extract. The most simplistic response to the LE story is that antioxidants are repeatedly invoked as part of anti-aging practice. (Which is not to say I'm discrediting the article.) I also use low dose naltrexone for it's anti-inflammatory effect.
Thanks, Ahmo. I see your point, having reviewed some of the controversy around Mercola, who I concluded was not
really involved in my original references (please see clarifying post above), at least not directly, if at all.
As for green tea, I have not tried it but I am at the point I would try green pine cones if there was a chance of efficacy,)
I barely drink a half liter of liquids daily. If I drank 3 liters I would be whizzing like Old Stewball (of legend) all night
long, and defeat its purpose by gobbling up sleep rxs to snooze! How do you deal with that phenom?
FWIW, Green Tea is on my list to try. Being frustrated with a lot of mainstream medicines I got into studying (and trying) the supplements/herbs (biochemistry) and their contributions to health (or not), including the methylation.
I see that green tea (extract) is offered in pills and in some places as an extract, ie tincture, both forms under various names. Have you tried these variants or how do you 'roll your own'; or do you lean towards one source over another? (Off the top of my head I recall in the cabinet, Japanese Sencha, Almond Jasmine, and several others - not sure of origins.)
@Stretched I did get some powdered green tea extract, but my body rarely wants it. I'm using a local brand of pesticide-free green tea, haven't bothered with anything fancy. I used to love rooibos, red tea, but it's fermented, similar to black teas, and adds to my histamine load, so no more. Forgot to add to original post, resveratrol is an excellent antiox. I unthinkingly began with red wine, then red wine combined with Japanese knotweed. Once I realized I was creating more stress with the histamines in red wine, I switched to knotweed only. I get it from a local ebay supplier, not sure if knotweed alone is available from iherb.
I don't regularly follow Mercola, don't know of the controversy around him, other than maybe dislike of him advising as well as selling supps. I certainly agree with your statement, There are a lot of once credible 'authorities' around who became questionable, including former gurus such as Cheney, Teitlebaum
<<I used to love rooibos, red tea, but it's fermented, similar to black teas, and adds to my histamine load, so no more. Forgot to add to original post, resveratrol is an excellent antiox. ... Once I realized I was creating more stress with the histamines in red wine, I switched to knotweed only>>
Curiously, I come across controversy on the benefits of green tea vs black tea but I'm not fully informed. It seems the
respective advocates make unique benefit claims while the other camp touts the benefits of ALL tea! Are you tuned in and knowledgeable?
I didn't consider that the black teas were fermented and added to histamine. (Fortunately, I only drink a couple of cups a day in am. I may give it a go without the Assam and Lapsang (great alone or together, if you like em strong. I do - clean tires with them,). BTW, Theafalin is the name of the powdered tea extract (in capsules); however, it's derived from black tea so I take the 5th (U.S. constitution - 'won't go any further so as not to step on my own' is the vernacular...).
I became a tea drinker long ago when coffee started eating my gut, especially when stressing; more so after inbibing. Also, 'gave up all the 'good time' juice as it was likely eating away at my brain ,) - no alcohol in many years. Hard at first but then substituted meditation and thinking at that time and after awhile I didn't miss the culture at all.
I like rooibos as well as Oolong (is this considered a green tea?) and many oriental teas (Sencha) but frankly, am just taking up the focus on green teas as a serious contribution to health. I'm looking into what the biochem interplays
with, given a regimen of over ~20 supplements per day . Like you, I already use reservatrol, primarily for circulation
health (inside vein and artery support), but acknowledge its overall positive effects. As for Japanese Knotweed,
I use it as well, in tincture form (in water) from woodlandessence.com (U.S., supposedly THE source for quality herbs, tinctures, and related, fwiw) as explained and referenced in one or more of Stephen Burner's recent bestseller books on healing and health at the molecular level. (You're probably aware of them by their respective category titles; excellent quick studies IMO, and easy to use - from downloads on Amazon.com.)
Lastly, re inhibiting histamines: are you familiar with the supplement that alleges to inhibit food released histamine?
I believe it's called Diamine Oxidase. I tried one brand last year and it seemed to work (here, during pollen season) but I don't recall if it really blocks food released histamine or counteracts systemic allergies?
BTW, 'much pollen/seasonally related in Australia?
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