Choline on the Brain? A Guide to Choline in Chronic Fatigue Syndrome
http://phoenixrising.me/research-2/the-brain-in-chronic-fatigue-syndrome-mecfs/choline-on-the-brain-a-guide-to-choline-in-chronic-fatigue-syndrome-by-cort-johnson-aug-2005
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Study reveals new, potent way to boost immunity and fight viruses

Discussion in 'Other Health News and Research' started by RYO, Oct 22, 2015.

  1. RYO

    RYO Senior Member

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  2. minkeygirl

    minkeygirl But I Look So Good.

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    Years ago docs used interferon to treat CFS

    Now cycloferon, that some use, is an interferon inducer. So it makes sense that this would have benefits for us.
     
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  3. halcyon

    halcyon Senior Member

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    Pretty interesting, especially in the context of enteroviruses (the encephalomyocarditis virus they were using in the study is also a picornavirus). I've been thinking for a while that interference with the STAT1 pathway might be part of why these chronic enterovirus infections in ME can persist for so long. One of the enterovirus proteases interferes with the IFNAR/STAT1/ISG pathway so even in the presence of elevated interferon, the infected cell might be unable to turn on it's innate antiviral pathways. It looks like what they did in this study is boosted expression of STAT1 which likely boosted transcription of the inteferon stimulated genes. Perhaps that helps work around this viral countermeasure.
     
    Last edited: Oct 23, 2015
    RYO likes this.
  4. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    australia (brisbane)

    Yep, eastern block countries have been treating viral infections for decades with substances to improve immune function such as interferon inducers.

    Wish i could read russian and had access to their research on this stuff.
     
    Antares in NYC and minkeygirl like this.
  5. minkeygirl

    minkeygirl But I Look So Good.

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    There are translation apps although on phones I don't know if you could translate the entire site.
     
  6. Hip

    Hip Senior Member

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    Recently I was experimenting with a protocol that boosts STAT-1, and inhibits STAT-3.

    STAT-1 conveys the interferon signal into the cell, so boosting STAT-1 should increase the antiviral effects of interferon.

    STAT-3 does the reverse, and puts the brakes on the interferon response, so therefore STAT-3 inhibitors should again help boost the interferon response.

    A STAT-1 deficiency was found in a subset of ME/CFS patients (refs: here and here), so I thought supplements to boost STAT-1 and inhibit STAT-3 might be helpful in ME/CFS.

    Searching PubMed, I found a number of supplements that boost STAT-1 and inhibit STAT-3, and from these, I devised the following protocol:

    STAT-1 Boosters
    NSAIDs
    like potentiate interferon alfa signaling by increasing STAT1 phosphorylation. Ref: 1
    Allicin 180 mg x 4 (allicin breaks down to diallyl disulfide, which increases STAT-1). Ref: 1
    Propolis 4000 mg (a potent COX-2 inhibitor — COX-2 inhibition increases STAT-1). Ref: 1
    Terminalia chebula 1400 mg (COX-2 inhibitor)
    Lycopene 25 mg (increases IGFBP-3, which in turn up-regulates STAT1). Ref: 1
    Methylation protocol (un-methylated STAT-1 is less active than methylated STAT-1). Ref: 1
    HDAC promoters
    increase STAT-1 (because histone deacetylase (HDAC) inhibitors block IFN-γ-induced STAT1 phosphorylation. Ref: 1


    STAT-3 Inhibitors
    Andrographis paniculata
    (10% andrographolide) 1200 mg — potent. Ref: 1
    Glycyrrhizin (I used dipotassium glycyrrhizinate 200 mg transdermal) — potent. Ref: 1
    Horny goat weed (Epimedium) 900 mg (icaritin from Epimedium inhibits STAT3) — potent. Ref: 1
    Bupleurum 1 heaped teaspoon (saikosaponin D from Bupleurum reduces STAT3) — potent. Ref: 1
    Zinc picolinate 50 mg Ref: 1
    Ursolic acid 50 mg Ref: 1
    Panax ginseng 500 mg Ref: 1
    Ecklonia cava
    (contains fucoxanthin) 400 mg Ref: 1
    N-acetyl-glucosamine 1400 mg Ref: 1
    Silibinin
    (from milk thistle) Ref: 1
    EGCG (from green tea) Ref: 1
    Apigenin Ref: 1
    Oxymatrine
    Refs: 1 2
    Matrine Refs: 1 2 3

    Note that the most potent STAT-3 inhibitors above are colored in green.

    IL-6 up-regulates the STAT-3 pathway, so IL-6 inhibitors may help reduce STAT-3: luteolin inhibited IL-6-induced STAT3 activation. Ref: 1

    I took nearly all of the above supplements once daily for a total of 22 days. I think they may have increased energy levels and improved my brain fog.

    Note: you can buy 98% andrographolide quite cheaply on AliExpress. You can also get high saikosaponin content Bupleurum on AliExpress.


    Factors that May Hinder:
    Myricetin inhibits STAT3, Ref: 1 but unfortunately also inhibits STAT1, which is undesirable. Ref: 1
    Curcumin inhibits STAT3 via activation of PIAS-3. Ref: 1 but unfortunately curcumin also inhibits STAT-1, which is undesirable. Ref: 1
    Nicotine increases STAT-3 activation. Ref: 1
    Mu opioid activation increases STAT-3. Ref: 1
    Exercise — STAT-3 is increased through exercise.



    STAT-1 Notes

    STAT I relays the IFN signal to the nucleus. 1

    Un-methylated STAT1 is less active since it can be bound and inactivated by its inhibitor, protein inhibitor of activated STAT1 (PIAS1). The treatment of cells with S-adenosyl-L-methionine (AdoMet, aka: SAM-e) and betaine could restore STAT1 methylation and improve IFN alpha signaling. Ref: 1

    Estimated half lives of STAT1 and STAT2 are on the order of days. 1

    p-STAT-1 = phosphorylated STAT-1. Interferons induce the phosphorylation of STAT-1, which is what activates STAT-1.

    STAT1 up-regulates genes due to IFN signal.

    PIAS1 = protein inhibitor of activated STAT1. This binds to STAT-1 and inhibits it.



    STAT-3 Notes

    Testosterone decreases STAT3 activation, meaning that testosterone will ultimately boost the type 1 interferon response, and thus should, I would think, help with clearance of intracellular infections.

    STAT3 is the essential regulator of Th17 cells, analogous to STAT4 and STAT1 in Th1 cells and STAT6 in Th2 cells. Ref: 1

    Interestingly, rituximab inactivates STAT-3 in B-non-Hodgkin's lymphoma; see here. So this might be another one of rituximab's benefits in ME/CFS: rituximab might be inactivating STAT-3 in ME/CFS, thereby increasing the intracellular immune response, and thus clearing out intracellular viral infections like non-cytolytic enteroviruses.

    Although note that reducing STAT-3 also helps fight autoimmunity: STAT-3 is involved with autoimmunity, and reducing STAT-3 activation was found to ameliorate experimental autoimmune uveitis; see this study.

    Testosterone decreases STAT3 activation, meaning that testosterone will ultimately boost the type 1 interferon response, and thus should, I would think, help with clearance of intracellular infections.

    Self-hacked's STAT-3 inhibitors: STAT3 Genes: Their Role in Gut Inflammation, Obesity and Cancer
     
    Last edited: Dec 15, 2016
    olegsel, pattismith, Lolinda and 3 others like this.
  7. halcyon

    halcyon Senior Member

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    Were you taking these with anything that would boost production of IFN α or β?
     
  8. Hip

    Hip Senior Member

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    Yes, I forgot to mention that. I was also taking the following interferon alpha inducers:

    Interferon Alpha Inducers:
    Astragalus extract 500 mg
    Reishi (40% polysaccharides) 800 mg
    Chinese skullcap (4:1 extract) 400 mg
    PABA 500 mg

    Plus the Bupleurum kaoi in my cocktail of STAT-3 inhibitors induces interferon alpha and beta.

    I had most of these supplements already in stock from years of trying various supplement experiments.



    Perhaps a much stronger protocol would be obtained by taking these STAT-1 boosters / STAT-3 inhibitors with a course of injectable interferon. I have not tried that.
     
    Last edited: Sep 5, 2016
    merylg likes this.
  9. halcyon

    halcyon Senior Member

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    Wonder how it would change things to throw a translation inhibitor like amantadine in that mix.
     
  10. Hip

    Hip Senior Member

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    I suppose every little thing helps.

    The trouble with such antiviral experiments is that you may have to take them for say 6 months before you get results. If you look at Valcyte treatment, which is a potent antiviral, it takes many months before improvements in ME/CFS symptoms are noticed.

    So it is possible that my above protocol might have effects if taken on a long term basis, but nobody is going to spend all that money on supplements to test it for say 6 months.

    Long term testing is always a bit of a problem. I have devised dozens of protocols over the years all involving up to dozen supplements taken simultaneously — NK cell boosting protocols, CD8 boosting protocols, mitochondrial cocktails, anti-TNF-alpha protocols, anti-Th17 protocols, anti-enterovirus protocols, anti-herpes protocols.

    Each protocol I may try for anything from a few weeks to a few months. Each is quite priciey in terms of supplement costs, so you cannot really afford to take a 12-supplement protocol indefinitely if benefits do not appear within say a month.

    Fortunately some treatments I have tried worked very quickly. Most of the supplements that I found had anti-anxiety effects would kick in fast, sometimes within hours of taking them. So in these cases, you don't have to test for months. You know very quickly that it is working.

    And the high dose selenium protocol I tried started showing benefits for ME/CFS after 10 days, so that was quite quick.
     
  11. RYO

    RYO Senior Member

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    Hopefully this research will lead to STAT1 inducing drug. I would take along with interferon gamma for 6 months.
     
    Hip likes this.
  12. Hip

    Hip Senior Member

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    When I was searching published studies, the most potent STAT-1 booster I could find was the drug tretinoin (aka: all-trans retinoic acid). This paper says:
    But oral tretinoin used to treat leukemia can have serious and fatal side effects. Even topical tretinoin (used for acne) has apparently been associated with fatalities.



    The other interesting thing I came across was this paper which notes that un-methylated STAT-1 is less active than methylated STAT-1 (un-methylated STAT1 is less active since it can be bound and inactivated by its inhibitor, PIAS1).

    So this might explain why the methylation protocol has often been helpful in ME/CFS — because methylation may boost STAT-1, which in turn boosts the antiviral action of interferon.
     
    Last edited: Oct 23, 2015
  13. pattismith

    pattismith Senior Member

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    interesting study in Schizo:


    Evidence of microglial activation following exposure to serum from first-onset drug-naïve schizophrenia patients

    Brain, Behavior, and Immunity
    Volume 67, January 2018

    abstract

    "Abnormal activation of brain microglial cells is widely implicated in the pathogenesis of schizophrenia. Previously the pathophysiology of microglial activation was considered to be intrinsic to the central nervous system. We hypothesised that due to their perivascular localization, microglia can also be activated by factors present in circulating blood.

    Through application of high-content functional screening, we show that peripheral blood serum from first-onset drug-naïve schizophrenia patients is sufficient to provoke microglial cell signalling network responses in vitro which are indicative of proinflammatory activation.

    We further explore the composition of the serum for the presence of analytes, with the potential to activate microglia, and the utility of the resultant microglial cellular phenotype for novel drug discovery."

    (complete article available)

    from the conclusion:

    "Taken together, these findings suggest that the over-activation of Stat3 and mTORC1 pathways in response to SCZ patient serum could represent a cellular phenotype in which discrete signalling motifs are synergistically geared towards proinflammatory microglia activation."
     

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