ME/CFS Research: Herpes Autoimmune Spectrum Disorder

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Hoosierfans

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Folks, just a word of caution...tread carefully with the mushrooms if you have any kind of clotting or blood disorder or are on blood thinners. I have a small procedure coming up in a few weeks, and my doc told me yesterday to stop taking the mushrooms for a week (or even better 2) prior to the procedure due to blood thinning risk with them. So tread carefully if you have any kind of dental or medical procedure coming up....
 
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Last questions before I try to do the hard part, what is high amylose starch ? am I supposed to eat that as a powder or find foods that contain it ? can I eat meat which is covered in breadcrumbs or batter ? the only vegetable I like is potato, parsnip, baked beans and if I have to kidney beans. The other thing is would it be better to stagger the introduction of the various components ? for example take the sodium benzoate and associated ones for a couple of days before adding in all the other stuff ( also only start vitamin c after stopping on the sodium one ). If the process generates a lot of nitrogen maybe it can be lower than normal before beginning ?
 

nerd

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NF-κB can be manipulated by many viral signals. I will go through them one by one eventually. It's possible that I miss some interactions. So please feel free to mention other ones as well and I will add them.

However, from my understanding of the viral alterations downstream of C-terminal Binding Protein, addressing this is/was the key - the triterpenes in Reishi appear to switch this altered cascade off (also silencing lytic and latent) while allowing apoptosis. (CtBP->SIRT4->NF-KB. p53 also normalised.)
The CtBP -| SIRT4 -| (PI3K -> Akt -> NF‑κB) interaction might be useful for certain kinds of viral mechanisms (10.1038/cddis.2014.587; 10.3892/mmr.2019.10161). However, if there aren't other helpful interactions with NF-κB signaling, I don't see all pathological cell cycle mechanisms covered. Fortunately, Reishi also suppresses MyD88 and IκB degradation (10.3892/etm.2013.895). Unrelated to NF-κB, but relevant for the cell cycle, it activates the Caspase pathways as well (10.1016/S2005-2901(10)60004-0). Am I missing other interactions?

EBV

EBV interacts with NF-κB activation via these pathways:
  1. dUTPase (lytic) triggers extrinsic TLR2 -> MyD88 -> IRAK -> TRAF6 -> IκB kinase -> NF-κB signaling (10.4049/jimmunol.182.2.851) * †
  2. Accumulated viral dsRNA and EBERs (predominantly latent) induce RIG-I -> MAVS ->TRAF6 -> IκB kinase -> NF-κB signaling (10.1038/sj.emboj.7601314) ** †
  3. TRAFs bound to LMP1 (latent and lytic) via TRADD induce NF-κB incuding kinase (NIK) activation and IκB kinase -> NF-κB signaling (10.1111/j.1600-065X.2011.01055.x; 10.1093/emboj/20.20.5678; 10.1016/j.cytogfr.2010.06.002) ** †
  4. LMP2a and LMP1 (latent and lytic) induce PI3K -> AKT -> mTOR -> NF-κB (10.5501/wjv.v1.i6.154) * ††
  5. BPLF1 (predominantly late lytic) partially suppresses TRAF6 -> IκB kinase -> NF-κB signaling by deubiquitination (10.1371/journal.ppat.1003960). This suppresses proliferation and immune recognition until reactivation. ¯
Moreover, apoptosis is triggered by viral dsRNA, EBER1 accumulation, and extrinsic Fas activation via PKR -> FADD -> Casp8 -> Bid -> Bax (10.1021/acs.biochem.0c00088; 10.1016/j.bbamcr.2012.07.003; 10.1099/jgv.0.000313; 10.1126/sciadv.aau9433).
This, however, is inhibited by:
  1. BHRF1 (lytic) -| Bid -> Bax (10.1073/pnas.0901036106) * †
  2. BARF1 (lytic) -> Bcl2 -| Bax (10.1007/s12038-015-9502-z) * †
  3. EBNA3A and EBNA3C (latent) -| Bim -| Bcl2 -| Bax (10.1631/jzus.B1200189) ** ††
Caspases are quite important for a healthy apoptosis. Considering how difficult it might be to normalize their function, and one of your protocols relies on apoptosis, it might be worth reading (10.1126/sciadv.aau9433).

As an end note, I found this paper that links glycolysis with NADH to NAD+ ratio and CtBP-mediated NF-κB transcription (10.1038/s41467-017-00707-0). This means, given a high NADH to NAD+ ratio, CtBP can also cause NF-κB-mediated inflammation.

* Interacts with Reishi
** Partial Interaction with Reishi
† Interacts with Ivermectin
†† Uncertain Interaction with Ivermectin
¯ Interaction is not desired
The interactions are concentration-dependent. It's unclear if effective concentrations can be achieved.
 
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Yes, pretty much. That was our old v2.x approach, which included a referral for spironolactone.

In this older version, I'd have typically chosen high dose ACV capsules over amber acid / succinate, as ACV contains other useful things, such as the acetic acid needed to make acetyl-coa. The amount of acetic acid / acetate in the capsules we used equated to around 350mg, 4x a day. Problem was, the popular sources / vendors for these products weren't forthcoming with product information when requested.

We had good success with some Australian and Kiwi brands, which labelled things accurately. I ran into problems with US vendors and after some frustrations, switched to using NAC as the acetate source. This was more reliable and included a cysteine donor.

We also included high dose R-ALA (400mg ballpark), 3-4x a day, along with a little over daily values for B12, B5, P5P.
Found this which seems to be supporting evidence
A neighbour who says she once suffered from ME for 15 years told me that she found that a weak solution of apple cider vinegar made her feel much better. I tried it and had a massive relapse - of course apple cider vinegar is the result of fermentation although I believe most of the alcohol is converted to acetic acid. So it makes me wonder if it's the alcohol or the fermentation that causes the problem. It also makes me wonder (probably unfairly) if my neighbour actually had ME!
https://forums.phoenixrising.me/threads/alcohol-tolerance-poll.6748/

I am fairly certain now that my cfs symptoms are caused by improper transfer of oxygen into muscle cells by the circulation, or other cells too, especially brain. This is an easy concept that most people can grasp which is nice, but it doesn't really help establish the root cause.
 

joshua.leisk

Joshua Leisk (Researcher)
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Found this which seems to be supporting evidence
https://forums.phoenixrising.me/threads/alcohol-tolerance-poll.6748/

I am fairly certain now that my cfs symptoms are caused by improper transfer of oxygen into muscle cells by the circulation, or other cells too, especially brain. This is an easy concept that most people can grasp which is nice, but it doesn't really help establish the root cause.
In our model there are multiple causes for hypoxia, however the primary one is a-KGDH being impaired by high ROS + impaired ROS scavenging, causing “mitochondrial fragmentation and no succinate being produced in the cycle, the eventual B12, GABA and/or P5P depletion affects the succinate backup pathways and then once aspartate runs out from the transamination at akg->glut+aspartate->oxaloacetate, then fumarate can’t be supplied by the urea cycle, also stopping the urea cycle.

This places more demand on phenylacetylglutamine for nitrogen extraction, thus causing further losses of phenylalanine, Acetyl-CoA and CoA. This causes all of the secondary effects, further impacting ROS scavenging, neurological disorders, etc.

Not an enjoyable experience.
 

godlovesatrier

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Sorry, what I meant was: it was ending the menopause that actually improved it (versus any other intervention that these post menopausal women may have been doing). That’s really interesting.
Hi. Not sure if anyone knows what the mechanism is for sure. But all these women were either just past the menopause or through it. I just wonder if there's a high incidence of women like 60% who match this criteria, or if it's just another subset say 20%. Because my friend from University - his mother must be approaching or just past 70 and her ME has been totally unabated by older age. Still suffering and very much reduced in ability. But the number of women I've heard from who work part time or go hiking post menopause who had ME, I've heard lots of those stories. As I say many were nurses who have taken my blood over the years.
 
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In our model there are multiple causes for hypoxia, however the primary one is a-KGDH being impaired by high ROS + impaired ROS scavenging, causing “mitochondrial fragmentation and no succinate being produced in the cycle, the eventual B12, GABA and/or P5P depletion affects the succinate backup pathways and then once aspartate runs out from the transamination at akg->glut+aspartate->oxaloacetate, then fumarate can’t be supplied by the urea cycle, also stopping the urea cycle.

This places more demand on phenylacetylglutamine for nitrogen extraction, thus causing further losses of phenylalanine, Acetyl-CoA and CoA. This causes all of the secondary effects, further impacting ROS scavenging, neurological disorders, etc.

Not an enjoyable experience.
Rephrasing it in terms that most people can understand though... it mean that the oxygen can get to the cells ok but is somehow wasted via chemical process ? ROS scavenging presumably restoring usable oxygen from these volatile compounds ? does that make big difference ? is there really such high turnover of ROS in normal cell ?
 

junkcrap50

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@joshua.leisk, can you provide a table of contents/outline of the different papers you've written that describes 1) the order in which they should be read, 2) brief 2-3 bullet points of purpose/what paper explains/how it differs from other papers. 3) differences between papers and protocols 4) changes and alterations to protocols and the reasoning.

I've been really brain fogged lately so it doesn’t seem straightforward to me. Can you read only the ME/CFS Paper and v3 Protocol and have enough background to understand your whole thesis? It seems many times you refer to other papers when answering questions, as if the information is not included in your ME/CFS paper, but in another. What does the autoimmune paper, for example, have in it that the ME/CFS paper doesn't? What's the difference between the various v1,v2,v3 protcols and why did you make changes to them? What's the advantage of one vs the other? Does one paper have the whole theory in it, and other papers just explain how it applies to various diseases, ME/CFS vs autoimmune?

A little bit of organizational context of the papers you've written would help me understand the order to learn them and what one paper offers vs another.
 
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On starting the full antiviral strategy my sensations are in line with the processes described in the theory paper, a sort of hollow feeling of starvation thats inconsistent with how much i've eaten and how recently, some reduction in me/cfs symptoms particularly pain and feeling of heavyness or stiffness, slight head pressure without major headache ( yet ).
 

xebex

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On starting the full antiviral strategy my sensations are in line with the processes described in the theory paper, a sort of hollow feeling of starvation thats inconsistent with how much i've eaten and how recently, some reduction in me/cfs symptoms particularly pain and feeling of heavyness or stiffness, slight head pressure without major headache ( yet ).
Thank you for being a guinea pig for us! I have followed you but I wonder if maybe you could set up your own post that we can follow your progress in?

Thanks :)
 

joshua.leisk

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NF-κB can be manipulated by many viral signals. I will go through them one by one eventually. It's possible that I miss some interactions. So please feel free to mention other ones as well and I will add them.



The CtBP -| SIRT4 -| (PI3K -> Akt -> NF‑κB) interaction might be useful for certain kinds of viral mechanisms (10.1038/cddis.2014.587; 10.3892/mmr.2019.10161). However, if there aren't other helpful interactions with NF-κB signaling, I don't see all pathological cell cycle mechanisms covered. Fortunately, Reishi also suppresses MyD88 and IκB degradation (10.3892/etm.2013.895). Unrelated to NF-κB, but relevant for the cell cycle, it activates the Caspase pathways as well (10.1016/S2005-2901(10)60004-0). Am I missing other interactions?

EBV

EBV interacts with NF-κB activation via these pathways:
  1. dUTPase (lytic) triggers extrinsic TLR2 -> MyD88 -> IRAK -> TRAF6 -> IκB kinase -> NF-κB signaling (10.4049/jimmunol.182.2.851) * †
  2. Accumulated viral dsRNA and EBERs (predominantly latent) induce RIG-I -> MAVS ->TRAF6 -> IκB kinase -> NF-κB signaling (10.1038/sj.emboj.7601314) ** †
  3. TRAFs bound to LMP1 (latent and lytic) via TRADD induce NF-κB incuding kinase (NIK) activation and IκB kinase -> NF-κB signaling (10.1111/j.1600-065X.2011.01055.x; 10.1093/emboj/20.20.5678; 10.1016/j.cytogfr.2010.06.002) ** †
  4. LMP2a and LMP1 (latent and lytic) induce PI3K -> AKT -> mTOR -> NF-κB (10.5501/wjv.v1.i6.154) * ††
  5. BPLF1 (predominantly late lytic) partially suppresses TRAF6 -> IκB kinase -> NF-κB signaling by deubiquitination (10.1371/journal.ppat.1003960). This suppresses proliferation and immune recognition until reactivation. ¯
Moreover, apoptosis is triggered by viral dsRNA, EBER1 accumulation, and extrinsic Fas activation via PKR -> FADD -> Casp8 -> Bid -> Bax (10.1021/acs.biochem.0c00088; 10.1016/j.bbamcr.2012.07.003; 10.1099/jgv.0.000313; 10.1126/sciadv.aau9433).
This, however, is inhibited by:
  1. BHRF1 (lytic) -| Bid -> Bax (10.1073/pnas.0901036106) * †
  2. BARF1 (lytic) -> Bcl2 -| Bax (10.1007/s12038-015-9502-z) * †
  3. EBNA3A and EBNA3C (latent) -| Bim -| Bcl2 -| Bax (10.1631/jzus.B1200189) ** ††
Caspases are quite important for a healthy apoptosis. Considering how difficult it might be to normalize their function, and one of your protocols relies on apoptosis, it might be worth reading (10.1126/sciadv.aau9433).

As an end note, I found this paper that links glycolysis with NADH to NAD+ ratio and CtBP-mediated NF-κB transcription (10.1038/s41467-017-00707-0). This means, given a high NADH to NAD+ ratio, CtBP can also cause NF-κB-mediated inflammation.

* Interacts with Reishi
** Partial Interaction with Reishi
† Interacts with Ivermectin
†† Uncertain Interaction with Ivermectin
¯ Interaction is not desired
The interactions are concentration-dependent. It's unclear if effective concentrations can be achieved.
This is a really great post. ☺️🙏🏻
From the early notes on my phone, the main functions I’d been looking were related to these:
Mito-related
[COLOR=var(--accent-color)]https://pubmed.ncbi.nlm.nih.gov/19041385/
https://pubmed.ncbi.nlm.nih.gov/19041385/

[COLOR=var(--accent-color)]https://europepmc.org/article/med/19123066[/COLOR]

EBV-related
[COLOR=var(--accent-color)]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585879/[/COLOR][/COLOR]

[COLOR=var(--accent-color)]https://www.nature.com/articles/s41598-019-55723-5
https://www.nature.com/articles/s41598-019-55723-5[/COLOR]

[COLOR=var(--accent-color)]https://onlinelibrary.wiley.com/doi/abs/10.1002/chin.200650268
https://onlinelibrary.wiley.com/doi/abs/10.1002/chin.200650268[/COLOR]


When I’m back in front of my computer, I’ll reply with more details.
 

joshua.leisk

Joshua Leisk (Researcher)
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@joshua.leisk, can you provide a table of contents/outline of the different papers you've written that describes 1) the order in which they should be read, 2) brief 2-3 bullet points of purpose/what paper explains/how it differs from other papers. 3) differences between papers and protocols 4) changes and alterations to protocols and the reasoning.

I've been really brain fogged lately so it doesn’t seem straightforward to me. Can you read only the ME/CFS Paper and v3 Protocol and have enough background to understand your whole thesis? It seems many times you refer to other papers when answering questions, as if the information is not included in your ME/CFS paper, but in another. What does the autoimmune paper, for example, have in it that the ME/CFS paper doesn't? What's the difference between the various v1,v2,v3 protcols and why did you make changes to them? What's the advantage of one vs the other? Does one paper have the whole theory in it, and other papers just explain how it applies to various diseases, ME/CFS vs autoimmune?

A little bit of organizational context of the papers you've written would help me understand the order to learn them and what one paper offers vs another.
So, first paper was the hard one - it was linking up all of the original dots to create the model. It shows a large number of the connections to the various downstream individual diseases. It hinted at the fasting method and an underlying set of causes.

The related v1.x protocol we were using then was enough to prove the 3 hotspots (a-KGDH, PDH, beta-oxidation impairments) and treat many of the main issues, however it did nothing for the ROS and the vast amounts of nitrogen being created. It also shutdown lytic phase replication using spironolactone and used sodium benzoate to entice the infected cells to go lytic, fail and be detected / replaced. It “worked” well enough to patch people up and give them a pretty good day, while slowly chipping away at the latent infection.

The second paper dug a layer deeper and showed the nutrient / metabolite depletions, via urine, that caused runaway ROS and the three hotspots. It hinted at a way to turn it all off, but I wasn’t there yet.

The related v2.x protocol became a process of filling up all of the metabolites being depleted and reducing the ROS. We still used spironolactone, etc for the antiviral angle. This works rather nicely, but I don’t do “slow” or settle for “bandaids”.

The third paper elaborated on the metabolite losses, detailed the root cause as the virally-altered protein expression profile and some ways to address that directly, allowing the immune system to work properly and efficiently replace the infected cells, while shutting down the cascade of issues.

The related v3.x protocol “turns it all off”, while including a number of remedial processes to start undoing various layers of problems with gut microbiome, etc.

The infected cells now signal for apoptosis and the immune system gets stimulated into making that a priority. You get “sick” (acute immune response), suffer through that for maybe 2 or so weeks once the liver becomes the focus - being utterly wiped out and stuck in bed.

Various tissues which have been previously problematic will flare up with an acute immune response and get efficiently remediated.

It’s going to be unpleasant for a few weeks and feel somewhat like you just got “mono” all over again...

and then you get better. ☺️

We are testing the success of this without earlier use of spironolactone now, as the research suggested it wouldn’t be needed. Early results are looking positive.

Some more details here, if this helps

https://forums.phoenixrising.me/threads/me-cfs-research-herpes-autoimmune-spectrum-disorder.83371/post-2335821
 
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Thank you for being a guinea pig for us! I have followed you but I wonder if maybe you could set up your own post that we can follow your progress in?

Thanks :)
I can try, I looked at the blog posting function before and I think it required you to create a superentity first that defines an ongoing blog, you couldn't just sort of post a one off story. I'm not used to getting so much attention normally lol. One thing I recommend although this might be common sense is making some sort of chart that has e.g. sunday monday etc subdivided by AM NOON PM NIGHT along the top, then on the left hand side write down all the drugs that you want to take, it could also be made up on a computer for printing then just write in the correct days at the top, it might also help to write in the dosage and max per day, because sometimes you gotta do 3 sometimes its 4, you could use shading to represent the time slots where you are not supposed to take it. I think this might be more useful for people with busy lives or if someone does start to feel very unwell due to immune response.
 
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