Ron Davis Update
- Thread starter BrightCandle
- Start date
- Tags itaconate pathway ron davis
Hi, the one indicated in the link could be a good starting point but not at that dosage! you must guarantee vitamins and minerals from the diet as a base and avoid as much as possible interactions with products rich in dyes, preservatives, or other chemical additives ... otherwise we would have misleading effects.
Another product that could be useful for mitochondrial health is methylene blue as an accepting and donor of electrons, even some quinons.
I would not take more than one product at a time otherwise you could just create confusion about how they work ...
Later I try to insert the links ... the key is to start as low as possible and evaluate the tolerance in the medium to long term.
Another product that could be useful for mitochondrial health is methylene blue as an accepting and donor of electrons, even some quinons.
I would not take more than one product at a time otherwise you could just create confusion about how they work ...
Later I try to insert the links ... the key is to start as low as possible and evaluate the tolerance in the medium to long term.
@Janet Dafoe thank you for the upland for all that you do. Will there be a listing of participants posted of those in the upcoming Zoom meetings?
@Janet Dafoe with apologies above… thank you for the update and all that you do…
The two theories/hypotheses are separate and distinct. I do not think the IDO1 metabolic trap can lead to the itaconate shunt, but I do think the itaconate shunt could lead to the IDO1 trap.
The reason this seems possible is that ACOD1 (the gene that codes for the first enzyme of the shunt) is just one of hundreds of genes that respond to interferon alpha (IFNa). We call those genes ISGs, or interferon-sensitive-genes. There is some evidence that IDO1 is also an ISG.
At a basic level, what the two theories have in common is transcriptional regulation. Many people think of the IDO pathway as 1) a way to make NAD, or 2) a way to make a neurotoxin or a neuroprotector. To me, however, the importance of the kynurenine pathway has always been kynurenine regulation of the AHR transcription factor. This parallels the importance of the IFNa signaling pathway in regulating the IRF transcription factors.
So, there are two parts of the itaconate shunt hypothesis. The first is the metabolic or mitochondrial part. That's what I talked about in Part 1 of the Janet Show. Second is the link between the innate immune system and the itaconate shunt. That's what I'll talk about in Part 2 on the Janet Show. Experimentally, we're testing Part 2 right now.
The reason this seems possible is that ACOD1 (the gene that codes for the first enzyme of the shunt) is just one of hundreds of genes that respond to interferon alpha (IFNa). We call those genes ISGs, or interferon-sensitive-genes. There is some evidence that IDO1 is also an ISG.
At a basic level, what the two theories have in common is transcriptional regulation. Many people think of the IDO pathway as 1) a way to make NAD, or 2) a way to make a neurotoxin or a neuroprotector. To me, however, the importance of the kynurenine pathway has always been kynurenine regulation of the AHR transcription factor. This parallels the importance of the IFNa signaling pathway in regulating the IRF transcription factors.
So, there are two parts of the itaconate shunt hypothesis. The first is the metabolic or mitochondrial part. That's what I talked about in Part 1 of the Janet Show. Second is the link between the innate immune system and the itaconate shunt. That's what I'll talk about in Part 2 on the Janet Show. Experimentally, we're testing Part 2 right now.
Well done, my friend.- Messages
- 166
- Likes
- 419
I really can’t thank you enough for answering my question. I was absolutely thrilled to see that you had responded. The info you provided was enlightening and exciting to me. Made my night.
If you have the time, I do have another question. And this may be something that your next video with Janet will answer. Does the fact that CFS patients usually have low NK cell function (I have it, verified through testing) play into the connection between the innate immune system and the itaconate shunt?
I just have always found it weird that people generally acknowledge that CFS patients have low NK cell function, yet as far as I am aware, little investigation has been done into why that is. Or how to fix it. It has always seemed like a major clue that has not been investigated. So I’m wondering if you have any opinions on it.
If you have the time, I do have another question. And this may be something that your next video with Janet will answer. Does the fact that CFS patients usually have low NK cell function (I have it, verified through testing) play into the connection between the innate immune system and the itaconate shunt?
I just have always found it weird that people generally acknowledge that CFS patients have low NK cell function, yet as far as I am aware, little investigation has been done into why that is. Or how to fix it. It has always seemed like a major clue that has not been investigated. So I’m wondering if you have any opinions on it.
This is a good question.
The NK cell finding originated with Nancy Klimas. It was intended, I believe, as a biomarker, but I agree with you that it stands as a unique feature of CFS.
The NK cell puzzle is on my mind every day. As you know, NK cells are part of the innate immune system. Textbooks emphasize that NK cells are activated by interacting with antigens presented by class I MHC, which they recognize as non-self, but they also say that NK cell activation can be stimulated by IL-12, IL-15, and IL-18 as well as IFNa.
I do not yet know what signals drive NK cells from blood to interstitial space. It puzzles me that people expect plasma NK cells to be activated in ME/CFS. It might be easier to understand this expectation if I knew what test is actually done to tell patients that they have low NK cell function. I imagine your NK cells were exposed to some infected or infectious cells perhaps with the addition of some cytokines. Do you know the details of how the test was done? I suppose I'd know if I was an immunologist, but I'm a physiologist.
I'll look up the original papers, but if you can find out exactly how your own clinical test was run, I'd like to know.
The NK cell finding originated with Nancy Klimas. It was intended, I believe, as a biomarker, but I agree with you that it stands as a unique feature of CFS.
The NK cell puzzle is on my mind every day. As you know, NK cells are part of the innate immune system. Textbooks emphasize that NK cells are activated by interacting with antigens presented by class I MHC, which they recognize as non-self, but they also say that NK cell activation can be stimulated by IL-12, IL-15, and IL-18 as well as IFNa.
I do not yet know what signals drive NK cells from blood to interstitial space. It puzzles me that people expect plasma NK cells to be activated in ME/CFS. It might be easier to understand this expectation if I knew what test is actually done to tell patients that they have low NK cell function. I imagine your NK cells were exposed to some infected or infectious cells perhaps with the addition of some cytokines. Do you know the details of how the test was done? I suppose I'd know if I was an immunologist, but I'm a physiologist.
I'll look up the original papers, but if you can find out exactly how your own clinical test was run, I'd like to know.
One thing i have wondered about the IDO trap is what if one eliminated their tryptophan intake for a time to reset it.
I don't have the ability to try it but it seems doable, i had posted this a while back.
Do you think it would have a measurable difference in patients and if it would affect the symptoms of ME/CFS?
I don't have the ability to try it but it seems doable, i had posted this a while back.
Do you think it would have a measurable difference in patients and if it would affect the symptoms of ME/CFS?
- Messages
- 166
- Likes
- 419
Thank you for that insightful reply. Extremely enlightening. All I know about my NK cell function test was that the test came back and said my NK cell function was a “5”. Which was classified as low. The was done through quest diagnostics. So I assume it was this one: https://testdirectory.questdiagnost...184/natural-killer-cells-functional?cc=MASTER
But Dr. Phair, I have a theory about why my NK cells might be low. I know it’s probably incorrect. But here it is:
I read this study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917661/#!po=14.3836), and table 1 caught my eye. Based on my own NK cell results, I deduced that the most likely NKD type for me would be “Subtype 1 (FNKD1)”. Which involves a gene defect in the “FCGR3A” gene. And the inheritance is autosomal recessive.
So I googled the “gene card” for FCGR3A. And found that diseases associated with FCGR3A include Immunodeficiency 20 and Herpes Zoster (shingles).
My father had shingles (herpes zoster), so that implies to me that this gene defect is possibly in my immediate family.
As for immunodeficiency 20, it says that it is “a rare autosomal recessive primary immunodeficiency characterized by functional deficiency of NK cells. Affected individuals typically present with severe herpes viral infections.”
This is interesting to me. Because of many doctors, including Dr. Jose Montoya and Dr. Bhupesh Prusty, who have said that they found evidence of activated herpes viruses in CFS patients and even believe that it is driving the disease.
So if my low functioning NK cells are allowing these herpes viruses to persist, then I wonder what the effect of NK cell therapy would be on CFS patients with verified low NK cell function, like myself. NK cell therapy, as I have read, involves taking healthy NK cells from a donor and then injecting them into someone with NK cell deficiency. Here is where I read about that: chttps://siteman.wustl.edu/treatment/specialized-programs/stem-cell-transplant-and-cellular-therapies-center/natural-killer-cell-therapy/
Even if that treatment seems far fetched, I still would love to investigate the FCGR3A gene. I am in the process of figuring out how to get it tested.
If this theory is ridiculous or not plausible for some reason please let me know. Or if you and Ron have already investigated the FCGR3A gene please let me know.
Thank you for everything you do for us. It gives me hope which keeps me going. I can’t thank you enough.
But Dr. Phair, I have a theory about why my NK cells might be low. I know it’s probably incorrect. But here it is:
I read this study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917661/#!po=14.3836), and table 1 caught my eye. Based on my own NK cell results, I deduced that the most likely NKD type for me would be “Subtype 1 (FNKD1)”. Which involves a gene defect in the “FCGR3A” gene. And the inheritance is autosomal recessive.
So I googled the “gene card” for FCGR3A. And found that diseases associated with FCGR3A include Immunodeficiency 20 and Herpes Zoster (shingles).
My father had shingles (herpes zoster), so that implies to me that this gene defect is possibly in my immediate family.
As for immunodeficiency 20, it says that it is “a rare autosomal recessive primary immunodeficiency characterized by functional deficiency of NK cells. Affected individuals typically present with severe herpes viral infections.”
This is interesting to me. Because of many doctors, including Dr. Jose Montoya and Dr. Bhupesh Prusty, who have said that they found evidence of activated herpes viruses in CFS patients and even believe that it is driving the disease.
So if my low functioning NK cells are allowing these herpes viruses to persist, then I wonder what the effect of NK cell therapy would be on CFS patients with verified low NK cell function, like myself. NK cell therapy, as I have read, involves taking healthy NK cells from a donor and then injecting them into someone with NK cell deficiency. Here is where I read about that: chttps://siteman.wustl.edu/treatment/specialized-programs/stem-cell-transplant-and-cellular-therapies-center/natural-killer-cell-therapy/
Even if that treatment seems far fetched, I still would love to investigate the FCGR3A gene. I am in the process of figuring out how to get it tested.
If this theory is ridiculous or not plausible for some reason please let me know. Or if you and Ron have already investigated the FCGR3A gene please let me know.
Thank you for everything you do for us. It gives me hope which keeps me going. I can’t thank you enough.
- Messages
- 1,727
- Likes
- 754
I believe Enlis said I had a SNP associated with Immune deficiency 20
My cfs doctor put me onto hydrolysed whey supplementation, based on the research by Armstrong. It's massively broken down dairy protein, I believe broken down to basically amino acids, or nearly. it is quick-absorbing and I associate it with a serious improvement in my ability to handle exercise. I take heroic quantities, like 4 big scoops a day.
Last edited:
- Messages
- 237
- Likes
- 390
Possibly. But beware the ammonia byproduct in the brain; may need to supplement away the ammonia. This is what I'm currently looking into. Still, Rob phair said the amino acid burning is about 43 per cent as efficient as sugar burning (if you were doing so if the shunt wasn't occurring), so supplementing amino acids isn't likely to give you a normal persons energy (although maybe just take heaps? Could have other effects so perhaps best not to).
I did take hydro whey for about 2 years from 2012 and then switched to regular, then 2 years later developed severe allergy against it. I have to say I miss the icecreamy taste of hydro+milk. I felt really good on it too. Before I crashed mid 2016 I was able to gain about 15kg's of muscle. Miss the weight lifting too. Good old times.
I bought some cannabis and rice protein locally but aside from the awful taste I see no change in energy levels. I'll be trying next some medical grade AA's, fermented from maize and another one from veggies.
I bought some cannabis and rice protein locally but aside from the awful taste I see no change in energy levels. I'll be trying next some medical grade AA's, fermented from maize and another one from veggies.
- Messages
- 884
- Likes
- 3,035
Itoconate Part 2
Summary Part 1 (He gives this)
========================
Innate immune system triggers Itoconate Shunt.
The shunt cuts off the citric acid cycle to bridge 2-OG to Succicante and OAA to Citrate.
We loose the ability to process lipids into energy.
Glumate becomes the only mechanism to produce power from amino acids but produces ammonia (a neurotoxin).
Itaconyl-CoA is produced with the shunt and it poisons B12.
Theory is this is cells that were near an infection event but not in it and hence have not been killed by the immune system.
A few enzymes can repair this in the cells - GAD2, GAD - glumate Decarboxylase, GABA transaminase and SSADH.
But these are inefficient and only allow you to burn amino acids.
This is really bad in the brain as glutmate and GABA are neurotransmitters
Burning these transmitters is probably where brain fog comes from.
Part 2
======
Either bacteria (LPS) or Virus is TLR sensed turns on NFkB inflammatory response
Produces TNFa, CCL2, CD80
TNFa - increases vascular infusion allowing more cells in
CCL2 - chemokines - signal path into the blood draw cells in
CD80 - remains on the cell signals it is infected
Second mechanism is the TLR's produce IRF7-Pi drives IFNa comes out of cell and talks to the neighbouring cells. Tells cells nearby to ready for infection.
The theory is that the bystander cells readiness state becomes chronic. That is ME/CFS (if the theory is right).
IFNa binds to IFNAR JAK1 signals to STAT1 and STAT2
Jak stat signalling pathway. Produces ISGF3. These turn on transcription genes that lead to Interferon A.
The reason to do this is to reduce the resources for replication for the virus/bacteria to use.
The itoconate shunt isn't the only response. IFNa is one of these thins produced, so there is a cycle of IFNa so it could signal itself.
Concern is the pathways that normally turn off IFNa production don't turn off in ME/CFS.
They are measuring IFNa.
Theory predictions
==================
IFNa appears increased median a 25-75%, its 4x. Should be more IFNa in blood for ME/CFS patients.
Unfortunately a couple of health controls have IFNa in their blood as high as severe ME/CFS patients. So its not a biomarker on its own. Those two individuals with high blood IFNa probably produce this in their blood cells not peripheral cells. They think the problem is intercellular in the tissue not in the blood for ME/CFS.
They will be measuring IFNa in cells and peripheral tissues.
Some ME/CFS patients are really low too below the level of detection.
Points to possibility that IFNa is higher than health controls.
Splitting the patients by Bell ability score (what they can and can't do), bell 0 is very ill, healthy has 100.
There is a progression from low IFNa to high IFNa for reducing Bell score.
Pathways to switch off IFNa - going to measure SOCS3 thought to be the major pathway is turned off or SOCS1.
Other mechanisms to turn off these pathway, need to be able to check if this is how it works for normal cells and if its broken in ME/CFS patients.
Heal or beak positive loop need to interupt the signalling. There are drugs for binding to IFNa and breaking the JAK-STAT pathway.
Significant side effects if we would need this all the time, we need IFNa signally to fight a virus/bacteria.
Hope is it would only have to be for a short period of time to break the positive feedback loop.
For the period of 1 or 3 days you would have to stay away from people/infection.
If that block doesn't work then they will need to identify the checkpoint pathway that isn't functioning. There are about 100 of these. Its doable to measure the mRNA and molecular biology.
The blood is the ocean and the sources of IFNa are the rivers of the world, we see it in the ocean in low concentrations in the ocean but we don't know which river is producing the pollutant.
Probably 10,000 fold lower in the blood compared to the problem area.
The low amount in the blood isn't a concern.
Intersection with Bhupesh Prusty.
========================
idea 1 - mRNA with reactivated HHV-6 could be sensed as foreign by innate immune system TLR. Constant production of mRNA could keep the innate immune system turned on.
idea 2 - mRNAs with reactivated HHV-6 could be targeting the innate immune system areas that turn off JAK-STAT pathway. Degrades it and you can't turn off IFNa and the direct cause of the positive feedback loop.
Q Timeline?
If possible to break feedback loop IFNa or JAK-STAT both have FDA approved drugs, treatment not fair off at all. Have to be sure its right and need the data properly explained.
Summary Part 1 (He gives this)
========================
Innate immune system triggers Itoconate Shunt.
The shunt cuts off the citric acid cycle to bridge 2-OG to Succicante and OAA to Citrate.
We loose the ability to process lipids into energy.
Glumate becomes the only mechanism to produce power from amino acids but produces ammonia (a neurotoxin).
Itaconyl-CoA is produced with the shunt and it poisons B12.
Theory is this is cells that were near an infection event but not in it and hence have not been killed by the immune system.
A few enzymes can repair this in the cells - GAD2, GAD - glumate Decarboxylase, GABA transaminase and SSADH.
But these are inefficient and only allow you to burn amino acids.
This is really bad in the brain as glutmate and GABA are neurotransmitters
Burning these transmitters is probably where brain fog comes from.
Part 2
======
Either bacteria (LPS) or Virus is TLR sensed turns on NFkB inflammatory response
Produces TNFa, CCL2, CD80
TNFa - increases vascular infusion allowing more cells in
CCL2 - chemokines - signal path into the blood draw cells in
CD80 - remains on the cell signals it is infected
Second mechanism is the TLR's produce IRF7-Pi drives IFNa comes out of cell and talks to the neighbouring cells. Tells cells nearby to ready for infection.
The theory is that the bystander cells readiness state becomes chronic. That is ME/CFS (if the theory is right).
IFNa binds to IFNAR JAK1 signals to STAT1 and STAT2
Jak stat signalling pathway. Produces ISGF3. These turn on transcription genes that lead to Interferon A.
The reason to do this is to reduce the resources for replication for the virus/bacteria to use.
The itoconate shunt isn't the only response. IFNa is one of these thins produced, so there is a cycle of IFNa so it could signal itself.
Concern is the pathways that normally turn off IFNa production don't turn off in ME/CFS.
They are measuring IFNa.
Theory predictions
==================
IFNa appears increased median a 25-75%, its 4x. Should be more IFNa in blood for ME/CFS patients.
Unfortunately a couple of health controls have IFNa in their blood as high as severe ME/CFS patients. So its not a biomarker on its own. Those two individuals with high blood IFNa probably produce this in their blood cells not peripheral cells. They think the problem is intercellular in the tissue not in the blood for ME/CFS.
They will be measuring IFNa in cells and peripheral tissues.
Some ME/CFS patients are really low too below the level of detection.
Points to possibility that IFNa is higher than health controls.
Splitting the patients by Bell ability score (what they can and can't do), bell 0 is very ill, healthy has 100.
There is a progression from low IFNa to high IFNa for reducing Bell score.
Pathways to switch off IFNa - going to measure SOCS3 thought to be the major pathway is turned off or SOCS1.
Other mechanisms to turn off these pathway, need to be able to check if this is how it works for normal cells and if its broken in ME/CFS patients.
Heal or beak positive loop need to interupt the signalling. There are drugs for binding to IFNa and breaking the JAK-STAT pathway.
Significant side effects if we would need this all the time, we need IFNa signally to fight a virus/bacteria.
Hope is it would only have to be for a short period of time to break the positive feedback loop.
For the period of 1 or 3 days you would have to stay away from people/infection.
If that block doesn't work then they will need to identify the checkpoint pathway that isn't functioning. There are about 100 of these. Its doable to measure the mRNA and molecular biology.
The blood is the ocean and the sources of IFNa are the rivers of the world, we see it in the ocean in low concentrations in the ocean but we don't know which river is producing the pollutant.
Probably 10,000 fold lower in the blood compared to the problem area.
The low amount in the blood isn't a concern.
Intersection with Bhupesh Prusty.
========================
idea 1 - mRNA with reactivated HHV-6 could be sensed as foreign by innate immune system TLR. Constant production of mRNA could keep the innate immune system turned on.
idea 2 - mRNAs with reactivated HHV-6 could be targeting the innate immune system areas that turn off JAK-STAT pathway. Degrades it and you can't turn off IFNa and the direct cause of the positive feedback loop.
Q Timeline?
If possible to break feedback loop IFNa or JAK-STAT both have FDA approved drugs, treatment not fair off at all. Have to be sure its right and need the data properly explained.
Last edited:
I've been involved in this illness and two other neurological illnesses for 35+ years now.
From the very beginning, Australia has been one of our strongest research partners and I would like to say "thanks" once again. Insofar as the Krebs cycle goes (and I understand very little of it, even after all these years), it has been implicated in a number of illnesses for a long time. It would be nice to have some answers...and will, someday.
Thanks, Janet, and our guest. I did listen and understood a smidgen more than I did. Yours, Lenora
From the very beginning, Australia has been one of our strongest research partners and I would like to say "thanks" once again. Insofar as the Krebs cycle goes (and I understand very little of it, even after all these years), it has been implicated in a number of illnesses for a long time. It would be nice to have some answers...and will, someday.
Thanks, Janet, and our guest. I did listen and understood a smidgen more than I did. Yours, Lenora