gregh286
Senior Member
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- 979
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- Londonderry, Northern Ireland.
Makes sense as I do really well on aminos and direct AAKG. But I agree would be nice to get closer to root than treat the branches.
Started TUDCA today.
Standard dose.
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)
- Thread starter deleder2k
- Start date
Makes sense as I do really well on aminos and direct AAKG. But I agree would be nice to get closer to root than treat the branches.
Started TUDCA today.
Standard dose.
deleder2k
Senior Member
- Messages
- 1,129
From Øystein Fluge's latest presentation in Norwich
- Messages
- 23
I think PDH block by PDK1 is a symptom of the greater dysregulation, the paper even says that. Many inflammatory, hypoxia, ROS triggered pathways lead to PDK1 increase as part of a Warburg effect induction.
PDK1 is up regulated, aconitase inhibited, LDH upregulated, fatty acid synthesis & gluconeogenesis are halted to stop the Krebs cycle and encourage glycolysis & lactate metabolism by everything from hypoxia to pseudohypoxia (NAD+ defiency) to inflammatory cytokine signaling, to cancer.
Thus I dont think fixing PDH will fix a ton.
(Btw, Ppl on this site already tried PDK inhibitor *dichloroacetate* with maybe some benefit.)
I think Fluge's paper actually fits really well with Navieux's (sp?) conclusion that every metabolic dysfunction seen in CFS can be explained by interruption of the ETC in mitochondria (resulting in low NADH, and in low NADPH)....which I believe is ultimately due to cytokine derrangements.
When cells are growing and rapidly dividing, they synthesize lipids & cholesterol for membranes, purines for nucleic acid synthesis and use up lots of ATP, so they keep the Krebs & ETC going full speed.
When cells are in hibernation just trying to survive (not grow/divide), they lower production of lipids, cholesterol, purines, and ATP -- those are the deficiencies seen in N's paper in CFS patients.
Now, since growth is regulated heavily via insulin/IGF-1/growth factors down the mTOR pathway, perhaps getting that pathway going could forceably reverse the dormancy.
However, if there is a block in the ETC that occurred (either as a result of all the NO produced, the ROS, etc.), then firing up mTOR may not help much as you can't supply the ATP needed to drive synthesis of the lipids, nucleic acids, etc.
So how do you unblock the ETC?
a. Reduce NO - NO in high levels ( CFS ppl have high NO) binds to the sites where oxygen should in certain ETC enzymes, blocking them.
- aminoguanidine blocks NOS, but had bad siDE effects which stopped its trials
-- increasing O2 a lot will knock NO off the ETC enzymes
- hyperbaric O2, dissolved O2 drops?
-block glutamate cytotox to reduce neuronal NO
- namenda
- avoid msg, aspartame
- glutaminase activators
- glutamine retake facilitators
- minocycline? Glial stabilizer?
b. Lower HIF1/2 - they modulate the blockades in Warburg effect triggered by hypoxia, pseudohypoxia (low NAD), and excessive NFKB signaling
i. make sure hypoxia not an issue
--treat OSA & silent UARS,
--hyperbaric O2
ii. NAD replacement (most Sirtuins block Hif1/2, but need NAD+ to do so, sirt1 also regulates circadian metabolic rhythm & NAD synth)
- IV or intranasal NAD (xpensive)
- MitoTrans (NAD xtended rls)
- Niagen
- Vitaflavan or Py.....smthg B2 (found in apples & grapeseeds in small amounts, makes ur hair grow...forgot name) - this increases DE Novo Nad synthesis from tryptophan...may not be the best idea if ur a kainic acid, QA, PA pathway person
- treat underlying sleep disorder
iii. Lower cytokines & immune responses that trigger NFKB
- TNF-a (tumeric, nicotine, ach, Vagas n. Stim)
- NfKB (EGCG, cannabinoid R agonists)
- Treat all infections...with no immune system to clean up, will take years to clear
- antivirals, cox2 inhibs, antibiotics, ozone, herbals, Ampligen....oh my!
- Rituximab????
Holy moly that's a lot of holes to plug in the ol bucket to get her working again!
So what about Rituximab?? Why can one drug that wipes out B cells do what ALL of the above only maybe can?
From this paper below, it appears Rituximab is skewing of the ratio of B-supressor and B-effector cells. (Yup, B-supressor, not a type-o.
B-effectors & B-regs primarily secrete cytokines and either halt (Breg) or cyclically enhance either TH2 (Be-2) or TH1 (Be-1) T cell responses. This paper explains it beautifully: (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2474694/#!po=19.1667).
But here's an attempt at a summary:
B-reg's primarily secrete either anti-inflammatory (IL-10, TGF-B) cytokines
Be-2 primarily secrete IL4 & some others and stimulate T cells to become Th2.
Be-1 secrete IL12, IFN-G, TNF-a, possibly Lymphotoxin. They are found in tonsils, blood, and likely are responsible for the lymphoid follicles formed in target organs of autoimmune attacks.
Be-1's perpetuate a local autoimmune attack by spewing TH1 cytokines that convert any incoming naive T cells to Th1 rather than Tregs, so the fire doesn't ever go out.
Of note, Be-1 don't need T cell activation to start spewing if a few TLR agonists and certain cytokines are present.
Looking at people with RA and Lupus who went into remission after Rituximab, several had no decrease in their auto-antibody levels despite clinical improvement! Antibodies are primarily made by plasma cells, the long lived ones aren't killed by Rituximab.
What Rituxan does do (at least in MS, RA, and SLE patients) is change the ratio of Be-1&2 to Bregs, leading to a "more suppressive or tolerogenic cytokine profile."
But wait... CFS/ME patients are TH2 dominant and TH1 immune suppressed already, aren't we? Sort of, but not exactly.
I'm going to use Hashimoto's thyroiditis as an example to illustrate this.
According to [1], Hashimotos patients develop lymphoid follicles in the thyroid full of Th1/Th17, B cells, etc. with high levels of IFN-g, IL12, TNF-a & very few Tregs in the thyroid. This is in contrast to the PBMC makeup in the blood of Hashimotos patients, who have a normal number of WBCs, but a higher percentage of them are Tregs! [1] The excessively elevated FOXP3 on those circulating Tregs in Hashi's patient blood is thought to be compensation for the inability to put the fire out in the thyroid (thanks largely to the excessive local Tcell stimulation towards TH1/17 by Be-1 cells). [1]
Locally out of control TH1 drives systemic state of peripheral immune supression --> latent viruses, mycoplasma, fungii, Lyme get to have a party! And all our poor body can do is batten down the hatches to try and ride out the storm by putting us in a hibernation state...like Naviaux's paper said.
Interestingly enough, when Hashimoto's patients with severe fatigue, muscle aches, malaise; hypothyroidism (treated); and antibodies >1000 had their thyroids surgically removed, the severe fatigue post surgery dropped to the levels of controls. [2]
So what if you can't just cut out whatever is driving your system wonky, or you don't want to?
a. Supression of Type IV immune responses to antigens is induced in animals by either oral repeated exposure or intranasal exposure to the antigen [3].
-- I believe this is akin to LDA/LDI therapy & oral allergy drops (just gotta find me some human, or bovine -87% homology-, TPO to snort lol....I may actually look into this)
b. Tolerance is also achieved by adoptive transfer of splenocytes from a healthy to the test rat - increased IL-10 was noted [3].
-- maybe someone can inject my thyroid with IL-10 producing cells from my spleen (T2 subset produce IL10), or with B or Tregs for that matter...
c -- Apparently injecting auto antigen into the thymus induces tolerance [4]
d -- Rituximab & maybe follow it with something to suppress Lymphotoxin &/or TNF-alpha (which start the process of autoimmune follicle formation)?
Hopefully I didnt misinterpret any of the papers.
Thoughts?
Refs
1. Hashimotos
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271310/#!po=39.1447
2. Hashimoto's Thyroidectomy
http://www.medpagetoday.com/meetingcoverage/ata/54177
3. Inducing tolerance to anticens via repeat intranasal exposure https://www.ncbi.nlm.nih.gov/pmc/articles/PMC299916/?report=reader
4. Thymic Injection of Antigen https://www.ncbi.nlm.nih.gov/pubmed/26996480
PDK1 is up regulated, aconitase inhibited, LDH upregulated, fatty acid synthesis & gluconeogenesis are halted to stop the Krebs cycle and encourage glycolysis & lactate metabolism by everything from hypoxia to pseudohypoxia (NAD+ defiency) to inflammatory cytokine signaling, to cancer.
Thus I dont think fixing PDH will fix a ton.
(Btw, Ppl on this site already tried PDK inhibitor *dichloroacetate* with maybe some benefit.)
I think Fluge's paper actually fits really well with Navieux's (sp?) conclusion that every metabolic dysfunction seen in CFS can be explained by interruption of the ETC in mitochondria (resulting in low NADH, and in low NADPH)....which I believe is ultimately due to cytokine derrangements.
When cells are growing and rapidly dividing, they synthesize lipids & cholesterol for membranes, purines for nucleic acid synthesis and use up lots of ATP, so they keep the Krebs & ETC going full speed.
When cells are in hibernation just trying to survive (not grow/divide), they lower production of lipids, cholesterol, purines, and ATP -- those are the deficiencies seen in N's paper in CFS patients.
Now, since growth is regulated heavily via insulin/IGF-1/growth factors down the mTOR pathway, perhaps getting that pathway going could forceably reverse the dormancy.
However, if there is a block in the ETC that occurred (either as a result of all the NO produced, the ROS, etc.), then firing up mTOR may not help much as you can't supply the ATP needed to drive synthesis of the lipids, nucleic acids, etc.
So how do you unblock the ETC?
a. Reduce NO - NO in high levels ( CFS ppl have high NO) binds to the sites where oxygen should in certain ETC enzymes, blocking them.
- aminoguanidine blocks NOS, but had bad siDE effects which stopped its trials
-- increasing O2 a lot will knock NO off the ETC enzymes
- hyperbaric O2, dissolved O2 drops?
-block glutamate cytotox to reduce neuronal NO
- namenda
- avoid msg, aspartame
- glutaminase activators
- glutamine retake facilitators
- minocycline? Glial stabilizer?
b. Lower HIF1/2 - they modulate the blockades in Warburg effect triggered by hypoxia, pseudohypoxia (low NAD), and excessive NFKB signaling
i. make sure hypoxia not an issue
--treat OSA & silent UARS,
--hyperbaric O2
ii. NAD replacement (most Sirtuins block Hif1/2, but need NAD+ to do so, sirt1 also regulates circadian metabolic rhythm & NAD synth)
- IV or intranasal NAD (xpensive)
- MitoTrans (NAD xtended rls)
- Niagen
- Vitaflavan or Py.....smthg B2 (found in apples & grapeseeds in small amounts, makes ur hair grow...forgot name) - this increases DE Novo Nad synthesis from tryptophan...may not be the best idea if ur a kainic acid, QA, PA pathway person
- treat underlying sleep disorder
iii. Lower cytokines & immune responses that trigger NFKB
- TNF-a (tumeric, nicotine, ach, Vagas n. Stim)
- NfKB (EGCG, cannabinoid R agonists)
- Treat all infections...with no immune system to clean up, will take years to clear
- antivirals, cox2 inhibs, antibiotics, ozone, herbals, Ampligen....oh my!
- Rituximab????
Holy moly that's a lot of holes to plug in the ol bucket to get her working again!
So what about Rituximab?? Why can one drug that wipes out B cells do what ALL of the above only maybe can?
From this paper below, it appears Rituximab is skewing of the ratio of B-supressor and B-effector cells. (Yup, B-supressor, not a type-o.
B-effectors & B-regs primarily secrete cytokines and either halt (Breg) or cyclically enhance either TH2 (Be-2) or TH1 (Be-1) T cell responses. This paper explains it beautifully: (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2474694/#!po=19.1667).
But here's an attempt at a summary:
B-reg's primarily secrete either anti-inflammatory (IL-10, TGF-B) cytokines
Be-2 primarily secrete IL4 & some others and stimulate T cells to become Th2.
Be-1 secrete IL12, IFN-G, TNF-a, possibly Lymphotoxin. They are found in tonsils, blood, and likely are responsible for the lymphoid follicles formed in target organs of autoimmune attacks.
Be-1's perpetuate a local autoimmune attack by spewing TH1 cytokines that convert any incoming naive T cells to Th1 rather than Tregs, so the fire doesn't ever go out.
Of note, Be-1 don't need T cell activation to start spewing if a few TLR agonists and certain cytokines are present.
Looking at people with RA and Lupus who went into remission after Rituximab, several had no decrease in their auto-antibody levels despite clinical improvement! Antibodies are primarily made by plasma cells, the long lived ones aren't killed by Rituximab.
What Rituxan does do (at least in MS, RA, and SLE patients) is change the ratio of Be-1&2 to Bregs, leading to a "more suppressive or tolerogenic cytokine profile."
But wait... CFS/ME patients are TH2 dominant and TH1 immune suppressed already, aren't we? Sort of, but not exactly.
I'm going to use Hashimoto's thyroiditis as an example to illustrate this.
According to [1], Hashimotos patients develop lymphoid follicles in the thyroid full of Th1/Th17, B cells, etc. with high levels of IFN-g, IL12, TNF-a & very few Tregs in the thyroid. This is in contrast to the PBMC makeup in the blood of Hashimotos patients, who have a normal number of WBCs, but a higher percentage of them are Tregs! [1] The excessively elevated FOXP3 on those circulating Tregs in Hashi's patient blood is thought to be compensation for the inability to put the fire out in the thyroid (thanks largely to the excessive local Tcell stimulation towards TH1/17 by Be-1 cells). [1]
Locally out of control TH1 drives systemic state of peripheral immune supression --> latent viruses, mycoplasma, fungii, Lyme get to have a party! And all our poor body can do is batten down the hatches to try and ride out the storm by putting us in a hibernation state...like Naviaux's paper said.
Interestingly enough, when Hashimoto's patients with severe fatigue, muscle aches, malaise; hypothyroidism (treated); and antibodies >1000 had their thyroids surgically removed, the severe fatigue post surgery dropped to the levels of controls. [2]
So what if you can't just cut out whatever is driving your system wonky, or you don't want to?
a. Supression of Type IV immune responses to antigens is induced in animals by either oral repeated exposure or intranasal exposure to the antigen [3].
-- I believe this is akin to LDA/LDI therapy & oral allergy drops (just gotta find me some human, or bovine -87% homology-, TPO to snort lol....I may actually look into this)
b. Tolerance is also achieved by adoptive transfer of splenocytes from a healthy to the test rat - increased IL-10 was noted [3].
-- maybe someone can inject my thyroid with IL-10 producing cells from my spleen (T2 subset produce IL10), or with B or Tregs for that matter...
c -- Apparently injecting auto antigen into the thymus induces tolerance [4]
d -- Rituximab & maybe follow it with something to suppress Lymphotoxin &/or TNF-alpha (which start the process of autoimmune follicle formation)?
Hopefully I didnt misinterpret any of the papers.
Thoughts?
Refs
1. Hashimotos
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271310/#!po=39.1447
2. Hashimoto's Thyroidectomy
http://www.medpagetoday.com/meetingcoverage/ata/54177
3. Inducing tolerance to anticens via repeat intranasal exposure https://www.ncbi.nlm.nih.gov/pmc/articles/PMC299916/?report=reader
4. Thymic Injection of Antigen https://www.ncbi.nlm.nih.gov/pubmed/26996480
Last edited:
nandixon
Senior Member
- Messages
- 1,092
The Warburg effect can't be in play here. If it were, the Akt/mTORC1 pathway would be up-regulated and this would lead to a down-regulation of SIRT4. But Fluge & Mella found that SIRT4 expression was increased in ME/CFS patients. All of the evidence instead appears consistent with an under-activated (or inhibited) Akt/mTORC1 pathway.
That's one of the ironies here, that Fluge & Mella, as oncologists and cancer specialists are attempting to treat a disease that at a very fundamental level seems to be the opposite of cancer.
- Messages
- 23
Yes, you are right, the quinestential Warburg effect is achieved through increased mTOR, which supresses SIRT4.
What I should have said was "Warburg-esque effects" referring to a state of Krebs cycle block, ETC block, & excess lactate production despite normoxia.
Elevation of Hif1 & 2 can create that Warburg-esque metabolic state described above without activating mTOR.
NFKB + STAT3 can induce transcription of Hif1a in response to cytokines & TLR activation without involving mTOR (cytokines via the JAK/STAT pthwy).
Both STAT3 & NFkB pathways are activated by cytokines, therefore it's plausable that the shift in cytokine signalling to an less inflammatory profile by Rituximab a) could improve the metabolic symptoms in patients, and b) could therefore be it's major means of benefit to CFS patients.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834864/)
Alternatively, activating SIRT7 could reduce Hif1/2.
(http://m.jbc.org/content/288/29/20768.full)
SIRT3 shifts things more towards oxidative metabolism, in part by lowering levels of Hif1a. Maybe sending SIRT3 into overdrive while inhibiting NFKB could be enough?
What I should have said was "Warburg-esque effects" referring to a state of Krebs cycle block, ETC block, & excess lactate production despite normoxia.
Elevation of Hif1 & 2 can create that Warburg-esque metabolic state described above without activating mTOR.
NFKB + STAT3 can induce transcription of Hif1a in response to cytokines & TLR activation without involving mTOR (cytokines via the JAK/STAT pthwy).
Both STAT3 & NFkB pathways are activated by cytokines, therefore it's plausable that the shift in cytokine signalling to an less inflammatory profile by Rituximab a) could improve the metabolic symptoms in patients, and b) could therefore be it's major means of benefit to CFS patients.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834864/)
Alternatively, activating SIRT7 could reduce Hif1/2.
(http://m.jbc.org/content/288/29/20768.full)
SIRT3 shifts things more towards oxidative metabolism, in part by lowering levels of Hif1a. Maybe sending SIRT3 into overdrive while inhibiting NFKB could be enough?
Last edited:
nandixon
Senior Member
- Messages
- 1,092
STAT3 is going to be under-activated in ME/CFS. We know this for a number of reasons, including finding low VEGF-A in patients. (Reference)
Given that, the possibility of increased HIF1α seems pretty unlikely, especially since mTORC1 is under-activated. Note also that Fluge & Mella specifically looked at HIF1α in their study and didn't find an increase.
Since the Fluge & Mella study, I've found it extremely helpful in understanding ME/CFS to adopt the paradigm of an under-activated Akt/mTORC1 pathway (i.e., the opposite of most other diseases). If an idea runs counter to that then it's not likely to be correct.
A.B.
Senior Member
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- 3,780
@nandixon do you think that eating frequently could be an attempt to compensate for an underactivated mTORC1?
This paper says mTORC1 is activated by growth factors and nutrients.
https://www.ncbi.nlm.nih.gov/pubmed/21428914
Do you think growth hormone would be a potentially useful treatment?
This paper says mTORC1 is activated by growth factors and nutrients.
https://www.ncbi.nlm.nih.gov/pubmed/21428914
Do you think growth hormone would be a potentially useful treatment?
gregh286
Senior Member
- Messages
- 979
- Location
- Londonderry, Northern Ireland.
With impaired PDH pathway, only limited glycosis making it to Krebs cycle.
So, i have found the best diet is high value carbs often, supplemented with high fats healthy foods (avocado, coconut, nuts, seeds). We need copious amounts of protein also, protein shakes best way to deliver it in my opinion as body uses this as alternative fuel source. I add glutamine to mine for additional kick.
http://www.nature.com/cr/journal/v26/n1/full/cr2015146a.html
"Duran et al.87,88 suggested that glutaminolysis, the double deamination of glutamine catalyzed by glutaminase (GLS) and glutamate dehydrogenase (GDH) to produce α-ketoglutarate (αKG), activates RAG-mTORC1 through prolyl hydroxylase (PHD). αKG is a co-factor for PHD. Leucine binds and activates GDH, the enzyme that catalyzes the second deamination step in glutaminolysis, leading to αKG production. Since glutaminolysis takes place in mitochondria, this mechanism is distinct from lysosomal sensing (Figure 1). The glutaminolysis model provides a sensing mechanism for the activation of mTORC1 by leucine and glutamine."
Last edited:
adreno
PR activist
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- 4,841
So side effects of treating ME thru boosting Akt/mTOR might be accelerated aging and an increased chance of cancer.
nandixon
Senior Member
- Messages
- 1,092
I was wondering when someone would have that thought. I don't think so because there are always multiple complicated signaling inputs that have to come together in that pathway (and interrelated ones) to promote cancer. Also, we're just trying to get that pathway back to normal, not over stimulate it.
Hopefully, though, we can use the knowledge that Akt/mTORC1 is likely under-activated to try to figure out the origin of the problem farther upstream, above Akt.
adreno
PR activist
- Messages
- 4,841
In theory, but how would you ensure that?
adreno
PR activist
- Messages
- 4,841
That wouldn't fit with an underactivated Akt/mTOR pathway.
nandixon
Senior Member
- Messages
- 1,092
I think most people with ME/CFS generally say they appear younger than their age, at least outwardly, although perhaps that's from not going outside as much as healthy people.
And if I remember correctly, I think the only statistically significant increase in cancer that's been found in ME/CFS is with respect to certain B cell cancers.
nandixon
Senior Member
- Messages
- 1,092
I made a new post on another thread here, that provides some additional insight into the drug ketamine that might be helpful for research purposes. Ketamine was Dr Jay Goldstein's all-time number 1 drug over the course of treating thousands of ME/CFS patients. Ketamine is a potent activator of the Akt/mTORC1 pathway.
gregh286
Senior Member
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- 979
- Location
- Londonderry, Northern Ireland.
Its possible with the increased oxidative stress but by same token we are resting an awful lot more than others. B cell lymphoma is increased but by very minor margin.
MeSci
ME/CFS since 1995; activity level 6?
- Messages
- 8,232
- Location
- Cornwall, UK
I don't think it's because of this, as I was selling plants (working outside) and going outside a great deal in the early years, and still looked young. I think I still do.
Snow Leopard
Hibernating
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- South Australia
From Øystein Fluge's latest presentation in Norwich
This diagram states the obvious and suggests (at least when the diagram was made), that they don't really know any more than we do.
I created a thread some time ago on possible oportunities of immunomodulation and anti-inflamatory agents in traditional psychedelic compounds. I think they (like ketamine) start a cascade of process that induce a change in immune mechanism, possibly mostly though sigma1 receptor agonisation.
Some people (me included) experience total relief of symptoms when using them that last for some weeks and then fade away.
Maybe you could check it out. MAPK, NF-kB, cytokines, grouth hormone and many other relevant factors are implied for example in the first study I presented in this thread (about n-n-DMT and LSD) http://forums.phoenixrising.me/inde...proaches-and-therapeutic-opportunities.42605/
Edit: Here are some more recent studies
Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection?
The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and Microglia-Like Immune Cells
Some people (me included) experience total relief of symptoms when using them that last for some weeks and then fade away.
Maybe you could check it out. MAPK, NF-kB, cytokines, grouth hormone and many other relevant factors are implied for example in the first study I presented in this thread (about n-n-DMT and LSD) http://forums.phoenixrising.me/inde...proaches-and-therapeutic-opportunities.42605/
Edit: Here are some more recent studies
Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection?
The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and Microglia-Like Immune Cells
Last edited: