Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)

[Pyrrhus]

Α good question would be : Why is there dysregulation of phospholipid metabolism in the first place ? Is it a consequence of mitochondrial dysfunction?

That's certainly a great question to ask.

To me, the lack of certain phospholipids could come down to a simple secondary nutrient deficiency, as is often seen in the case of oxidative stress or chronic inflammation. As an example, oxidative stress might lead to a lack of methyl donors, which would disrupt the activity of Phosphatidyl-ethanolamine methyl-transferase (PEMT) in the liver, compromising the CDP-ethanolamine pathway to the eventual synthesis of phosphatidyl-choline. In this case, the observed lack of certain phospholipids would also be seen in other conditions with oxidative stress or chronic inflammation.

 

[Aidan Walsh]

They sell Choline supplements & other products, I think Amazon sells her items now Dr. Diana Driscoll

www.potscare.com

 

[mariovitali]

Here is something possibly of interest cc: @Janet Dafoe

I used an Information retrieval system i specifically implememted for ME research. It scans 773 medical concepts directly or indirectly related to ME research. I queried these concepts using the following query :

hyperosmotic stress AND red cell deformability

Recall that these are concepts used by Ron Davis during his research with the nano-needle. Here are the results :


Note : "........" denote concepts that are part of active research and have been removed from this list.

phospholipid_human.csv=1.2504535
glucose_6_phosphate.csv=1.2061515
prostaglandin.csv=1.1950134
glycolysis.csv=1.1939175
.............
acetaldehyde.csv=1.1273894
phosphates.csv=1.1272447
free_fatty_acids.csv=1.1001698
nac.csv=1.0557141
phosphatidylcholine.csv=1.0167357
tocopherol.csv=1.0009141
choline.csv=0.9838646
calmodulin.csv=0.95515966
hypoxia.csv=0.9411563
protein_kinase_a.csv=0.9191257
heparin.csv=0.9173651
............
phosphorylation.csv=0.90558237
g_actin.csv=0.87740237
lactate.csv=0.8605659
f_actin.csv=0.856518
glycine.csv=0.8444515
na_k_atpase.csv=0.8443683
glycoproteins.csv=0.83597994
vasoconstriction.csv=0.81866467
epinephrine.csv=0.8121168
leptin.csv=0.77789605
gaba_human.csv=0.7740025
gsh.csv=0.7735821
xanthine_oxidase.csv=0.76674366
nitric_oxide.csv=0.7653496
...................
il_6.csv=0.7196213
h2o2.csv=0.71518743
mitochondria_human.csv=0.71494347
nitric_oxide_synthase.csv=0.71477365
mitochondrial_dysfunction.csv=0.70873874
bilirubin.csv=0.70670485
tau.csv=0.70494086
vitamin_k.csv=0.6885573
heme.csv=0.67370784
heme_biosynthesis.csv=0.65428793
uric_acid.csv=0.65383637
ckd.csv=0.65187293
gpcr.csv=0.64800596
glycosylation.csv=0.6447042
insulin_resistance.csv=0.6297432
catalase.csv=0.6295128
adrenergic_receptors.csv=0.62404096
porphyrins.csv=0.6108846
nucleotides.csv=0.5973406
tnf_alpha.csv=0.55461264
hydrolysis.csv=0.52908313
lactic_acid.csv=0.490879
inflammatory_cytokines.csv=0.45143282
l_arginine.csv=0.4363921
coa.csv=0.38389474
inflammatory_response.csv=0.32453233
copper.csv=0.31508273
igg.csv=0.31243867


I find it extremely interesting that the most higly ranked concept are phospholipids.

 

[Learner1]

They sell Choline supplements & other products, I think Amazon sells her items now Dr. Diana Driscoll
www.potscare.com

It is more than just choline and phosphatidyl choline. One needs ALL the membranes phospholipids. Please see my links above...

Here is something possibly of interest cc: @Janet Dafoe

I used an Information retrieval system i specifically implememted for ME research. It scans 773 medical concepts directly or indirectly related to ME research. I queried these concepts using the following query :

hyperosmotic stress AND red cell deformability

Recall that these are concepts used by Ron Davis during his research with the nano-needle. Here are the results :


Note : "........" denote concepts that are part of active research and have been removed from this list.

phospholipid_human.csv=1.2504535
glucose_6_phosphate.csv=1.2061515
prostaglandin.csv=1.1950134
glycolysis.csv=1.1939175
.............
acetaldehyde.csv=1.1273894
phosphates.csv=1.1272447
free_fatty_acids.csv=1.1001698
nac.csv=1.0557141
phosphatidylcholine.csv=1.0167357
tocopherol.csv=1.0009141
choline.csv=0.9838646
calmodulin.csv=0.95515966
hypoxia.csv=0.9411563
protein_kinase_a.csv=0.9191257
heparin.csv=0.9173651
............
phosphorylation.csv=0.90558237
g_actin.csv=0.87740237
lactate.csv=0.8605659
f_actin.csv=0.856518
glycine.csv=0.8444515
na_k_atpase.csv=0.8443683
glycoproteins.csv=0.83597994
vasoconstriction.csv=0.81866467
epinephrine.csv=0.8121168
leptin.csv=0.77789605
gaba_human.csv=0.7740025
gsh.csv=0.7735821
xanthine_oxidase.csv=0.76674366
nitric_oxide.csv=0.7653496
...................
il_6.csv=0.7196213
h2o2.csv=0.71518743
mitochondria_human.csv=0.71494347
nitric_oxide_synthase.csv=0.71477365
mitochondrial_dysfunction.csv=0.70873874
bilirubin.csv=0.70670485
tau.csv=0.70494086
vitamin_k.csv=0.6885573
heme.csv=0.67370784
heme_biosynthesis.csv=0.65428793
uric_acid.csv=0.65383637
ckd.csv=0.65187293
gpcr.csv=0.64800596
glycosylation.csv=0.6447042
insulin_resistance.csv=0.6297432
catalase.csv=0.6295128
adrenergic_receptors.csv=0.62404096
porphyrins.csv=0.6108846
nucleotides.csv=0.5973406
tnf_alpha.csv=0.55461264
hydrolysis.csv=0.52908313
lactic_acid.csv=0.490879
inflammatory_cytokines.csv=0.45143282
l_arginine.csv=0.4363921
coa.csv=0.38389474
inflammatory_response.csv=0.32453233
copper.csv=0.31508273
igg.csv=0.31243867


I find it extremely interesting that the most higly ranked concept are phospholipids.

Er, exactly what does this list denote?

 

[mariovitali]

Er, exactly what does this list denote?

It shows a possible association between phospholipid metabolism and Ron Davis's work on RBC Deformability

 

[Learner1]

It shows a possible association between phospholipid metabolism and Ron Davis's work on RBC Deformability

Of course. It's a no brainer...

 

[Violeta]

Here is something possibly of interest cc: @Janet Dafoe

I used an Information retrieval system i specifically implememted for ME research. It scans 773 medical concepts directly or indirectly related to ME research. I queried these concepts using the following query :

hyperosmotic stress AND red cell deformability

Recall that these are concepts used by Ron Davis during his research with the nano-needle. Here are the results :


Note : "........" denote concepts that are part of active research and have been removed from this list.

phospholipid_human.csv=1.2504535
glucose_6_phosphate.csv=1.2061515
prostaglandin.csv=1.1950134
glycolysis.csv=1.1939175
.............
acetaldehyde.csv=1.1273894
phosphates.csv=1.1272447
free_fatty_acids.csv=1.1001698
nac.csv=1.0557141
phosphatidylcholine.csv=1.0167357
tocopherol.csv=1.0009141
choline.csv=0.9838646
calmodulin.csv=0.95515966
hypoxia.csv=0.9411563
protein_kinase_a.csv=0.9191257
heparin.csv=0.9173651
............
phosphorylation.csv=0.90558237
g_actin.csv=0.87740237
lactate.csv=0.8605659
f_actin.csv=0.856518
glycine.csv=0.8444515
na_k_atpase.csv=0.8443683
glycoproteins.csv=0.83597994
vasoconstriction.csv=0.81866467
epinephrine.csv=0.8121168
leptin.csv=0.77789605
gaba_human.csv=0.7740025
gsh.csv=0.7735821
xanthine_oxidase.csv=0.76674366
nitric_oxide.csv=0.7653496
...................
il_6.csv=0.7196213
h2o2.csv=0.71518743
mitochondria_human.csv=0.71494347
nitric_oxide_synthase.csv=0.71477365
mitochondrial_dysfunction.csv=0.70873874
bilirubin.csv=0.70670485
tau.csv=0.70494086
vitamin_k.csv=0.6885573
heme.csv=0.67370784
heme_biosynthesis.csv=0.65428793
uric_acid.csv=0.65383637
ckd.csv=0.65187293
gpcr.csv=0.64800596
glycosylation.csv=0.6447042
insulin_resistance.csv=0.6297432
catalase.csv=0.6295128
adrenergic_receptors.csv=0.62404096
porphyrins.csv=0.6108846
nucleotides.csv=0.5973406
tnf_alpha.csv=0.55461264
hydrolysis.csv=0.52908313
lactic_acid.csv=0.490879
inflammatory_cytokines.csv=0.45143282
l_arginine.csv=0.4363921
coa.csv=0.38389474
inflammatory_response.csv=0.32453233
copper.csv=0.31508273
igg.csv=0.31243867


I find it extremely interesting that the most higly ranked concept are phospholipids.

@mariovitali, do you think some are 'cause' and some are 'result' or 'effect'?

 

[mariovitali]

@Violeta

Good question. Unfortunately we do not have cause and effect information as this system only helps identify potential research subjects, given a query of medical topics.

FWIW, when i was logging my symptoms (for a total of 434 days) i found that going fat free induced my symptoms and when i was eating cholesterol-rich foods -especially- i would feel much better.

 

[Violeta]

@Violeta

Good question. Unfortunately we do not have cause and effect information as this system only helps identify potential research subjects, given a query of medical topics.

FWIW, when i was logging my symptoms (for a total of 434 days) i found that going fat free induced my symptoms and when i was eating cholesterol-rich foods -especially- i would feel much better.

"The ER, together with the Golgi apparatus, is a major site of de novo bulk membrane lipid synthesis, and recent experiments demonstrate a link between phospholipid synthesis and secretion from this compartment."

"The smooth endoplasmic reticulum functions in many metabolic processes. It synthesizes lipids, phospholipids as in plasma membranes, and steroids."

Let me see if I can find out what goes wrong.

Maybe something in the mevalonate pathway.

 

[Violeta]

Just to give my two cents. Please see below a thread where a Network Analysis graph is shown (2017) :

https://forums.phoenixrising.me/threads/machine-learning-assisted-research-on-cfs.51283/#post-846815

Choline deficiency, Peroxisome proliferators have been identified as potentially "Central" concepts of ME/CFS.


Ever since i've been trying to identify why these concepts (along with others) have been there. One of the major nodes (not shown on the thread post above) is Hepatotoxicity. Please note that the Network Analysis shown was run taking into account a number of other syndromes including Gulf War Ilness syndrome, Post-accutane syndrome, Post-Finasteride syndrome etc.

The hypothesis generated was that we have a Liver Injury that takes place via toxic substances, certain medications and =of course- certain viruses. This is the common factor between all ME/CVFS triggers.

Vitamin K is also there as a central node (NO avoidance or supplementation of Vitamin K is implied). The full version of the network analysis generated is the following :


View attachment 43780




We see nodes related to Oxidation, Bile acids metabolism (CYP7B1, CYP27A1), Liver issues (NAFLD, Steatohepatitis), Peroxisomes (peroxisome, pparalpha,ppargamma) , Mitochondria (PGC1) .

Hydrolysis is way to broad of subject but it may be helping us if Hydrolysis matches a broader hypothesis on the main mechanism.

We just have to use such techniques where all past and present findings will be added and we should then investigate "where all ends meet"

Thank you. I think you are right that this is where all the symptoms intersect. Very interesting.

 

[Violeta]

That's a nice find.

Garth Nicolson, after doing a lot of research to understand membranes and their dynamics,

https://science.sciencemag.org/content/175/4023/720

has worked to develop treatment, described in this paper:

https://www.sciencedirect.com/science/article/pii/S0005273613004070

"Lipid Replacement Therapy, the use of functional oral supplements containing cell membrane phospholipids and antioxidants, has been used to replace damaged, usually oxidized, membrane glycerophospholipids that accumulate during aging and in various clinical conditions in order to restore cellular function.​

​

This approach differs from other dietary and intravenous phospholipid interventions in the composition of phospholipids and their defense against oxidation during storage, ingestion, digestion and uptake as well as the use of protective molecules that noncovalently complex with phospholipid micelles and prevent their enzymatic and bile disruption. Once the phospholipids have been taken in by transport processes, they are protected by several natural mechanisms involving lipid receptors, transport and carrier molecules and circulating cells and lipoproteins until their delivery to tissues and cells where they can again be transferred to intracellular membranes by specific and nonspecific transport systems. Once delivered to membrane sites, they naturally replace and stimulate removal of damaged membrane lipids. Various chronic clinical conditions are characterized by membrane damage, mainly oxidative but also enzymatic, resulting in loss of cellular function.​

​

This is readily apparent in mitochondrial inner membranes where oxidative damage to phospholipids like cardiolipin and other molecules results in loss of trans-membrane potential, electron transport function and generation of high-energy molecules.​

​

Recent clinical trials have shown the benefits of Lipid Replacement Therapy in restoring mitochondrial function and reducing fatigue in aged subjects and patients with a variety of clinical diagnoses that are characterized by loss of mitochondrial function and include fatigue as a major symptom."​

and this diagram from the paper explains it :

View attachment 43844
He was driven to learn about this to help his daughter, who had Gulf War Illness and his wife, who had a mycoplasma infection. He found that several infections cause membranes to be damaged (from oxidative and nitrosative stress - a known feature of ME/CFS - see paper I posted above).

He then formulated this product licensed to Allergy Research, Nutricology, and Researched Nutriceuticals, containing the phospholipid constituents of membranes, in the correct ratios, to repair the damaged membranes:

https://www.pureformulas.com/nt-fac...mQeYc1u8vvSs6G8ooOV752hmUtsIdpcgaAkhFEALw_wcB

This strategy, of beating back the virus causing the mito fragmentation, reducing peroxynitrites (oxidative and nitrosative stress) with the Pall protocol (folate, MB12, C and BH4), then replenishing lipids with NT Factor, has he'd to measurable gains of function and in labs for me over the past 3 years.

Which is what Nicolson found and then he also worked with Thomas Seyfried, Dominic D'Agostino and others to publish the mito correction paper, also posted above. He's done other trials finding lipid replenishment reduces fatigue.

With respect to the mycoplasma, in RA, at least, it does have a connection to the mevalonate pathway.

We, previously, reported that glycolipid-antigens (GGPL-I and III) are the major antigens of M. fermentans. Monoclonal antibody against the GGPL-III could detect the existence of the GGPL-III antigens in synovial tissues from RA patients. GGPL-III antigens were detected in 38.1% (32/84) of RA patient’s tissues, but not in osteoarthritis (OA) and normal synovial tissues. Immunoelectron microscopy revealed that a part of GGPL-III antigens are located at endoplasmic reticulum. GGPL-III significantly induced TNF-α and IL-6 production from peripheral blood mononulear cells, and also proliferation of synovial fibroblasts

https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26743

 

[Violeta]

EBV also related to mevalonate pathway.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008030

 

[Learner1]

EBV also related to mevalonate pathway.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008030

Wonder what the conclusion means:

"These studies identify multiple EBV-induced metabolic enzymes important for B-cell transformation, including potential therapeutic targets."

 

[Violeta]

Here is something possibly of interest cc: @Janet Dafoe

I used an Information retrieval system i specifically implememted for ME research. It scans 773 medical concepts directly or indirectly related to ME research. I queried these concepts using the following query :

hyperosmotic stress AND red cell deformability

Recall that these are concepts used by Ron Davis during his research with the nano-needle. Here are the results :


Note : "........" denote concepts that are part of active research and have been removed from this list.

phospholipid_human.csv=1.2504535
glucose_6_phosphate.csv=1.2061515
prostaglandin.csv=1.1950134
glycolysis.csv=1.1939175
.............
acetaldehyde.csv=1.1273894
phosphates.csv=1.1272447
free_fatty_acids.csv=1.1001698
nac.csv=1.0557141
phosphatidylcholine.csv=1.0167357
tocopherol.csv=1.0009141
choline.csv=0.9838646
calmodulin.csv=0.95515966
hypoxia.csv=0.9411563
protein_kinase_a.csv=0.9191257
heparin.csv=0.9173651
............
phosphorylation.csv=0.90558237
g_actin.csv=0.87740237
lactate.csv=0.8605659
f_actin.csv=0.856518
glycine.csv=0.8444515
na_k_atpase.csv=0.8443683
glycoproteins.csv=0.83597994
vasoconstriction.csv=0.81866467
epinephrine.csv=0.8121168
leptin.csv=0.77789605
gaba_human.csv=0.7740025
gsh.csv=0.7735821
xanthine_oxidase.csv=0.76674366
nitric_oxide.csv=0.7653496
...................
il_6.csv=0.7196213
h2o2.csv=0.71518743
mitochondria_human.csv=0.71494347
nitric_oxide_synthase.csv=0.71477365
mitochondrial_dysfunction.csv=0.70873874
bilirubin.csv=0.70670485
tau.csv=0.70494086
vitamin_k.csv=0.6885573
heme.csv=0.67370784
heme_biosynthesis.csv=0.65428793
uric_acid.csv=0.65383637
ckd.csv=0.65187293
gpcr.csv=0.64800596
glycosylation.csv=0.6447042
insulin_resistance.csv=0.6297432
catalase.csv=0.6295128
adrenergic_receptors.csv=0.62404096
porphyrins.csv=0.6108846
nucleotides.csv=0.5973406
tnf_alpha.csv=0.55461264
hydrolysis.csv=0.52908313
lactic_acid.csv=0.490879
inflammatory_cytokines.csv=0.45143282
l_arginine.csv=0.4363921
coa.csv=0.38389474
inflammatory_response.csv=0.32453233
copper.csv=0.31508273
igg.csv=0.31243867


I find it extremely interesting that the most higly ranked concept are phospholipids.

I am intermittently going through this list and looking for how the things on the list affect the cell wall. So far, if I search the word with Endoplasmic Reticulum, I find something applicable.

I searched for acetaldehyde and found this study. I should look for a study, though, that actually mentioned phospholipids. Right now I am thinking anything that damages ER would have a negative effect on phospholipid production. If that thinking is wrong, please let me know. Thank you.

Therefore, ADE induces neurotoxicity of HT22 cells via oxidative stress- and Ca2+ imbalance-mediated ERS.


https://www.hindawi.com/journals/omcl/2019/2593742/

 

[Violeta]

Vitamin K, as seen on mariovitali's list, is protective. I searched with K2 and not just K.

These results suggested that vitamin K2 alleviated mitochondrial damage, ER stress and tauopathy-mediated neuronal cell death, which highlights its role as new antioxidative therapeutics targeting related cellular processes.

https://pubmed.ncbi.nlm.nih.gov/34202933/

 

[Violeta]

EDS, being common among those with ME/CF, has ER stress as a possible cause.

The fragile collagen fibrils in vEDS might form as a result of ER stress and that small, newly formed collagen fibrils may appear. This research revealed a novel prospect regarding an issue that has been unclear for a long time, which is the reason for the abnormal sizes of collagenous fibrils in vEDS.

https://pubmed.ncbi.nlm.nih.gov/33523542/

 

[Violeta]

Wonder what the conclusion means:

"These studies identify multiple EBV-induced metabolic enzymes important for B-cell transformation, including potential therapeutic targets."

I have seen mention of HMG-CoA inhibitors, such as the statins, being used. What a dangerous way to address the problem, though.

 

[Violeta]

With respect to anti-cardiolipin antibodies, since EBV can hijack the mevalonate pathway where phospholipids are made, I wondered if EBV was involved in the anti-cardiolipin antibodies and found this.

Anti-cardiolipin antibodies in infectious mononucleosis react with the membrane of activated lymphocytes.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC1541872/

Our data suggest that the autoantibody response in IM is restricted to two classes of autoantigens: cytoskeletal and cell membrane antigens. The appearance of antigenic epitopes on EBV-transformed lymphocytes could be a mechanism for the generation of anti-cardiolipin antibodies in infectious mononucleosis. Similar mechanisms could operate in autoimmune rheumatic disease.

Here's a study about that.

https://www.sciencedirect.com/science/article/pii/S0163782721000151

 

[Learner1]

With respect to anti-cardiolipin antibodies, since EBV can hijack the mevalonate pathway where phospholipids are made, I wondered if EBV was involved in the anti-cardiolipin antibodies and found this.

Anti-cardiolipin antibodies in infectious mononucleosis react with the membrane of activated lymphocytes.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC1541872/

Our data suggest that the autoantibody response in IM is restricted to two classes of autoantigens: cytoskeletal and cell membrane antigens. The appearance of antigenic epitopes on EBV-transformed lymphocytes could be a mechanism for the generation of anti-cardiolipin antibodies in infectious mononucleosis. Similar mechanisms could operate in autoimmune rheumatic disease.

Here's a study about that.

https://www.sciencedirect.com/science/article/pii/S0163782721000151

EBV also triggers a myriad of other antibodies.

 

[Violeta]

I wonder if all the antibodies involved in autoimmune diseases, which would mean, for example, the autoantibodies of Hashimoto's, are actually caused in some way by EBV.


"Epstein-Barr infects B cells—a type of white blood cell in the immune system. This may explain the association between Epstein-Barr and the EBNA2 disorders: All seven are autoimmune diseases, conditions involving an abnormal immune response to a normal body part." But what if the immune response to the body part is because the body part is infected with EBV?

and the disorders:

"Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease."

and this is an unexpected find:

"The NHANES data revealed that adolescents who consumed beans, red meat and 100 percent fruit juice daily might see increased odds of EBV as compared with adolescents who consumed the same products on a monthly basis."