Seeking participants for clinical study: Potential Role of Tetrahydrobiopterin Deficiency in ME/CFS - Stanford, California, USA

[forestglip]

Stanford Medicine: Potential Role of Tetrahydrobiopterin Deficiency in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

You are invited to participate in a research study of chronic, unexplained fatigue, which is a kind of fatigue that does not improve with rest. Medically unexplained fatigue is a symptom of Chronic Fatigue Syndrome and it may be present in other chronic diseases and conditions. Our overarching goal is to learn what causes this form of fatigue, how to diagnose and treat patients with this debilitating symptom, and how to differentiate the mechanisms of illness in ME/CFS from other complex multi-system illnesses. This research study is specifically designed to address whether individuals with fatigue have a deficiency of the cofactor tetrahydrobiopterin, or BH4.


Please confirm that none of these conditions apply to you:

• I am below the age of 18.
• I am pregnant or lactating.
• I have been diagnosed with an inborn error of metabolism that requires me to restrict protein intake. (e.g. hyperphenylalaninemia.)
• I have severe anemia, active bleeding, or other medical conditions whereby the removal of extra blood tubes can endanger my well-being.
• I have a chronic infection with Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HPC).
• I have been diagnosed with cancer, chronic renal disease, or other clinically significant medical issue that could explain my ME/CFS symptoms.
• I am currently using illegal or illicit substance(s).

Link

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Also from the email about this:

We are also recruiting healthy volunteers to participate in this study. Please note that healthy volunteers must not have any blood relations with you. If you know anyone who might be interested, please feel free to forward this email to them.

Instructions for Healthy Volunteers:

• Visit our Studypage to learn more and fill out an interest form. Studypage Interest form for The Potential Role of Tetrahydrobiopterin Deficiency in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
• If you want to enroll in the study, go to this link - "Link to enroll in The Potential Role of Tetrahydrobiopterin (BH4) Deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)".
• Send an email to bh4_research @ stanford.edu stating you are a healthy volunteer and have completed the above two steps.

 

[Mary]

@forestglip - this looks very interesting, thanks for posting! I just filled out the brief form on the page below (name and email address) to express interest in the study. Apparently it's open to anyone in the U.S. who has either ME/CFS or Long Covid, and they will have some healthy controls also.

Here's a link to the page where you can express your interest:

https://studypages.com/s/study-to-i...h4-deficiency-in-mecfs-and-long-covid-525299/

And you don't have to go to Stanford to participate -

 

[Viala]

This study is a very good idea, looking forward to see the results.

 

[forestglip]

I just filled out the brief form on the page below (name and email address) to express interest in the study.

FYI, the other link in the post is a more in depth form (age, diagnoses, etc) to actually apply for the study, in case you didn't see.

 

[wabi-sabi]

I just signed up too!

 

[datadragon]

This research study is specifically designed to address whether individuals with fatigue have a deficiency of the cofactor tetrahydrobiopterin, or BH4.

It is expected that individuals with inflammation or fatigue will have BH4 deficiency. That is due to reduction of the cofactors including zinc during states of inflammation of infection as zinc is required in the regulation of tetrahydrobiopterin (BH4) production and its normal requirement for PPAR-a pathway.

Under inflammation a number of changes happen to put your body into an inflammatory state similar to a see saw. One of those changes is the lowering of Tetrahydrobiopterin (BH4). Under conditions of oxidative stress, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation of highly oxidative free radicals including superoxide and peroxynitrite. This is mainly due to the reduced uptake and availability of zinc during inflammation/infection.

Guanosine 5′-triphosphate cyclohydrolase-I(GTPCH-I), encoded by the GCH-I gene, is the rate-limiting enzyme in BH4 synthesis. Continuing along the de novo BH4 synthesis pathway, H2NTP is next converted to 6-pyruvoyl tetrahydropterin by the zinc-dependent enzyme, PTPS. Although GTPCH is rate limiting to BH4 synthesis in most cells, PTPS has been suggested to be rate limiting in some, most notably human hepatocytes. PTPS may become rate limiting in other tissues and cells, after stimulation with cytokines and other immunological stimuli that induce BH4 synthesis by up-regulation of GTPCH expression https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038990/

The PPAR-α agonist Fenofibrate upregulates Tetrahydrobiopterin (BH4) level through increasing the expression of Guanosine 5′-Triphosphate Cyclohydrolase-I (GTPCH) in human Umbilical Vein Endothelial Cells. Guanosine 5′-triphosphate cyclohydrolase-I(GTPCH-I), encoded by the GCH-I gene, is the rate-limiting enzyme in BH4 synthesis. https://www.hindawi.com/journals/ppar/2011/523520/

All PPAR agonists tested lost their potency to downregulate the TNF-α–induced inflammatory response in zinc-deficient cells. However, if zinc was added back, all PPAR agonists significantly downregulated the TNF-α–mediated induction of inflammatory transcription factors NF-κB and AP-1 and significantly reduced the expression of their target genes, VCAM-1 and IL-6 https://www.sciencedirect.com/science/article/pii/S0022316623029346?via=ihub

Our previous study demonstrated that homocysteine impairs coronary artery endothelial function by decreasing the level of BH4 in patients with hyperhomocysteinemia. Our previous study also showed that plasma level of BH4 was significantly increased by PPARα agonist fenofibrate in patients with hypertriglyceridemia https://journals.physiology.org/doi/full/10.1152/ajpendo.00367.2010

Homocysteine has recently been found to be a competitive inhibitor of the nuclear transcription factors: Peroxisome proliferator activated receptors (PPARs) alpha and gamma https://link.springer.com/article/10.1186/1475-2891-3-4 Homocysteine that rises from that not only increases ER Stress but also NLRP3 inflammasome activation as well from the studies mentioned before in other posts of mine so it seems its all part of the shift to an inflammatory state.

Tetrahydrobiopterin (BH4) is a critical cofactor for the rate limiting enzymes in the synthesis of the monoamine neurotransmitters. BH4 is necessary for the conversion of phenylalanine to tyrosine by PAH, tyrosine to L-DOPA by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine, and tryptophan to 5-HTP leading to the production of serotonin.

Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Zinc inhibits iNOS-dependent nitrite accumulation in endothelial cells. Zinc decreases cytokine-induced iNOS expression in endothelial cells. Zinc inhibits iNOS promoter activity. NF-kB silencing abolishes cytokine-induced iNOS expression. Zinc inhibits the transactivation activity of NFκB. https://www.sciencedirect.com/science/article/pii/S2213231714000834

 

[Violeta]

I just googled tetrahydrobiopterin in ME/CFS, and there are more than one studies saying that people with ME/CFS tend to have higher levels of BH4 than controls.

From Simmaron Research:

https://x.com/RedefiningMECFS/status/1852800624641089914

 

[Mary]

FYI, the other link in the post is a more in depth form (age, diagnoses, etc) to actually apply for the study, in case you didn't see.

I filled out the first form which just said I'm interested, and got an email today with a link to the in-depth form linked here, which I just filled out.

So yes, one can just skip the first form and just fill out the in-depth one

 

[datadragon]

just googled tetrahydrobiopterin in ME/CFS, and there are more than one studies saying that people with ME/CFS tend to have higher levels of BH4 than controls.

Yes I posted the below in a different thread about the higher levels of BH4 in this case.

Normally inflammation at first under conditions of oxidative stress, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation instead of INOS and highly oxidative free radicals including superoxide and peroxynitrite. This is mainly due to the reduced uptake and availability of zinc during inflammation/infection states since its involved in BH4 synthesis pathways as well as INOS switching (see below).

However then, GCH1, which is normally the rate-limiting enzyme for BH4 synthesis, is increased up to 100-fold by interferon-gamma (IFN-y) or IL-1B (usually in response to a pathogen). At this point, the other enzymes in the biosynthetic pathway become the rate-limiting factors https://pmc.ncbi.nlm.nih.gov/articles/PMC8573752/ Perhaps this is to help boost INOS for a short time to deal with an invader/pathogen as well as histamine and serotonin release as below.

Researchers have found that overexpression of GCH1, which drives higher BH4 production, causes increased histamine and serotonin release from mast cell degranulation. Mast cells are a part of the innate immune response. They can respond rapidly to allergens and pathogens by degranulating and releasing histamine, serotonin, cytokines, and more. https://pubmed.ncbi.nlm.nih.gov/30450838/

Also again, things like infection, heavy exercise and even high glucose or fructose all increase IFN-y. Elevated BH4 levels could be a natural response to elevated ifn-y in a reactivated Epstein-Barr infection as but one example.
https://pubmed.ncbi.nlm.nih.gov/21448390/
https://pubmed.ncbi.nlm.nih.gov/34867935/

Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Zinc inhibits iNOS-dependent nitrite accumulation in endothelial cells. Zinc decreases cytokine-induced iNOS expression in endothelial cells. Zinc inhibits iNOS promoter activity. NF-kB silencing abolishes cytokine-induced iNOS expression. Zinc inhibits the transactivation activity of NF-κB. https://www.sciencedirect.com/science/article/pii/S2213231714000834

 

[Violeta]

Yes I posted the below in a different thread about the higher levels of BH4 in this case.

Normally inflammation at first under conditions of oxidative stress, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation instead of INOS and highly oxidative free radicals including superoxide and peroxynitrite. This is mainly due to the reduced uptake and availability of zinc during inflammation/infection states since its involved in BH4 synthesis pathways as well as INOS switching (see below).

However then, GCH1, which is normally the rate-limiting enzyme for BH4 synthesis, is increased up to 100-fold by interferon-gamma (IFN-y) or IL-1B (usually in response to a pathogen). At this point, the other enzymes in the biosynthetic pathway become the rate-limiting factors https://pmc.ncbi.nlm.nih.gov/articles/PMC8573752/ Perhaps this is to help boost INOS for a short time to deal with an invader/pathogen as well as histamine and serotonin release as below.

Researchers have found that overexpression of GCH1, which drives higher BH4 production, causes increased histamine and serotonin release from mast cell degranulation. Mast cells are a part of the innate immune response. They can respond rapidly to allergens and pathogens by degranulating and releasing histamine, serotonin, cytokines, and more. https://pubmed.ncbi.nlm.nih.gov/3045083/

Also again, things like infection, heavy exercise and even high glucose or fructose all increase IFN-y. Elevated BH4 levels could be a natural response to elevated ifn-y in a reactivated Epstein-Barr infection as but one example.
https://pubmed.ncbi.nlm.nih.gov/21448390/
https://pubmed.ncbi.nlm.nih.gov/34867935/

Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Zinc inhibits iNOS-dependent nitrite accumulation in endothelial cells. Zinc decreases cytokine-induced iNOS expression in endothelial cells. Zinc inhibits iNOS promoter activity. NF-kB silencing abolishes cytokine-induced iNOS expression. Zinc inhibits the transactivation activity of NF-κB. https://www.sciencedirect.com/science/article/pii/S2213231714000834

Oh gosh, thank you. I tried to read and understand that message, but my brain couldn't handle it. That's so interesting. Will be interesting to see the results of the Stanford study.

 

[datadragon]

Oh gosh, thank you. I tried to read and understand that message, but my brain couldn't handle it. That's so interesting. Will be interesting to see the results of the Stanford study.

BH4 is normally lowered and then we switch to INOS. But it appears that BH4 synthesis, is increased up to 100-fold by interferon-gamma (IFN-y) or IL-1B so it can be boosted as well at that point. This can then release things like histamine and serotonin from mast cells. Increasing GCH1 or increasing BH4 caused increased T-cell activation and proliferation also https://pmc.ncbi.nlm.nih.gov/articles/PMC6438708/ which is good but perhaps could contribute to autoimmune problems.

 

[wabi-sabi]

This can then release things like histamine and serotonin from mast cells

Is this how ME/CFS is related to MCAS?

 

[datadragon]

Is this how ME/CFS is related to MCAS?

This research seems to confirm that possibility. https://pubmed.ncbi.nlm.nih.gov/3045083/
Mast cells are a part of the innate immune response. Mechanistically, GCH1 overexpression increased BH4, nitric oxide and hydrogen peroxide, and these changes were associated with increased release of histamine and serotonin and degranulation of mast cells. LysM‐driven GCH1 knockout had opposite effects, and pharmacologic inhibition of GCH1 provided even stronger itch suppression.

Mast cells are inflammatory immune cells, which produce various inflammatory factors including TNF-α, IL-6, histamine and tryptase. Butyrate can reduce mast cells to secret these pro-inflammatory factors through HDAC inhibition which also requires zinc. Many HDACs are actually zinc-dependent enzymes which require the zinc ion for the catalytic reaction, yet another reason I keep mentioning zinc in tandem with other solutions. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009916/ Butyrate is a strong HDAC inhibitor, as is 4-phenylbutyric acid. https://www.nature.com/articles/s41598-018-36941-9 and https://onlinelibrary.wiley.com/doi/full/10.1002/kjm2.12376 Butyrate levels also were shown to be lowered via a zinc deficiency state in animal studies. Increased propionic acid production and a corresponding reduction in butyric acid were also associated with zinc deficiency in young lambs as one example. https://www.sciencedirect.com/science/article/abs/pii/S002231662314346X?via=ihub
Butyrate, a gut-derived environmental signal, regulates tyrosine hydroxylase gene expression via a novel promoter element https://pubmed.ncbi.nlm.nih.gov/16165221/

Vitamin D binds to its receptor, called the vitamin D receptor (VDR), which is present in almost all immune system cells. The literature suggests that a vitamin D deficiency can activate Mast Cells, and vitamin D is necessary for Mast Cell stabilization. https://pmc.ncbi.nlm.nih.gov/articles/PMC10528041/ Interestingly the VDR functions of Vitamin D also involve Zinc. The vitamin D receptor (VDR) binds zinc, and the activity of vitamin D dependent genes in cells is influenced by intracellular zinc concentrations. With increasing amounts of Zn(2+), additional Zn(2+) ions were detected bound to VDR and RXR alpha https://pubmed.ncbi.nlm.nih.gov/11400211/
https://forums.phoenixrising.me/threads/dang-those-vitamin-d3-levels.91152/post-2450071

Zinc is required in multiple steps of FcεRΙ-induced mast cell activation on the other side, including degranulation and cytokine production.so it can boost immune/mast cell responses. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286780/

 

[kushami]

I wonder whether they looked at BH4 in that new BioBank study. I’m afraid I’m too tired to look it up right now.

Just spent ten minutes wandering around kitchen forgetting to take my Vitamin D supplement after being reminded of it by this thread!

Now also wonder whether they looked at Vitamin D. I should print out the list of 116 things.

 

[Violeta]

I was wondering what GCH1 does, and found this:
The GCH1 gene provides instructions for making an enzyme called GTP cyclohydrolase.

It's a genetic link for Parkinson's. I guess that's because BH4 is in the pathway of dopamine production.

So then, what is GTP cyclohydrolase?

GTP cyclohydrolase I (GTPCH) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways.