Unfolded Protein Response and A Possible Treatment for CFS

[Deltrus]

I've been playing around with some ideas in my head:

High homocysteine causes ER stress, NMDA channel calcium leaks, reduced mitochondrial membrane potential: http://www.ncbi.nlm.nih.gov/pubmed/26547950

Alpha lipoic acid is shown to ameliorate some forms of homocysteine induced ER stress: http://www.ncbi.nlm.nih.gov/pubmed/27133040

Acetylaldehyde inhibits methionine synthase, the enzyme which metabolizes homocysteine: http://gotmag.org/mg-deficiency-affects-mthfr-really/

Aldehyde Dehydrogenase requires calcium and magnesium as cofactors: http://www.ncbi.nlm.nih.gov/pubmed/6634825

Aldehyde oxidase requires molybdenum: https://en.wikipedia.org/wiki/Dietary_element

Calcineurin activates in the presence of intracellular calcium, dephosphorylates (deactivates) some TRP channels: https://www.caymanchem.com/article/2116?figure=3

Full article:https://www.caymanchem.com/article/2116

Many TRP channels are used in cation transport.

Adenosine triphosphate is used in phosphorylation.

ATP is only bioactive when attached to magnesium: https://en.wikipedia.org/wiki/Magnesium_in_biology#Essential_role_in_the_biological_activity_of_ATP

You can see how all of these add together. Low magnesium -> low atp bioavailability -> low phosphorylation -> impaired TRP cation transport -> impaired aldehyde detoxification (low magnesium, molybdenum) -> high levels of homocysteine -> ER stress, high calcium -> impaired TRP cation transport.

Low ATP bio-availability might also impair the SERCA pump which pumps calcium into the endoplasmic reticulum. This might cause more ER stress, and a response of increasing intracellular calcium even further.

I haven't confirmed that all TRP channels act like TRPV1.

I haven't confirmed exactly how phosphorylation works. (the wiki page on it is pretty dam long and complicated)

I haven't confirmed that ER stress impairs TRP channels. It seems like ER stress can impair function of ion channels but I haven't done enough research.

I haven't confirmed that TRP channels are the only non-selective cation channels in certain areas of the body. Although it seems it might be likely.


Solution based on my model would be to: Reduce ER stress + reduce intracellular calcium + Increase intracellular cation levels, especially trace minerals and magnesium.

I have some theories on ways to increase TRP channel function as well.

 

[Deltrus]

If anyone wants to try TUDCA, please dear god BUY THE PILLS. This stuff tastes extremely bitter, extremely chemically, and has a hint of sourness. And it sticks to the inside of your mouth for like 5 minutes.

I'l eat all this stuff because I'm not a baby but it wont be fun lol.

Alpha-GCP powder tastes fine though. Granular like sugar, but very little taste.

 

[Biarritz13]

Recently I have been looking at ER stress from the point of view of its central role in the development of leptin resistance. Leptin resistance is where leptin receptors become more insensitive to this hormone, so that as a consequence, leptin levels in the body rise to try to compensate.

Leptin is of major significance to ME/CFS, since fatigue levels in ME/CFS correlate to leptin levels (see here). As leptin levels go up, this increases fatigue in ME/CFS. So any leptin resistance would presumably lead to increased fatigue in ME/CFS.

Now it seems that ER stress induces leptin resistance. Refs: 1 2

I found two study on Selfhacked:

In vivo regulation of intestinal absorption of amino acids by leptin.

"The results of the present work indicate that luminal leptin decreases absorption of amino acids in vivo in a short-term manner and in a reversible way. These results, together with our previous findings, make it evident that leptin can be considered as a hormone which provides the intestine with a control mechanism to handle absorption of nutrients."

Leptin Inhibits Glucose Intestinal Absorption via PKC, p38MAPK, PI3K and MEK/ERK

"These results suggest that leptin reduces glucose absorption by activating PKC"


The amino acids here being glutamine , proline, and β-alanine, maybe it's a naive question but can it be related somehow with the Australian metabolite study?

 

[sflorence]

I am trying to make my way through all 83 pages of this thread!

But I have a question, it seems like people are getting similar results with the Jarrow Bile Factors and TUDCA?
I can get the bile factors for about half the price.

Thanks!

 

[mariovitali]

@sflorence

I will be making a new Thread as soon as i have info/evidence of complete recoveries. In a nutshell :

TUDCA/UDCA/Bile Acids from jarrows appear to be working almost equally well. I would say that the order of effectiveness appears to be the following :

1. TUDCA
2. UDCA
3. Bile Acids from Jarrows

The protocol uses :

1) UDCA or TUDCA or Bile Acids from Jarrows
2) Methylation support (especially Metafolin and P5P)
3) Molybdenum and/or Zinc and/or Manganese for Copper Level control if it is found to be high
4) Selenium


Note : It appears that this regimen requires many Months to show its effects.

 

[sflorence]

@mariovitali

Brilliant, thank you.

I think a new thread would be much appreciated by many, this is a very interesting approach to CFS.

To add to the discussion: I have quite low levels of copper, and when I supplement it at about 4 to 6mg daily it gets rids of lots of agitation for me. It basically cured my restless legs. I had a copper serum test done at it was in the lower quartile. But I need to watch it, because it can really supress my zinc and I can tell when I need to add zinc into my daily regimen.

 

[sflorence]

I have a question as well. My labs showed that I was SEVERLY deficient in EVERY single fatty acid. Could this somehow relate to a TUDCA deficiency? Because if my body isn't making enough bile, then how can it convert fats into fatty acids?

 

[mariovitali]

@sflorence

Good question.

See this :

Bile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. We tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end, stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5-dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high-fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%.

CONCLUSION:
The data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease.

Look the concepts that match LCFA in the software i use (If you have read all 82 pages of the Thread then this will make more sense) :

*********************************Topic : lcfa ******************************************
acyl-coa.csv : 1.02 %
fads2.csv : 0.83 %
scfa.csv : 0.71 %
l_carnitine.csv : 0.65 %
fas.csv : 0.62 %
fatty_acid.csv : 0.59 %
adrenal_insufficiency.csv : 0.57 %
acetyl_coa_carboxylase.csv : 0.53 %
fads1.csv : 0.50 %
peroxisome.csv : 0.46 %
coa.csv : 0.44 %
abc_transporter.csv : 0.40 %
steatohepatitis.csv : 0.35 %
acetyl-coa.csv : 0.34 %
oxidation.csv : 0.32 %
lxr.csv : 0.29 %
rxr.csv : 0.21 %
bile_acid.csv : 0.12 %
omega3.csv : 0.12 %
redox_homeostasis.csv : 0.11 %
lipoic_acid.csv : 0.10 %
mitochondria_human.csv : 0.08 %
atf4.csv : 0.08 %
fxr.csv : 0.08 %
phospholipid_human.csv : 0.06 %
butyrate.csv : 0.06 %
flavoprotein.csv : 0.06 %
hepatocytes.csv : 0.06 %
hydroxysteroid_dehydrogenase.csv : 0.06 %
oxidative_phosphorylation.csv : 0.06 %
pyruvate_carboxylase.csv : 0.05 %
mitochondrial_dysfunction.csv : 0.05 %
astrocytes.csv : 0.05 %
leptin.csv : 0.05 %
neuroinflammation.csv : 0.05 %
exercise_intolerance.csv : 0.05 %
phosphatidylserine.csv : 0.05 %
er_stress.csv : 0.05 %
hexosamine.csv : 0.04 %
redox_regulation.csv : 0.04 %
phosphatidylcholine.csv : 0.04 %
catalase.csv : 0.04 %
insulin_resistance.csv : 0.04 %
glycolysis.csv : 0.04 %
microglia.csv : 0.04 %
nafld.csv : 0.04 %
glycoproteins.csv : 0.04 %
inducible_nos.csv : 0.03 %
histone_deacetylase.csv : 0.03 %
mtor.csv : 0.03 %
pantothenic_acid.csv : 0.03 %
glucose-6-phosphatase.csv : 0.03 %
solute_carrier.csv : 0.03 %
cholecystokinin.csv : 0.03 %
pomc.csv : 0.03 %
nadph.csv : 0.03 %
igd.csv : 0.03 %
p5p.csv : 0.03 %
liver_disease.csv : 0.03 %
rar.csv : 0.03 %
hydrolysis.csv : 0.03 %
h2o2.csv : 0.02 %
ros.csv : 0.02 %
nac.csv : 0.02 %
ghrelin.csv : 0.02 %
pdhc.csv : 0.02 %
microbiome_humans.csv : 0.02 %
steroidogenesis_human.csv : 0.02 %
sshl.csv : 0.02 %
hmgcoa.csv : 0.02 %
endothelial_nos.csv : 0.02 %
cortisol_levels.csv : 0.02 %
nad.csv : 0.02 %
cyp2e1.csv : 0.02 %
inflammatory_response.csv : 0.02 %
dhea.csv : 0.02 %
nadh_dehydrogenase.csv : 0.02 %
oxidative_stress_markers.csv : 0.02 %
ikk_beta.csv : 0.02 %
cortisol.csv : 0.02 %
upr.csv : 0.02 %
misfolded_proteins.csv : 0.02 %
protein_kinase_c.csv : 0.02 %
gut.csv : 0.02 %
glutathione_peroxidase.csv : 0.02 %
ggt.csv : 0.02 %
thermoregulation.csv : 0.02 %
detoxification.csv : 0.02 %
dht.csv : 0.02 %
caloric_restriction.csv : 0.02 %
adhd.csv : 0.01 %
anorexia.csv : 0.01 %
phosphorylation.csv : 0.01 %
stat3.csv : 0.01 %
tbars.csv : 0.01 %
p450.csv : 0.01 %
testosterone_production.csv : 0.01 %
triiodothyronine_levels.csv : 0.01 %
thioredoxin.csv : 0.01 %
inflammatory_cytokines.csv : 0.01 %
creatine.csv : 0.01 %
inositol.csv : 0.01 %
cofactor.csv : 0.01 %
il_6.csv : 0.01 %
adrenal_hyperplasia.csv : 0.01 %
riboflavin.csv : 0.01 %
methionine.csv : 0.01 %
n-acetylglucosamine.csv : 0.01 %
igf-1.csv : 0.01 %
dexamethasone.csv : 0.01 %
il_10.csv : 0.01 %
probiotics.csv : 0.01 %
p450oxidoreductase.csv : 0.01 %
tnf_alpha.csv : 0.01 %
acetylation.csv : 0.01 %
lactobacillus.csv : 0.01 %
ubiquitination.csv : 0.01 %
l-arginine.csv : 0.01 %
polyamines.csv : 0.01 %
caspase_human.csv : 0.01 %
protease_inhibitor.csv : 0.01 %
glycosylation.csv : 0.01 %
taurine.csv : 0.01 %
pbmc.csv : 0.01 %
metronidazole.csv : 0.01 %
gsh.csv : 0.01 %
cholestasis.csv : 0.01 %
adrenergic_receptor.csv : 0.01 %
sulfur.csv : 0.01 %
beta-glucuronidase.csv : 0.01 %
heat_shock_protein.csv : 0.01 %
hypoxia.csv : 0.01 %
human_semen.csv : 0.01 %
serotonin_levels.csv : 0.01 %

 

[ahmo]

Here's a discussion of UDCA relationship w/ mast cell issues.

And I listened to this radio presentation this AM. There's reference to unfolded proteins, but I wasn't listening closely enough, and haven't listened again, to see if it's about what's going on with this thread.

 

[sflorence]

@mariovitali

Thanks for the info, very interesting.
I just picked up the Bile Factors by Jarrow. Do you take yours with or without food? I will definitely be taking it with my fatty acids.

 

[mariovitali]

@mariovitali

Thanks for the info, very interesting.
I just picked up the Bile Factors by Jarrow. Do you take yours with or without food? I will definitely be taking it with my fatty acids.

I take it with food, in the middle of my Lunch.

 

[dannybex]

@mariovitali -- do you know if TUDCA has any diuretic aspects/qualities? Taurine seems to, I suppose depending on the patient. The last time I tried it I thought it made my dry eye situation worse, but at the same time it's supposed to be good for the eyes (and liver function).

I also pee like a racehorse as it is, so don't need to make that worse. That just slipped out.

But seriously, have you or anyone else experienced any sort of diuretic issues when taking TUDCA?

 

[mariovitali]

@dannybex I am not aware of any such problem.

 

[Gondwanaland]

I also pee like a racehorse as it is, so don't need to make that worse.

Have you tried B2, Danny?

 

[dannybex]

Have you tried B2, Danny?

Tried it? I'm probably taking what you'd consider monstrous amounts.

 

[Gondwanaland]

Tried it? I'm probably taking what you'd consider monstrous amounts.

Whaaaat? More than 4mg????


Just recently I found out that B2 and vit A increase testosterone conversion into DHT and they both affect me badly with it

 

[dannybex]

Way more. I'm trying different amounts lately, but if I cut back, I develop symptoms of B2 deficiency within 2 days or so, especially eye symptoms. May be due to low glutathione levels, connected to a persistent sinus infection.

But I can see why you'd want to keep it low if you have uric acid issues. Do you have a reference for the testosterone-DHT conversion claim?

I lost a pile of hair about 10 years ago -- long before B2 -- but it calmed way down about 8 years ago.

 

[Gondwanaland]

if I cut back, I develop symptoms of B2 deficiency within 2 days or so, especially eye symptoms.

I started getting it too from taking low amounts, then I stopped it altogether because I knew I would have bigger problems from ramping up (esp. since I don't have access to R5P locally).

But I can see why you'd want to keep it low if you have uric acid issues.

I actually never had worsening of uric acid issues by taking B2. Folate and Nicotinamide instead put gasoline on fire for me.

Do you have a reference for the testosterone-DHT conversion claim?

I wish I could remember where I read it. I think it was on a book about nutrition and metabolism.

 

[GreatGig]

@sflorence

I will be making a new Thread as soon as i have info/evidence of complete recoveries. In a nutshell :

TUDCA/UDCA/Bile Acids from jarrows appear to be working almost equally well. I would say that the order of effectiveness appears to be the following :

1. TUDCA
2. UDCA
3. Bile Acids from Jarrows

The protocol uses :

1) UDCA or TUDCA or Bile Acids from Jarrows
2) Methylation support (especially Metafolin and P5P)
3) Molybdenum and/or Zinc and/or Manganese for Copper Level control if it is found to be high
4) Selenium


Note : It appears that this regimen requires many Months to show its effects.

Would you mind briefly explaining the rationale behind each of the supplements in this list from items 2-4 and how they tie back into bile acid supplementation and your theories?

I am in the category of people which see improvement on jarrow bile acid factors but don't respond favorably to tudca. Interestingly I felt the best I had in years taking molybdenum for a couple weeks a while back. It lost its effect though. I had similar experiences with the other supplements you mentioned except for selenium which gives me fatigue and a headache without fail.

 

[mariovitali]

@GreatGig

First of all : I would be interested to see your DNA Data. Do you take P5P/Metafolin? Have you tried taking less TUDCA (ie 150 mg per day)

I believe that the missing link for CFS/Fibro symptoms (and many other syndromes with similar symptoms) is Bile acid dysregulation.

In a nutshell : I believe that Bile Acids are way more important than we think. NR1H4 is one of the most commonly mutated Genes among the sample of DNAs that i have (39 in total at the moment)

See here : http://www.genecards.org/cgi-bin/carddisp.pl?gene=NR1H4


See also screenshot on Page 82 which shows the process of identifying most commonly affected Genes among us :

http://forums.phoenixrising.me/inde...nd-a-possible-treatment-for-cfs.37244/page-82

P5P : It's role is becoming way more important than previously thought . P5P + Metafolin are used for Methylation support. I tried stopping P5P+Metafolin or taking them one day per week but symptoms creeped in so i have them back in my regimen on a daily basis.

Molybdenum is a Copper antagonist. Have you checked your Ceruloplasmin/Zinc/Copper Levels?

Studies also indicate that molybdenum may be a rate-limiting nutrient for the conversion of sulfite to sulfate so supplementation may be indicated. Unfortunately SUOX is not being analysed by 23 and me.

@Deltrus Regarding phosphorylation, see this :

Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the beta-oxidation system located inside peroxisomes. As a consequence, C(27)-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that C(27)-bile acids are especially toxic and contribute to the liver disease associated with peroxisomal disorders. For this reason, we investigated the toxicity of C(27)-bile acids and the underlying mechanisms. We studied the effects of conjugated and unconjugated C(27)-bile acids on cell viability, mitochondrial respiratory chain function and production of oxygen radicals in the rat hepatoma cell line McA-RH7777. Cell viability decreased progressively after incubation with increasing concentrations of different bile acids with dihydroxycholestanoic acid (DHCA) being clearly the most cytotoxic bile acid. In addition, the different bile acids caused a dose-dependent decrease in ATP synthesis by isolated mitochondria oxidizing malate and glutamate. Finally, there was a dose-dependent stimulation of ROS generation in the presence of C(27)-bile acids. In conclusion, our studies showed that C(27)-bile acids are more cytotoxic than mature C(24)-bile acids. In addition, C(27)-bile acids are potent inhibitors of oxidative phosphorylation and enhance mitochondrial ROS production by inhibiting the respiratory chain.

So Unconjugated Bile acids are bad for OXPHOS. Maybe we do not transform C27-Bile acids to a non-toxic form?


As a side note : From the results/feedback i am getting i am even more confident for this protocol. I have cases of two women that had CFS/Fibro for 20/24 years respectively that started two months ago. They both said that "they feel significantly better as never before" on all the years they have CFS/Fibro and that results seem to last.


There are two cases of complete remission : Me and another Male. We both followed the protocol for around 10 to 12 months before becoming symptom-free.