Unfolded Protein Response and A Possible Treatment for CFS

[dannybex]

@Violeta, the Urban Moonshine is continuing to work. Stools are a normal color, compared to the pale, pale color they were before. And am not using any ox bile anymore, although I still have some, and might consider using it when I have dairy (as I read somewhere that one needs bile to absorb calcium properly -- not sure if that's true though).

I haven't gained any muscle though, just stopped the loss, which is fine for now. Have just started doing the stairs in my building -- for the first time in three years -- so hopefully that will change. I only climb them once a week though, and it's actually harder to walk down them than up. But I think one needs exercise to put on muscle, for the most part anyway.

Having said that, I should add that Susan Owens posted pictures of her mom's arm -- before and after 10-11 months of calcium-d-glucarate supplementation -- which she says helped her put on muscle while she was bedridden. It did look like there was a muscle gain. And her mom is over 90 years old! Owen's contention was that the body uses it's own muscle to help with detoxification, hence the d-glucarate which helps w/glucuronidation. She also posted a link to this wiki page on Gluconeogenesis which she implied was also implicated in tissue breakdown:

https://en.wikipedia.org/wiki/Gluconeogenesis

@Eastman, I would think that any time one provides a substance that mimicks one's own -- like bile -- that while it may not cause the body to totally stop production, it wouldn't seem like it would encourage it to stimulate production. I did notice a darkening in my stool sometimes when I took ox bile, but it wasn't consistent, and the fact that it's an alkaline substance would seem to possible interfere with stomach acid levels/production. The bitters have kept the stool color consistent.

I'll attach the FB post from Dr. Rostenberg. Note that there's some conflicting info regarding glutamine for ammonia reduction, which he acknowledge later on, so we went w/glutatamic acid (the main amino acid in almost all protein sources) which mops up ammonia during the process of conversion to glutamine.

Hope that is helpful. Best to run this by your docs.

 

[Eastman]

I would think that any time one provides a substance that mimicks one's own -- like bile -- that while it may not cause the body to totally stop production, it wouldn't seem like it would encourage it to stimulate production.

Indeed, this is what Wikipedia says:

As surfactants or detergents, bile acids are potentially toxic to cells, and so their concentrations are tightly regulated. Activation of FXR in the liver inhibits synthesis of bile acids, and is one mechanism of feedback control when bile acid levels are too high. Secondly, FXR activation by bile acids during absorption in the intestine increases transcription and synthesis of FGF19, which then inhibits bile acid synthesis in the liver.

I did notice a darkening in my stool sometimes when I took ox bile, but it wasn't consistent, and the fact that it's an alkaline substance would seem to possible interfere with stomach acid levels/production. The bitters have kept the stool color consistent.

I found this paper, Bile flow in the rat after enteral administration of bile salts.

Abstract
The effects of enteral administration of various bile salts on bile output were investigated in the rat. After intraduodenal administration, all bile salts significantly increased bile flow and total bile output. Dehydrocholate had the greatest effect on bile flow. Cholate was next in degree of effectiveness followed by taurocholate, deoxycholate, and taurodeoxycholate. Bile output was significantly lower after ileal or gastric intubation of sodium dehydrocholate or taurocholate than after duodenal administration of these compounds. Conjugation of the bile salts tended to depress the overall effect on bile flow. These effects are discussed in terms of possible differences in the absorption of conjugated and unconjugated bile salts. Comparison of the effects of sodium dehydrocholate and taurocholate after intraduodenal and intravenous or intraperitoneal administration suggests that absorption rate or efficiency of absorption markedly influences the intensity of apparent choleretic activity. A relationship was observed between the structure of the bile salt and bile flow stimulation: the triketo form was more effective than the trihydroxy form and that, in turn, was more effective than the dihydroxy form. This is difficult to explain in terms of differences in absorbability but is consistent with a choleresis mechanism involving osmotic pressure effects. At a dose of 100 µmoles, in the rat, dehydrocholate does not function simply as a hydrocholeretic agent. Nevertheless, on the basis of the relative amount (percent) of solids in stimulated bile, there are clear differences in the nature of the choleretic activity of dehydrocholate and cholate.

Thanks for the reply and the attachment, dannybex.

 

[mariovitali]

This is why we need an expert on Bile Acid Synthesis. There are lots of factors. Consider the following possible issues :

1) Not enough bile being produced
2) Bile is produced but is not being circulated properly
3) Bile is produced and circulated properly but Toxic bile is not being eliminated as it should. Remember, bile acids should be conjugated to a non-toxic form.

I also believe that when you take Bile acids your body's synthesis is stopped because of FXR Receptor activation. Of course we need an expert to confirm this.

So perhaps Bile Acid supplementation is beneficial for all three scenarios (a hypothesis), since by supplementing with Bile Acids your body is then able to absorb key nutrients (if Scenarios 1/2 are happening) and also for Scenario 3.

What @dannybex is probably doing with taking bitters is to produce more Bile Acids. So this is scenario 1. If he had problems with BA Conjugation then that would not be a good idea since more toxic BAs would be produced.


In scenario 3 your body cannot change some Bile Acids into their non-toxic form so perhaps it is more convenient to take Bile Acids and stop your Body's own production through FXR Activation (because toxic Bile Acids are being created) and let your body use the conjugated form of Ox Bile to absorb key nutrients.

Again, this is just a hypothesis.

I believe that my Body does not conjugate properly its own BA production but i am willing to give bitters a try to confirm this.

 

[ahmo]

Notwithstanding Natasha Campbell-McBride's recommendation for its ongoing use, does anyone have a more definitive answer to this?

When I resumed ox bile, and then even more so w/ the Jarrows bile factors. my elimination improved.

 

[Eastman]

When I resumed ox bile, and then even more so w/ the Jarrows bile factors. my elimination improved.

Thanks. I just ordered the Jarrow's.

 

[Eastman]

There are some studies showing beneficial effects from bile acid sequestrants (compounds that combine with bile acids and prevent their reabsorption in the gut), primarily lowering of LDL cholesterol and glucose. Anybody has suggestions on their implication for bile salt supplementation?

The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.

Abstract
The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (p less than .05) of the primary end point--definite CHD death and/or definite nonfatal myocardial infarction--reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v 8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.

Bile Acid Sequestrants for Lipid and Glucose Control

Abstract
Bile acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including bile acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile acid sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which bile acid–mediated activation of FXR and TGR5signaling pathways regulate lipid and glucose metabolismand the potential implications for bile acid sequestrant–mediated regulation of lipid and glucose levels in T2DM.

 

[Eastman]

I was looking for alternatives to TUDCA, UDCA and bile salts and thought of silymarin.

An internet search found the following studies comparing silymarin to UDCA:

Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.
In patients with primary biliary cirrhosis responding suboptimally to UDCA, silymarin did not provide benefit.

Use of ursodeoxycholic acid combined with silymarin in the treatment of chronic ethyl-toxic hepatopathy.
30 patients affected by chronic ethylic hepatopathy were treated with 450 mg/day of UDCA. After six months, a significant decrease of serum hepatic enzymes was noted. The addition of silymarin (400 mg/day) to UDCA in another 30 patients induced a further improvement of hepatic function.

Study of Hepatoprotective Effect of Silymarin and Ursodeoxycholic Acid in Chronic Hepatitis C Patients
In chronic hepatitis C patients, a statistically significant improvement in mean serum levels of ALT, AST, and bilirubin was obtained with UDCA therapy either when administered alone or combined with silymarin. However, silymarin treatment failed to significantly affect liver function tests.

Comparison between Ursodeoxycholic acid and Silymarin in Anticonvulsive drugs induced Hypertransaminasemia
Children aged between 4mo-14yr with anticonvulsant induced hypertransaminasemia were given either UDCA or silymarin. After one month trial transaminases decreased in both groups significantly (P< 0.05) except for γGT in UDCA group. Normalization of transaminases (AST and ALT less than 40 IU/l) occurred in 3 patients in silymarin group and 5 patients in UDCA group. Comparing between UDCA and silymarin, ALT changes were better in silymarin group (P= 0.017).

 

[Bloom]

@mariovitali
http://cancerres.aacrjournals.org/content/75/15_Supplement/1052.short
I don't know how familiar all you guys are with epigenetics. But treatment with LPS and TNF-alpha inhibitors inhibited an enzyme called methyltransferase 1 (DNMT1). Increased DNMT1 activity seems to lead to increased methylation of SRD5A2 leading to it's down regulation. I wonder if this is applicable to SRD5A3?

 

[mariovitali]

@ahmo @Gondwanaland @Deltrus @whodathunkit @dannybex @Violeta @adreno

and to many others who i forget right now


I think that something potentially very important has been found. Out of 42 DNAs in total ALL 42 have a homozygous mutation to a particular Gene. MAF = close to 0.1

I thinks this is a Major one and it also fits very nicely with the Theory discussed here.

I will write a new Thread with all the information.


NOTE TO WHOEVER IS FOLLOWING THIS THREAD: Please PM me if you could send me your DNA Data (in case that you haven't already done so)

 

[Valentijn]

Out of 42 DNAs in total ALL 42 have a homozygous mutation to a particular Gene. MAF = close to 0.1

23andMe has a few systemic errors, and reports literally everyone to have a very rare mutation which they don't actually have.

 

[mariovitali]

@Valentijn

How many systemic errors? How likely can this happen on the same rs number? If this is so doesnt 23andme provide a list of specific rs numbers that have these systemic errors?


Please answer with a specific percentage (e.g 0.01%)


Remember : Science needs Numbers!

 

[Valentijn]

How many systemic errors? How likely can this happen on the same rs number? If this is so doesnt 23andme provide a list of specific rs numbers that have these systemic errors?

They're all on the same rsID for the relevant chip version. You can compare it to "control" data by downloading from opensnp.org and seeing if the supposed mutation appears for everyone. Or google the SNP, since the errors tend to generate a lot of discussion.

 

[mariovitali]

@Valentijn

Still, this means according to your theory that ALL Chips have the same problem on the same rs number. Correct?
Or, that all 42 DNA Data files were analyzed on the same chip (which are not by the way)

Please forgive me if i offended you.

 

[skwag]

What's the rs number of the snp you're looking at, @mariovitali?

 

[mariovitali]

@skwag

As i write on my post, ideally i would like to have more (say 10 more DNA Data files). More Data is almost always better in this case.

Interestingly, the DNA files that i have include people having Post-Accutane, Post-Finasteride,CFS and Fibromyalgia symptoms. I do not have any DNA Files from individuals having the Gulf war Syndrome and Post-Lyme treatment syndrome however.

Apart from this, the only person that has a heterozygous mutation did not have typical symptoms of CFS, i remember saying that to him in one of our e-mail between us.

As previously discussed, my Theory is that All of these Syndromes are connected, basically having the same root cause.

I will collect all findings and post them as soon as i have more DNA Data on a summarised post.

 

[skwag]

@mariovitali

Big claims followed by withholding basic information. Seems like like 42 out of 42 would be plenty satisfying as far as statistics goes. Do you really need 10 more DNA profiles before revealing the snp?

 

[mariovitali]

@skwag

I am with you and i am really sorry. Things are happening behind the scenes (including filing for a Patent on how this Research took place.)

I hope you -and everyone here- understands. Ideally i would like for everything to be reviewed by medical Specialists and then for the hypothesis to be tested using specific Scientific practices.

 

[Valentijn]

Still, this means according to your theory that ALL Chips have the same problem on the same rs number. Correct?
Or, that all 42 DNA Data files were analyzed on the same chip (which are not by the way)

Different chip versions (such as V3 or newer V4) can generate the same error for everyone tested by the same chip. This isn't a theory, but rather a widely known problem.

23andMe probably doesn't acknowledge it, just as they deny that their "i" numbers are used to hide pathogenic SNPs even when those SNPs already have an established "rs" number. But a small amount of errors is to be expected from this sort of genetic testing. Most likely the chip was testing for an incorrect common allele, not detecting it, and thus labeling everyone with the other (extremely rare) allele.

To the best of my knowledge, it only effects one of the very rare SNPs, rs8176928, on the DNASE1 gene. Though I've seen it since on at least one more common SNP. SNPedia mentions the error at http://www.snpedia.com/index.php/Rs8176928 as do several other sites.

 

[whodathunkit]

I'm on the chip V4 or whatever the latest version is. I just got it done last year. I think most of those people @mariovitali tagged had other versions. I know at least a few of them got analyzed long before me.

Fair enough. I still don't really understand why you are withholding the rs number of the specific snp, though.

Probably so no one scoops him on his research. Although I maybe shouldn't comment since I'm not a science head and can't elucidate correctly. But I do understand. I think mario is a straight shooter and this internet cloak and daggery regarding established members gets OLD. What good does such sniping at established members do? And what if he really is onto something?

That said, I would like to know more, too.

I need to get back into this thread. I've been thinking about it but busy with other stuff. I'm doing pretty good. TUDCA and UDCA have really helped me, and I've found TUDCA to be particularly good when paired with glycine. Like @dannybex my stools are mostly normal color these days (gotta find out more about that "urban moonshine" ), and I haven't had a gallbladder/gastroparesis attack in months even when eating a crap-ton of fat. Been under quite a bit of stress, too, and even with that I'm doing good. Energy still not entirely normal but good enough. The majority of my CFS symptoms are gone, and when I do get them the severity is much, much lessened. On my way to normalcy but who knows if I'll ever actually get there.

Coffee enemas (@ahmo! ) and some sound/frequency/subtle energy therapies have really helped, too. I mean, given me a big push. But since I never got any good out of any energy therapy I tried in the past, I'm beginning to believe for those to work properly we maybe have to have some little reservoir of ordered energy already available. When I attempted them in the past, I didn't have that.[/QUOTE]

 

[mariovitali]

OK it was too good to be true, lesson learned from this one.

I saw an allele for the specific rs number which Livewello had incorrectly tagged as Variant Allele. I immediately entered this information to my software and then saw that everyone has this Allele.

After cross-checking with dbsnp i realized that this was not the case. I also saw a Livewello report of a later version and they have corrected the erroneous information themselves.

So, this was a false alert.

Nevertheless, i am confident that there is something going on here so i would kindly ask anyone to tell me how i should move this Research forward. Meaning, who should i contact?

It goes with out saying that i would like to properly evaluate the validity of the hypothesis being discussed here, i think that the time has come.

Thanks to the DNA Data that i have, i managed to form some hypotheses as to the differences between individuals with CFS and individuals that suffer from Post-Finasteride or Fibromyalgia.

So if anyone can give me some guidance to this, it will be much appreciated. Unfortunately things where i live are not moving fast at all.

The people that i talk with will happily give their real names to any Research team (but not to this forum or ANY forum) along with their Symptoms, history and the changes that happened to them.

I know who to contact when it comes to Post-Finasteride and i also have contacted a Journalist in for this purpose who is a Post-Finasteride Syndrome sufferer himself. However, i need help when it comes to CFS and Fibromyalgia.