Unfolded Protein Response and A Possible Treatment for CFS

[Valentijn]

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.

You could start by comparing your findings with existing research into SNPs in CFS patients versus Fibromyalgia. There is at least one such study, from what I recall - though it was Fukuda study, without mandatory PEM, so not really relevant to ME. Though perhaps that isn't an issue if you're looking at non-ME CFS patients as well.

Another important point is to consider whether any results you've found are statistically significant. False positives are very common in SNP research, due to the inevitability of randomly different results when comparing thousands of SNPs. This can be mitigated somewhat if only specific genes have been looked at, or only SNPs which can have a sizeable impact (UTR regions, exons, etc).

If you find the other papers comparing SNPs of CFS and FM patients to each other, those authors might be worth contacting to see if they're interested in what you've found.

 

[mariovitali]

My oh my. Let us please focus on the problem. Please.

@Valentijn

Thank you this is a good idea. However -in my opinion- this is the next step.

Although i am not aware of what the most relevant study design would be in this case (so i would rather not say much about this), i would think that a group of people receives treatment and a placebo and relevant data are then being recorded by using both questionnaires and bio markers. I think that a parallel group is probably not suitable.

Metabolomics may be quite handy in this case (?).

Anyway, if ANYONE can get me in contact with CFS Researchers do let me know.

 

[Undisclosed]

This thread is being temporarily closed for moderation purposes. It should be reopened either later today or tomorrow.

 

[Undisclosed]

This thread is open again.

The last time we had to moderate this thread, we added a warning that if we had to moderate it again, we would close it permanently. On reflection, that would be unfair to those who wish to continue the conversation in an amicable fashion. Therefore, any member who posts any further personal attacks on this thread will be banned from the thread. That seems like a fairer compromise.

Thank you.

 

[skwag]

@mariovitali

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.

What exactly is the hypothesis? I've followed this entire thread, and I don't recall a clear, testable statement of a hypothesis. Let me know if I've missed or forgotten it.

 

[Gondwanaland]

EFFECTS OF URSODESOXYCHOLIC ACID ON THE AMOUNT OF URINARY THIAMINE AND RIBOFLAVIN
FROM PATIENTS WITH PULMONARY TUBERCULOSIS

Ursodesoxycholic acid (UDCA), 3α,7β-dioxycholanic acid, has been isolated from the bile of the bear by Shoda (1). Onishi (2) reported that certain kinds of cholic acids were effective to phosphorylate thiamine in vivo, the UDCA being most effective. The same author (3) also observed that the UDCA accerelated the absorption of riboflavin through the intestinal canal and phosphorylated the vitamin too. Many authors, on the other hand, have suggested the presence of metabolic anomalies of thiamine and riboflavin in the patients with tuberculosis. This paper is concerned with the study of the effects of UDCA on the metabolism of those vitamins in the patients with pulmonary tuberculosis.

 

[whodathunkit]

@Gondwanaland: nice find, Izzy. Thanks!

@mariovitali: I forgot to mention that I believe low-dose alpha GPC is really, really helping me, in addition to the TUDCA + glycine and UDCA. I usually only take the TUDCA and UDCA "on demand" (with meals containing more than about 20% fat), but I usually do TUDCA + glycine with my biggest meal of the day regardless of fat content. Point is I'm not taking the bile acids on a set schedule (the way you were in the beginning of your regimen).

Anyway, the choline: I've come to believe there's a big element of liver dysfunction in those of us who exhibit a conglomeration of CFS symptoms and extreme energy depletion, and choline deficiency is at least partially the cause of the liver problems. I suspect but cannot prove via literature or any other avenue other than my own experience and anecdotes I've read that the liver dysfunction is one root of our metabolic problems. Choline deficiency is a big part of this dysfunction. BUT supplementing choline is not the entire answer and may be detrimental or cause bad sides in the doses we are most commonly advised to take it in, which are typically for nootropic purposes. Also without the support of other B vitamins and in presence of other deficiencies. THAT is not what we need. Nootropic doses cause overstimulation and bad sides in us.

IMO fat in the liver is probably also another root cause, and I suspect it can be in subacute levels not normally detectable by standard lab tests for liver function or NAFLD.

I chose alpha GPC to supplement with because it's supposed to contain 40% choline by weight, which is much higher than the other "nootropics" like citicholine (18% choline by weight) or choline bitartrate (lower % although not sure exactly the amount). In addition to having more useful choline available for the liver, alpha GPC turns into acetylcholine by different avenues that other forms of choline like bitartrate or citicholine. That may or may not be of benefit when it comes to not causing overstimulation in the way that citicholine or bitartrate can, at least in people like us with cognitive impairments apparently related to dysfunction of energy production.

Point being: have you experimented with alpha GPC? I can't remember. How are your symptoms these days?

 

[Gondwanaland]

I seem to turn all choline I touch (both diet & supps) into TMAO

 

[whodathunkit]

I seem to turn all choline I touch (both diet & supps) into TMAO

Izz, how's your liver in general? I've been on a "clean liver spree" for months now, and it seems to be working. Again, I believe it's entirely possible (probable?) that even people with good liver function according to lab tests have poor liver function for some reason, esp. if there are energy problems present.

It's a long process getting to the bedrock gunk in the liver, though. A few months may not even do it, unless the problems are mild or the person is young. Low fat being a key and a primary hurdle for many of us. Perhaps even very, very low fat necessary for some, at least for a while.

 

[Gondwanaland]

Izz, how's your liver in general? I've been on a "clean liver spree" for months now, and it seems to be working. Again, I believe it's entirely possible (probable?) that even people with good liver function according to lab tests have poor liver function for some reason, esp. if there are energy problems present.

My liver is unhappy, despite the perfect enzyme numbers. Serum urea always above range, though.

It's a long process getting to the bedrock gunk in the liver, though. A few months may not even do it, unless the problems are mild or the person is young. Low fat being a key and a primary hurdle for many of us. Perhaps even very, very low fat necessary for some, at least for a while.

I am considering vegetarianism even.

 

[globalpilot]

Izz, how's your liver in general? I've been on a "clean liver spree" for months now, and it seems to be working. Again, I believe it's entirely possible (probable?) that even people with good liver function according to lab tests have poor liver function for some reason, esp. if there are energy problems present.

It's a long process getting to the bedrock gunk in the liver, though. A few months may not even do it, unless the problems are mild or the person is young. Low fat being a key and a primary hurdle for many of us. Perhaps even very, very low fat necessary for some, at least for a while.

I have long suspected choline deficiency in myself. I also have SIBO and bacteria can metabolize choline into TMAO (I'm sure some more than others but I dont have that data handy). I have also had really high TMAO. So how to increase the choline without feeding the SIBO ? I have also had fatty liver which points to possible choline deficiency.

 

[Gondwanaland]

So how to increase the choline without feeding the SIBO ?

I tried it transdermally, that is when I found out I turn it into TMAO - it smelled like rotten fish So I can't supplement orally, transdermally or via diet (no more eggs for me).

I have also had fatty liver which points to possible choline deficiency.

I was lucky to reverse my NAFLD after 2 months on a gluten-free diet (ultrasound showed a clean liver), ALT has pretty much always been below 25 even when I had NAFLD.

 

[Eastman]

@mariovitali: ...have you experimented with alpha GPC? I can't remember. How are your symptoms these days?

@whodathunkit, I think he stopped.

I have a very important update. In the past month or so i began having some strange symptoms which i never had. These were :

-Nausea
-Body chills
-Tears in my right eye without a reason
-Intestinal Bloating
-Loss of Appetite

Of course all the above were hardly noticeable, but as time passed by they became worse.

The past 5 days i hardly had any food and some water and lost 6 pounds...this was really scary. Luckily, i then found References that High Acetylcholine Levels may lead to these symptoms.


So i completely stopped Alpha GPC and TMG and my Symptoms have subsided. Yesterday i was able to eat and drink again.

Which leads to my question: Did Alpha GPC affect your appetite? How much did you take?

 

[whodathunkit]

I tried it transdermally, that is when I found out I turn it into TMAO - it smelled like rotten fish So I can't supplement orally, transdermally or via diet (no more eggs for me).

Izzy, EVERYONE will smell like rotten fish if using choline transdermally!! One time a few years back I decided to make liposomal vitamin C with lecithin to use transdermally for an anti-aging strategy. Figured if water-based vitamin C serum was good for my skin liposomal would be 100x better. But lecithin has lots of choline and WOW!!! Did I start to *stink*. Took me a couple days to put 2+2 together and track it back to the choline in the lecithin, but when I stopped the transdermal application of liposomal C, the odor went away. So yeah, transdermal choline is not a good idea. I'm curious...where did you read that transdermal choline was a good way to supplement if you were deficient?

And eggs...IMO and IME eggs ARE NOT a sufficient source of choline for those who are deficient and/or who have a compromised liver and/or digestion. I've always eaten plenty of eggs and it's become apparent to me that I've probably been severely choline deficient for a long time. Also, a fatty liver condition may inhibit our livers using choline appropriately, which in turn causes more fatty liver. Can't prove that but we know around here about how those kinds of vicious deficiency/supplmentation merry-go-rounds can happen. Plus, eggs have a lot of other potential problems with them, including being a fairly fatty food in and of themselves (at least, they're fatty for those of us with fatty liver issues), an allergen for some, high in sulfur, etc. And the homocysteine(sp?) and other stuff you mentioned in other places. So IMO eggs are not a good way to come back from a severe deficiency. Eggs and choline are synonymous in the minds of many of us, but that's a fallacy, especially if your digestion isn't all that great. Which seems to be the case for many if not most of us around here.

You might consider trying a very low dose (like 100mg/day) alpha GPC supplement. NOT citicholine and not choline bitartrate. I like powder cuz it's easy to titrate dose. IMO and IME if we get any kind of nootropic or noticeable response from choline right away, even if pleasant or beneficial, we've taken too much. The response should be subtle and occur over time. Probably pass unnoticed except by people like us who have been tinkering with out bodies for years and know what subtle reactions are and how to trace them back to the source. You have to figure out what's right for you, of course, but IME the two ways you've tried choline are not sufficient to overcome a long-standing or severe deficiency, even if it's "subclinical" (no longer symptomatic according to mainstream tests).

Also when taking choline we need to beware taking other acetylcholine (ACh) boosters like ALCAR, or acetylcholinesterase (AChE) inhibitors like coffee or some herbal supplements. AChE inhibitors can amplify unpleasant nervous system effects, especially on when it comes to cognition, agitation, anxiety, and hyper gastric motility. IME any other ACh boosters, as well as AChE inhibitors, are a no-no when taking any dose of supplemental choline. Especially for people like us.

 

[whodathunkit]

I have long suspected choline deficiency in myself. I also have SIBO and bacteria can metabolize choline into TMAO (I'm sure some more than others but I dont have that data handy). I have also had really high TMAO. So how to increase the choline without feeding the SIBO ? I have also had fatty liver which points to possible choline deficiency.

global, I coincidentally did a lot of work on my gut and my liver this past summer. I've done a 180 when it comes to the use of antibiotics and gut health. Have you tried abx yet?

I had IBSD symptoms for years that just kept getting worse, and finally peaked when I went on a very low fat diet for a couple months starting around this past May. It was *terrible*. I felt terrible in my head and in my innards, and my cognition was about as bad as it's ever been. So after doing some reading around I took a short course of strong broad spectrum antibiotics, along with strong herbals like pau d'arco and oil of oregano and some other things to address candida. Plus colonics and coffee enemas to help with gut health and liver clean-up. I don't think I would have been able to detox from the abx and the herbals without the exogenous aids to keep my bowels and liver clean during the extra stress of detox. All these measures in combination REALLY helped me, and I think the antibiotics were a key. I don't get IBS symptoms any more, and I don't seem to be having any "gallbladder" episodes of gastroparesis, either.

Of course I'm still taking the bile acids, too, which is huge when it comes to eliminating gastroparesis or "gallbladder" problems, and I suspect may help with things like SIBO simply by killing bad bacteria in the stomach where it's supposed to be killed if we ingest it. BTW, I keep putting quotes around the word gallbladder because I've come to believe that a lot of problems (maybe most problems) attributed by mainstream medicine to the gall bladder, which surgeons love to yank out, probably isn't gall bladder at all. It seems like it's all about the liver and also choline status. I have no doubt that if I'd gone to the doctor with my recurring problems in 2015 and very early this year that they would have suggested if not pushed me to have my gall bladder out since I had one ultrasound that showed gallstones. But now I've managed to resolve my problems. And incidentally, the second ultrasound I had about seven months after the first showed NO STONES and no "sludge", even though I had the ultrasound in the midst of an attack.

Anyway, antibiotics: this is not to say that I think you should take them, if you haven't tried them already. That's a personal decision, and requires research and getting informed before trying. Maybe a doctor's help if you can get it, although I didn't have it. But I now believe a course of antibiotic therapy is entirely appropriate in the presence of SIBO, especially if we take measures to ensure detox and elimination are working properly while we're taking them. And perhaps most crucially, if we take measures afterwards to ensure we don't get overrun again with crappy bacteria. One of the main things I do is make sure I don't eat a lot of crappy processed food. I suspect processed food is where a lot of our bad bacteria come from, since it can sit around for a while without going obviously bad, allowing it to collect a lot of questionable and foreign bacteria before we eat it. Also I used probiotics to repopulate the gut with beneficial strains.

I don't know how bacteria would react to actual choline supplements as opposed to eggs, though. Like I said, I think eggs have a bunch of potential problems for a lot of people. Have you ever tried alpha GPC in low doses?

Definitely recommend trying to get rid of some of the bacteria *somehow*, before trying choline, too.

I'm coming on kind of strong for choline, but I'm doing so because it seems like something that a lot of us around here probably have a long-standing deficiency in. It does seem to be a key in normalizing energy metabolism, although at what stage of the game it's best to tinker with it is anybody's guess. I don't know if there's official literature on it...I'm just going on what I read (of other's experiences with it and also of the symptoms of people who try it, successfully or unusuccessfully) and what I've experienced. Since my choline flu back at the end of 2014 I've thought it was a key but just haven't been able to put any productive strategies with it into place until recently. I strongly believe it's crucial to use it the right way at the appropriate time, or we won't get very good results, or maybe even bad results. And the doses commonly recommended in literature and on websites for nootropic effects are NOT the right way.

Also, I think a low fat diet is very important in helping to clear fat from the liver, which IME helps the liver utilize choline properly.

I don't want to derail mario's thread, but I do think this is relevant since one of his premises for recovery is reducing ER stress in the liver, and choline may indeed do that. Very low fat definitely seems to reduce inflammation, too, which may be a result of reduced ER stress.

 

[dannybex]

@mariovitali -- I haven't had any DNA tests done, except for the overpriced Yasko stuff about 4 years ago.

 

[Violeta]

I don't want to derail mario's thread, but I do think this is relevant since one of his premises for recovery is reducing ER stress in the liver, and choline may indeed do that. Very low fat definitely seems to reduce inflammation, too, which may be a result of reduced ER stress.

I think somewhere in this thread the smooth endoplasmic reticulum was mentioned, and that might be the tie in to the "fat".

 

[Eastman]

Following up on the choline theme and my previous post:

A cholinergic basal forebrain feeding circuit modulates appetite suppression

Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.

 

[mariovitali]

@Eastman

It appears that Choline has helped many people i talk to (including my self). CHDH and MTHFD1 mutations are all over the place among us. Then we have this :

Choline intakes of 930 mg/d restored partitioning of dietary choline between betaine and CDP-PC among NP (MTHFR rs1801133 and MTRrs1805087 WT) and lactating (MTHFD1 rs2236225) women with risk genotypes. Overall, our findings indicate that loss-of-function variants in folate-metabolizing enzymes strain cellular PC production, possibly via impaired folate-dependent phosphatidylethanolamine-N-methyltransferase (PEMT)-PC synthesis, and suggest that women with these risk genotypes may benefit from choline intakes exceeding current recommendations

http://www.fasebj.org/content/early/2016/06/28/fj.201500138RR




As you correctly pointed out, after supplementation of 8 months i had to stop because my appetite had stopped.

Fast forward, I am under the suspicion that complete recovery may be taking place, meaning no need of taking Bile Acids, TUDCA/UDCA or anything similar. I will report back.

 

[Violeta]

@whodathunkit , you aren't derailing mario's thread.

The smooth endoplasmic reticulum (abbreviated SER) has functions in several metabolic processes. It synthesizes lipids, phospholipids, and steroids. Cells which secrete these products, such as those in the testes, ovaries, and sebaceous glands have an abundance of smooth endoplasmic reticulum.[9] It also carries out the metabolism of carbohydrates, drug detoxification, attachment of receptors on cell membrane proteins, and steroid metabolism.[1"

"In liver cells the smooth ER contains enzymes for the detoxification of harmful drugs and metabolic by-products. In the reproductive organs, smooth ER in the cells produces the steroid hormones testosterone and estrogen."

The only thing I can think of is that problems in the smooth endoplasmic reticulum somehow can be a cause of rough ER stress(where protein folding takes place). After all, finasteride does raise heat shock protein, but finasteride's action seems to take place on the smooth ER.

So the choline or lecithin, or whatever you do to relieve the stress to the smooth ER relieves the problems with protein folding.