Unfolded Protein Response and A Possible Treatment for CFS

mariovitali

mariovitali

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Z

zippy

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Thanks Mario for your original post. I'm yet to read the entire thread.

I ended up here while researching why ryegrass (with a parasitic fungus almost identical to tunicamycin, an inhibitor of of n linked glycolisation that I think you mentioned) causes me to vomit frequently while others who live nearby simply get hayfever or asthma symptoms from it (it's very bad this year). I also ended up with what I would call excitotoxicity last night so have been researching today to avoid it happening again. My research led me to glycolisation then UPR, and I found your post. I was interested in the correlations between your list of UPR impairment factors (methylation, choline, environmental toxins, homocysteine etc.) since I'm already addressing most of those due to chemical sensitivities and histamine issues (with success). So your post confirmed for me that it's all related. Maybe with just a bit more tweaking of my supplements I can get on top of it. Much appreciate that you shared, thanks!
 
Lolinda

Lolinda

J'aime nager dans le froid style Wim Hof.. 🏊‍♀️🙃
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Coffee helps against ER stress.

I post the excerpt of the paper with some additional context:
https://www.ncbi.nlm.nih.gov/pubmed/25291138
Regarding the mechanism by which coffee exerts its effects on steatosis and fibrosis, there is a quantity of convincing evidence that it is able to reduce the rate of fat and collagen deposition in the liver. In a rat model of fatty liver disease, we showed that animals fed with high-fat diet and decaffeinated coffee showed lower levels of hepatic fat and collagen, reduced liver oxidative stress, and improved liver inflammation and fibrosis.43,44 In a recent study, our group demonstrated that decaffeinated coffee consumption is able to modulate the expression of endoplasmic reticulum and mitochondrial chaperones both under standard diet and high-fat diet conditions. Among proteins upregulated by coffee consumption, there seems to be a particularly significant induction of the chaperone glucose-related protein 78 (GRP78), a master regulator of endoplasmic reticulum homeostasis, belonging to the heat shock protein 70 (HSP70) family. Consistent with GRP78 induction, coffee increases the expression of mitochondrial HSP70, which plays a pivotal role in endogenous antitumour defense against different cancers through activation of both innate and adaptive immune systems. In addition, coffee induces the expression of another chaperone called DJ-1, which plays a role in autophagy, and is also a redox-sensitive protein that scavenges reactive oxygen species by increasing glutathione synthesis. Finally, coffee induces the expression of antioxidant and stress sensor proteins, in particular peroxiredoxin 1 (PRDX1), which is able to catalyze the peroxide reduction of H2O2, organic hydroperoxides, and peroxynitrite. The PRDX1 induction leads to inhibition of JNK activation, which has been involved in NASH pathogenesis.45

I post this because several people were interested in this topic:

jump44 said:
Found some stuff online that said coffee may be protective against ER stress
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Violeta said:
I don't have the answer to this, but I do know that more than one of the supplements that help with ER stress are osmolytes. I think coffee is an osmolyte antagonist, (causes dehydration) Correct me if I'm wrong, somebody
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Violeta said:
Speaking of coffee, did you see that they use caffeine to drain Ca+ from the ER? I still don't know what's downstream from that, but it doesn't sound good.
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Hip said:
@mariovitali, you may be interested in this post, in which I speculate that coffee enemas, which increase bile secretion from the liver, may also reduce endoplasmic reticulum stress, as cholic acid, one of the primary bile acids secreted by the human liver, reduces ER stress.

It's also interesting that @douglasmich, who suffers from post-finasteride syndrome, is benefiting from coffee enemas.
Click to expand...

Reading this, I started drinking decaf coffee several times per day. I benefitted greatly.
 
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Lolinda

Lolinda

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A question to everyone on this thread: how does misfolded protein response feel? How does improvement thereof feel?

What I mean by these questions:
Misfolded protein resonse is a cellular event. But having too much of it overall, or reducing its occurrence in the body could have some aspects that one can feel. So for example, if you tried remedies that are recommended on this thread, was there some common thing you felt with several of these?

People on PR usually know me as a researcher posting more often than not scientific papers :). But I like a lot to look at how things feel. While feelings have obvious problems such as big variance among individuals, they also have great advantages such as fast feedback at home, without a lab.

Are there any labs for measuring ER stress? I can imagine that some proteins associated with ER sress leak into the bloodstream and could be tested there...
 
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Gondwanaland

Gondwanaland

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Please take a look at microbiome and bile !
E.g.
Curr Opin Gastroenterol. 2014 May;30(3):332-8. doi: 10.1097/MOG.0000000000000057.
Bile acids and the gut microbiome.

PURPOSE OF REVIEW:
We examine the latest research on the emerging bile acid-gut microbiome axis and its role in health and disease. Our focus revolves around two key microbial pathways for degrading bile salts, and the impact of bile acid composition in the gut on the gut microbiome and host physiology.
RECENT FINDINGS:
Bile acid pool size has recently been shown to be a function of microbial metabolism of bile acids in the intestines. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. Bile acids are emerging as regulators of the gut microbiome at the highest taxonomic levels. The role of bile acids as hormones and potentiators of liver cancer is also emerging.
SUMMARY:
The host and microbiome appear to regulate bile acid pool size. The host produces a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in intestine and liver. Members of the microbiome utilize bile acids and their conjugates resulting in agonism of FXR in intestine and liver resulting in a smaller, unconjugated hydrophobic bile acid pool. Hydrophilicity of the bile acid pool is associated with disease states. Reduced bile acid levels in the gut are associated with bacterial overgrowth and inflammation. Diet, antibiotic therapy, and disease states affect the balance of the microbiome-bile acid pool.

PMID: 24625896 PMCID: PMC4215539 DOI: 10.1097/MOG.0000000000000057
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Lolinda

Lolinda

J'aime nager dans le froid style Wim Hof.. 🏊‍♀️🙃
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Gondwanaland said:
Please take a look at microbiome and bile !
E.g.
Click to expand...
Reading the paper, I asked myself: can I get tested to find out what is in my bile acid pool? Now, I followed up some references provided in the paper, and the ones I have found do bile acid tests in the duodenum (or in the stool, but thats not the bile acid pool but the bile acids lost). For example, there is one paper on humans referenced:
https://www.ncbi.nlm.nih.gov/pubmed/16299351
This then refers in turn to studies like this one:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC301505/
Which then says:
"The percent composition of individual bile acids in specimens of duodenal bile was determined according to the method described for fecal bile acids by Grundy, Ahrens, and Miettinen (12). Samples of bile were aspirated from the duodenum via a Rehfus tube (Davol, Inc., Providence, R. I) that was positioned under fluoroscopic guidance. Cholecystokinin (obtained from the late Professor Erik Jorpes, Karolinska Institute, Stockholm, Sweden) was injected intravenously to facilitate gall-bladder bile flow."
Well... I do not fancy yetanother duodenoscopy nor any cholecystokinin injections... :eek: I would want a convenient blood test of bile acids.
  • But is a blood test of bile acids valid?
  • At what time has it to be done compared to meals?
  • And who on earth offers that? I just checked Synlab and Unilabs, the two major labs here. They do a bile acid test, but thats only a single bile acid, cholylglycine (=glycocholic acid) and not any profile...
 
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Gondwanaland

Gondwanaland

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Lolinda said:
  • But is a blood test of bile acids valid?
  • At what time has it to be done compared to meals?
  • And who on earth offers that? I just checked Synlab and Unilabs, the two major labs here. They do a bile acid test, but thats only a single bile acid, cholylglycine (=glycocholic acid) and not any profile...
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I just checked and my local lab offers total biliary acids in blood (8h fasting). I will ask my dr for it next week! :thumbsup:
 
Gondwanaland

Gondwanaland

Senior Member
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The lab suggested the following references:

Chiang JYL. Bile acids: regulation of synthesis. J Lipid Res 2009; 50(10): 1955-66.

Staels B, Fonseca VA. Bile Acids and Metabolic Regulation. Mechanisms and clinical responses to bile acid sequestration. Diab Care 2009; 32(Suppl 2): S237-S45.
 
A

alicec

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Gondwanaland said:
I just checked and my local lab offers total biliary acids in blood (8h fasting)
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I doubt that this will tell you what you want to know. Less than 1% of the bile acid pool is present in the peripheral circulation. Elevation reflects liver damage - ie the failure of the normal enterohepatic circulation where the bile acid pool is normally confined.

In other words, this is a test of liver function, not a determination of the composition of the bile acid pool. It gives only a single measurement, total bile acids.
 
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dannybex

dannybex

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Just wanted to update that I switched from the bitters a couple months ago to artichoke extract (cynara scolymus). I buy it in powder form from bulksupplements and add a teaspoon or two to meals. It seems to be working just as well, if not slightly better. Stools are still a darkish copper-brown color. Am still a little too constipated, but hope to add some relevant probiotics to the mix when I win the lotto.
 
mariovitali

mariovitali

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@dannybex

If i recall correctly you do not have DNA Data from 23andme available (?)

As an update : Next week i am expecting an answer from the PFS (Post-Finasteride) Foundation on whether we could work together by submitting my Research to them, so looking forward to their answer.

Please note that according to the theory of this thread, CFS, Fibromyalgia, Gulf war Syndrome etc have the same biological basis.
 
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M

Marshl1

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mariovitali, just discovered this website and your post. Thank you for sharing your findings it's very encouraging. Unfortunately for me this stuff is extremely complex and I don't really have the time to try and understand it all. If I were to see a doctor to help me with this protein folding disorder what type of Doctor would I need to see?

Thanks so much for your time,
Lee
 
mariovitali

mariovitali

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Dear All,

I am posting again a major update since more results from analysing data relevant to CFS are out.

Please look at the following outputs of 2 out of several Machine Learning Methods i've been using for my research :


2.png



and

Screen Shot 2017-02-19 at 09.46.13.png



In a nutshell below are new Hypotheses about the major "Components" of CFS/PFS etc :


a) Sulfation becomes a major issue for CFS/PFS/ Fibromyalgia. Notice the selection of sulfatide, sulfation, PAPSS, Sulfur. Note also that sulfation is a major detox Pathway

b) Notice the selection of FXR (Farnesoid X Receptor) and CAR receptor all having to do with Bile Acid Metabolism.

c) (a) + (b) are connected since effective Sulfation is also needed for proper Bile Acid Metabolism (among other things)

d) Adrenal Insufficiency (?) : Note the selection of Dexamethasone, adrenal_insufficiency, Cortisol, POMC

e) HPA Axis : GNRH. HPA Axis is also associated with Adrenal Insufficiency

f) Methionine, Cystathionine, Glycine, Cysteine Metabolism

g) Glutathione : (GSH) and glutathione s-transferase (GST)


I also added cardiolipin after looking at this entry in Wikipedia :


Chronic Fatigue syndrome[edit]
Chronic Fatigue Syndrome is debilitating illness of unknown cause that often follows an acute viral infection. According to one research study, 95% of CFS patients have anti-cardiolipin antibodies.[35]
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Obviously, i was expecting that at least one of the techniques i've been using would select Cardiolipin as important. As you can see, an algorithm has indeed selected Cardiolipin on the top 20 Topics relevant to CFS/PFS etc (among 567 Topics being analysed).

Some topics had to be covered for reasons that i cannot disclose at the moment.
 
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