Unfolded Protein Response and A Possible Treatment for CFS

[Violeta]

Sorry, I have brain fog from ME/CFS, I can't reread the thread for you.

 

[Hip]

Sorry, I have brain fog from ME/CFS, I can't reread the thread for you.

So explain it in your own words, or does brain fog prevent that too.

 

[Violeta]

I can't think of a good enough reason to do that, sorry. I don't have time right now. If you really want to know, I'm sure you will find it. Look how much time you have already spent here, use your time wisely.

 

[Hip]

I can't think of a good enough reason to do that, sorry.

You are a kind and helpful person.

 

[Violeta]

You are a kind and helpful person.

Thanks, yeah, sometimes.

 

[Violeta]

So are you.

 

[mariovitali]

@Hip

I will refrain from going into an argument with you. I will re-visit this Thread when i have sufficient evidence from several individuals that this regimen works ....or that it doesn't work so i do not waste anyone's time. I will also be posting information which i feel that is important to be shared.

I do not believe that i am doing anything more than telling people to try a regimen always under the supervision of a certified professional. So did Freddd and Rich. I am sure that i am not the only member here which suggests things. Right?

Whatever happens i will have made what i had to do. You see, i wouldn't want to not give a good try into letting people know about the fact that i got well after 9 years of repeated failures and a bag full of Supplements. It is true however, that if i stop this regimen Symptoms come back. In my signature i write that i am "Symptom-free" for a reason.

Best wishes to you and i hope you have a full recovery soon.

 

[mariovitali]

@Hip

Endoplasmic reticulum stress in liver disease.
Malhi H1, Kaufman RJ.
Author information

Abstract
The unfolded protein response (UPR) is activated upon the accumulation of misfolded proteins in the endoplasmic reticulum (ER) that are sensed by the binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78). The accumulation of unfolded proteins sequesters BiP so it dissociates from three ER-transmembrane transducers leading to their activation. These transducers are inositol requiring (IRE) 1α, PKR-like ER kinase (PERK), and activating transcription factor (ATF) 6α. PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) resulting in global mRNA translation attenuation, and concurrently selectively increases the translation of several mRNAs, including the transcription factor ATF4, and its downstream target CHOP. IRE1α has kinase and endoribonuclease (RNase) activities. IRE1α autophosphorylation activates the RNase activity to splice XBP1 mRNA, to produce the active transcription factor sXBP1. IRE1α activation also recruits and activates the stress kinase JNK. ATF6α transits to the Golgi compartment where it is cleaved by intramembrane proteolysis to generate a soluble active transcription factor. These UPR pathways act in concert to increase ER content, expand the ER protein folding capacity, degrade misfolded proteins, and reduce the load of new proteins entering the ER. All of these are geared toward adaptation to resolve the protein folding defect. Faced with persistent ER stress, adaptation starts to fail and apoptosis occurs, possibly mediated through calcium perturbations, reactive oxygen species, and the proapoptotic transcription factor CHOP. The UPR is activated in several liver diseases; including obesity associated fatty liver disease, viral hepatitis, and alcohol-induced liver injury, all of which are associated with steatosis, raising the possibility that ER stress-dependent alteration in lipid homeostasis is the mechanism that underlies the steatosis. Hepatocyte apoptosis is a pathogenic event in several liver diseases, and may be linked to unresolved ER stress. If this is true, restoration of ER homeostasis prior to ER stress-induced cell death may provide a therapeutic rationale in these diseases. Herein we discuss each branch of the UPR and how they may impact hepatocyte function in different pathologic states.

I am fairly certain that you can find many more relevant entries.


I would also appreciate your comments regarding this.

 

[Valentijn]

@mariovitali - A free basic course combining genetics and programming started up just today on Coursera. It lasts 8 weeks and estimates 6-10 hours of work per week, but will probably go a lot faster for you since you seem to have some programming background.

At any rate, it's a great way to learn the basics regarding genetics.

 

[mariovitali]

@Valentijn

I appreciate your message. I wish i had the time to do this but i am swamped with work and doing much more important things. Trust me...

FYI : I've been programming since 1998 which means i have solid programming skills.


Anyway, Thanks.

 

[Hip]

I would also appreciate your comments regarding this.

I imagine that the activation of the unfolded protein response in liver disease, and the consequent stress placed on the endoplasmic reticulum, will remain local to the liver. So then it is hard to see how this might affect the central nervous system, causing the mental symptoms of ME/CFS such as brain fog.

Also, there is generally not much wrong with the liver in ME/CFS.

 

[halcyon]

So then it is hard to see how this might affect the central nervous system, causing the mental symptoms of ME/CFS such as brain fog.

If liver function is affected this can affect the CNS, as in hepatic encephalopathy. Not saying that I agree that this is what's happening in ME.

 

[mariovitali]

I imagine that the activation of the unfolded protein response in liver disease, and the consequent stress placed on the endoplasmic reticulum, will remain local to the liver. So then it is hard to see how this might affect the central nervous system, causing the mental symptoms of ME/CFS such as brain fog.

Also, there is generally not much wrong with the liver in ME/CFS.

I assume that by using the word "imagine" this means that you hypothesise.

Are you also aware of the fact that the only way to be certain that there is no Liver disease is to take a Liver sample?


https://books.google.com/books?id=HfPU99jIfboC&pg=PA205&lpg=PA205&dq=liver sample confirm&source=bl&ots=B8bjM2p9ex&sig=a6hYcuFU5D-_kE1czY6_WgG4FfU&hl=en&sa=X&ved=0ahUKEwjgweqim8nKAhVFiCwKHUKNCn4Q6AEIPzAG#v=onepage&q=liver sample confirm&f=false


Also, did you really make a good search for "Liver" here in PR?

 

[Hip]

If liver function is affected this can affect the CNS, as in hepatic encephalopathy. Not saying that I agree that this is what's happening in ME.

A quick check on Wikipedia reveals that in hepatic encephalopathy, it is the build up of toxins in the blood due to liver failure that affects the CNS. But in ME/CFS liver function tests usually shown no abnormalities.

In the case of hepatitis C infection of the liver, you do get fatigue, brain fog, and symptoms similar to ME/CFS. I don't think anyone has looked into the mechanism by which these brain symptoms arise in hep C, but I wonder whether the liver inflammation that occurs in hepatitis C might cause these mental symptoms by a sickness behavior mechanism. The vagus nerve innervates the liver, and under inflammatory conditions, the vagus may well induce sickness behavior.

I assume that by using the word "imagine" this means that you hypothesise.

It means I don't know, so am guessing.

Are you saying you know a mechanism by which liver dysfunction can cause body-wide endoplasmic reticulum stress?

Are you also aware of the fact that the only way to be certain that there is no Liver disease is to take a Liver sample?

Coxsackievirus B, a virus strongly linked to ME/CFS, can replicate in the liver (as well as numerous other organs such as the brain, meninges, heart, stomach, spleen, pleura and pancreas). One can speculate that it is possible that some ME/CFS patients may have a chronic non-cytolytic enterovirus infection of the liver, and if so, one might speculate that a sickness behavior mechanism could arise from that, leading to brain fog and fatigue.

Whether it is possible to have such a non-cytolytic liver infection without liver enzymes such as ALT or AST being raised and detected in blood tests, I don't know.

In hepatitis C infection, ALT and AST are raised in blood tests.

 

[mariovitali]

@Hip

I do not know anything about Coxsackievirus B unfortunately.

Are you saying you know a mechanism by which liver dysfunction can cause body-wide endoplasmic reticulum stress?

Needless to say is that i am not a medical professional and so i cannot give you a definitive answer on this. But if you search the Thread you will see many mentions about Liver, Bile Acids / Enterohepatic circulation, Acetylcholine and PDHC (Pyruvate dehydrogenase Complex).

I know that the Thread is huge. I wish i had the time to formulate all this in a concise way. No time to do it.

 

[wastwater]

And for those with a befuddled ME/cfs mind I recommend the game crossy road.

 

[Violeta]

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.



1. Introduction
The liver plays a central role in whole body lipid homeostasis. Metabolic signals such as carbohydrates and dietary fatty acids regulate hepatic gene expression leading to glycolytic and lipogenic signalling pathways. In addition, the pancreatic hormones, insulin and glucagon, play a pivotal role in the transcriptional and posttranslational regulation of lipogenesis and lipid oxidation

So of course cells outside of the liver have endoplasmic reticulum, and once the lipid metabolism in the liver is messed up, it affects the cells outside of the liver through smooth endoplasmic reticulum stress caused by messed up lipids. That's why taurine and choline help resolve issues all over the body, they improve lipid metabolism by reversing NAFL.
.

 

[Violeta]

So then it is hard to see how this might affect the central nervous system, causing the mental symptoms of ME/CFS such as brain fog.

And watch out, because insulin resistance can cause dementia.

http://www.ncbi.nlm.nih.gov/pubmed/21335659

 

[Hip]

In ME/CFS, one study showed that there is elevated lipid peroxidation, from the general oxidative stress found in ME/CFS. Taurine inhibits lipid peroxidation.

However, this lipid peroxidation is a body-wide phenomenon.

 

[aquariusgirl]

I supplement with Biotin 1000 mcg (it is listed in my regimen, taken at 08:00). The reason being that i have 2 heterozygous SNPs for Biotinidase enzyme functionality (rs13078881 and rs7651039)

Mario....I am GG for rs13078881 and no call for the other one...what does that mean? oops maybe SNPedia