Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

Since the problem with Forums is the dispersion of Knowledge among the posts, i am making sure that as many people as possible get an understanding of the latest developments :

The latest addition to the protocol is making sure that efficient Redox is taking place. This may be MORE important than ER Stress or it may well be that managing both ER Stress and Redox have synergistic effect.

Notice that 2 supplements that are key to Redox homeostasis existed already to my regimen, namely Selenium and Vitamin C. However @ppodhajski talked about using cofactors for key genes that Regulate redox homeostasis and he added things like Riboflavin / FMN, Molybdenum, Magnesium, Zinc (if i am not mistaken).

I feel that you get a significant boost from adding agents that handle ER Stress, at least at the beginning of the regimen and especially if liver function is impaired.

The more i look into this, the more convinced i am that the liver gets a "hit"...and if your genes are not helping you then you fall into a vicious cycle of Redox/ER Stress.

As a side note : I continue to feel that my hearing is getting better and better. I am certain that the photophobia i had for years is gone, i do not need to wear my Sunglasses every day. This all is so new and so exciting and i am really trying to not get overly excited with all the changes that are happening to me.

 

[mariovitali]

Dear All,


Here is an update on my regimen. a day ago i dropped TUDCA for the first time in more than 5 months...fingers crossed.

I lowered the TUDCA dose from 500 mg to 250 mg (did this for a week) and then yesterday i stopped it completely.

At the moment my regimen looks as follows (NOTE : TAURINE HAS BEEN ADDED) :


08:00

Biotin 1000 mcg
Dibencozide 1/4 tablet
FMN half tablet
Metafolin 2000 mcg

Breakfast : 200 grams of Navy Beans for Molybdenum

10:00
Choline bitartate, Inositol 1000 mg
Taurine 200 mg


12:00
P5P 50 mg
Selenium 100 mcg

14:00
Vitamin C 500 mg

20:00
Selenium 100 mcg
Vitamin C 500 mg

24:00
Choline 350 mg

Please also note that i haven't had ANY alcohol for more than 3 months and i do not know whether i will drink for another 3 months. If liver is involved then alcohol (even the slightest intake) may not be helpful.

Regarding Taurine : I always felt great with it and i decided to re-introduce it for many reasons : Glutamate excitotoxicity but more importantly, Taurine helps Phase II Liver detoxification and Calcium homeostasis (see Wikipedia entry). Not too much is needed : 200 mg along with any meat protein source should be ok.

 

[Violeta]

I was actually going to suggest that one reason for PEM might be raising levels of hsp, but I thought I would wait on that.

But since you bring it up, actually, exercise induces hsp 70, which for most people is a good thing.

However, some viruses enjoy and benefit from raised levels of hsp 70.

This is an extreme, but an example of hsp and EBV.

http://www.ncbi.nlm.nih.gov/pubmed/8986292

I was working outside this evening, (yes, second time today, reishi is a miracle mushroom for me), and although it's October I started to get overheated. I thought, oh no, I'm going to pay for this tomorrow and I have to go to work.

A thought came into my mind! (Yes, reishi even improves my brain power!) This winter I will try to find out if I do NOT get PEM when I overdo it when I'm cold. In other words, if I stay cold the entire time I'm exerting myself, such as shoveling snow or walking the dogs, will I NOT experience PEM, and to the contrary, will I actually feel better the next day!

I am basing this on the possibility that PEM is brought on by hsp and whatever virus I have is benefiting from the hsp, making recovery difficult because it actually enpowers the virus to do whatever it is doing that is robbing me of energy.

 

[Gondwanaland]

I will try to find out if I do NOT get PEM when I overdo it when I'm cold

My husband feels even worse when exerting in cold weather

 

[Violeta]

I have to admit, I hate cold weather, and I have a hard time even getting myself moving to do anything. Except for those mornings when you wake up and the sun is shining and there has been a light to medium snow fall. It makes me feel like shoveling snow, and that always makes me feel better. Well, it does now, for quite a few years I had something wrong with my heart and I would get some sort of palpitations. It took two doctors to find out that it was mitral valve prolapse, but I got over it, somehow, and now I can shovel snow again. And dirt.

Shoveling dirt in the summer does give me PEM, and I can't remember if shoveling snow makes me feel better for a little while but then knocks me out. This is just a theory, we'll see how it goes.

I am also looking for ways to decrease cellular stress. I see stress hormones do cause stress on the cellular level, surprise surprise.

 

[Gondwanaland]

and now I can shovel snow again. And dirt.

Yay?

 

[Violeta]

Yay?

That's what my husband says, but more with this kind of expression.

 

[mariovitali]

Dear All,

Please let me know what your PDILT Gene looks like?

PDILT = rs11864909, Risk Allele ='T'


Thanks!

 

[skwag]

I'm CC for rs11864909 . SNPedia shows CC is by far the most common variant, but also lists C as a possible risk allele related to kidney health. Please share what you're thinking mariovitali.

 

[mariovitali]

@skwag


I ran another analysis for Associations between CFS Topics. This is what it looks like :

Note 'peroxiredoxin'. I then add PRDX4 (Peroxiredoxin) to my software :

*********Topic : prdx4 ***************
oxidative_protein_folding.csv : 1.87 %
ero1.csv : 1.72 %
peroxiredoxin.csv : 0.83 %
redox_homeostasis.csv : 0.16 %
pdi.csv : 0.14 %
ptp1b.csv : 0.07 %
er_stress.csv : 0.04 %
thioredoxin.csv : 0.03 %
hmgb1.csv : 0.03 %
zinc_supplementation.csv : 0.02 %
oxidative_stress_protection.csv : 0.02 %
misfolded_proteins.csv : 0.02 %
hsp70.csv : 0.02 %
vcam-1.csv : 0.01 %
curcumin.csv : 0.01 %
oxidative_stress_markers.csv : 0.01 %
nafld.csv : 0.01 %
h2o2.csv : 0.01 %
ros.csv : 0.01 %
insulin_resistance.csv : 0.01 %


So i looked at some documents that i have and found that Protein Disulfide Isomerase is of interest. I searched for relevant genes and found PDILT



Here is mine :

4.4% Frequency!


and then i look this gene to Biograph. Look how many associated functions this gene has! :

 

[skwag]

Unfortunately there's not much research on this SNP, so we can't really say how it effects the function of the PDILT gene.

However, I like the way you research. It's times like this, I wish we had the full genome to work with and another 20 years of PubMed research to comb through.

 

[Valentijn]

PDILT = rs11864909, Risk Allele ='T'

I don't see any indication in research that T is a risky allele for that SNP.

TT is present in up to 20% of some ethnic samples.

 

[mariovitali]

I think i may have found yet one more cause for my problems (recall my previous post about PDI, PRDX4) :

Vitamin K epoxide reductase contributes to protein disulfide formation and redox homeostasis within the endoplasmic reticulum



The transfer of oxidizing equivalents from the endoplasmic reticulum (ER) oxidoreductin (Ero1) oxidase to protein disulfide isomerase is an important pathway leading to disulfide formation in nascent proteins within the ER. However, Ero1-deficient mouse cells still support oxidative protein folding, which led to the discovery that peroxiredoxin IV (PRDX4) catalyzes a parallel oxidation pathway. To identify additional pathways, we used RNA interference in human hepatoma cells and evaluated the relative contributions to oxidative protein folding and ER redox homeostasis of Ero1, PRDX4, and the candidate oxidants quiescin-sulfhydryl oxidase 1 (QSOX1) and vitamin K epoxide reductase (VKOR). We show that Ero1 is primarily responsible for maintaining cell growth, protein secretion, and recovery from a reductive challenge. We further show by combined depletion with Ero1 that PRDX4 and, for the first time, VKOR contribute to ER oxidation and that depletion of all three activities results in cell death. Of importance, Ero1, PRDX4, or VKOR was individually capable of supporting cell viability, secretion, and recovery after reductive challenge in the near absence of the other two activities. In contrast, no involvement of QSOX1 in ER oxidative processes could be detected. These findings establish VKOR as a significant contributor to disulfide bond formation within the ER.

Note : Proper Disulfide Bond Formation is essential for protein folding.


I then enter VKOR (vitamin K epoxide reductase) to my software :

*********Topic : vkor ***************
oxidative_protein_folding.csv : 1.87 %
ero1.csv : 1.15 %
vitamin_k.csv : 0.50 %
redox_cofactor.csv : 0.23 %
pdi.csv : 0.19 %
redox_homeostasis.csv : 0.11 %
thioredoxin.csv : 0.11 %
redox_regulation.csv : 0.09 %
disulfide_bonds.csv : 0.06 %
cofactor.csv : 0.05 %
nlinkedglycosylation.csv : 0.03 %
nad.csv : 0.03 %
peroxiredoxin.csv : 0.03 %
er_stress.csv : 0.02 %
chaperones.csv : 0.01 %
calcium_homeostasis.csv : 0.01 %
nac.csv : 0.01 %

I look up VKORC1 at Promethease :

Then we have this :

Identification of VKORC1 interaction partners by split-ubiquitin system and coimmunoprecipitation.
Schaafhausen A1, Rost S, Oldenburg J, Müller CR.
Author information

Abstract
Since the discovery of vitamin K epoxide reductase complex subunit 1 (VKORC1), the key enzyme for the regeneration of vitamin KH₂, numerous studies have addressed the role of VKORC1 in the posttranslational modification of vitamin K-dependent proteins. VKORC1 is also the target protein of anticoagulant drugs of the coumarin type (e.g. warfarin). Genetic variants in VKORC1 have recently been shown to significantly affect the coumarin dose and international normalised ratio level. In the present study, we have used the split-ubiquitin yeast two-hybrid system to identify potential interaction partners of VKORC1. With this system we could identify 90 candidates. Out of these, we focused on VKORC1 itself, its paralog VKORC1L1, emopamil binding protein (EBP) and stress-associated endoplasmic reticulum protein 1 (SERP1). By coimmunprecipitation and colocalisation experiments, we were able to demonstrate evidence for the interaction of these proteins. Mutations in the EBP gene cause X-linked dominant chondrodysplasia punctata (CDPX2) which can be considered as a phenocopy of warfarin embryopathy. The interaction could be a link between these phenotypes. SERP1 represents an oxidative stress-associated endoplasmatic reticulum protein with chaperon-like functions. Antioxidant capacities have been described for vitamin K hydroquinone, the substrate of VKORC1. Both VKORC1 and SERP1, might have a synergistic function in eliminating reactive oxygen species generated during the VKOR redox process. Further studies are needed to investigate the role of these proteins in the vitamin K pathway.

@Valentijn any thoughts? Please have in mind that i am making a hypothesis here

 

[Valentijn]

@Valentijn any thoughts? Please have in mind that i am making a hypothesis here

In the paper which found increased risk associated to the T allele of rs9934438, the p-value was ridiculously high for a SNP study with over 7,000 participants. They also admit that they did not correct for making multiple comparisons.

The study's junk, and there's nothing showing that the SNP is relevant to anything other than drug response.

 

[mariovitali]

In the paper which found increased risk associated to the T allele of rs9934438, the p-value was ridiculously high for a SNP study with over 7,000 participants. They also admit that they did not correct for making multiple comparisons.

The study's junk, and there's nothing showing that the SNP is relevant to anything other than drug response.

The interesting thing is that you do not look at the *possible* compounding effect of several SNPs @Valentijn

Are you in any position to dismiss the possibility that several SNPs (and their combinations) can lead to something bigger? Please let us know!

 

[Valentijn]

The interesting thing is that you do not look at the *possible* compounding effect of several SNPs @Valentijn

Are you in any position to dismiss the possibility that several SNPs (and their combinations) can lead to something bigger? Please let us know!

Nope, anything's possible. But it's very unlikely, and there is no rational way to reach conclusions based on blind guesses. If there's no research showing that a SNP causes a problem, then that's just how it is.

 

[mariovitali]

@Valentijn

So what i write here is just Blind Guesses? Like the Infinite Monkey Theorem?


I am really happy you made the statement above.


Verba volant, scripta manent

 

[Valentijn]

So what i write here is just Blind Guesses?

Yes, if you suggest there is some relevance in SNPs which have no research showing that they are associated with any risks.

 

[mariovitali]

Yes, if you suggest there is some relevance in SNPs which have no research showing that they are associated with any risks.

Again, You are contradicting your own words here.

In your previous message you said that you are in no position to reject my hypothesis simply because you are in no position to contradict the Theory that a combination of SNPs may have a different outcome.

For the second time : Are you in a position to make a *statement* that my hypothesis is wrong? Yes or No?

If the answer is 'Yes' then please make the statement and support it (in a scientific way that is).

If the answer is 'NO' then please try to use the appropriate language as suggested by Standard Scientific Practice (which i am sure you learned in your Statistics course(s)).

 

[Valentijn]

For the second time : Are you in a position to make a *statement* that my hypothesis is wrong? Yes or No?

No idea. What's your hypothesis?

All I know is that the SNPs being listed usually are not relevant.