Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

I couldn't see any research on the link you posted. It's possible my browser is not displaying the page correctly. Is there a particular paper or two that you are basing the risk on?

The CYP8B1 SNP is not on my chip. There are couple papers regarding this mutation at SNPedia. They both appear to be on a small number of Chinese subjects. The P-values are high, around .025 . I'd consider this pretty weak evidence of risk.

The link i sent shows the website from which i take the Risk Allele for each rs# i add.

Regarding CYP8B1 and all other genes listed here :

I mentioned on the document i sent that we are not in a position to know the -possible- compounding effect of several Non-pathogenic (or with inconclusive research) genes and what kind of symptoms this compounding effect may have. (1)

A lot of us here (i think most of us) want to feel better and for this reason we are trying some hypotheses (2)


Considering (1) and (2) i propose a Hypothesis which people may try out if they wish. This hypothesis may be true or false (or partially true/false)

If the hypothesis is TRUE then our bodies are under uncontrolled Oxidative Stress (again, My Hypothesis) and this state for prolonged time -for some individuals- may cause irreversible damage (3)

So for readers that believe that the Research behind the hypothesis of this Thread is inconclusive i would like to ask the following questions, taking also (3) into consideration :

1. Assuming that the Hypothesis is TRUE or Partially TRUE :
a) What is the cost from not trying the regimen
b) What is the cost from trying the regimen

2. Assuming that the Hypothesis is FALSE or Partially FALSE :
a) What is the cost from not trying the regimen
b) What is the cost from trying the regimen


Regarding the latest genes i posted about Bile Acids (as an example CYP7B1) :

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway in the liver, which converts cholesterol to bile acids. This reaction is the rate limiting step and the major site of regulation of bile acid synthesis, which is the primary mechanism for the removal of cholesterol from the body. Polymorphisms in the promoter of this gene are associated with defects in bile acid synthesis. [provided by RefSeq, Feb 2010]

http://www.genecards.org/cgi-bin/carddisp.pl?gene=CYP7A1

So maybe this association (defect in Bile Synthesis) is not powerful enough statistically-wise. However -in this case- we are looking only at CYP7B1 and not all other Genes which have similar or associated function (say Cholestasis). As a result we do not look at the problem using multiple Factors and we do not know the actual effect these interaction of Genes has .

I Really do not know how to explain this in a better way...

 

[skwag]

I think I understand the the issue now. At least one of them.

When you look at any particular SNP, there are two alleles. Roughly speaking, the wildtype allele is the common version that most of the population has. The mutant version or variant is the less common one. The notation "G > A" tells you that the G is the wild type and A is the mutant version.

That notation, however, does not tell you anything about risk. When an allele is labelled as "risk", it generally means that there is some research to back it up. So when you write,

rs2273061 Risk A - JAG1 AG

I think to myself that there is some research somewhere that shows that the A allele is risky.

So the confusion is over language. Personally, I don't think the label "risk" should be used for the variant alleles that you are considering as part of your hypothesis, and that don't have much research behind them.

This is my understanding of these terms. I hope someone will correct me if I've got it wrong.

 

[mariovitali]

@skwag

No problem. I will change the used term 'Risk' to 'Mutant' or Low Frequency Allele (i prefer the "Low Frequency" to be honest).

 

[mariovitali]

@skwag

I would appreciate your comment regarding the following :

So for readers that believe that the Research behind the hypothesis of this Thread is inconclusive i would like to ask the following questions, taking also (3) into consideration :

1. Assuming that the Hypothesis is TRUE or Partially TRUE :
a) What is the cost from not trying the regimen
b) What is the cost from trying the regimen

2. Assuming that the Hypothesis is FALSE or Partially FALSE :
a) What is the cost from not trying the regimen
b) What is the cost from trying the regimen

and this :

So maybe this association (defect in Bile Synthesis) is not powerful enough statistically-wise. However -in this case- we are looking only at CYP7B1 and not all other Genes which have similar or associated function (say Cholestasis). As a result we do not look at the problem using multiple Factors and we do not know the actual effect these interaction of Genes has .

 

[ahmo]

If the hypothesis is TRUE then our bodies are under uncontrolled Oxidative Stress

2015 has been my year of trying to get on top of oxidative stress. Most recently, I realized that too little protein and fat was pushing my body in this direction, stressing adrenals. Since increasing these, my subjective feelings of OS has diminished significantly.

 

[skwag]

So for readers that believe that the Research behind the hypothesis of this Thread is inconclusive i would like to ask the following questions, taking also (3) into consideration :

1. Assuming that the Hypothesis is TRUE or Partially TRUE :
a) What is the cost from not trying the regimen
b) What is the cost from trying the regimen

2. Assuming that the Hypothesis is FALSE or Partially FALSE :
a) What is the cost from not trying the regimen
b) What is the cost from trying the regimen

First of all, I think the ER stress regimen is worth trying. I tried it. I got good results while I was on it.

However, the rhetorical questions you ask above, which are meant to argue in favor of people trying your protocol, are not at all convincing. You could say the same thing about any regimen which claims to cure any particular disease.

So maybe this association (defect in Bile Synthesis) is not powerful enough statistically-wise. However -in this case- we are looking only at CYP7B1 and not all other Genes which have similar or associated function (say Cholestasis). As a result we do not look at the problem using multiple Factors and we do not know the actual effect these interaction of Genes has .

I don't disagree with anything you said here.

 

[mariovitali]

@skwag

OK Thanks.

I didn't mean to be rhetorical or have any sort of 'attitude'. If my way of writing appeared like that then i am sorry.

 

[skwag]

No worries @mariovitali. A rhetorical question is just a question that is not really intended to be answered. I in no way meant to impy there was any attitude anywhere.

Your questions may not have even been rhetorical. I just interpreted it that way.

 

[Valentijn]

So the confusion is over language. Personally, I don't think the label "risk" should be used for the variant alleles that you are considering as part of your hypothesis, and that don't have much research behind them.

This is my understanding of these terms. I hope someone will correct me if I've got it wrong.

You've got it right. There is no association between the minor allele of SNPs in general, and the presence of risk.

No problem. I will change the used term 'Risk' to 'Mutant' or Low Frequency Allele (i prefer the "Low Frequency" to be honest).

The proper term is "Minor Allele" (MA). Minor alleles are often not low frequency, so to call them "low frequency" wouldn't be accurate most of the time. The more common allele is the "Major Allele".

 

[gefinauser]

Feel free to pm me if you want.

@ahmo Yes, let's talk in PM . (how can I do this?? i leave a message in your profile, or in the weird chat at the low toolbar or...? sorry, new to this forum stuff).

But I do love your experimentation and ideas in general! Great ideas re: transdermal/sublingual ideas, I tried adopting the metafolin in upper lip - idea but unfortunately my upper lip is STUFFED with sublingual tabs lol!

@mariovitali, i'll look into these... stay tuned.

@skwag i agree with mariovitali that we "beggars can't be choosers". anything that works, works. I started doing mariovitali's supps and spinach recenctly, and... my tinnitus disappeared. and my MSG-related tinnitus is INTENSE and on all the damn time. thanks to mariovitali and his no-bs, openminded, logical attitude.
only way to gather data whether something works in practice is to try it and properly. yes, if you put it that way - that anything could be used with that rhetoric - then you are ABSOLUTELY RIGHT lol. because it's true!! it's impossible to know if some stuff works in practise until you try it, anything else is just talk and imagination, theories and politics... having a high standards of "theory must explain everything" is mostly OCD-perfectionism / risk aversion and just another Catch 22 to follow. I did that to my fill for 6 years of sickness, now i've fucken had it LOL.

anyways, peace bro... we're all sick, we all want the best for ourselves and others. let us know how you progress!

 

[mariovitali]

@Valentijn

Can a Minor Allele be at the same time a Risk Allele ?
Can a Major Allele be at the same time a Risk Allele?

The website i am taking the data from pulls data directly from dbSNP.

https://www.pharmgkb.org/variant/rs3808607?previousQuery=rs3808607

So this :

G>T

According to the website is an "Allele Change". It does not say anything about it being a Minor Allele. Please hover over the question mark to get an explanation.

 

[Valentijn]

Can a Minor Allele be at the same time a Risk Allele ?
Can a Major Allele be at the same time a Risk Allele?

Yes, either a major or minor allele can be associated with an increase risk of something, but there is no way to predict which allele is risky or beneficial. Usually neither allele is risky or beneficial.

The only way to know is via scientific research. But some of that research is better than others. Typically research which looks at levels or activity of the resulting enzymes is most accurate. That's how we know that MTHFR C677T +/- results in a 30% reduction in MTHFR enzyme activity, and MTHFR C677T +/+ results in a 65% reduction in MTHFR enzyme activity. And in some cases, like CBS C699T +/+, the rarer result is the better one, so it's misleading to say that the more common result is riskier. Really that more common result is just normal, and the rarer result is beneficial.

G>T

According to the website is an "Allele Change". It does not say anything about it being a Minor Allele. Please hover over the question mark to get an explanation.

Typically that means that G is the ancestral (wild type) allele, and T is the variant/variation. But that is based on genetic evolution, not which allele is most common now. So G could be the ancestral allele, but T might have become more common since then.

So you can't conclude that T is the minor allele, and that's where dbSNP tends to be much more useful, since it lists the Minor Allele and its frequency at the top, and a lot of frequency data for various ethnic groups at the bottom.

It can get more complicated when different ethnic groups have very different allele frequencies for the same SNP. So Asians might clearly have T as the minor allele, while Africans have G as the minor allele. Thus it makes most sense to use the global figures in determining which is the minor allele.

So basically I don't find the G>T notation to be at all useful. It's simply too unreliable to use it for determining the minor allele.

 

[mariovitali]

@Valentijn

The only way to know is via scientific research. But some of that research is better than others. Typically research which looks at levels or activity of the resulting enzymes is most accurate. That's how we know that MTHFR C677T +/- results in a 30% reduction in MTHFR enzyme activity, and MTHFR C677T +/+ results in a 65% reduction in MTHFR enzyme activity. And in some cases, like CBS C699T +/+, the rarer result is the better one, so it's misleading to say that the more common result is riskier. Really that more common result is just normal, and the rarer result is beneficial.

That makes perfect sense (regarding enzyme activity). So this means that although we know that +/+ to MTHFR means less activity, unfortunately we cannot tell the same for other genes. I wonder whether we can find information about the genes i listed in my document and their activity.

OTOH : All this appears to me so non-deterministic.

Anyway, i will use the term "Allele Change" in my document.

 

[Valentijn]

That makes perfect sense (regarding enzyme activity). So this means that although we know that +/+ to MTHFR means less activity, unfortunately we cannot tell the same for other genes.

C677T is a single SNP on the MTHFR gene. So data about C677T doesn't really tell us about what other SNPs on the MTHFR gene do. Some very complicated predictions can be made for missense mutations where there's no research yet, but otherwise we can't even begin to guess.

I wonder whether we can find information about the genes i listed in my document and their activity.

dbSNP links to research for all identified SNPs (if there is any research), and http://scholar.google.com/ can be a good resource too. Though older papers on google scholar won't have an rsID, which makes it a lot harder to search for the nomenclature they used in any particular paper.

OTOH : All this appears to me so non-deterministic.

Mostly there's just a huge lack of data regarding SNPs, and we can't even begin to guess what most of them are doing. Due to most known variations not having an impact, the safest assumption for now is that individual unstudied SNP variations also have no impact - until proven otherwise.

Though when a SNP does have an impact, there really are just two basic outcomes: upregulation (more of the enzyme produced, slower break down of it, or increased efficiency of it) or downregulation (less of the enzyme produced, it breaks down faster, or decreased effectiveness of it). But there's no easy way to guess which variation will result in which difference in behavior, even when a pathogenic prediction algorithm says it's very likely to have an impact. I suppose 3D modeling of the enzyme and the things it interacts with might predict the exact type of impact, or even the degree of impact. But that's way over my head.

 

[mariovitali]

I am trying a new kind of Analysis using Decision Trees. This is the output of the algorithm :

The algorithm chose Lactic Acidosis as the most discriminating factor between Symptoms and a Lack of Symptoms.

I then look to find whether lactic acidosis is discussed in the forum and indeed it is.


I then try to find the causes of Lactic Acidosis. From wikipedia :

Other

• Hypoxia and hypoperfusion
• Hemorrhage
• Polymyositis
• Fibromyalgia
• Ethanol toxicity
• Sepsis
• Shock
• Hepatic disease
• Diabetic ketoacidosis
• Excessive exercise (Overtraining)
• Regional hypoperfusion (bowel ischemia, marked cellulitis...)
• Non-Hodgkin's and Burkitt lymphomas

From another link :


http://emedicine.medscape.com/article/167027-overview


Discusses Renal or Hepatic Dysfunction as probable causes.

So -i theorize that- the algorithm has chosen yet another Symptom of CFS

 

[skwag]

@skwag i agree with mariovitali that we "beggars can't be choosers". anything that works, works. I started doing mariovitali's supps and spinach recenctly, and... my tinnitus disappeared. and my MSG-related tinnitus is INTENSE and on all the damn time. thanks to mariovitali and his no-bs, openminded, logical attitude.
only way to gather data whether something works in practice is to try it and properly. yes, if you put it that way - that anything could be used with that rhetoric - then you are ABSOLUTELY RIGHT lol. because it's true!! it's impossible to know if some stuff works in practise until you try it, anything else is just talk and imagination, theories and politics... having a high standards of "theory must explain everything" is mostly OCD-perfectionism / risk aversion and just another Catch 22 to follow. I did that to my fill for 6 years of sickness, now i've fucken had it LOL.

Hi @gefinauser ,

I really couldn't agree more with the thrust of your comment. But since you directed towards me, I'm assuming you believe that there is something in it I do disagree with.

only way to gather data whether something works in practice is to try it and properly

I absolutely agree. I've said as much a few times. In fact, I believe the regimen should stand on its own, without trying to explain itself through DNA.

That is not to say that pursuing explanations using SNPs is not worthwhile. I think it is. But, for the most part, it is still a bunch of theory and conjecture that is very hard to test at this point.

On the other hand, the basic regimen is much easier to test and if more people try it and report results we might actually get some data. But presently, the number of people that have reported any results can be counted on one hand.

 

[mariovitali]

But presently, the number of people that have reported any results can be counted on one hand.

More correctly : We must know the proportion of people that have tried the full regimen and they've seen results as opposed to the number of people that have tried the regimen and saw no effect.

Personally i would like to see how many people DID try the regimen in its entirety and saw no results.

 

[mariovitali]

I wanted to look further to Glucocorticoid Receptor and there was an association with AKR1D1. I theorize that Finasteride brought us CFS by inhibiting 5-AR and as a result impaired Bile acid synthesis and regulation


Recall the following post for AKR1D1

http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-50#post-652171




What AKR1D1 does :

• The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]

Regarding Bile acids :

Bile acids are the most abundant 5β-reduced steroids. About 500 mg of cholesterol is converted to bile acids in adult human liver each day (~2 g total bile acid pool) [3, 7]. Bile acids solubilize dietary cholesterol, lipids, and fat soluble vitamins (A, D, E, and K) by forming mixed micelles and facilitate absorption of nutrients [8]

Role of Bile Acids to Intestinal Flora composition, Vitamin D Receptor, CYP3A4, Immunomodulation, Intestinal Permeability, Cardiac Function, Vascular Tone.

For a long time, bile acids were considered solely as steroidal detergents and emulsifying agents. But now their roles as regulatory/signaling molecules have been recognized. They are ligands for the orphan nuclear receptors FXR and PXR. Through activating FXR, bile acids regulate many genes in the liver and intestine, which modulate the biosynthesis and metabolism of bile acids and lipoproteins and determine the composition of the intestinal flora and fuana [3, 7, 8, 17, 18]. Recently, δ-aminolevulinate synthase, the rate limiting
enzyme of porphyrin-heme synthesis, has also been identified as a gene regulated by FXR, indicating a role of bile acids and their precursors in regulating hepatic heme biosynthesis [19]. The secondary bile acid, lithocholic acid activates PXR [20] and the vitamin D receptor [21, 22]. PXR in turn regulates the expression of CYP3A4, which encodes the major drug and xenobiotic catabolizing P450 isozyme in human liver. The secondary bile acid, ursodeoxycholic acid activates the glucocorticoid receptor and exerts immunomodulatory effects [23–25]. Bile acids also activate several signaling pathways including the c-Jun NH2- terminal kinase (JNK) 1/2 pathway (to feedback inhibit bile acid biosynthesis) [8], the protein kinase B (AKT) pathway (to regulate glucose metabolism) [8, 26], FXR, short heterodimer partner (SHP), liver X receptor (LXR), and the sterol regulatory element- binding protein (SREBP)-1c pathway (to regulate lipid metabolism) [8, 27], the extracellular-signal-regulated kinases (ERK) pathway (to prevent apoptosis) [28, 29], and the epidermal growth factor receptor (to modulate intestinal permeability) [30]. A recently identified G protein-coupled bile acid receptor (TGR5) [31] further expands the function of bile acids and their roles in energy metabolism [32], inflammation [33, 34], and gallbladder contractility [35]. Bile acids also affect cardiac function by regulating vascular tone and myocardial contractility, but the underlying mechanism for this remains largely unknown [36].

Link : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971473/

 

[mariovitali]

@Hip

Regarding your post here :

http://forums.phoenixrising.me/index.php?threads/is-this-a-sick-joke.32429/page-7#post-501584

In addition to this sheer fatigue, I developed many classic ME/CFS symptoms, like: brain fog, sound sensitivity, emotional sensitivity, circadian rhythm disruption and sleep cycle inversion (awake at night, asleep in the day), unrefreshing sleep, PEM from mental exertion, POTS, blurred vision, dry mouth, sudden onset of periodontal disease, burping, flatulence, cold hands and feet, occasional chest pains. I had gut symptoms too, but I already had IBS prior to catching the virus. IBS is I believe the most common ME/CFS comorbidity, and may therefore be a risk factor to developing ME/CFS.

see this :


Novel antioxidative nanotherapeutics in a rat periodontitis model: Reactive oxygen species scavenging by redox injectable gel suppresses alveolar bone resorption.
Saita M1, Kaneko J2, Sato T3, Takahashi SS4, Wada-Takahashi S4, Kawamata R5, Sakurai T5, Lee MC6, Hamada N3, Kimoto K1, Nagasaki Y7.
Author information

Abstract
The excessive production of reactive oxygen species (ROS) has been implicated in a variety of disorders, but to date, ROS scavengers have not been widely used for local treatment of inflammation, because they are rapidly eliminated from the inflamed site. We have designed a novel redox injectable gel (RIG) that is formed at 37 °C after disintegration of nano-assembled flower micelles allowing nitroxide radicals to act locally as specific ROS scavengers for the treatment of periodontitis. In the present study, we have confirmed retention of the RIG in the periodontal region, along with its antioxidant-related anti-inflammatory effects, and we have subsequently evaluated the inhibitory effect of the RIG against Porphyromonas gingivalis (P. gingivalis)-induced alveolar bone loss attributed to ROS. Alveolar bone loss was estimated by morphometry, gingival blood flow was measured using laser Doppler flowmetry, and osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase staining. The results show that the RIG can inhibit P. gingivalis-induced bone loss by antioxidant-related anti-inflammatory actions, and this suggests that the RIG is a promising novel therapeutic agent for the treatment of P. gingivalis-induced periodontitis.



I am also certain that my severe Periodontitis has stopped progressing but i will check with my Doctor first before making any claims.

 

[Violeta]

I wanted to look further to Glucocorticoid Receptor and there was an association with AKR1D1. I theorize that Finasteride brought us CFS by inhibiting 5-AR and as a result impaired Bile acid synthesis and regulation


Recall the following post for AKR1D1

http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-50#post-652171




What AKR1D1 does :




Regarding Bile acids :



Role of Bile Acids to Intestinal Flora composition, Vitamin D Receptor, CYP3A4, Immunomodulation, Intestinal Permeability, Cardiac Function, Vascular Tone.





Link : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971473/

Something in this post made me wonder if finasteride messes up cholesterol production and I found this.

http://www.endocrine-abstracts.org/ea/0029/ea0029p277.htm