Unfolded Protein Response and A Possible Treatment for CFS

[Valentijn]

We discussed previously about the "lack of Research" so i will not get into this sort of Conversation with you again.

It's still a serious problem which needs to be addressed.

At the very least I suggest you begin the SNP section by informing people that there is no research or other scientific basis for suspecting those SNPs to cause problems.

 

[mariovitali]

It's still a serious problem which needs to be addressed.

At the very least I suggest you begin the SNP section by informing people that there is no research or other scientific basis for suspecting those SNPs to cause problems.

Well, this is clearly stated in the Hypothesis section since it is mentioned as a Hypothesis after all...

 

[jop]

Thanks for this info @mariovitali, it's really clearly laid out. I like the way you formed your hypotheses and think it could be worth becoming a guinea pig. It will be a while till I've done the basic gut steps and got my 23andme though.

 

[Tunguska]

I extracted the SNPs from your document minus the no-calls.

MTHFD1

rs2295639 TT risk:G match:N
rs10498514 AA risk:C match:N
rs2236225 GG risk:T match:N
rs2236224 GG risk:T match:N
rs803422 GG risk:T match:N
rs6922269 GG risk:A match:N

5.3 BH4 Metabolism

GCH1

rs4411417 TT risk:C match:N
rs752688 CC risk:T match:N
rs8007267 CC risk:T match:N


5.4 Riboflavin Metabolism
rs2501925 TT risk:T match:Y

rs11144870 CT risk:T match:Y

5.5 Vitamin K Metabolism

VKORC1
rs9934438 GG risk:A match:N

5.7 Glutamate Metabolism

GAD1

rs769407 GG risk:C match:N
rs3791878 GT risk:A match:N
rs3791851 TT risk:G match:N
rs12185692 AC risk:A match:Y
rs3828275 TT risk:A match:N
rs2241165 TT risk:G match:N
rs3749034 GG risk:T match:N

5.8 Thioredoxin / Glutaredoxin / Peroxiredoxin

TXNRD2
rs3788317 GG risk:T match:N

TXNRD3
rs9637365 CC risk:T match:N

PRDX1
rs12151144 AA risk:C match:N

PRDX2
rs10427027 TT risk:C match:N

5.9 NOS1 / NOS2 / NOS3

NOS1
rs561712 CT risk:A match:N
rs1879417 CT risk:C match:Y

NOS2
rs2779251 AG risk:A match:Y
rs16949 CT risk:C match:Y
rs4795067 AG risk:G match:Y

NOS3
rs1800779 AG risk:G match:Y

5.10 Gluten Intolerance

MYO9B
rs2305764 AG risk:T match:N

SH2B3
rs3184504 CC risk:T match:N

5.11 ROS / ER Stress Genes

PDILT
rs11864909 CC risk:T match:N

ATF6
rs2499846 AA risk:A match:Y
rs10918270 AG risk:A match:Y

NFE2L2
rs1962142 GG risk:G match:Y

EIF2AK3
rs1805165 AC risk:A match:Y

XBP1
rs2239815 TT risk:C match:N

NDUFS7
rs2332496 GG risk:A match:N
rs1142530 TT risk:T match:Y

NOX4 (NADPH Oxidase)
rs957140 GG risk:A match:N

NQO1
rs1800566 GG risk:A match:N

5.13 Glutathione Function

GSTP1
rs1695 AA risk:G match:N
rs1871042 CT risk:T match:Y


GSTM1
rs9642880 GG risk:T match:N

5.14 Methionine Metabolism
MSRA
rs4509385 AG risk:G match:Y
rs10903323 AA risk:G match:N

5.15 Bile Acids
CYP7A1
rs3808607 GG risk:T match:N
rs3824260 AA risk:G match:N

5.16 Cholestasis
JAG1
rs2273061 AA risk:A match:Y

NR1H4
rs35724 GG risk:C match:N

5.17 Glucocorticoid Receptor
NR3C1
rs4912911 AG risk:G match:Y
rs10052957 GG risk:G match:Y
rs1866388 AA risk:G match:N
rs852977 AA risk:G match:N
rs7701443 GG risk:G match:Y
rs10482682 CC risk:G match:N

Glucuronidation

UGT1A1
rs4148323 GG risk:A match:N
rs4124874 TT risk:G match:N

UGT1A9
rs2070959 AA risk:G match:N

Sulfation
rs2219078 GG risk:A match:N
rs1402467 CC risk:G match:N
rs2547231 AA risk:A match:Y
rs182420 TT risk:T match:Y

Acetylation
NAT2
rs1208 AG risk:G match:Y
rs1799929 CC risk:T match:N
rs1801280 CT risk:C match:Y

I did it for you. I don't have faith left in these SNPs beyond a vague picture of slow CYP enzymes from elsewhere. I already know without doubt that riboflavin and nitric oxide are of significance to me. I suppose that lines up, but who hasn't reacted to them?

Chronic Fatigue Syndrome (CFS),
Fibromyalgia, Post-finasteride Syndrome (PFS), people who suffer from Permanent side-
effects from Accutane, Fluoroquinolone Toxicity Syndrome and also people suffering from
Post-Lyme Disease Syndrome
all share the same mechanism : Namely uncontrolled
Oxidative and Endoplasmic Reticulum stress that originated from a given stressor (Virus
such as EBV, Finasteride use, Accutane use, Ciprofloxacin use, Lyme disease)

I have multiple and I'm certain it does not cover fluoroquinolone toxicity syndrome adequately.

Alpha GPC or Citicoline appear to be better than Choline Bitartate (based on User Comments).

Alpha GPC is right but citicoline is closer to a uridine source than a choline source.

 

[mariovitali]

@Tunguska

First things first :


1) The fact that i don't have a sufficient amount of cases (=their DNA Data) of People that do not have CFS/PFS/Accutane/..//.. Syndromes is a serious limitation.

2) Even if that Data existed, there are so many other factors (Gender, Age, Environment, etc etc) that further make things even more difficult.

3) To make things even worse, there are so many genes involved with the Topics that are being discussed in this Thread.



A couple of things that i don't know about you (if possible please send them as a PM) :

1) How did you get CFS?
2) When you say "i have multiple" what do you mean? You have CFS *and* Post-Lyme Disease *and* PFS ...??
3) How are your P450 CYPs according to Nutrahacker?

Some notes regarding the Alleles you sent me :

1. I would like to first point your attention to your ATF6 Alleles: One homozygous to ATF6, 1 hetero to ATF6. Then you have 1 homozygous to Cholestasis, several to NOS2, Several to Sulfation, several to NR3C1. Finally homozygous to NFE2L2 aka NRF2. Did you see NRF2 and ATF6 towards the top of the list on the snapshot of the Data Mining tool ?

2. Of course this (= the alleles) may not mean a thing. There may be so many others here that do not have -say- ATF6 alleles and NRF2 alleles and yet they have CFS. What i am trying to say is : Try to see the Big picture. There are several holes in the Redox system : Choline, Methylation, Sulfation, Glucuronidation, ER Stress Response, P450 CYPs activity, Redox co-factors, etc, etc. ..and ALL of these paint the Big Picture.




Regarding Choline i do not know what is best unfortunately.


@Tunguska I am willing to work with you. So if you want to give this a chance let's go for it. Then you will be able to say exactly what happened to all members of the Forum.


Let me know what you think.

 

[Valentijn]

Of course this (= the alleles) may not mean a thing.

It's not just a possibility that it doesn't mean a thing. It's extremely likely that it doesn't mean a thing. If you want it to be meaningful, you need to read the research to find out which SNPs have an impact.

 

[ahmo]

@mariovitali Thanks for the great explanation above. It suddenly jumped out at me, is this thread essentially about oxidative stress? Which has been exactly my focus of this year.

OK, so another anecdotal report. I started MitoQ a couple weeks ago, as part of the non-placebo arm of the study. I took 5mg first day, did ok, went to the recommended 10mg. After about a week, I realized I was experiencing adrenal stress, several symptoms accummulating. I dropped to 5mg/day, but was still needing high rate of antioxidants. I'm now alternating 5mg every other day w/ ubiquinone. My body has also never wanted large doses ubiquinone, I take just 100mg.

Thanks for your efforts on this thread. It's greatly appreciated.

 

[Valentijn]

And what are the odds that the hypothesis is correct, given that there is no reason to believe that many/most/all of the SNPs can cause problems? Virtually nil.

 

[mariovitali]

@ahmo

The hypothesis is discussed in the PDF which you can find here :

http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-63#post-671106

I tried MitoQ before and i felt strange with it. I am not saying it was not good but just strange (maybe a little bit edgy).


The theory is that both Oxidative and ER Stress take place which bring havoc to many body functions. May i ask how did you get CFS?

 

[mariovitali]

@ahmo
Please see here regarding CFS and Oxidative Stress :


Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms

Non-technical summary
The body contains highly reactive molecules called free radicals. They are normally kept under control by natural processes which remove them from the circulation, but when an imbalance occurs they can be left to cause damage unchecked. This damage is called oxidative stress. In particular, free radicals can change our normal ‘good’ cholesterol into something more harmful, leading to heart and circulation problems.

We found that patients with ME/CFS had higher than normal levels in their blood of chemical markers which indicate oxidative stress, as well as lower levels of their ‘good’ cholesterol.

This suggests that the normal processes controlling free radicals are not working properly in patients with ME/CFS.

http://www.meresearch.org.uk/our-research/completed-studies/oxidative-stress/

 

[Valentijn]

Redacted by moderator.

Your statements about SNPs are inaccurate. That is not an attack on you.

 

[mariovitali]

Your statements about SNPs are inaccurate. That is not an attack on you.

I did not attack you personally in any way. I just let other member forums understand and break down the associated risks based on my Hypothesis and your comments.

 

[jop]

And what are the odds that the hypothesis is correct, given that there is no reason to believe that many/most/all of the SNPs can cause problems? Virtually nil.

Science is a process of exploration and gaining new knowledge. It begins with observing patterns and trends and forming new hypotheses from the observations. It then involves creating new strategies to rigorously test the hypotheses.

Applying existing knowledge is for technicians, not scientists.

In my view, one of the reasons medicine has made such poor progress in understanding the complex etiology of chronic illness, is that they don't have the necessary analytical or data processing skill. They can't identify important patterns from bulk raw data, yet that is a crucial skill for understanding complex systems.

 

[ahmo]

The theory is that both Oxidative and ER Stress take place which bring havoc to many body functions. May i ask how did you get CFS?

I had symptoms of pyroluria and B12 deficiency forever, also under-treated thyroid. there was a terrible flu-like illness, from which point I started researching CFS, eventually calling myself chronically fatigued. 4 years later a heat-stroke incident, amid intense emotional and physical stress, caused my collapse, w/ symptoms of ME.

Thanks for sending me back to the pdf summary, I hadn't yet read it.

 

[mariovitali]

@ahmo

OK Thank you. Anytime you want we can talk over Skype and exchange ideas.


@jop

That goes for you too. Just send me a PM and we will arrange it.


I think that this :

Science is a process of exploration and gaining new knowledge. It begins with observing patterns and trends and forming new hypotheses from the observations. It then involves creating new strategies to rigorously test the hypotheses.

Says it all. Thank you!

 

[mariovitali]

Dear All,

FYI : @ahmo, @jop, @leela, @Gondwanaland, @Violeta


I sent an E-Mail to Dr Klimas at INIM. I got no response so far.However i do not believe that the problem lies to the Immune system as you well know.



I believe that the Research done in University of Dundee is very close to my theory on what happens to us (recall that NRF2 shows towards the top of the table generated from my data Mining tool) :

Over the past decade, ME Research UK-funded researchers at the University of Dundee have uncovered a range of biological abnormalities in ME/CFS patients (see below), including high levels of apoptotic (dying) white blood cells and increased arterial stiffness. Their main finding, however, has been that people with ME/CFS have high levels of reactive oxygen molecules, which can harm blood vessels and muscles. These molecules are formed in the body during biological processes that use oxygen, such as exercise. In healthy people they are counter-balanced by antioxidants that detoxify the oxygen molecules to prevent damage, but sometimes an imbalance can lead to increased ‘oxidative stress’ and an increased risk of cardiovascular disease.

It is important to discover the origin of these molecules, so that ways of counteracting oxidative stress-related cardiovascular damage can be developed. For this reason, the research team in Dundee has received funding from ME Research UK to investigate the role of ‘nuclear factor erythroid-derived 2’ (Nrf2). This is an extremely important regulatory protein in the body, and is now believed to be a master activator of the body’s natural defence against oxidative stress. When reactive oxygen species are generated, Nrf2 is activated, stimulating the body’s antioxidant pathways and thereby providing a buffer against oxidative stress.

The researchers’ aim is to test whether Nrf2 activity is low (in quantity and in gene expression) in blood samples from ME/CFS patients, and whether Nrf2 levels are related to levels of oxidative stress. Importantly, the team will also examine whether the Nrf2 antioxidant system of ME/CFS patients can be activated by certain foodstuffs and by some therapeutic drugs. At present, several drugs that stimulate the Nrf2 pathway are being assessed as treatments for other diseases, including multiple sclerosis in which oxidative stress is involved, but this is the first time ME/CFS patients have been studied.

http://www.prohealth.com/library/showarticle.cfm?libid=20285

I also strongly believe that acetylcholine is involved to many of our Symptoms (because some predictive models show it which i haven't posted as the way they were produced is highly experimental). Sure enough, these guys are spot on :

In modern science, real breakthroughs come at the end of a programme of painstaking work by a specialist group of researchers. One of the few examples of such a programme on ME/CFS, anywhere in the world, is the work at the Vascular Diseases Research Unit, University of Dundee. This group has received a number of grants from ME Research UK in the past 13 years. In a step-by-step progression involving both adults and young people with the illness, the group has discovered:

• Unusual sensitivity of blood flow to acetylcholine (a neurotransmitter)
  
  
• Increased levels of isoprostanes (a gold standard marker of oxidative stress in the bloodstream)
  
  
• An unexpected increase in dying (apoptotic) white blood cells, consistent with an activated inflammatory process or persistent infection
  
  
• Increased cardiovascular risk factors with arterial stiffness in patients
  
  
• Biochemical anomalies in children mirroring those found in adults with the illness
  
  
• Dysfunction of the vascular endothelium (the lining of blood vessels)
  
  
• An association between vitamin D and markers of cardiovascular risk

The "persistent infection" is not highlighted because it does not match with the Theory discussed here. However Inflammatory process does.


I contacted Dr Faisel Khan by E-Mail but unfortunately he is out of the office until December 14th.


I will contact ME Research UK today by phone, perhaps i can speak to someone else. I will keep you updated.

 

[Valentijn]

@mariovitali - Could you please explain the basis for your belief that most or all SNPs have a variation which contributes to dysfunction of the gene which they are on? The information which I am aware of strongly contradicts such a belief. As a very basic example, from the first paragraph of the "Allele" entry on Wikipedia:

Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation. However, most genetic variations result in little or no observable variation.

In light of this, it would seem unreasonable to conclude that any specific SNP is relevant to gene function unless research into that specific SNP has shown otherwise. If guessing that a SNP has an impact, in the absence of proof either way, that guess will most likely be wrong.

Hence the most rational approach is to assume that all unresearched SNPs are not causing problems unless/until there is some data indicating otherwise. That data usually is in the form of carefully conducted scientific research, often by comparing the rates of alleles in patients with a disease to healthy controls. Another way is directly observing how the structure, function, or amount of the resulting enzyme is changed as a result of the variation. And in the case of missense mutations in the exons, the impact of the variation can be predicted with some degree of accuracy.

If your purpose is to test for yourself the impact of alleles by trying treatments, I think the methodology is completely wrong. First of all, only a few SNPs are being considered, when there are usually hundreds on the gene. Hence even if an impact is attributable to a problem on the gene, you still can't know which SNPs are causing the problems. The other problem is that many genes contribute to similar or the same problems. The same treatment may therefore compensate for something completely unrelated to the SNPs being arbitrarily labeled as "risky".

Regarding the ethics of such a "trial and error" approach, by someone with no medical or genetic background, and over the internet, there is your inherent assumption that every SNP on the gene causes the same type of problem when it malfunctions. Some SNPs do result in problematic down-regulations ... but others result in problematic up-regulations. In the absence of solid research, there is absolutely no way to know which SNP malfunctions in which direction, if it malfunctions at all.

Thus in the unlikely event that you are right, and a variation does result in a significant change in gene function, your guess about the effects of that malfunction could be completely wrong. If you are guessing that a SNP results in a gene slowing down, and choline being necessary when that gene is slow, someone here could be following exactly the worst advice in taking more choline if that SNP actually results in the gene speeding up. This sort of guessing is very dangerous when it is accompanied by medical advice regarding treatment.

 

[mariovitali]

@skwag

I would appreciate your Input to the following :

1. I am aware that you do not agree with me on listing specific Genes and Alleles. Perfectly fine. Do you think that the Hypothesis of this Thread is a probable one ? (Liver stressor -> Liver Injury <-> Oxidative Stress->CFS


2. Could you comment on the following post?

Now let's look at the cost (=Health-wise) involved for each of the two outcomes. At this point i must say that if my hypothesis is correct then your body is essentially left vulnerable to uncontrolled oxidative stress. Please look at the relevant research on oxidative stress and -more importantly- its repercussions and the various diseases that this leads to.

...So@Valentijn

1-What is the cost that is involved if someone DOES follow this regimen and my hypothesis is correct?
2-What is the cost that is involved if someone DOES NOT follow this regimen and my hypothesis is correct?
3-What is the cost that is involved if someone DOES follow this regimen and my hypothesis is incorrect?
4-What is the cost that is involved if someone DOES NOT follow this regimen and my hypothesis is incorrect?

Obviously, cases 2 and 3 are of particular interest.


Regarding case 3: If my hypothesis is incorrect (and assuming that a qualified Medical practitioner monitors the process as stated in the PDF) there is most likely no cost (Health-wise) given the fact that currently there is no Cure for CFS. If a cure existed,then this would change things (=the associated cost for NOT choosing to follow the correct regimen).

Regarding case 2 : If my hypothesis is correct and you are incorrect and there are people here that listen to you and choose NOT to follow this regimen, what is the cost then?

3. How are you feeling Symptom-wise as you haven't posted for a while?



Thanks

 

[skwag]

Hi Mario,

1. I am aware that you do not agree with me on listing specific Genes and Alleles. Perfectly fine. Do you think that the Hypothesis of this Thread is a probable one ? (Liver stressor -> Liver Injury <-> Oxidative Stress->CFS

I don't think the hypothesis is true in general, no. It could certainly be true in some cases, though. There are many different ideas about the causes of CFS. Presently, I'm more inclined to believe that an autoimmune process is at play, at least in good percentage of CFSers. There are at least a couple threads here that discuss positive outcomes with Rituximab, which is believed to slow or halt the autoimmune process in some cases.

It may be that liver injury or oxidative stress should be considered triggers for an autoimmune process, in which case your hypothesis would dovetail into the autoimmune theory. But I haven't seen any grounding for this conjecture. Anyway, it gets complicated. Lots of possibilities.

Could you comment on the following post?

I commented on this line of argument in an older post.

How are you feeling Symptom-wise as you haven't posted for a while?

No big changes. I feel like I'm improving a little relative to my last update, but I can't really attribute it to anything I've done or taken.

 

[mariovitali]

@skwag

OK Thanks. So you have taken some parts of the regimen which you feel have helped and try other things on top of that. Is this correct?