Unfolded Protein Response and A Possible Treatment for CFS

aquariusgirl

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just read that Prof Nancy Klimas is asking patients to share their 23andme results with her for some research project....so maybe you could share your work with her...???\
 

mariovitali

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1,214
just read that Prof Nancy Klimas is asking patients to share their 23andme results with her for some research project....so maybe you could share your work with her...???\

I assume you are referring to me. I do not think that it is easy for a Professor to accept the possibility.

Nevertheless, Thank you... i will try to contact her and see what happens.


EDIT : I just saw her CV. Her specialty is in immunology and i do not think that the main culprit of CFS is the immune system
 
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mariovitali

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Dear All,

I am preparing a document in which i will summarise the Theory, relevant genes and generally all that you have to know.

And one question perhaps for the oldest members of the Forum :


--How many cases we have with complete remission of CFS Symptoms after following the Methylation protocol (Either Rich's or Fredd's) ?
 
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7
One very severe symptom of me is general anxiety disorder. The problem with this:

Its a vicious cycle... too much stress response on every small stimuli. Im actually trying Lyrica / Pregabalin, which is a potent VGCC blocker. Normally, people get very tired on this drug. However, it gives me great energy. My Depression is still severe but energy problems and anxiety is much better on it.

I think the first thing to do is to reduce severe anxiety, otherwise healing is not possible as the permanent stress and kills all benefits of every protocol. That's my opinion at the moment.

Whats your opinion?

Im reading at the moment the book "Why isnt my brain working" from Dr. Kharrazian.

@mario did you read this? Very brilliant stuff, im wondering where the connection to ER stress is.
 

skwag

Senior Member
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226
Trial Update Day 50

In the following, changes from my last update will be in bold.

I'm currently taking,
  • 250 mg TUDCA : cut down from 2x250 mg
  • 3x1400 mg NAG
  • 25 mg FMN ( B2 ) : just a brand switch
  • 100 mcg selenium
  • 3x250 mg citicoline : bumped up from 2x250mg
  • 3x300 mg alpha gpc : new addition
  • 3x500 mg choline bitartrate : reintroduced
  • 750 mg inositol
  • 3x100 mg Pantothenic Acid ( B5 ) :new addition
  • 2x1000mg Taurine new addition
along with methylation supplements. I have also been on the autoimmune paleo diet for 34 days.

Improvements:
  • 50% lightening of sun damge/ liver spots on forearm ( onset one year ago )
  • decreased urinary frequency. Now I go every 2-3 hours vs every hour
  • lighter urine color
  • better urinary flow ( probably due to less prostate inflammation )
  • 60% improvement in folloculitis on arms and legs ( onset one year ago ) : up from 50%
  • 80% improvement in noise intolerance
  • 95% improvement in headaches. up from 80%
  • 95% improvement in lower back pain ( onset one year ago )
  • 33% improvement in energy levels
  • 60% improvement in groin pull injury up from 50% ( onset 5 months ago, little improvement over previous 4 months )
  • 33% improvement in nasal congestion
  • POTS: Poor man's tilt table test results: 30-40 bpm :This is down from the 40-50 bpm average that I posted last time, and a slight improvement over the 35-40 bpm baseline when I started the trial.
No change:
  • eye floaters ( onset one year ago )
  • skin texture/ wrinkling ( onset one year ago )

I have been incrementally increasing my choline without any negative side effects. The Alpha GPC and citicholine are both expensive, so I plan on moving towards more choline bitartrate which can be purchased cheaply in bulk powder form. I am getting a slightly euphoric feeling after taking a dose of choline, along with better sense of clarity. I also feel like I am much more resistant to overwhelming negative thoughts. I suspect the increased choline is responsible for my near absence of headaches recently.

I am hopeful that the increased choline may improve my POTS type symptoms. There is a discussion of this here:

Dizziness and POTS may respond to Choline

There are some signs that this may be true. My Poor Man's tilt table test results are slightly improved over baseline. I have also noticed the veins on the backside of my hand and forearm are less ropey, suggesting more vasoconstriction there.

I had a brief trial of TMG(betaine) in an attempt to spare choline. Within 12 hours, my mood was deteriorating with increased noise intolerance, irritability, and return of some back pain. Those symptoms vanished within a day of stopping supplementation. I am still pondering what this means. It could just be coincidence.

Tomorrow I will discontinue TUDCA supplementation as I finish off my second bottle of TUDCA today.

We have had a couple weather fronts move in and out in the last couple weeks, one of them with a significant temperature drop. There was no correlation with any of my symptoms.
 
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jump44

Senior Member
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122
Thought Id give an update as well

Been taking for last 10 days:

100mg resveratrol(usually take 2 days on 1 day off)
12.5 mg fmn same dosing as res
500mg Tudca/day
200mcg seleniumj (started 4 days ago)
and today I introduced 250mg choline bit/250mg inositol in a combined supp(hope this is ok) was pretty
cheap at vitamin shoppe
also started 1 mg LDN from my cfs doc 14 days ago
vit c 1000 mg/day
digestive enzymes
1000mcg adeno b12/methyl b12 combo supp/day
30mg armour/25mcg synthroid(been on for over 2 yrs)

I will say that the TUDCA has provided a noticeable boost, although from time to time I feel tired and get liver/GB pain( like stuffs moving?) after dosing. when I introduced selenium there was as if another layer of fog was removed. And today after taking my first choline/inositol dose I felt tired for a while but within a few hours I noticed a boost in mental function/mood. My skin looks better and less gray/yellow/pale in fact it somehow looks like Ive been tanning lol which I havent done in forever due to sun intolerance. Sleep has been uninterrupted for the last four nights for the first time in years. Muscles feel a bit fuller and more "pumped" which is nice for me as an ex athlete one of the more devestating effects of this has been my body deterioration. THe Ldn introduction preceded all except FMN and resveratrol so although its hard to be exactly sure whats causing what my states have shifted noticeably as I said with the introduction of each new supp. appetite is also way up which is actually a welcome change as since this illness started I have went from 170lbs down to 152..Also just for completeness I am on a version of the "perfect health" diet which Ive been doing for the past 4-5 months so that cant really account for these changes . I will keep everyone updated, fingers crossed that these changes hold/
 
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mariovitali

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1,214
@skwag , @jump44

Really glad you both are feeling better. Your feedback is very important, no need to explain more why this is so.


Some comments :

@skwag

1. Seeing your dosages, you are taking an awful lot of Choline. This means that your TMAO levels will skyrocket which is not good in the long run. I seriously advise you to cut back on Choline.

2. You might be stopping TUDCA too early. Of course i do understand that TUDCA is expensive. Nevertheless what i suggest is that you eliminate alcohol completely for a couple of months and re-evaluate. Remember that Liver functioning can be a major player for your recovery.


@jump44

You said :

when I introduced selenium there was as if another layer of fog was removed. And today after taking my first choline/inositol dose I felt tired for a while but within a few hours I noticed a boost in mental function/mood. My skin looks better and less gray/yellow/pale in fact it somehow looks like Ive been tanning lol which I havent done in forever due to sun intolerance. Sleep has been uninterrupted for the last four nights for the first time in years.

This is what i am talking about : The fact that you handle Oxidative stress and ER Stress in various areas so these are the results (in a "Layer" fashion) that should be expected! :thumbsup:


Continue what you are doing, there *will* be minor setbacks (not sure if i am using the correct word) but just continue the regimen. Again, this will take time.


@all

As an analyst i would also like to see people who gave a serious try the regimen and have failed. But the "serious try" involves looking at several genes and finding out your problems (Note : this is a theory) along Redox Functioning, ER Stress handling, Choline metabolism, Vitamin K metabolism, Gluten Intolerance etc. I am trying to finish the Summary Document ASAP, unfortunately i am swamped from work that i have to finish..

I also attached a screenshot at this post, please ignore for now.
 

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skwag

Senior Member
Messages
226
Thanks for the comments @mariovitali

1. Seeing your dosages, you are taking an awful lot of Choline. This means that your TMAO levels will skyrocket which is not good in the long run. I seriously advise you to cut back on Choline.

Yes, I'm currently taking 1700 mg choline/day, which is about half the UL ( set in 1998 ) of 3500 mg. There are reasons to believe that high choline doses may be helpful with POTS. See Dizziness and POTS may respond to Choline.

Although I haven't studied the TMAO issue extensively, I suspect it has been overblown. Chris Kresser makes some arguments regarding this issue here.

2. You might be stopping TUDCA too early. Of course i do understand that TUDCA is expensive. Nevertheless what i suggest is that you eliminate alcohol completely for a couple of months and re-evaluate. Remember that Liver functioning can be a major player for your recovery.

I agree that the liver is a prime suspect in a lot of my problems. It is also likely TUDCA has been beneficial in that department. If I experience any back sliding I'll definitely pick up some more.
 
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jump44

Senior Member
Messages
122
@mariovitali

Thanks for your comments. I was actually going to ask you if you had any ups and downs when starting this treatment, as Ive had besides the improvements some days of gb/liver aching and some diarrhea, although I have even on these days felt physically better if that makes sense. Today is one of those days actually where Im having stomach issues and right side aching but feel better mentally. Im wondering if this is some sort of "detox" (not sure if I really believe in such a thing but),hoping its not the choline/inositol I started yesterday as its provided a nice mental boost! So Im curious if you had days like this when starting this suite of supplements. THanks again for all your help!
 

jump44

Senior Member
Messages
122
@mariovitali

I still have to get my results back Im still waiting on them, but I will when I get them. Youre talking about the 23 and me stuff correct? Btw the stomach discomfort stopped at about 6 tonight, I am thinking it may be being caused by some filler in my LDN. I am having the next batch compounded at a pharmacy who will send me a liquid w no fillers just to be sure. I took another dose of choline/inositol at dinner and had no discomfort so its either the ldn or the Tudca I believe causing it, but my money is on the Ldn as its apparently common for the fillers to cause problems in sensitive people which I surely am lol. Either that or its some sort of detoxification occuring. Idk how to tell whats what, though.
 

Violeta

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3,190
Does anyone remember what biotin was for? I can't remember and I don't feel good enough to look for it. Thanks.
 

mariovitali

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1,214
@Violeta

Yes, it was suggested by @ppodhajski, check your Biotinidase genes :


rs13078881 (C)
rs7651039 (C)


@jump44

I suggest that you stop TUDCA and re-evaluate. If TUDCA is not the problem then remove LDN, re-evaluate etc

@Naibaf

I totally agree with you. Anxiety must be addressed, you must check your DNA for possible SNPs that cause Panic Disorder, Depression etc. Although i know nothing about it, Methylation Supplementation may help you on this area (but check with people that are knowledgeable in Methylation)
 
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7
Im getting better and better, however I do not strictly use mariovital protocoll but Vit C is a key component in my regime (which is not completed yet). It's still to early to give a detailed update.

However, I tend to a low blood pressure and im taking Grape Seed Extract. My think my blood pressure drops down after intake (106 / 65, 78) which increases light headedness. However, Grape Seed Extract contains many flavonoids and im wondering how I get these flavonoids (which I think, that they help me) by taking Resveratrol.

Any Idea?
 

mariovitali

Senior Member
Messages
1,214
@Naibaf

There are many things that can be happening. You will understand more after I post some thoughts later today.

Dear All,

Thanks to ppodhajski and a conversation we had, I completely forgot about the importance of CYPs although this is discussed in my first post of this Thread.

The picture is getting much bigger than we thought, I will post more later today.

Have handy your Detox reports from Genetic Genie.. ;)
 
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jump44

Senior Member
Messages
122
@mariovitali

I will cease Tudca for a few days and see what happens. Also, after reading through your first post again I noticed you warned against testosterone induction/therapy as it can contribute to ER stress. I found this interesting because the few times Ive felt closer to "normal" during this shitshow(pardon the term haha) has been when I was on Testosterone replacement.. Dhea also causes some improvements.Now this couldve just been because my libido/sexual function improved somewhat and when this is working better other symptoms become much more tolerable(for me at least) because like the post fin guys for some reason this illness has really decimated my sex drive/function etc. Also I found a few(nothing definitive just correlations) things online that DHT itself may be protective against ER stress and even oxidative stress. Just curious if you had any thoughts on this. thanks.
 

Violeta

Senior Member
Messages
3,190
http://bscb.org/learning-resources/softcell-e-learning/endoplasmic-reticulum-rough-and-smooth/

Anyone interested in the smooth ER? Lipids and hormones?

"Organelles called ‘rough endoplasmic reticulum’ and ‘smooth endoplasmic reticulum’ are separate networks of membrane enclosed flattened tubules found in eukaryotic animal and plant cells.
  • The rough ER, studded with millions of membrane bound ribosomes, is involved with the production, folding, quality control and despatch of some proteins.
  • Smooth ER is largely associated with lipid (fat) manufacture and metabolism and steroid production hormone production. It also has a detoxification function"
 

mariovitali

Senior Member
Messages
1,214
Dear All,

I have the following alleles in P450 CYPs :

CYP1A1 C2453A rs1799814 GT +/-
CYP1A2 164A>C rs762551 AC +/-
CYP1B1 L432V rs1056836 GG +/+
CYP2C19*17 rs12248560 CT +/-
CYP2D6 S486T rs1135840 GG +/+
CYP2D6 100C>T rs1065852 AA +/+

GSTP1 I105V rs1695 AG +/-
NAT2 I114T rs1801280 CT +/-
NAT2 K268R rs1208 AG +/-

Perhaps the worst is CYP7B1 :


Screen Shot 2015-10-15 at 20.47.05.png


with a 2.7% Frequency. Note that the second version is ok.


CYPs are essentially the P450 System that i discuss at the beginning of this post (talking especially about P450scc).

So what i wanted to say is that almost everything that we discuss here : Oxidation/Reduction, FAD, Cofactors..they have to do with Phase I and Phase II functioning of the liver.

Now i am not certain for what i am saying, i do not have the knowledge as i am not a medical professional but you can check this out as well.

All i know is that i was feeling really bad when unknowingly i would take P450 Inhibitors (hence the entry on my first post). Of course you could try it but i'd rather prefer that you do not try such thing.


@jump44

You discuss about feeling better with DHEA. My hypothesis is that the reason is this :


Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor α (PPARα)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected.

Again, the hypothesis is that Liver Function is very much involved in CFS/PFS/Accutane symptoms. It is NOT the immune system (as the basis of our problems)

Continuing my hypothesis, it goes like this : I think that it is extremely unlikely that someone -assuming he has impaired Liver function- will feel better just by using cofactors in order to handle Redox homeostasis.

If we have an impaired Liver, then we need to stop further Liver damage by using agents such as TUDCA and Choline (?) and at the same time use cofactors to stop Oxidative Stress.

I am in my 4th day of not using TUDCA, time will tell.
 
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