Unfolded Protein Response and A Possible Treatment for CFS

[Violeta]

Has anyone used Powder City as a source for their sups? Getting ready to buy but always concerned about source and purity.

No, @leela, I've never heard of Powder City. Do they have good prices?

 

[Ema]

It seems like Ribogen might help with proper protein folding too.

 

[mariovitali]

Today I found this:
https://en.wikipedia.org/wiki/Benfotiamine

I am trying that for one week before giving him other Bs. Luckily I have Benfotiamine at home. He clearly has low B1 symptoms when taking other Bs - B2 for instance gives him bad dreams - and also B1 is needed for better Mfolate absorption/metabolism (link in my sig).

I seem to finally being able to apply all the info I gathered here fo 1.5 years

I believe that Benfotiamine is problematic. I used it in my software and got these results :

*********Topic : benfotiamine ***************
benfotiamine.csv : 75.00 %
hexosamine.csv : 0.49 %
advanced_glycation_end.csv : 0.47 %
lipoic_acid.csv : 0.26 %
vitamin_b6.csv : 0.10 %
glycosylation.csv : 0.06 %
oxidative_stress_markers.csv : 0.04 %
p5p.csv : 0.03 %
n-acetylglucosamine.csv : 0.02 %
l_carnitine.csv : 0.02 %
oxidative_stress_protection.csv : 0.02 %
resveratrol.csv : 0.01 %
taurine.csv : 0.01 %

Notice that hexosamine pathway is second, and advanced_glucation_end (AGEs) is third.

It appears that Benfotiamine blocks the hexosamine pathway and as a result it blocks UDP-Glcnac (Uridine diphosphate N-acetylglucosamine)

Then we have this :

Thus, crosstalk between ER stress and hexosamine biosynthesis suggests that there may be therapeutic applications for hexosamine metabolites in degenerative diseases (see Vincenz and Hartl).

Link : http://stke.sciencemag.org/content/7/319/ec83

The study has not been made in humans so all of the above may not be applicable to humans.

The study shown however is the reason for using N-Acetylglucosamine in my regimen.

 

[Gondwanaland]

I believe that Benfotiamine is problematic. I used it in my software and got these results :

Notice that hexosamine pathway is second, and advanced_glucation_end (AGEs) is third.

It appears that Benfotiamine blocks the hexosamine pathway and as a result it blocks UDP-Glcnac (Uridine diphosphate N-acetylglucosamine)

Then we have this :

Link : http://stke.sciencemag.org/content/7/319/ec83

The study has not been made in humans so all of the above may not be applicable to humans.

The study shown however is the reason for using N-Acetylglucosamine in my regimen.

But he was with back pain and 20mg Benfo relieved it (placebo? I told him it would help his pain But i told him before with other supps as well and they didn't)

His creatinine is close to the top of the range and his fasting insulin is sky high (fasting glucose normal)

I might have a chance to get hold of NAG... Hoping it will help with crystals... Any recomendation (must be low cost)?

 

[Ema]

But he was with back pain and 20mg Benfo relieved it (placebo? I told him it would help his pain But i told him before with other supps as well and they didn't)

His creatinine is close to the top of the range and his fasting insulin is sky high (fasting glucose normal)

I might have a chance to get hold of NAG... Hoping it will help with crystals... Any recomendation (must be low cost)?

Hops can reduce fasting insulin and also is antiinflammatory so may help reduce pain.

 

[Gondwanaland]

Hops can reduce fasting insulin and also is antiinflammatory so may help reduce pain.

I had never herd of it before! Thanks for the tip!

 

[Ema]

I had never herd of it before! Thanks for the tip!

Let's all have a beer or three!

 

[Gondwanaland]

Let's all have a beer or three!

For several decades local beer is being fermented with cabbage rather than hops
That is why I always preferred imported ones
Too bad with my non-celiac gluten intolerance I can't enjoy them anymore

 

[Violeta]

You're not kidding! That is kind of upsetting. There has to be a way around it. Hoping, anyway.

I'm getting out my pau d'arco and making a covenant with myself to drink some every day. I think vuruses need something instead of being folded correctly, you don't fold dirty laundry!

Pau d'arco stops it from replicating, but I don't know how to help the ER.
@mariovitali , you don't have signs of virus, do you?

 

[Mogwai]

I've yet to try the choline bitartrate, as my POTS flared up these last few weeks! Could have been from a lack of choline... http://www.ncbi.nlm.nih.gov/pubmed/25466896

I'm feeling a bit better after getting on top of my electrolytes - so I'm going to try a few things.

Updating my SNPs:

ER Stress response

rs13045 (EIF2AK3-PERK) : Risk C - CT
rs2239815(XBP1) : Risk C - CT
rs10918270(ATF6) : Risk A - AG
rs391957 (HSPA5 aka BIP aka GPR78) : Risk C - CT

GCH1, associated with lower levels of BH4 (low BH4 => ER Stress)

rs10483639 : ( Risk C) - GG
rs3783641 : (Risk A) - TT
rs8007267 : (Risk T) - CC
rs12147422 : (Risk C) - CT
rs3783637 : (Risk T) - CT
rs3783641 : (Risk A) - TT
rs41298442 : (Risk T) - TT - but everyone seems to have this one...
rs4411417 : (Risk C) - TT
rs752688 : (Risk T) - CC
rs841 : (Risk A) - GG
rs998259 : (Risk T) - CT
rs7147286 : (Risk A) - AG

Choline Metabolism (impaired Choline absorption => impaired TMAO => ER Stress+UPR)

rs3733890 (Risk A) - AG
rs2461823 (Risk C) - CT
rs7643645 Risk G - AG
rs7946 (Risk T) - TT
rs4244593 (Risk G) - GG
rs2236225 (Risk A) - AA
rs9001 (Risk G) - TT

I also have haemochromatosis - homozygous for the C282Y mutation - so taking Vitamin C is out of the question.

My latest LFTs are good - all in range.

I think I've found a B complex that agrees with me - so I'll take that + my B12. Then add choline bitartrate (350mg to start).

Changing up my diet, as in eating less meat(!). I've been trying - but I need some protein or else I'll waste away. Maybe a couple of eggs for dinner instead of a slab of meat?

Any other suggestions? Sorry, I'm playing catch-up in this thread...

 

[mariovitali]

I'm getting out my pau d'arco and making a covenant with myself to drink some every day. I think vuruses need something instead of being folded correctly, you don't fold dirty laundry!

Pau d'arco stops it from replicating, but I don't know how to help the ER.
@mariovitali , you don't have signs of virus, do you?

Can you be more specific @Violeta? I do have a lot of sneezing going on epsecially in the morning when i wake up (probably allergic rhinitis)

 

[leela]

@mariovitali could you please remind me why you suggest not taking CB when taking choline?

 

[Ema]

@mariovitali could you please remind me why you suggest not taking CB when taking choline?

The theory is that it reduces TMAO which assists in protein folding.

 

[mariovitali]

I've yet to try the choline bitartrate, as my POTS flared up these last few weeks! Could have been from a lack of choline... http://www.ncbi.nlm.nih.gov/pubmed/25466896

I'm feeling a bit better after getting on top of my electrolytes - so I'm going to try a few things.

Updating my SNPs:

ER Stress response

rs13045 (EIF2AK3-PERK) : Risk C - CT
rs2239815(XBP1) : Risk C - CT
rs10918270(ATF6) : Risk A - AG
rs391957 (HSPA5 aka BIP aka GPR78) : Risk C - CT

GCH1, associated with lower levels of BH4 (low BH4 => ER Stress)

rs10483639 : ( Risk C) - GG
rs3783641 : (Risk A) - TT
rs8007267 : (Risk T) - CC
rs12147422 : (Risk C) - CT
rs3783637 : (Risk T) - CT
rs3783641 : (Risk A) - TT
rs41298442 : (Risk T) - TT - but everyone seems to have this one...
rs4411417 : (Risk C) - TT
rs752688 : (Risk T) - CC
rs841 : (Risk A) - GG
rs998259 : (Risk T) - CT
rs7147286 : (Risk A) - AG

Choline Metabolism (impaired Choline absorption => impaired TMAO => ER Stress+UPR)

rs3733890 (Risk A) - AG
rs2461823 (Risk C) - CT
rs7643645 Risk G - AG
rs7946 (Risk T) - TT
rs4244593 (Risk G) - GG
rs2236225 (Risk A) - AA
rs9001 (Risk G) - TT

I also have haemochromatosis - homozygous for the C282Y mutation - so taking Vitamin C is out of the question.

My latest LFTs are good - all in range.

I think I've found a B complex that agrees with me - so I'll take that + my B12. Then add choline bitartrate (350mg to start).

Changing up my diet, as in eating less meat(!). I've been trying - but I need some protein or else I'll waste away. Maybe a couple of eggs for dinner instead of a slab of meat?

Any other suggestions? Sorry, I'm playing catch-up in this thread...

Many SNPs in ER Stress response, GCH1 and Choline Metabolism.

Try to get hold of TUDCA and limit too much protein intake. Do you have the MTHFR Mutation? If you do, try taking at least 2000 mcg of Metafolin per day (this should also boost BH4 levels since you cannot take Vitamin C)

Notice how many Homozygous SNPs you have in Choline metabolism. I am certain that you will feel much better with Choline supplementation but it will take some time. Choline will also help you boosting TMAO. So higher levels of TMAO + TUDCA will give you the right tools to handle ER Stress and Protein Misfolding

 

[mariovitali]

Production of trimethylamine from supplemental choline (27mM) has been noted in humans up to 18mM with Choline Chloride and 10mM with Choline stearate, but none with Lecithin.[12] Similar lack of effects have been noted with lecithin and betaine elsewhere.[7] A later study, however, did see an increase in TMAO upon phosphatidylcholine challenge conisting of eating two hardboiled eggs along with deuterium-labelled phosphatidylcholine; this increase was ablated when broad-spectrum antibiotics were administered to reduce intestinal microflora, suggesting that TMAO can be produced by intestinal microflora from choline sources.[13] A prospective observational study also linked TMAO blood levels to adverse cardiovascular events, with those in the highest quartile of TMAO levels having a hazard ratio of 2.54 (95% CI 1.96 to 3.28) compared to the highest quartile.[13]

http://examine.com/supplements/Choline/

@leela, @Ema


TMAO is generated from Choline+Gut Bacteria, it is proatherogenic but also a potent chaperone which folds proteins in the Endoplasmic Reticulum. My point here is that since our SNPs suggest a Choline deficiency then that means that TMAO levels should be also low. Supplementing with Choline means that TMAO levels will rise, hopefully to normal (but not high) levels.

Despite this fact there is a risk of making too much TMAO.

At the moment i am taking 700 mg of Choline per day. If i eat Eggs or meat, i limit this to 350 mg per day which means that my Choline intake is roughly 700 mg per day (150 mg more than RDA)

 

[leela]

@mariovitali but what has this to do with CB? Butyrate might cause choline to overproduce TMAO?

 

[mariovitali]

@mariovitali but what has this to do with CB? Butyrate might cause choline to overproduce TMAO?

CB creates Butyrate and Butyrate reduces TMAO :

Urine and feces samples were collected and analyzed by NMR-based metabolomics. Cheese and milk consumption decreased urinary choline and TMAO levels and increased fecal excretion of acetate, propionate, and lipid. Compared with milk intake, cheese consumption significantly reduced urinary citrate, creatine, and creatinine levels and significantly increased the microbiota-related metabolites butyrate, hippurate, and malonate. Correlation analyses indicated that microbial and lipid metabolism could be involved in the dairy-induced effects on blood cholesterol level.

Read more at: http://phys.org/news/2015-04-piece-french-paradox-puzzlecheese-metabolism.html#jCp

Now, if you are Choline deficient then most likely you also have low levels of TMAO. When you add CB to the mix then Butyrate is generated which lowers TMAO even more.

My theory is that people who try CB and feel worse can be attributed to very low TMAO levels and as a consequence even more inefficient Protein Folding capacity.

I think you can create a "CFS perfect storm" if you take CB and Whey Protein at the same day.

 

[Violeta]

@mariovitali This is interesting, I just remembered from when I was reading in the MTHFR forum that more than one person developed Parkinsonian symptoms from methylfolate. It was about 1.5 years ago, and I haven't read there much since then because I stopped the push on methylation, besides taking B2 and taking choline, which was my way of working on methylation. Back then no one was talking about ER stress, so I don't remember anyone tying it into that, and maybe it doesn't have anything to do with that part of Parkinson's, but maybe you will be the one to figure out if it does or not. Although I guess taking relatively large doses of methylfolate doesn't bother you.

 

[Violeta]

Can you be more specific @Violeta? I do have a lot of sneezing going on epsecially in the morning when i wake up (probably allergic rhinitis)

I don't know that sneezing would indicate a virus, but maybe a mast cell degranulation symptom (allergy). but since it only happens in the morning when you wake up, hypoxia could be part of it.

Most of the time the neurological diseases have a viral component, and I've been wondering if it's universal for some reason.

It can be difficult to nail if there's a virus involved because they are so stealth. Sometimes just chronic fatigue can be the main symptom. I was thinking about that last night, how the virus can be causing ER stress during dormancy, and no one ever thinks to look for a virus. Then some sort of trauma can bring it out full blown over night.

So unless someone is tested or has had the very obvious herpes cold sores, symptoms might appear to be simply the regular ER symptoms, which as the information you have provided shows can be caused by so many different things.

Maybe someone else knows how to tell if you have a virus causing the problem.

 

[mariovitali]

@mariovitali This is interesting, I just remembered from when I was reading in the MTHFR forum that more than one person developed Parkinsonian symptoms from methylfolate. It was about 1.5 years ago, and I haven't read there much since then because I stopped the push on methylation, besides taking B2 and taking choline, which was my way of working on methylation. Back then no one was talking about ER stress, so I don't remember anyone tying it into that, and maybe it doesn't have anything to do with that part of Parkinson's, but maybe you will be the one to figure out if it does or not. Although I guess taking relatively large doses of methylfolate doesn't bother you.

My theory is discussed on the first post of this Thread. In a nutshell : Methylation is only one part of the solution and mainly works by reducing Homocysteine (Hcy) levels which in turn reduces ER Stress.

But we all know by now that Methylation is not a solution. It does make you feel much better but it is not the solution.

I have no idea how CFS started to all of you. For me (and many others) it began when i took Finasteride, a 5-ar inhibitor. The condition is called PFS (Post-Finasteride Syndrome). But i believe that CFS = PFS. This mechanism also applies i believe for people that took Accutane as well.

Finasteride seriously impaires N-Linked Glycosylation which in turn has caused me severe ER Stress (add to the equation my DNA SNPs on Choline, Methylation, ER Stress control which already existed). I will never forget the first time i crashed. I had several episodes of Tinnitus, Urticaria (Hives) all over my body, difficulty swallowing, Red spots in my hands and feet..my whole body was in a mess. It took me 6 months to feel better.

Then i believe that a vicious cycle has happened. Uncontrolled ER Stress started affecting slowly my liver, my intestinal function, libido, brain function, platelet aggregation, NO production, Thyroid function, HPA Axis. A total mess... But the most important organ that was affected by ER Stress was -you guessed it right- the liver. Because this meant that each day that was passing by and ER Stress was uncontrollable my liver would take "ER Stress hits" and as a consequence the functioning of my liver was deteriorating slowly but steadily. Impaired Liver Function means that my body was less able to perform Methylation in a proper manner and to create important neurotransmitters and enzymes necessary for proper body functions including ER Stress control. After that ,all is going down hill on a vicious circle.

So the solution lies to making sure that the vicious cycle is stopped and time is given to your body to heal, starting from the liver.