Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

@JPV @Mogwai


Did you have any positive effects from the regimen?


I will update with new information and regimen options. N-Acetylglucosamine appears to be very important and it has been tried by other members with positive results.

@JPV how are you doing with Miyarisan? It appears that mine never made it here so i will have to contact the seller at EBay

 

[JPV]

Did you have any positive effects from the regimen?

@JPV how are you doing with Miyarisan? It appears that mine never made it here so i will have to contact the seller at EBay

Sorry, I only did it for a week so there is very little to report. Nothing negative though. I will probably try again soon but I seem to finally be making progress with Miyarisan, after 2 months, so I'd like to focus on that for now. In the past I have made the mistake of trying too many things at once so I will probably go back on your regimen once I determine the extent of how much the Miyarisan can help me. I however did add a Bifido complex probitotic this weekend but at least it's another probiotic, which is my main focus for now.

 

[Mogwai]

@mariovitali I received the Choline Bitartate last week, but haven't started on it yet.

I've been talking a multi-vit/mineral for a very short time - which I am tolerating well. I will introduce the CB in a week or two.

 

[Tunguska]

This jumped out at me: https://proteincyclingdiet.wordpress.com/article/protein-cycling-diet-2s3nmvrwklbxs-1/

This book presents how inducing autophagy by diet manipulation may delay or prevent the neurodegenerative diseases of aging and unlucky genetics.

3 Protein Folding

 

[mariovitali]

This jumped out at me: https://proteincyclingdiet.wordpress.com/article/protein-cycling-diet-2s3nmvrwklbxs-1/

@Tunguska
Thank you for the link.

Dear All,

I will update the first post of this thread with the latest information.

My current regimen has changed from the one discussed at the first post. Curcumin and Resveratrol is out, NAG is added and Mucuna Dopa. Mucuna Dopa is part of my regimen because of specific SNPs that impair Dopamine production. Note that N-Acetylglucosamine (NAG) becomes a very important supplement because it prevents Protein Misfolding by boosting UDP-Glcnac (see below why this is important) *and* suppresses T-Cell hyperactivity.

Multiple Sclerosis Attacks Suppressed By Glucosamine-Like Supplement

In mouse models of MS-like autoimmune disease, Demetriou and his team found that GlcNAc given orally to those with leg weakness suppressed T-cell hyperactivity and autoimmune response by increasing sugar modifications to the T-cell proteins, thereby reversing the progression to paralysis.

The study comes on the heels of others showing the potential of GlcNAc in humans. One reported that eight of 12 children with treatment-resistant autoimmune inflammatory bowel disease improved significantly after two years of GlcNAc therapy. No serious adverse side effects were noted.

and

Preventing Stress with Sugar

Denzel et al. identified three alleles of gfat1 in Caenorhabditis elegans that conferred resistance to tunicamycin exposure, which inhibits N-linked glycosylation and causes ER stress and death. Genetic and siRNA analyses indicated that these alleles produced dominant gain-of-function mutations, and gfat1-overexpressing worms also resisted tunicamycin-induced lethality. gfat1 mutant worms had increased abundance of free UDP-HexNAcs (a pool of UDP-GlcNAc and UDP-N-acetyl-galactosamine), and supplying worms with exogenous GlcNAc or UDP-GlcNAc inhibited tunicamycin-induced lethality. Worms given exogenous GlcNAc or with gfat1 mutations had reduced aggregation of overexpressed mutant proteins that misfold in the ER. Worms with gfat1 mutations or overexpressing gfat1, or those given moderate amounts of exogenous GlcNAc lived longer in the absence of tunicamycin

and finally

(Note : HBP=Hexosamine Biosynthetic Pathway, HBP Metabolites include UDP-Glcnac which is boosted by N-Acetylglucosamine ) :

Sugarcoating ER Stress

ER stress-induced HBP activity may lead to a general improvement of cellular protein folding capacity via N-glycosylation but, in addition, may regulate specific cellular processes. Indeed, it is somewhat surprising that HBP activity causes induction of protein degradation pathways when considering that enhanced glycosylation should improve protein folding efficiency. Interestingly, Denzel et al. (2014) did not observe global changes in N-glycosylation upon HBP activation and suggest that proteins of the ERAD and autophagy machinery may be directly regulated by glycosylation. Thus, activating the clearance of misfolded proteins, rather than improving folding efficiency, may be the primary protective mechanism of the HBP upon ER stress.
The UPR and the HBP play important roles in neurodegenerative and metabolic diseases. The new studies highlight a physiologically significant mechanistic link between these pathways and could open avenues to new therapeutic approaches. In particular, the protective effects of supplementation with HBP metabolites may represent a promising therapeutic strategy.

My current regimen is as follows :


8:00 AM : Metafolin 1000 mcg, Dibencozide, N-Acetylglucosamine 700 mg, Mucuna Dopa 100 mg

10:00 Choline 350 mg

12:00 P5P 50mg, Selenium 100 mcg, Taurine 500 mg

16:00 TUDCA 250 mg, N-Acetylglucosamine 700 mg

20:00 N-Acetylglucosamine 700 mg


Not only i continue to feel great, my friends are telling me i am looking younger!! ;-)

 

[Violeta]

@mariovitali Is there a particular diet you would recommend as being helpful? I see the protein recycling diet mentioned above, does that have any merit?

 

[mariovitali]

@mariovitali Is there a particular diet you would recommend as being helpful? I see the protein recycling diet mentioned above, does that have any merit?

First, please check the section titled "STAY AWAY FROM" in my first post of this thread.

Most of the information contained in the Protein Recycling diet seems to be spot on and it is aimed on minimizing Protein Misfolding.

Regarding my diet : I do eat Protein although not too much. I also do not eat too much Bread, Pasta and Gluten sources since as it appears i have Gluten Intolerance although not that bad. Whey Protein causes serious problems since it loads our bodies with Protein that cannot be properly folded within the ER of the cell.

Make no mistake about it: The more you let ER Stress taking place, many vital organs are being affected and you have to stop this. Liver, Kidneys the HPA Axis, Neurons, you name it. This is why there are so many symptoms in CFS.

I remember when i decided not to have any source of Protein for 15 days. Then one night i ate lots of meat. Sure enough a couple of hours later i had a very nasty reaction of Sensorineural Hearing Loss (SSHL) due -of course- to Protein Misfolding and a subsequent Unfolded Protein Response.

See below that tunicamicyn inhibits N-Acetylglucosamine transferase :

A novel animal model of hearing loss caused by acute endoplasmic reticulum stress in the cochlea.
Fujinami Y1, Mutai H, Mizutari K, Nakagawa S, Matsunaga T.
Author information
Abstract
Many stimuli such as ischemia, hypoxia, heat shock, amino acid starvation, and gene mutation, exhibit a cellular response called endoplasmic reticulum (ER) stress. ER stress induces expression of a series of genes, leading to cell survival or apoptosis. Previously, we found that in an animal model of hearing loss caused by acute mitochondrial dysfunction, several ER stress markers including C/EBP homologous protein were induced in the cochlear lateral wall. To elucidate the mechanism of hearing loss caused by ER stress, we established a novel animal model of hearing loss by perilymphatic perfusion of tunicamycin, an ER stress activator that inhibits N-acetylglucosamine transferases. Subacute and progressive hearing loss was observed at all sound frequencies studied, and stimulation of ER stress marker genes was noted in the cochlea. The outer hair cells were the most sensitive to ER stress in the cochlea. Electron microscopic analysis demonstrated degeneration of the subcellular organelles of the inner hair cells and nerve endings of the spiral ganglion cells. This newly established animal model of hearing loss from ER stress will provide additional insight into the mechanism of sensorineural hearing loss.

 

[mariovitali]

Unfortunately i cannot edit my previous post regarding my latest regimen. Some minor mistakes there so i am writing here my Regimen again. Whatever comes with a (*) means that i consider this supplement something applicable for me, based on my SNPs which means that Mucuna Dopa and 5-HTP may not be applicable to you.


8:00 - (Try not to eat anything for an hour)

-NAG (N-Acetylglucosamine) 700 mg
-Dibencozide (Tablet is 8.6 mg, i take 1/4 of a tablet)
-Metafolin 2000 mcg (note that i made a mistake and wrote 1000 mcg in my previous post)
-Mucuna Dopa 200 mg (*)


10:00
-Choline 350 mg

12:00
-Selenium
-P5P
-Taurine 500 mg


16:00

-TUDCA 250 mg
-NAG 700 mg

20:00
-Vitamin C 500 mg
-NAG 700 mg
-5-HTP 100 mg (*)

 

[Gondwanaland]

Whey Protein causes serious problems since it loads our bodies with Protein that cannot be properly folded within the ER of the cell.

I would say that the dosage makes the poison here. I have been taking whey for about 4 months now and finding it very beneficial. The high lysine content eliminates my ammonia issues plus it is proven to be preventive against oxalate issues. I take only 3 tsps daily and feels much better than suplementing Lysine HCl.

 

[Violeta]

@mariovitali , Thank you for your reply, and actually for the whole thread. This is very interesting and all the material you've provided in this thread will take me some time to understand. I think it will all be helpful to me. I've had chronic fatigue, headaches, and symptoms of Lyme for a long time.

Food does cause me a lot of issues. I had very obvious issues caused by protein for many years, but never thought of considering protein folding. Although I was fairly sure that if I didn't figure things out I would surely end up with one of the severe diseases that affect the brain, such as Alzheimer's.

I also unfortunately have a hard time finding carbs that don't bother me, too, so figuring out how to increase carb intake and now reduce protein will be a challenge.

I found the thread because of finding something that made me interested in the mevalonate pathway and was surprised to see that many of your suggestions to avoid and to supplement match my current bottom line.

I've been looking into receptor channels recently, especially TRPV1, so I googled to see if there is a connection to ER stress, and yes, there is. But I have to admit I don't understand the topic very well. I do understand on the surface calcium channels, but I'm still rather surprised at the extent of the damage related to them.

http://www.ncbi.nlm.nih.gov/pubmed/17332266
I do wonder if there is a necessity for pretoxicity of some sort for trpv1 agonists to cause stress or damage, I don't know the right term.

Thanks again

 

[mariovitali]

I would say that the dosage makes the poison here. I have been taking whey for about 4 months now and finding it very beneficial. The high lysine content eliminate my ammonia issues plus it is proven to be preventive against oxalate issues. I take only 3 tsps daily and feels much better than suplementing Lysine HCl.

Hi Gondwanaland,

Could you tell me which symptoms has Whey Protein ameliorated and which symptoms you currently have which seem to persist?

Which supplements are you currently taking?

 

[mariovitali]

@Violeta

Thank you for mentioning TRPV1. I am using certain analytical techniques to go through thousands of PubMed entries and then trying to find associations between our symptoms, genes, etc.

I will let you know as soon as i fins something more concrete regarding TRPV1.

 

[Gondwanaland]

Hi Gondwanaland,

Could you tell me which symptoms has Whey Protein ameliorated and which symptoms you currently have which seem to persist?

Which supplements are you currently taking?

It got rid of my morning brain fog (ammonia) and I suppose it is acting synergistically with my other supps to abate oxalate problems (joint pain above all). My current protocol is here. Increasing doses tomorrow.

 

[mariovitali]

It got rid of my morning brain fog (ammonia) and I suppose it is acting synergistically with my other supps to abate oxalate problems (joint pain above all). My current protocol is here. Increasing doses tomorrow.

I had a look at your SNPs. How come you are not taking Metafolin (since you are Homozygous to MTHFR A1298C)?

 

[Gondwanaland]

I had a look at your SNPs. How come you are not taking Metafolin (since you are Homozygous to MTHFR A1298C)?

Because of +/+MAO-A. The anxiety is unbearable. Apparently MTHFR has been working acceptably, and MAO-A seems more like the problem.

I will have to titrate MFolate carefully also due to uric acid issues. Last time I tried 50mcg and couldn't handle it. I am hoping to put my hands on some FMN/R5P soon, so I can balance folate and see things go smoothly

For the 1st time now I am tolerating regular riboflavin b/c I am having proper thyroid replacement. It is a snowball!!!

 

[mariovitali]

@Gondwanaland

Are you hypothyroid? If yes, is it Subclinical / Hashimoto's?

 

[Gondwanaland]

@Gondwanaland

Are you hypothyroid? If yes, is it Subclinical / Hashimoto's?

Hashi's and started treating with a TSH of 4 due to antibodies being too high. I take compounded T4/T3 and apparently this is key to tolerate riboflavin. It also gave me a cognition boost.

I forgot to add the multimineral I am taking to my regime list (Zn 8mg, Cu 500mcg, Mn 300mcg, Se 80mcg).

 

[Violeta]

@Violeta

Thank you for mentioning TRPV1. I am using certain analytical techniques to go through thousands of PubMed entries and then trying to find associations between our symptoms, genes, etc.

I will let you know as soon as i fins something more concrete regarding TRPV1.

Thank you, can you put dopamine in that search, or will it automatically come up if it's involved, which I do see that it is.

 

[Violeta]

Hashi's and started treating with a TSH of 4 due to antibodies being too high. I take compounded T4/T3 and apparently this is key to tolerate riboflavin. It also gave me a cognition boost.

I forgot to add the multimineral I am taking to my regime list (Zn 8mg, Cu 500mcg, Mn 300mcg, Se 80mcg).

@Gondwanaland I was just looking up n-aceyl-glucosamine and saw several people saying that it's good for an oxalae symptom.

http://www.amazon.com/Source-Natura..._121_cr_2?ie=UTF8&refRID=1GFB3HP7CWM908PY37KQ

Taurine is good for oxalate issues, too, forgive me if you already know this.

 

[mariovitali]

@Violeta

FYI, I suffer from impaired production of Dopamine and also impaired metabolism of it.

@Gondwanaland

Please be aware that Manganese (Mn) if taken in excess, it induces ER Stress.