Unfolded Protein Response and A Possible Treatment for CFS

[Countrygirl]

I just finished another set of analysis and i was hoping that i could take some feedback from all of you regarding some questions that i have :

a) Do you feel that CFS symptoms are less noticeable while you have a Cold / Flu?
b) Do you feel generally better during the summer and worse during the winter time?
c) How many of the childhood illnesses have you had?


Thanks in advance

I have posted again to answer question c. I had suspected polio aged 4, a severe bout of measles and mumps. I also took about twice as long as any of my peers to recover from infections, I recall.The onset of the ME followed a tetanus vaccine shortly before a very severe infection (not identified) with encephalitis which became severe after having my timber-framed house sprayed with organochlorines.

 

[mariovitali]

@Countrygirl

Makes sense. The Theory discussed here is that this incident has generated ER Stress. If you have Methylation problems then that means that the handling of ER Stress is even more impaired. If you are getting stressed easily then add yet another fact with negative impact.

 

[mariovitali]

@Countrygirl @Ema @adreno @JPV @Gondwanaland


Since you are most active in this Thread, i would really appreciate if you could read the following because i believe it is very important information. ( this was added on the original post today) :

Some Causes for Misfolded Proteins / ER Stress (i will be updating the list as necessary) :

a) Methylation problems
b) Celiac Disease (Gluten Intolerance)
c) Impaired BH4 (Tetrahydrobiopterin) Production & Phenylketonuria
d) Impaired N-Linked Glycosylation (e.g from Statins , HmG-CoA Inhibitors)
e) Certain viruses (Credit to @@adreno - see his post below)
f) Impaired Calcium Homeostasis
g) Methamphetamine Use (Possibly)
h) Sedentary Lifestyle
i) Insulin Resistance
j) Obesity
k) High Cortisol from Stress and Weather Changes (Credit to @Ema - see her post about Weather Changes and how it could be affecting us below)


Now imagine the following scenario : There exists a bucket which is filled by any of the above causes with water. If you do not act either by avoiding filling the bucket with water and/or by making sure that some of the water is thrown at regular intervals then the bucket will eventually overfill. And this means trouble.

In other words, if you have ANY of the above stressors, your "Bucket" is being filled and you must stop this. My theory is that this is the problem behind the Methylation Support Regimen that was proposed by Fredd / Rich Van Konynenburg. They dealt with one aspect of ER Stress only (namely Methylation). But if you have more than one Stressor going around then you will not have a full recovery.

 

[adreno]

Point e) would be pathogens in general, not limited to viruses. My post was actually about bacteria.

 

[JPV]

You might want to include any number of environmental toxins to the list...

Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance

Roundup induced the opening of L-type voltage dependent calcium channels as well as ryanodine receptors, initiating ER stress and leading to calcium overload and subsequent necrosis. Glutathione was depleted due to upregulation of several glutathione-metabolizing enzymes. This suggests that Roundup would interfere with spermatogenesis, which would impair male fertility.

 

[mariovitali]

@JPV That's Great, Thanks. Added to original post.

 

[JPV]

Here's another study...

Roundup disrupts male reproductive functions by triggering calcium-mediated cell death in rat testis and Sertoli cells.

Glyphosate is the primary active constituent of the commercial pesticide Roundup. The present results show that acute Roundup exposure at low doses (36 ppm, 0.036 g/L) for 30 min induces oxidative stress and activates multiple stress-response pathways leading to Sertoli cell death in prepubertal rat testis. The pesticide increased intracellular Ca(2+) concentration by opening L-type voltage-dependent Ca(2+) channels as well as endoplasmic reticulum IP3 and ryanodine receptors, leading to Ca(2+) overload within the cells, which set off oxidative stress and necrotic cell death.

If I'm not mistaken infertility seems to be a major component of Post-Finasteride Syndrome. Perhaps there are several different environmental toxins at work here causing a cumulative effect. The ones you are focusing on may be the "straw that broke the camel's back" but might not be the only or even the main cause.

BTW, the premise of the BBC series "Utopia" revolves around a major corporation colluding with the government in a population control scheme that involves putting additives in the food supply that causes infertility.

 

[mariovitali]

@JPV

It could be, although the most probable mechanism is that we all used Propecia for hairloss. The chain goes like this :

Finasteride -> 5AR inhibition -> SRD5A3 downregulation -> Impaired N-Linked Glycosylation -> Improper Folding of Proteins -> ER Stress -> Unfolded Protein Response

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.

N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5alpha-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

and this :

Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins.


Endoplasmic reticulum (ER) stress in intestinal secretory cells has been linked with colitis in mice and inflammatory bowel disease (IBD). Endogenous intestinal glucocorticoids are important for homeostasis and glucocorticoid drugs are efficacious in IBD. In Winnie mice with intestinal ER stress caused by misfolding of the Muc2 mucin, the glucocorticoid dexamethasone (DEX) suppressed ER stress and activation of the unfolded protein response (UPR), substantially restoring goblet cell Muc2 production. In mice lacking inflammation, a glucocorticoid receptor antagonist increased ER stress, and DEX suppressed ER stress induced by the N-glycosylation inhibitor, tunicamycin (Tm). In cultured human intestinal secretory cells, in a glucocorticoid receptor-dependent manner, DEX suppressed ER stress and UPR activation induced by blocking N-glycosylation, reducing ER Ca(2+) or depleting glucose. DEX up-regulated genes encoding chaperones and elements of ER-associated degradation (ERAD), including EDEM1. Silencing EDEM1 partially inhibited DEX's suppression of misfolding-induced ER stress, showing that DEX enhances ERAD. DEX inhibited Tm-induced MUC2 precursor accumulation, promoted production of mature mucin, and restored ER exit and secretion of Winnie mutant recombinant Muc2 domains, consistent with enhanced protein folding. In IBD, glucocorticoids are likely to ameliorate ER stress by promoting correct folding of secreted proteins and enhancing removal of misfolded proteins from the ER.

Add to the 'mix' that i have impaired Methylation / BH4 Production, i took Finasteride and therefore the "bucket" filled up quite fast. The result was a major crash (=UPR) and then it appears that my body felt into a vicious cycle that had to be stopped.

Do you see how this all makes sense?

 

[JPV]

I understand, I just think it would be hard to point to any single toxic environmental factor when we are exposed to so many of them. There's always the possibility that Propecia just dealt the final blow to a bucket that was already almost filled. I've never used it but have similar symptoms so it certainly wasn't a factor in my illness.

If my time on this forum has taught me anything, it's that you shouldn't be too confident in any theory because at some point you're going to have a major hole punched into it. I think that a lot of the theories that people come up with work by an entirely different mechanisms than what they have imagined. The body and it's interactions are just too complex to define so easily. If this wasn't the case, we all would have been cured by now.

 

[mariovitali]

I understand, I just think it would be hard to point to any single toxic environmental factor when we are exposed to so many of them. There's always the possibility that Propecia just dealt the final blow to a bucket that was already almost filled. I've never used it but have similar symptoms so it certainly wasn't a factor in my illness.

If my time on this forum has taught me anything, it's that you shouldn't be too confident in any theory because at some point you're going to have a major hole punched into it. I think that a lot of the theories that people come up with work by an entirely different mechanisms than what they have imagined. The body and it's interactions are just too complex to define so easily. If this wasn't the case, we all would have been cured by now.

I see your point there @JPV, i do get carried away easily don't i? ;-)

It's just the fact that i tried everything, spent thousands of Dollars to Supplements/Doctors and after so many attempts suddenly everything works.

Time will tell.

 

[JPV]

I understand, I think everyone gets that way when they've made such a breakthrough. You obviously know how debilitating these sorts of conditions can be and seem to be sharing your knowledge out of empathy for others. I think it's very generous for you to come here to share it with other people in need. Just don't be disappointed if people are hesitant to try something new as so many here have been disappointed with such things in the past.

My supplements should arrive today so I should have something to report back sometime next week.

 

[mariovitali]

@JPV

Thank you, i really appreciate what you said and everyone's comments and feedback.


Good Luck with the regimen.

 

[JPV]

Beyond The Mitochondria: Endoplasmic Reticulum Stress

Mitochondrial interventions are the mainstay of many ME/CFS and fibromyalgia treatment protocols. Well known mitochondrial nutrients such as CoQ10, NADH, D-ribose, carnitine among others, likely make up your supplement drawer.

These nutrients function to relieve mitochondrial stress which is characterized by inadequate ATP production and oxidative stress. These all are valuable supports and provide mild relief for many patients. But why do some experience no relief with mitochondrial nutrients?

Could it be because mitochondrial damage is NOT the prime driver, but a consequence of something else?

Could it be that mitochondrial damage comes about as a consequence of damage to another key cellular organelle?

Enter the endoplasmic reticulum...

Inside the cell, the main function of the endoplasmic reticulum (ER) is to fold and transport proteins. Like a busy laundromat, the ER can only handle a finite amount of protein folding before it reaches capacity. If overloaded, the ER institutes a shutdown mechanism in an attempt for quality control. In a complex cascade of events, the ER begins to unfold proteins, halting new folding, and cleaning up misfolded proteins in an effort to get back on track.

If the machinery still can’t catch up with its duties, the alarms go off that signal the ultimate demise of the entire cell--apoptosis. Chronic ER stress is believed to be involved in a number of degenerative diseases including Parkinson’s, Alzheimer’s, ALS, cardiovascular disease, diabetes, bipolar disorder, cancer, autoimmunity, and others.

 

[mariovitali]

@JPV

That is very interesting, Thank you!


Since you will be trying the regimen, try to slowly add each Supplement so you know what works and what doesn't.

I would try with the following order :


1) Methylation ( i am assuming you already do that according to your mutations if they are present) , Magnesium (ensure Calcium Homeostasis), D3, Vitamin C

2) Selenium

and then, the "Big Guns"

4) Curcumin (Use empty tablets of 250 mg, fill them up and have 2 daily with food or use at rice/salads sprinkled)
<wait 3 days>
5) TUDCA
<wait 3 days>
6) Resveratrol

 

[JPV]

@mariovitali, LOL, I already took everything, but the Curcumin, all at once yesterday

I pretty much already had everything on your list except for the TUDCA and Resveratrol, which I ordered from Amazon. I have some Turmeric in the kitchen but I think it may not be the most effective way to get Curcumin. Looks like there's only 136mg of Curcumin per tablespoon of Turmeric. How critical do you suppose the Curcumin is?

I also noticed, on the solvepfs.com forum, that you mentioned that you're going to be trying to cut down on the supplements that you're taking and TUDCA was first on your list. Is this because you feel that it's not as effective as the other items or does it purely come down to cost? All the other supplements have been widely used by many people on this forum, with generally marginal success, however I've never heard of anyone here experimenting with TUDCA. I have a sneaking suspicion that if this protocol is indeed effective, TUDCA may be the key component.

 

[mariovitali]

@JPV ,

LOL

It's great that you had a look over solvepfs as well.

Please notice that i said in my post in this forum that the regimen i am proposing for CFS is somewhat different from what you saw on the solvepfs forum. The difference being in upregulation of SRD5A3 gene through Spinach consumption (Spinach contains Dolichol). SRD5A3 is a key gene for proper N-Linked Glycosylation and this could also be a key component (and perhaps i should clarify this to my first post).

You are right, taking Curcumin is a bit of a problem. Meriva Extract is very potent and i it could be a DHT Inhibitor. What i usually do is to take empty capsules and put Turmeric in them and then have two of these with Food.

Unfortunately, this is all experimental so i am not in any position to know if CFS Sufferers should also get Dolichols from their diet. However, N-Linked Glycosylation is a key function of Proper Protein Folding within the Endoplasmic Reticulum.

Apart from TUDCA, please notice that the regimen is not just about supplements, because It lists specific Topics/Actions/Foods that should be avoided (DHT Inhibitors, P450 Inhibitors, HmG-CoA inhibitors, MSG, Aspartame, etc)


Good Luck!

 

[JPV]

@mariovitali, I did see the dietary recommendations. I've pretty much been following the Perfect Health Diet for several months now. I also cut out a lot of histamine containing foods so I have a pretty limited diet consisting of mainly beef, chicken, white rice, potatoes and various vegetables such as lettuce, zucchini, carrots, onions, etc.. I rarely eat any fruits.

I'm also taking Resistant Starch, in the form of Potato Starch, and a Japanese probiotic called Miyarisan that contains Clostridium butyricum. This is one of the best things that I've found for my condition so far. I feel that modifying gut microbiota may well prove to be one of the more promising treatments to provide relief from numerous chronic health conditions.

Of the tree main items, TUDCA, Curcumin and Resveratrol, how would you rate them in order of importance?

 

[mariovitali]

@JPV,

I have no idea what works better unfortunately. Maybe it is all synergistic.


FYI Curcumin+Selenium+Resveratrol+TUDCA+ Miyarisan are all HDAC1 inhibitors!



http://www.ncbi.nlm.nih.gov/pubmed/16850746

http://www.fasebj.org/cgi/content/meeting_abstract/24/1_MeetingAbstracts/413.1

http://www.ncbi.nlm.nih.gov/pubmed/25538147

http://www.ncbi.nlm.nih.gov/pubmed/24023672

 

[JPV]

FYI Curcumin+Selenium+Resveratrol+TUDCA+ Miyarisan are all HDAC1 inhibitors!

My focus with Clostridium butyricum is in increasing Butyric Acid, for gut repair, and the possibility that it may act as a potential antagonist against such pathogens as Candida albicans and H. pylori, as I suspect I may be suffering from some sort of fungal infection.

Of course, as I mentioned before, these interventions may work in either different ways than what we suspect or on multiple biochemical functions at the same time. Even with scientific papers backing up the research, It's all still guesswork. Bottom line, as much as we may like to intellectualize these things... I think it's still just a hit-and-miss random process. Either we get lucky, or we don't.

One thing for sure, I strongly believe that inflammation is a major contributor to most chronic illnesses. Anything that helps to alleviate it is bound to be helpful.

 

[mariovitali]

@JPV,

FYI, It is possible that some days after you start the regimen you will get flu-like symptoms. The best way to describe it is that i felt as i was about to get sick but i never did. I also had a similar feeling when i started the Methylation protocol.

This lasted for about 10 days if i am not mistaken.


And something else which i believe is very interesting : I can hear better than i used to. I confirmed it with a special app that is used as a Dog Whistle. In other words the frequency response of my ears has improved!

I know that i shouldn't get excited lol

Oxidative Stresses and Mitochondrial Dysfunction in Age-Related Hearing Loss

Age-related hearing loss (ARHL), the progressive loss of hearing associated with aging, is the most common sensory disorder in the elderly population. The pathology of ARHL includes the hair cells of the organ of Corti, stria vascularis, and afferent spiral ganglion neurons as well as the central auditory pathways. Many studies have suggested that the accumulation of mitochondrial DNA damage, the production of reactive oxygen species, and decreased antioxidant function are associated with subsequent cochlear senescence in response to aging stress. Mitochondria play a crucial role in the induction of intrinsic apoptosis in cochlear cells. ARHL can be prevented in laboratory animals by certain interventions, such as caloric restriction and supplementation with antioxidants. In this review, we will focus on previous research concerning the role of the oxidative stress and mitochondrial dysfunction in the pathology of ARHL in both animal models and humans and introduce concepts that have recently emerged regarding the mechanisms of the development of ARHL.

Caloric Restriction induces HSP-70 (So is Curcumin, Resveratrol and TUDCA)