Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

@Violeta
Regarding Finasteride problems I believe that the culprit was SRD5A3 downregulation which subsequently impairs N-linked glycosylation.

Although we can never be sure
;-)

 

[Violeta]

@Violeta
Regarding Finasteride problems I believe that the culprit was SRD5A3 downregulation which subsequently impairs N-linked glycosylation.

Although we can never be sure
;-)

Yes, just thought this was an interesting tangent. I remember that you explained the problem that finasteride causes at the beginning of the thread.

 

[Violeta]

If one would ask me what this all means is that it is very probable that all problems originate from the liver.

Not sure if anyone would find this interesting, but NAFLD, uric acid, and endoplasmic reticulum.

http://www.ncbi.nlm.nih.gov/pubmed/25111690

 

[Violeta]

@mariovitali , are you eating the spinach?

 

[mariovitali]

I don't eat it everyday now but once every ten days for sure. Spinach contains dolichol which aids proper protein folding

 

[Violeta]

I don't eat it everyday now but once every ten days for sure. Spinach contains dolichol which aids proper protein folding

Yeah, I was reading at the forum you linked on the first page of this thread. Ingenious.

And thanks again for bringing the information over here.

 

[Violeta]

Endoplasmic reticulum stress and liver diseases.

http://www.ncbi.nlm.nih.gov/pubmed/21145844

 

[mariovitali]

@JPV

Probably you have seen this but i also post it here for reference :

Protective effects of phosphatidylcholine on oxaliplatin-induced neuropathy in rats.

PC attenuated oxidative stress by increasing antioxidant levels. In histopathological evaluation, the PC administrated group maintained normal morphologic appearance of sciatic nerves, similar to the control group. In spinal cords, however, no significant difference between the oxaliplatin-alone group and the oxaliplatin+PC group was observed. In the immunohistochemical evaluation, PC administration ameliorated oxaliplatin-induced microglial activation.
It is suggested that PC has a therapeutic potential against oxaliplatin-induced peripheral neuropathy due to its antioxidant property and modulation of microglial activities.

Here is a snapshot from the software i use. Notice the association found between Choline deficiency and "Microglia" and other elements of the regimen (Curcumin, Resveratrol) but also Butyrate.

 

[girlinthesnow]

@mariovitali Just curious, have you ever added calorie restriction to your searches?

 

[mariovitali]

@mariovitali Just curious, have you ever added calorie restriction to your searches?

No but this is probably a good idea. Caloric Restriction up-regulates HSP-70 which according to the theory of this Thread is a good thing.

I will add the PubMed entries for Caloric Restriction, re-run the analysis and post the results

 

[mariovitali]

New info regarding TUDCA :

The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases.

Tauroursodeoxycholic acid (TUDCA) is the taurine conjugate of ursodeoxycholic acid (UDCA), a US Food and Drug Administration-approved hydrophilic bile acid for the treatment of certain cholestatic liver diseases. There is a growing body of research on the mechanism(s) of TUDCA and its potential therapeutic effect on a wide variety of non-liver diseases. Both UDCA and TUDCA are potent inhibitors of apoptosis, in part by interfering with the upstream mitochondrial pathway of cell death, inhibiting oxygen-radical production, reducing endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response (UPR). Several studies have demonstrated that TUDCA serves as an anti-apoptotic agent for a number of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition,TUDCA plays an important role in protecting against cell death in certain retinal disorders, such as retinitis pigmentosa. It has been shown to reduce ER stress associated with elevated glucose levels in diabetes by inhibiting caspase activation, up-regulating the UPR, and inhibiting reactive oxygen species. Obesity, stroke, acute myocardial infarction, spinal cord injury, and a long list of acute and chronic non-liver diseases associated with apoptosis are all potential therapeutic targets for T/UDCA. A growing number of pre-clinical and clinical studies underscore the potential benefit of this simple, naturally occurring bile acid, which has been used in Chinese medicine for more than 3000 years.

 

[mariovitali]

Dear All,


FYI : A Case of NAFLD in the forum :


http://forums.phoenixrising.me/inde...1-years-of-cfs-me-diagnosed-with-nafld.38383/

 

[Gondwanaland]

@mariovitali is there any sigificant difference between NAG and glucosamine sulfate? I can't get NAG locally, and currency conversion is getting prohibitive by the minute...

 

[mariovitali]

@mariovitali is there any sigificant difference between NAG and glucosamine sulfate? I can't get NAG locally, and currency conversion is getting prohibitive by the minute...

I found references only for N-Acetylglucosamine (NAG) but you could give it a try.

 

[Hip]

Very interesting thread and very interesting protocol, @mariovitali.

It appears that the subject that contains the largest percentage of mentions on Misfolded Proteins is HSP70, then Calcium Homeostasis.

That software you wrote looks very interesting. I can see how you made the link to HSP70, but can I ask, how did you work out that increasing HSP70 would be beneficial for reducing endoplasmic reticulum stress?


By the way, although I am not too clear about how your software works (I will have to re-read your posts a few times to try to understand it), I see that you are keyword searching through downloaded PubMed abstracts to find significant associations between medical terms.

So my question is: could you perform the same kind of association search just using the PubMed advanced search page?

For example, if you advanced search PubMed for the term "Misfolded Proteins" in the title/abstract field, and for "Calcium Homeostasis" in the in the title/abstract field, you get 24 results that contain both terms (see here).

Or would that not work?

I broke into Hives and had Tinnitus, Joint Pains, Difficulty swallowing,Impotence and Red Spots in my palms. The Doctors couldn't understand what was happening but now i know : Egg whites contain a lot of Phenylalanine. By taking Finasteride and at the same time being BH4 deficient i triggered a severe Unfolded Protein Response.

You may be interested that coxsackievirus B, which is strongly linked to ME/CFS, can sometimes produce the symptoms of red spots on the hands, because it can cause hand, foot and mouth disease (HFMD). See here for images of the red spots from HFMD. Although normally it is coxsackievirus A that mainly causes HFMD; coxsackievirus A is not linked to ME/CFS.

I know you said that finasteride appeared to cause your ME/CFS, but even if this drug played a significant causal role in your ME/CFS, might it be possible that you unknowingly caught a virus around the time you were taking finasteride, causing those red spot symptoms, and then the combination of finasteride + virus led to ME/CFS?

Generally I think ME/CFS is caused by a combination of factors.


Incidentally, coxsackievirus B, like many other viruses, affects the endoplasmic reticulum:

• The 2B protein of coxsackievirus B inhibits apoptosis by altering intracellular calcium. The 2B protein decreases calcium levels in the endoplasmic reticulum and the Golgi apparatus (resulting in a down-regulation of calcium signaling between these and the mitochondria), and increases the influx of extracellular calcium. Ref: 1

• The 3A protein of coxsackievirus B interferes with endoplasmic reticulum-to-Golgi transport. Ref: 1

 

[mariovitali]

Hi @Hip and Thanks!


Increasing HSP70 is very beneficial (given that the Theory of this thread is correct). Here is why :

The role of Hsp70s in the folding of non-native proteins can be divided into three related activities: prevention of aggregation, promotion of folding to the native state, and solubilization and refolding of aggregated proteins. In the cellular milieu, Hsp70s exert these activities in the quality control of misfolded proteins and the co- and posttranslational folding of newly synthesized proteins. Mechanistically related but less understood is the role of Hsp70s in the disassembly of protein complexes such as clathrin coats, viral capsids and the nucleoprotein complex, which initiates the replication of bacteriophage λ DNA. A more complex folding situation exists for the Hsp70-dependent control of regulatory proteins since several steps in the folding and activation process of these substrates are assisted by multiple chaperones.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773841/

Anything that either :

-Prevents Misfolded Proteins from being generated in the ER
-Enhances the Quality Control Mechanism of the ER
-Facilitates the proper re-folding of Proteins

...is our friend

Actually, you are absolutely right for not understanding how the software works since i haven't given any reasonable explanation for it! At the moment i am at Holidays but as soon as i come back i will give all necessary explanations.

I am pretty confident (although you can never be sure) that the Crash i got was from Finasteride (actually when i quitted Finasteride) and not a virus since the exact chain of events (Quitting Finasteride=>Crashing=>Symptoms) occurred to all of us that had problems (Post-Finasteride Syndrome) from quitting Finasteride.

Regarding PubMed : The example you gave could work since i can submit programmatically any query to the PubMed server.


Hope this helps!


Mario

 

[Hip]

I am pretty confident (although you can never be sure) that the Crash i got was from Finasteride (actually when i quitted Finasteride) and not a virus since the exact chain of events (Quitting Finasteride=>Crashing=>Symptoms) occurred to all of us that had problems (Post-Finasteride Syndrome) from quitting Finasteride.

Are you saying that you had post-finasteride syndrome (PFS), which has many symptoms in common with ME/CFS (and may conceivably share many of the same metabolic pathophysiologies), and your innovative HSP70-boosting protocol, which reduces endoplasmic reticulum stress, cured your PFS, and so may well have benefits for ME/CFS as well?

I am certainly going to be trying this protocol. It looks very promising.



Have you posted your success story in treating your PFS condition on a post-finasteride syndrome forum like this one? Your success could provide tremendous help to other PFS sufferers, if it works equally well for them.

I am hoping it is going to be helpful for ME/CFS patients like myself whose condition was triggered by a virus.



Can I ask: once you started taking the supplements in your HSP70-boosting protocol, how long did it take before you noticed the first improvements in your symptoms, and how long before you were fully recovered? Was it a matter of days, weeks, or months?

Do you think you are now fully cured, in the sense that if you stopped taking your protocol, you would remain recovered and symptom-free? Or do you think some PFS symptoms might return if you stopped taking the supplements?



I don't want to disturb your holiday, though, so I am happy to wait for your explanations when you come back.

 

[Violeta]

Sometimes you might want more HSP 70, and sometimes you might want less.

"HSP 70 is overexpressed in malignant melanoma[11] and underexpressed in renal cell cancer"

 

[mariovitali]

@Hip

Are you saying that you had post-finasteride syndrome (PFS), which has many symptoms in common with ME/CFS (and may conceivably share many of the same metabolic pathophysiologies), and your innovative HSP70-boosting protocol, which reduces endoplasmic reticulum stress, cured your PFS, and so may well have benefits for ME/CFS as well?

Correct. The same applies i believe for people having Permanent side effects from Accutane, but for them their ER Crash occurred from up-regulation of RXR receptor or some other mechanism which i do not know at the moment.

Regarding Finasteride : It down-regulates SRD5A3 which impairs N-Linked Glycosylation and as a consequence proper Protein Folding within the ER.

So we have an initial stressor (Finasteride, Accutane, Virus) which disrupts proper protein folding within the ER and then it goes downhill on a vicious cycle. Of course this vicious cycle happens only for those people that have impaired Methylation function, Impaired Tetrahydrobiopterin Production, etc.

Have you posted your success story in treating your PFS condition on a post-finasteride syndrome forum like this one? Your success could provide tremendous help to other PFS sufferers, if it works equally well for them.

Yes i have! Log in to solvepfs.com and take a look at the thread SRD5A3/Mevalonate Pathway.

Can I ask: once you started taking the supplements in your HSP70-boosting protocol, how long did it take before you noticed the first improvements in your symptoms, and how long before you were fully recovered? Was it a matter of days, weeks, or months?

Do you think you are now fully cured, in the sense that if you stopped taking your protocol, you would remain recovered and symptom-free? Or do you think some PFS symptoms might return if you stopped taking the supplements?

Major improvements occurred in just 10 days. However it took me a couple of months for all symptoms to wear off and believe me, i had many of them (see my initial post).

Right now i have no problems. I was again on Holidays (Lucky Guy!) 15 days ago and couldn't keep up with my regimen. I felt some minor symptoms like Heart palpitations and minor Orthostatic Intolerance. I am waiting till September though where there will be a major test to the Regimen, simply because the change of season was always a big stressor for me which would make me "crash" every single time.

At another situation i stopped TUDCA and also decided to stop protein intake for quite some time. When i re-introduced meat to my diet i had a severe Sensorineural Hearing Loss incident which is just another name of ER Stress.

I am waiting for people from the forum to try the protocol and report back but it has to be tried appropriately in the sense that no other supplements (unless necessary) should be taken and also individual SNPs should be taken into account.

No problem with answering during my Holidays, i will just not be answering very quickly

 

[Violeta]

Sometimes you might want more HSP 70, and sometimes you might want less.

"HSP 70 is overexpressed in malignant melanoma[11] and underexpressed in renal cell cancer"

What made me curious about this is that green tea and the antioxidants it contains are NOT recommended in the list of things to avoid, and gee, that didn't make sense to me. Especially since the antioxidants in green tea actually would prevent the need of heat shock proteins because they antioxidize oxidants.

So probably what you would want to do is try to inhibit the need for excess HSP 70.
http://www.ncbi.nlm.nih.gov/pubmed/11193027

This is about mortalin, HSP 70 of the mitochondria.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030873/