Unfolded Protein Response and A Possible Treatment for CFS

[swan]

@mariovitali
Hi Mario,

I've searched this thread and no one has mentioned post exertional malaise yet - how does this common symptom fit with your treatment concept?

Thanks much.

This is actually a main reason I am here and why I am looking into this protocol.

I cannot exercise for extended periods of time without feeling terrible. Everytime I have attempted to start a gym routine I have had to stop because I feel overly exhausted the following days and experience feverish symptoms sometimes. This usually kicks in after 1-2 weeks of 3-4 day 1 hour routines. The longest I ever went was one month then my physical labor at work increased and I was trashed.

This is among other things, but even some days of work have left me waking up the next day feeling like my muscles have nothing to give. I can sit here right now and squeeze my fist as hard as I can for what I assume is a minute or two, but a bad day it's like I have 5 seconds of clenching power. Apply this across the body and that's what exercise induces.

Oddly enough I have been experiencing tinnitus in my right ear and I have to believe it's the changing season and incoming cold weather.

 

[Violeta]

Oxidative stress? ROS without the redox?

Oxidative stress occurs when there is a lack of dynamic balance (or "imbalance") between the production of oxidants and the concentration of antioxidant defenses, leading to cellular damage.

You probably already know about tinnitus and peroxinitrate, but I'll link an article anyway.

http://www.life-enhancement.com/mag...nitus-may-be-caused-by-peroxynitrite-no-oh-no

http://www.sciencedirect.com/science/article/pii/S209525461300029X

The complex role of physical exercise and reactive oxygen species on brain

 

[swan]

Let's say I have a 2/3s full ER bucket, this allows me to get on with daily life, but things like extra physical exertion fill my bucket with ensuing spillover and symptoms.

With additional supplements I hoping the bucket starts less full and/or any additional ER stress fills the bucket less.

The research on chemical chaperones such as TUDCA seems to say it does attenuate ER stress.

 

[mariovitali]

@mariovitali
Hi Mario,

I've searched this thread and no one has mentioned post exertional malaise yet - how does this common symptom fit with your treatment concept?

Thanks much.

My Question is : Do all people with CFS experience Post-exertional malaise?

So here is what the situation was for me : As i discussed in the beginning of the thread, i was keeping a very detailed log about what i was eating, how the weather was, how i was feeling, when i was going to the gym, etc.

I did this for more than 400 days (not sure about the number but it is more than a year) and then analyzed this information.This allowed me to find patterns that are really-really interesting. I will not get into these patterns now but i will wait until the theory of this Thread proves to be successful.

So here is what was happening to my body after the exercise : I would get various symptoms around 1 hour after the exercise...does this "time window" make any sense to you or you have fatigue *right after* your workout? My symptoms were mainly Irregular Heartbeat, Brain Fog and Neurological Pain in various parts of my body.

We know that CFS is a multi-systemic disease and that it has many faces. But we have to treat the cause and not the symptoms (assuming that you have CFS).

 

[mariovitali]

That was my thinking too. It may be an increase in aceytcholine that has made it worse, or maybe it's just a random fluctuation.



I know there is some confusion around, but I believe there is no difference between R5P ( riboflavin 5-phosphate ) and FMN. I've been taking 30 mg R5P ( Douglas brand ) daily. I am awaiting an order of the Source Naturals Coenzymated B2, which I believe is the recommended brand.

I have had 23andme testing done. If you direct me to the latest list of relevant snps, I'll post my results.

Cheers

Ah yes, now i remember, sorry about asking you for the second time in a row.

Here it is (Credit to @ppodhajski)- , it needs more work of course. Could you let us know which SNPs you have?

 

[ScottTriGuy]

My Question is : Do all people with CFS experience Post-exertional malaise?

So here is what the situation was for me : As i discussed in the beginning of the thread, i was keeping a very detailed log about what i was eating, how the weather was, how i was feeling, when i was going to the gym, etc.

I did this for more than 400 days (not sure about the number but it is more than a year) and then analyzed this information.This allowed me to find patterns that are really-really interesting. I will not get into these patterns now but i will wait until the theory of this Thread proves to be successful.

So here is what was happening to my body after the exercise : I would get various symptoms around 1 hour after the exercise...does this "time window" make any sense to you or you have fatigue *right after* your workout? My symptoms were mainly Irregular Heartbeat, Brain Fog and Neurological Pain in various parts of my body.

We know that CFS is a multi-systemic disease and that it has many faces. But we have to treat the cause and not the symptoms (assuming that you have CFS).

@mariovitali

Thanks for replying.

My experience with pem has changed over time, depending on the intensity of symptoms - the sicker I am, the more immediate I feel malaise, nausea, pain back of head - currently I cannot walk for more then 10 minutes (on flat ground, definitely no hills) without symptom onset, so its not even 'post' exertional, its present-exertional.

I also do not have any of the choline snps you listed in your original post - not sure if that is relevant. I do not have 23andme results for the other 2 groups you list: GCH1 and PAH.

I was a high performing triathlete before I got sick with m.e., so lots of aerobic history of swim, bike, run - I think I remember reading in this thread that lots of aerobic work could negatively impact hsp70.

 

[Violeta]

I was actually going to suggest that one reason for PEM might be raising levels of hsp, but I thought I would wait on that.

But since you bring it up, actually, exercise induces hsp 70, which for most people is a good thing.

However, some viruses enjoy and benefit from raised levels of hsp 70.

This is an extreme, but an example of hsp and EBV.

http://www.ncbi.nlm.nih.gov/pubmed/8986292

 

[skwag]

@mariovitali ,

That was a long list of snps! There appears to be a number of errors in risk alleles. I have a number of heterozygous mutations with neither allele corresponding to the risk allele.

 

[mariovitali]

@skwag

At the moment i am swamped with having to do lots of work but very quickly :

-Make sure you take Vitamin C 500 mg
-Take Omega 3 and limit Omega 6
-Make sure you take P5P
-ER Handling regimen is beneficial for you due to NOX4 Homozygous mutation
-Avoid Phenylalanine sources
------>Have you suffered/suffering from Panic Disorder? (COMT). To be honest i do not know how COMT mutations should be handled, perhaps someone more knowledgeable could help you, same applies for BHMT SNPs

- I assume you are following the Methylation protocol for your MTHFR

-You could benefit from Selenium supplementation due to ENOX1 Mutation which is associated with Oxidoreductase activity.


That's all for now!

 

[mariovitali]

OK so after the last 7-hour run, we have the following :


First of all : Which Topics under consideration matched more frequently?

Looking at the topics, of interest is dopamine,ros,phospholipids, hepatocytes but also the entry for catalase. FYI : Taurine increases catalase liver activity and induces Phase II detoxification



and specifically for glutamate the elements that match :

Of interest here is butyrate but also the addition of kainate (NMDA Agonist).

 

[Valentijn]

My Question is : Do all people with CFS experience Post-exertional malaise?

Yes. It is required by the proper ME/CFS definitions. Definitions which do not require PEM are quite vague and would most certainly encompass a wide variety of unrelated illnesses.

So here is what was happening to my body after the exercise : I would get various symptoms around 1 hour after the exercise...does this "time window" make any sense to you or you have fatigue *right after* your workout? My symptoms were mainly Irregular Heartbeat, Brain Fog and Neurological Pain in various parts of my body.

These are symptoms consistent with Orthostatic Intolerance, and not nearly delayed enough to constitute PEM.

 

[mariovitali]

Yes. It is required by the proper ME/CFS definitions. Definitions which do not require PEM are quite vague and would most certainly encompass a wide variety of unrelated illnesses.

These are symptoms consistent with Orthostatic Intolerance, and not nearly delayed enough to constitute PEM.

I get your point.

The truth is, that i arrived in this forum from another route, namely i have been a victim of the Post-Finasteride syndrome. However i saw that there are many overlapping symptoms with CFS. The same applies for people who took Accutane.

It may well be the case that what i had has nothing to do with CFS. OTOH there is not enough knowledge that can reject the hypothesis that CFS, PFS and Post-Accutane users have a condition which originates from the same basis.

So, My hypothesis is that we all (CFS, PFS, Accutane users) arrive at more or less the same symptoms from different routes.

The result is Redox/ER Stress handling dysregulation. This may be initiated by :

a) Finasteride use which impairs 5-AR Production (actually inhibits it) and as a result impairs Mevalonate Pathway and its products which results to ER Stress and/or Redox dysregulation

b) Accutane use which impairs 5-THF levels which leads to lower 5-AR levels which leads to ER Stress/Redox dysregulation

c) Virus or other stressor which dysregulates ( possibly through liver insult - don't know if i am using the right word here ) Redox/ ER Stress regulation.


So, another aspect of my hypothesis is that the Liver is heavily involved into these (all 3) conditions.

 

[swan]

I get your point.

The truth is, that i arrived in this forum from another route, namely i have been a victim of the Post-Finasteride syndrome. However i saw that there are many overlapping symptoms with CFS. The same applies for people who took Accutane.

It may well be the case that what i had has nothing to do with CFS. OTOH there is not enough knowledge that can reject the hypothesis that CFS, PFS and Post-Accutane users have a condition which originates from the same basis.

So, My hypothesis is that we all (CFS, PFS, Accutane users) arrive at more or less the same symptoms from different routes.

The result is Redox/ER Stress handling dysregulation. This may be initiated by :

a) Finasteride use which impairs 5-AR Production (actually inhibits it) and as a result impairs Mevalonate Pathway and its products which results to ER Stress and/or Redox dysregulation

b) Accutane use which impairs 5-THF levels which leads to lower 5-AR levels which leads to ER Stress/Redox dysregulation

c) Virus or other stressor which dysregulates ( possibly through liver insult - don't know if i am using the right word here ) Redox/ ER Stress regulation.


So, another aspect of my hypothesis is that the Liver is heavily involved into these (all 3) conditions.

@mariovitali, the more I read/research, ER stress is kind of a unifying theory of disease setting a stage where distress first takes place and then it's cascading effects.

Interesting links with aggregated proteins, oxidative stress, etc, and the involvement in Alzheimers, heart disease, diabetes, ibd, and many major diseases.

Something I never knew about and has become quite a fascinating topic.

Thanks for the insight

 

[Violeta]

@mariovitali, the more I read/research, ER stress is kind of a unifying theory of disease setting a stage where distress first takes place and then it's cascading effects.

Interesting links with aggregated proteins, oxidative stress, etc, and the involvement in Alzheimers, heart disease, diabetes, ibd, and many major diseases.

Something I never knew about and has become quite a fascinating topic.

Yes, exactly!

 

[Gondwanaland]

A few days ago I read something from a molecular biologist that I considered meaningful for us

https://twitter.com/gerdosi/status/643090318611619840
Oxidative stress => mitochondrial dysfunction => Insulin Resistance => hyperinsulinemia => inflammation => disease (cancer, Cardiovascular Disease, Type 2 diabetes etc)

Where does the ER hypothesis fit, before or after the mitochondrial dysfunction?
Then it got me wondering how many of us has insulin resistance (I do not because I don't overeat on carbs right now but it is very likely it was a real issue for me sometime ago, but my husband does).

 

[swan]

A few days ago I read something from a molecular biologist that I considered meaningful for us

Where does the ER hypothesis fit, before or after the mitochondrial dysfunction?
Then it got me wondering how many of us has insulin resistance (I do not because I don't overeat on carbs right now but it is very likely it was a real issue for me sometime ago, but my husband does).

ER stress is before and there is cross talk with mitochondria using things such as calcium which is why calcium homeostasis is so important and can produce ros from mitochondria.

BTW I followed your link a few days ago and that man's twitter sent me searching and taught me some more, thanks.

 

[Violeta]

BTW I followed your link a few days ago and that man's twitter sent me searching and taught me some more, thanks.

Do tell! What did you find thanks to Gondwanaland's link? I missed that link!

 

[Gondwanaland]

Do tell! What did you find thanks to Gondwanaland's link? I missed that link!

It was something I posted in reply to your research results

I don't know how to link a tweet here, but this morning I found this interesting:
https://twitter.com/gerdosi (his tweets of September 13, 2015)

And today I figured out how to post the link to the exact tweet
https://twitter.com/gerdosi/status/643090318611619840

 

[Gondwanaland]

There appears to be a number of errors in risk alleles. I have a number of heterozygous mutations with neither allele corresponding to the risk allele.

Remember that A pairs with T and C pairs with G.

For instance if risk allele is A and you have T, you have the risk allele.

Does this make sense?

 

[mariovitali]

There is overwhelming evidence that in many cases ER-stress related pathologies are accompanied or even caused by intracellular redox disturbances. Importantly, these disturbances can be upstream and downstream of ER stress or UPR and therefore have the potential to foster vicious circles that further amplify the initial disturbance (Figs 2 and 3). Depending on the context, the self-amplifying pathological redox imbalance can be oxidizing, as exemplified by ROS, or reducing, as outlined in the recent hypothesis that ER hypo-oxidation contributes to the etiology of diseases as diverse as type 2 diabetes, Alzheimer’s disease and cancer (Watson, 2014). However, it should be noted that connections between the redox state and UPR, so far, have been mostly derived from cell culture-based observations, and studies showing their in vivo relevance are scarce. Thus, examinations using suitable mouse models and genome-wide association and exome studies in humans are needed to fill this gap

Very good paper!


http://jcs.biologists.org/content/early/2014/08/07/jcs.153643.full.pdf