Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

@Violeta

I tried so many antioxidants and they just didn't work. Green tea is in the "STAY AWAY" list because it is a DHT-Inhibitor. Quite possibly, this should not be applicable for women but i believe for Men it is a definite "STAY AWAY".

Thank you for the post for HSP-70 and -i guess- it makes sense. Too much of anything is probably not a good thing.

It goes without saying that i want to cut down as many supplements as i can and to only take those that are absolutely necessary for a symptom-free Life.

 

[Violeta]

@Violeta

I tried so many antioxidants and they just didn't work. Green tea is in the "STAY AWAY" list because it is a DHT-Inhibitor. Quite possibly, this should not be applicable for women but i believe for Men it is a definite "STAY AWAY".

Thank you for the post for HSP-70 and -i guess- it makes sense. Too much of anything is probably not a good thing.

It goes without saying that i want to cut down as many supplements as i can and to only take those that are absolutely necessary for a symptom-free Life.

Green tea is also inadvertently in the avoid because of HSP 70 list because it contains myricetin and quercetin.

Good that it may be good for women, it's more of a pleasure than a supplement.

 

[Violeta]

@Violeta

I tried so many antioxidants and they just didn't work. Green tea is in the "STAY AWAY" list because it is a DHT-Inhibitor. Quite possibly, this should not be applicable for women but i believe for Men it is a definite "STAY AWAY".

Thank you for the post for HSP-70 and -i guess- it makes sense. Too much of anything is probably not a good thing.

It goes without saying that i want to cut down as many supplements as i can and to only take those that are absolutely necessary for a symptom-free Life.

Actually, I wasn't even suggesting that you take green tea, myricetin, or quercetin, I was just suggesting that those things might actually be helpful for the overall situation because they reduce the NEED for heat shock protein, which is a better way to deal with the situation.

 

[mariovitali]

Actually, I wasn't even suggesting that you take green tea, myricetin, or quercetin, I was just suggesting that those things might actually be helpful for the overall situation because they reduce the NEED for heat shock protein, which is a better way to deal with the situation.

I am not sure i understand but for the record, whenever I had any myricetin or quercetin sources, i would immediately get symptoms. Both of them are HSP70 Antagonists and never worked in a favourable way for me. If the theory is correct, one could induce a major CFS incident by taking quercetin, myricetin and tunicamycin. Although I would NOT recommend this to anyone for any reason!

 

[Violeta]

I am not sure i understand but for the record, whenever I had any myricetin or quercetin sources, i would immediately get symptoms. Both of them are HSP70 Antagonists and never worked in a favourable way for me. If the theory is correct, one could induce a major CFS incident by taking quercetin, myricetin and tunicamycin. Although I would NOT recommend this to anyone for any reason!

What I am wondering or theorizing, is that quercetin and myricetin are not actually antogonists, but antioxidants that reduce the need for HSP 70.

So another way to look at it is that green tea might just inhibit endoplasmic reticulum stress? I didn't google that yet, I just thought of that just now.

Which would mean that green tea would cause CFS?

 

[mariovitali]

What I am wondering or theorizing, is that quercetin and myricetin are not actually antogonists, but antioxidants that reduce the need for HSP 70.

I see what you are trying to say. The question is, why do other very potent antioxidants didn't make me feel right such as NAC and SOD? Why Quercetin/Myricetin are special? I had an initial good effect with NAC and SOD but then i was back to square 1.

So another way to look at it is that green tea might just inhibit endoplasmic reticulum stress? I didn't google that yet, I just thought of that just now.

So what you are saying is that since Green Tea has an antioxidant function then it should prevent ER Stress. My understanding is that ER Stress and Oxidative Stress are closely linked but they are not the same thing.

I believe that antioxidants do provide some help in relieving ER Stress as long as they do not mess around with HSP-70 levels (as quercetin and myricetin do). At least this is what happened in my case.

You could try both regimens. I suggest you first start with taking Quercetin and/or Myricetin and if this works then fine. If it doesn't then you could start the regimen discussed here and see for yourself!

 

[Violeta]

I see what you are trying to say. The question is, why do other very potent antioxidants didn't make me feel right such as NAC and SOD? Why Quercetin/Myricetin are special? I had an initial good effect with NAC and SOD but then i was back to square 1.



So what you are saying is that since Green Tea has an antioxidant function then it should prevent ER Stress. My understanding is that ER Stress and Oxidative Stress are closely linked but they are not the same thing.

I believe that antioxidants do provide some help in relieving ER Stress as long as they do not mess around with HSP-70 levels (as quercetin and myricetin do). At least this is what happened in my case.

You could try both regimens. I suggest you first start with taking Quercetin and/or Myricetin and if this works then fine. If it doesn't then you could start the regimen discussed here and see for yourself!

Do you mean you haven't tried quercetin or myricetin?

I did google green tea plus er stress, and I'll get some links to what I found.
http://www.ncbi.nlm.nih.gov/pubmed/24842709
http://onlinelibrary.wiley.com/doi/10.1111/cpr.12102/abstract?systemMessage=Wiley Online Library will have intermittent access on 8th August 2015 from 10:00-16:00 BST / 05:00-11:00 EDT / 17:00-23:00 SGT for essential maintenance. Apologies for the inconvenience.

I know that quercetin, luteolin, myricetan, and egcg chelate copper and iron, I don't know what nac and sod antioxidize but I'll look it up.



NAC and SOD might not mess around with, i.e. lower, hsp 70 levels because they don't prevent er stress. So what I'm guessing is that hsp 70 levels being lowered by those antioxidants happens because they are preventing er stress.

I would rather drink green tea than take the supplements. I did list earlier which supplements I had been taking that you have in your protocol.

Edited to remove studies on luteolin as they seemed contradictory.

 

[Hip]

I found some other compounds/factors that induce HSP-70:

L-arginine increases HSP-70 in the liver (in pigs). 1

Leptin down-regulates HSP-70 gene expression in chicken liver and hypothalamus. 1 So possibly supplements which reduce leptin levels may help increase HSP-70. Leptin can be high in conditions of leptin resistance; chromium improves leptin resistance. The weight loss herb Garcinia cambogia lowers leptin in mice. 1 Irvingia gabonensis (African mango) is also thought to lower leptin.

Whey protein hydrolysate enhances the exercise-induced HSP-70 response in rats. 1

Ascorbic acid and alpha lipoic acid increase HSP-70 in liver and kidneys of chickens exposed to heat stress. 1

Growth hormone increases HSP-70 expression in whole blood preparations from silver sea bream. 1

Blueberries restores the HSP-70 response to LPS in old rats. 1

Chia oil induces HSP-70 expression in skeletal muscle. 1

Zinc and copper may affect HSP-70 expression. 1

 

[Hip]

This article talks about heat shock protein abnormalities in ME/CFS patients.

 

[Violeta]

This study talks about taurine lowering hsp 70 which was raised due to er stress.

http://www.jbiomedsci.com/content/17/S1/S26

 

[mariovitali]

@Violeta

We have to take into account different possible explanations. Consider the following two statements :

1) Taurine lowers HSP-70 levels
2) HSP-70 levels were found to be lower in the presence of Taurine

The first one implies that Taurine has a direct effect to HSP70 while the second suggests a possible link between Taurine levels and HSP-70..but it does not suggest that Taurine lowers HSP-70.

In this case, i believe that Taurine first lowers ER Stress and as a consequence it lowers HSP-70 expression :

ER stress marker expression was reduced when worms were treated with taurine

Based on the ER stress marker expression, taurine appears to have exerted an inhibitory effect on the progression of ER stress. When the cells were treated with taurine after their ER stress exposure, the level of hsp-70 significantly increased relative to the other ER stress markers. The significant upregulation of the ER stress markers suggests that taurine retards ER stress. The level of hsp70 expression showed typical dose-dependence, along with the amount of the tunicamycin that was added (Fig. 1). When the worms were incubated with various taurine concentrations, however, taurine downgraded the hsp-70 protein expression depending on the taurine concentration. The data imply that taurine lessens the intensity of ER stress caused by tunicamycin.

In other words, HSP-70 levels were found to be lowered because Taurine ameliorated ER Stress. In the absence of Taurine ER Stress would be higher, resulting in increased levels of HSP-70


Of course it would be great to be able to lower ER Stress (through Taurine and by other means) in the first place!


Perhaps we are talking about the same thing here

 

[Violeta]

@Violeta

We have to take into account different possible explanations. Consider the following two statements :

1) Taurine lowers HSP-70 levels
2) HSP-70 levels were found to be lower in the presence of Taurine

The first one implies that Taurine has a direct effect to HSP70 while the second suggests a possible link between Taurine levels and HSP-70..but it does not suggest that Taurine lowers HSP-70.

In this case, i believe that Taurine first lowers ER Stress and as a consequence it lowers HSP-70 expression :




In other words, HSP-70 levels were found to be lowered because Taurine ameliorated ER Stress. In the absence of Taurine ER Stress would be higher, resulting in increased levels of HSP-70


Of course it would be great to be able to lower ER Stress (through Taurine and by other means) in the first place!


Perhaps we are talking about the same thing here

Yes, we are.

 

[mariovitali]

@Hip

Thank you for the list you provided. I found the regimen suggested in this Thread by self-experimentation, logging on a daily basis the supplements i was using, my symptoms and various other parameters. Then this data were analyzed in order to find what differentiated good days vs bad days.

-Whey protein was a definite no-no.

-L-Arginine possibly beneficial

-Blueberries were beneficial

-Capers (we use them a lot in Salads where i am based) were a definite no-no because their consumption was associated with severe brain fog and other symptoms. I am not sure if this occurred because of high levels of Quercetin existing in Capers.

@Violeta

Sorry Violeta, i skipped the following in your post so it all went downhill from there :

NAC and SOD might not mess around with, i.e. lower, hsp 70 levels because they don't prevent er stress. So what I'm guessing is that hsp 70 levels being lowered by those antioxidants happens because they are preventing er stress.

I would rather drink green tea than take the supplements. I did list earlier which supplements I had been taking that you have in your protocol.

 

[mariovitali]

@Violeta

There might be a different explanation : What if -for some reason- the mechanism that generates Proteins within the ER in a proper -folded- way is impaired and/or the mechanism that controls the Quality of Proteins is impaired? If this is the case, then agents that control ER Stress would be helpful but they would not solve the problem.

I will have to do more reading to fully understand how Proteins are created in the ER and how they are controlled.

 

[aquariusgirl]

Where are folks getting TUDCA from?

 

[mariovitali]

Where are folks getting TUDCA from?

This is a good one :


http://www.amazon.com/Premium-Powders-TUDCA-Tauroursodeoxycholic-Capsules/dp/B00CFOQAWQ

 

[whodathunkit]

@mariovitali: how long will your break from TUDCA be? Is it just a regular prophylactic-type break, or did you stop it for another reason.

I just started taking it regularly. Even though I'd be willing to bet a significant sum of $$$ that ER stress has been a problem with me for a long time, I was on the fence about it because of some of the warnings. But then I had a few [what I now think were] episodes with gallstones, and since it can reportedly help dissolve gallstones I decided it was serendipity/synchronicity that I'd already gotten some thanks to your rec.

Just FYI, I've recently and very deliberately lost quite a bit of weight in a short period of time, and from what I understand gallstones can form when that happens. Poop got kind of pale and then turned almost white after the last episode a couple weeks ago (sorry for TMI), which is classic gallstone symptom. I started the TUDCA religiously about 1.5 weeks ago, and stools turned brown again pretty quickly. The abdominal ultrasound I got on Tuesday didn't show any gallstones. No inflammation of pancreas or liver, either. Dunno if that's due to TUDCA or what.

Anyway, just curious about how you're doing with it. Also what your future plans are with it, given the cautions about long-term use. Thanks. Keep up the great work!

 

[Hip]

I found the regimen suggested in this Thread by self-experimentation, logging on a daily basis the supplements i was using, my symptoms and various other parameters.

Ah right, so you were working backwards from experimental data, trying to find the best biochemical theory that fits your data.

I did a similar thing when I was suffering from severe generalized anxiety disorder: I started testing hundreds of supplements, and noted down every supplement which had some ability to reduce my anxiety levels. Then I started reading about the various metabolic pathways that each supplement acted on, in the hope of finding a pathway common to all or most of the supplements, that might explain their anti-anxiety effects.

After a year or so, I realized that most of my anti-anxiety supplements reduced brain inflammation (neuroinflammation) in one way or another. So I started to think that brain inflammation might be causing my anxiety symptoms. This tied in to new research about brain inflammation and immune activation being linked to various mental conditions, such as depression, bipolar, schizophrenia, OCD.

Once I hit upon this theory of brain inflammation causing my anxiety symptoms, I was then able to find further supplements and drugs that were anti-inflammatory, and found that some of these also had an anti-anxiety effect.

I think you have already seen my thread of the anti-anxiety effects of N-acetyl-glucosamine, turmeric, flaxseed oil, etc.



I am looking forward to learning about your data science techniques.

Such a data science technique could be useful for people trying to work out why a supplement helps them. Often people on this forum notice that several supplements or drugs will improve one or more of their symptoms, but usually they cannot figure out why these improvements occur, so they may post a thread on the forum asking if anyone has a good biochemical explanation. Then people may respond with their guesses as to what is going on biochemically.

As you certainly appreciate, once you hit on the what looks like the right biochemical explanation, you can then try other supplements and drugs that work on the same biochemical pathway, and this may further improve your symptoms.

 

[Hip]

@Marco wrote this very interesting article on the neuroinflammatory model of ME/CFS, which covers the role of heat shock proteins in protecting against oxidative stress and glutamate excitotoxicity.

Here are some article excerpts:

Two groups of researchers however have independently found a defective (attenuated) HSP response to oxidative stress induced by exercise in ME/CFS patients (Thambirajah et al, 2008, Jammes et al 2009, 2011). In the 2011 Jammes study it should be noted that this dysfunction was most strongly associated with those reporting a prior viral illness or previously engaging in high intensity exercise

Furthermore, heat shock proteins also protect the brain against glutamate excitotoxicity (Mokrushin et al, 2005) and play a role in the immune response to viral infection (Santoro, 1994).

 

[Violeta]

"Two groups of researchers however have independently found a defective (attenuated) HSP response to oxidative stress induced by exercise in ME/CFS patients (Thambirajah et al, 2008, Jammes et al 2009, 2011). In the 2011 Jammes study it should be noted that this dysfunction was most strongly associated with those reporting a prior viral illness or previously engaging in high intensity exercise
Furthermore, heat shock proteins also protect the brain against glutamate excitotoxicity (Mokrushin et al, 2005) and play a role in the immune response to viral infection (Santoro, 1994)."

Thank you, these are good clues for getting to the basis of the problem.

Heat shock protein inducement is a response to a negative situation. One situation that seems to cause a need is reduced intracellular water.

Here's an article that is looking for metabolic issues that set up tissue for glutamate excitotixicity.
http://www.sciencedirect.com/science/article/pii/0301008296000068
"Metabolic inhibition predisposes neurons to glutamate-mediated “excitotoxic” damage. The exact mechanism of this increased susceptibility is yet to be defined, but may involve, singly or in combination, decreased voltage-dependent Mg2+blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, abnormalities in cellular Ca2+ homeostasis, or elevated production of reactive oxygen species. It is believed that enhancement of excitotoxicity by impaired metabolism may be a ubiquitous mechanism of neuronal death in neurological disease. Further elucidation of the exact mechanism of this enhancement may lead to the discovery of new targets for therapeutic intervention."

Do you think this study forgot to look at endoplasmic reticulum stress, or does one of those issues cover it?

PS: I bet finasteride would be an HSP 70 "agonist".