Unfolded Protein Response and A Possible Treatment for CFS

[skwag]

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?

Understood. I believe however that there are examples which cannot be so easily worked out. For example,

CG rs4987219 C SLC23A2

Now, I know I carry one risk allele here, but what about someone who is homozygous? We must know the proper orientation to determine risk.

 

[Gondwanaland]

Now, I know I carry one risk allele here, but what about someone who is homozygous? We must know the proper orientation to determine risk.

Right, I have stumbled upon this one before too

 

[Violeta]

It was something I posted in reply to your research results

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

I don't remember seeing that post, @Gond

Did you read the information at Amy's site? I started, but couldn't stick with it.

 

[Gondwanaland]

I don't remember seeing that post, @Gond

Did you read the information at Amy's site? I started, but couldn't stick with it.

Nope, that is just TMI for me right now

 

[Violeta]

Nope, that is just TMI for me right now

Yeah, same here.

 

[Violeta]

Nope, that is just TMI for me right now

Oh, are you sick, @Gondwanaland ?

 

[Gondwanaland]

Oh, are you sick, @Gondwanaland ?

Nope, just too busy with, overwhelmed by and stuck in my everyday drama
You?

 

[Violeta]

No, I thought your smiley meant you were sick, I'm glad you're not.

I had a headache for part of the day, though.

 

[mariovitali]

@Valentijn

If my memory serves me well you are taking NAC. How are you feeling at the moment?

I used to take NAC and after some point i would "crash". Now i found this and perhaps you should be aware of it :

The early finding that glucose-regulated UPR target genes are induced by treatment with reducing agents, which antagonize the formation of disulfide bonds, was made before the actual discovery of the UPR (Kim and Lee, 1987). Nowadays, disulfide-reducing agents such as dithiothreitol (DTT) are widely being used as rapid inducers of ER stress (DuRoseet al., 2006), and it has been shown that even an excess of the endogenous ER reductant GSH can activate the UPR by compromising oxidative protein folding (Kumar et al., 2011).

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


NAC increases GSH, correct?

 

[skwag]

@Valentijn

If my memory serves me well you are taking NAC. How are you feeling at the moment?

I used to take NAC and after some point i would "crash". Now i found this and perhaps you should be aware of it :




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


NAC increases GSH, correct?

This is very interesting! I have never tried NAC. I heeded @Freddd 's warning based on the poor (devastating, actually) results he and nine other people had after supplementing NAC or other glutathione precursors. Freddd had a theory that the excess glutathione combines with B12 and is flushed from the body, resulting in B12 deficiency. You have provided an interesting alternative scenario.

 

[Valentijn]

@Valentijn
If my memory serves me well you are taking NAC. How are you feeling at the moment?

I've been taking it for several years with no apparent problems. It's still effective in letting me get to sleep, and to stay asleep through the night.

NAC increases GSH, correct?

Usually. But perhaps that's only a problem if glutathione levels are normal to start with. My cysteine has tested low, while my glutamate and glycine tested high. Testing 2.5 years ago also showed that my anti-oxidant activity is ramped up quite a bit higher than the normal range, so I could very well be needing extra help from NAC in producing extra glutathione.

Cysteine has also been tested long term (at least a year) in HIV patients with the results published. No real side effects have been observed, aside from kidney stones in people who are predisposed to form them from cysteine.

But everyone is different, especially when different diseases are involved, so I would not expect my experience to apply to everyone. And I also wouldn't expect Freddd's or others' dire and largely unsubstantiated warnings to apply to everyone, especially since it is pretty well established in the published scientific research that NAC is beneficial in several circumstances.

 

[mariovitali]

I've been taking it for several years with no apparent problems. It's still effective in letting me get to sleep, and to stay asleep through the night.

Usually. But perhaps that's only a problem if glutathione levels are normal to start with. My cysteine has tested low, while my glutamate and glycine tested high. Testing 2.5 years ago also showed that my anti-oxidant activity is ramped up quite a bit higher than the normal range, so I could very well be needing extra help from NAC in producing extra glutathione.

But everyone is different, especially when different diseases are involved, so I would not expect my experience to apply to everyone. And I also wouldn't expect Freddd's or others' dire warnings to apply to everyone, especially since it is pretty well established in the published scientific research that NAC is beneficial in several circumstances.

Cysteine has also been tested long term (at least a year) in HIV patients with the results published. No real side effects have been observed, aside from kidney stones in people who are predisposed to form them from cysteine.

I see, however my question on how you feel was not random. If 10 = perfectly normal and 0 = being at bed all the time not able to do anything how do you feel from 0 to 10? Does the activity level that you state (=3) matches your current situation?

 

[Valentijn]

CG rs4987219 C SLC23A2

Now, I know I carry one risk allele here, but what about someone who is homozygous? We must know the proper orientation to determine risk.

The large majority of SNPs don't have any risky alleles.

In this case, there's no research into rs4987219 yet, but the prevalence of both alleles is nearly 50%. So 25% of the population is CC, 25% is GG, and 50% is CG. Since all genotypes are so common, it's highly unlikely that any of them cause problems.

 

[Valentijn]

I see, however my question on how you feel was not random. If 10 = perfectly normal and 0 = being at bed all the time not able to do anything how do you feel from 0 to 10? Does the activity level that you state (=3) matches your current situation?

I have ME, and it's stable regardless of taking NAC, except insofar as NAC allows me to sleep.

 

[skwag]

The large majority of SNPs don't have any risky alleles.

In this case, there's no research into rs4987219 yet, but the prevalence of both alleles is nearly 50%. So 25% of the population is CC, 25% is GG, and 50% is CG. Since all genotypes are so common, it's highly unlikely that any of them cause problems.

I tend to agree with you here, but in this example I was just trying to illustrate the importance of knowing which orientation you are working with.

 

[mariovitali]

OK so i used another software with Text Mining techniques to analyze PubMed entries for Redox homeostasis.

The software essentially picks up important (statistically significant) 2-word phrases using Chi-Square and Pointwise Mutual Information (PMI) in the Research text.


Regarding Redox Homeostasis we have :

Look how NOS heat_shock proteins, NAD, pentose phosphate pathway, catalase,inflammation, aging, endoplasmic_reticulum, CYP450, thioredoxin reductase, innate immune response (among others) are selected by the algorithm.

 

[swan]

I am still searching for the best price and place for tudca in canada. Looks like I will probably have to order online. If anyone from CA has info I'm all ears.

Oddly enough while searching tudca and reading the reviews, someones offhand comment about trying the supplement because of a forum post lead me to google 'mrfritz parkinsons udca'. Well there is a 50 page thread I found which I have not completely read but provides more n1 experiences and alleviation of parkinson's symptoms for some users of udca and its taurine conjugate tudca.

Some people seemed to experience minor acid reflux as a side. mrfritz is going on 2 years mainly tremor free I believe and the man is 70.

I didn't post a link because I am not brushed up on the linking policies to other forums even though I'm sure it would be alright. And I have provided the search parameters for those inclined. Plus just wanted to highlight the fun goose chase this sends me on sometimes.

 

[skwag]

Oddly enough while searching tudca and reading the reviews, someones offhand comment about trying the supplement because of a forum post lead me to google 'mrfritz parkinsons udca'. Well there is a 50 page thread I found which I have not completely read but provides more n1 experiences and alleviation of parkinson's symptoms for some users of udca and its taurine conjugate tudca.

Yes, I've gone through those 50 pages. There seems to be Mr. Fritz and one other that have posted good results. There are also statements that others have had good results, but no other first hand accounts.

The timing of starting Tudca and changes in other Parkinson's medications makes it more difficult to rely on this anecdotal evidence, but it is certainly interesting.

I found it strange that there were so many posters that seemed so anti-Tudca, but had not tried it.

I should add, Mr Fritz believes that the TUDCA is slowing the progression of his disease, but not reversing it.

 

[swan]

Yah, definitely unwarranted attacks in some of the posts, but it is good to be skeptical.

TUDCA is definitely not a single miracle worker, but as an adjunct to other approaches, it appears to have merit because the er stress and upr is definitely implicated with all the wonderful research people are providing.

I believe if one wants to reduce er stress it will require a large protocol not only supplemental, but physical as well.

In developing a supplement protocol a chemical chaperone is definitely required as a backbone. The most researched seem to be udca/tudca and 4-pba. If you want to follow @mariovitali 's approach and were able to get a prescription for one of the latter compounds to save $$ they would be substitutable.

oddly enough methylene blue has been studied wrt alzheimers and als and it attenuates er stress.

I believe methylene blue, and DMSO are relatively cheap, and could be added to an er stress reducing stack. I lack knowledge on any of these chemicals interactions with each other and do not know if they would have additive, synergistic, or deleterious effects together.

http://www.ncbi.nlm.nih.gov/pubmed/23567652

http://europepmc.org/articles/PMC3429545

 

[skwag]

Redox Controls UPR to Control Redox

The early finding that glucose-regulated UPR target genes are induced by treatment with reducing agents, which antagonize the formation of disulfide bonds, was made before the actual discovery of the UPR (Kim and Lee, 1987). Nowadays, disulfide-reducing agents such as dithiothreitol (DTT) are widely being used as rapid inducers of ER stress (DuRoseet al., 2006), and it has been shown that even an excess of the endogenous ER reductant GSH can activate the UPR by compromising oxidative protein folding (Kumar et al., 2011).The early finding that glucose-regulated UPR target genes are induced by treatment with reducing agents, which antagonize the formation of disulfide bonds, was made before the actual discovery of the UPR (Kim and Lee, 1987). Nowadays, disulfide-reducing agents such as dithiothreitol (DTT) are widely being used as rapid inducers of ER stress (DuRoseet al., 2006), and it has been shown that even an excess of the endogenous ER reductant GSH can activate the UPR by compromising oxidative protein folding (Kumar et al., 2011).

I used to take NAC and after some point i would "crash"

I heeded @Freddd 's warning based on the poor (devastating, actually) results he and nine other people had after supplementing NAC or other glutathione precursors. Freddd had a theory that the excess glutathione combines with B12 and is flushed from the body, resulting in B12 deficiency. You have provided an interesting alternative scenario.

But everyone is different, especially when different diseases are involved, so I would not expect my experience to apply to everyone. And I also wouldn't expect Freddd's or others' dire and largely unsubstantiated warnings to apply to everyone, especially since it is pretty well established in the published scientific research that NAC is beneficial in several circumstances.

Of course you are right @Valentijn, there are very few absolutes. Freddd was always quick to point out that his n=10 study involved people who had all experienced significant improvements using his protocol. Now, if we assume Freddd's protocol serves to alleviate ER stress ( in the people who respond, at least ), it makes sense that excess glutathione might just throw a wrench in the works. Perhaps the mechanism by which ER stress reduction is achieved in Freddd's protocol is especially vulnerable to excess glutathione. So, this idea might unify the experiences of Freddd and mariovitali.

In others who don't respond to Freddd's protocol or have low glutathione, NAC might be beneficial, because there is still not enough glutathione to stress the ER.