Unfolded Protein Response and A Possible Treatment for CFS

[Violeta]

Do you mean glucocorticoid drugs?
Sorry, but I know less than zilch about this subject.

Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.

and:

Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to osteoporosis), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids.

 

[Violeta]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC514821/

壽The mammalian endoplasmic reticulum as a sensor for cellular stress
Yanjun Ma and Linda M. Hendershot

This is what I'm looking for.

壽The mammalian endoplasmic reticulum as a sensor for cellular stress
Yanjun Ma and Linda M. Hendershot



ALTERATIONS IN THE ER ENVIRONMENT AFFECT PROTEIN FOLDING AND ACTIVATE A PROTECTIVE RESPONSE
Changes in the normal physical environment of the cell (eg, decreases in pH, energy, oxygen, glucose, or other nutrients) can affect the normal biosynthesis of proteins in the ER

 

[ppodhajski]

We do need our share of glucocorticoids.

"GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. "

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674691/

Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
Indrajit Das, Chin Wen Png, [...], and Michael A. McGuckin

YES! And I think this is bad for us to try to lower cortisol. The cortisol is being released because we are producing too many Reactive Oxyegen Species (ROS). I the stress we feel is created by the increased cortisol to lower our ROS. By lowering our ROS we will naturally lower cortisol. This is the definition of an auto-immune disease, we are making too many ROS but we have no illness.

http://www.ncbi.nlm.nih.gov/pubmed/9667222
This inhibition of ROS generation by HC (and other glucocorticoids) may have a role to play in mediating the antiinflammatory action of corticosteroids.

I feel a better focus than trying to find out what effects the ER is to find out why one is creating, or cannot handle all the ROS. All ROS effect the ER. We can find this out by looking at our lifestyle AND our genetics.

http://www.pnas.org/content/105/47/18525.full
Antioxidants reduce endoplasmic reticulum stress and improve protein secretion

 

[Violeta]

Some of us have to find out what else is creating problems in the ER.

 

[ppodhajski]

Some of us have to find out what else is creating problems in the ER.

I need to explain this more I think. Whatever effects the ER does so because it increases ROS. Whatever you find that effects the ER you will find it effects the ER because it increases ROS. ROS production, either in the cytosol or the mitochondra is the root of all ER stress.

By trying to find and avoid all the things that effect the ER you will end up being like the Bubble Boy becasue life itself increases ER stress. However, if you make yourself less sensitive to these thing you can live healthy outside of the bubble.

http://www.ncbi.nlm.nih.gov/pubmed/19011102
The findings indicate that reactive oxygen species are a signal generated by misfolded protein in the ER that cause UPR activation and cell death. Genetic or chemical intervention to reduce reactive oxygen species improves protein folding and cell survival and may provide an avenue to treat and/or prevent diseases of protein misfolding.

http://www.ncbi.nlm.nih.gov/pubmed/25354680
Heat stress and Reactive oxygen species
Nowadays, a variety of diseases and degenerative processes such as cancer, Alzheimer's and autoimmune diseases are mediated by oxidative stress. Heat stress was suggested to be an environmental factor responsible for stimulating ROS production because of similarities in responses observed following heat stress compared with that occurring following exposure to oxidative stress.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023740
The ER stress pathway is induced partially or fully as a consequence of hyperthermia in parallel with induction of Hsp70. These findings suggest that the ER and cytoplasm of cells contain parallel pathways to coordinately regulate adaptation to febrile hyperthermia associated with disease or infection.

http://www.ncbi.nlm.nih.gov/pubmed/25968954
Antioxidant metallothionein alleviates endoplasmic reticulum stress-induced myocardial apoptosis and contractile dysfunction.
Taken together, our data favor a beneficial effect of metallothionein against ER stress-induced cardiac dysfunction possibly associated with attenuation of myocardial apoptosis.

 

[Violeta]

Are you meaning that we should reduce the causes of ER stress? If so, that's exactly what I'm thinking.


I see hypoxia is a cause of ER stress, does hypoxia cause rise in ROS? I plan on focusing how to avoid hypoxia.

I realize metals are oxidants, and that's why metallothionein alleviates ER stress. Other antioxidants do the same, such as quercetin and luteolin. EGCG is very good for alleviating oxidative metals. I am working on not only alleviating oxidative stress with antioxidants, but also finding out how to avoid oxidative stress to begin with. For example, from what I learned about cortisol, I think alleviating as many issues that cause excess cortisol or even inadequate cortisol, will help alleviate ER stress. If what the book by Weber was correct about cortisol injuring ceruloplasmin production, that might be why copper toxicity and biounavailability is so common. It's also a good reason to take the correct B vitamins that are responsible for helping metal regulation. etc.

Hyperthermia....I was thinking about this with respect to what someone with Traditional Chinese Medicine told me. If you cool down the cells the toxins will come out. I don't know if we have the correct definition of heat stress yet, just as we didn't realize that protein folding in the ER does not mean that protein from what we eat is being folded in the ER.

I don't know a lot about ROS. I'm trying to learn, though.

 

[ahmo]

@Violeta Martin Pall's work on nitric oxide cycle, and chronic/degenerative diseases related to this, focusses on antioxidants. If my porous memory is correct, you've already been involved in discussions including Pall's recommendations. I have a couple links in my sig, but his own site is no longer available, unfortunately. The lat 20 minutes of the vid shows lists of suggested antioxidants.

@ppodhajski is metallothionein available as a supplement? From my cursory look at it, it seems as it's significance is in removing toxic metals. Is this correct, or my leaping to conclusions? Here's a small ref: http://www.healing-arts.org/children/mtpromotion.htm#nutrient

 

[Violeta]

@Violeta Martin Pall's work on nitric oxide cycle, and chronic/degenerative diseases related to this, focusses on antioxidants. If my porous memory is correct, you've already been involved in discussions including Pall's recommendations. I have a couple links in my sig, but his own site is no longer available, unfortunately. The lat 20 minutes of the vid shows lists of suggested antioxidants.

@ppodhajski is metallothionein available as a supplement? From my cursory look at it, it seems as it's significance is in removing toxic metals. Is this correct, or my leaping to conclusions? Here's a small ref: http://www.healing-arts.org/children/mtpromotion.htm#nutrient

Thanks, ahmo, yes, I have seen Pall spoken of in one thread I was reading, and meant to try to read some of his stuff but got side tracked.

I've seen ROS mentioned along with NO, NOS, and iNOS, which I did do some reading about with respect to Lyme. And then I did read a little bit about peroxynitrite, too. Still need to try to figure out exactly what we're talking about.

If it's okay, I will say what I know about a metallothionein supplement. There is no way to actually take metallothionein, your body must produce it. There is, however, a supplement out there for promoting metallothionein. So you put these components into your body, and voila???? Of course it's not that easy, we are just fooling ourselves. But I'm sure some information will show up about why/what causes a shortage and how to move the body in the right direction.

Carl Pfeiffer is a name that you can google for looking into it.

 

[ppodhajski]

@Violeta Martin Pall's work on nitric oxide cycle, and chronic/degenerative diseases related to this, focusses on antioxidants. If my porous memory is correct, you've already been involved in discussions including Pall's recommendations. I have a couple links in my sig, but his own site is no longer available, unfortunately. The lat 20 minutes of the vid shows lists of suggested antioxidants.

@ppodhajski is metallothionein available as a supplement? From my cursory look at it, it seems as it's significance is in removing toxic metals. Is this correct, or my leaping to conclusions? Here's a small ref: http://www.healing-arts.org/children/mtpromotion.htm#nutrient

My Opinion is that you don't want to take glutathione or metallithione as a supplement. You want to stimulate the pathways that create more of the antioxidants.

Metallathionine binds to both biological and xenobiotic metals. Here is a good write up.
http://flipper.diff.org/app/items/6366

It is important in regards to glutathione as well.

Note that it needs a zinc pool to help antioxidantion and Catecholamines are also able to activate MT-1 and MT-2 gene transcription.

http://www.ncbi.nlm.nih.gov/m/pubmed/10022625/
Zinc therapy increases duodenal concentrations of metallothionein and iron in Wilson's disease patients.

I just started looking at the MT genes.

 

[ahmo]

High zinc was one of the first things I did, per Klinghardt. It was my first intervention, along w/ high se, and less high molybd, manganese, to pull out toxic metals. Eventually I had a dramatic dump, after which my body wanted a huge handful of zinc. After that moment, I never needed high doses of zinc. Klinghardt talks about how toxic metals occupy zinc receptors. Once the toxic sludge was flushed out of my system, zinc could re-occupy its sites.

 

[mariovitali]

@ppodhajski

Wow! Just wow! Look how many topics are matched by the algorithm on FMN.


I will have to re-check but until then, here we go :

 

[Gondwanaland]

hmmmm so the problem with Phenylalanine foods could be B2 deficiency?

 

[ppodhajski]

I

hmmmm so the problem with Phenylalanine foods could be B2 deficiency?

It could be one of many. I think it is my issue since I have the double GCH1 deficiency. GCH1 uses FAD as a cofactor and GCH1 is in the pathway to make BH4 which is needed to metabolize phenylalanine

Note that FAD is a cofactor to MAKE and BREAK DOWN catecholamines ( serotonin, dopamine, epinephrine ) it is also needed to help breakdown external amines as well, like the tyrannies you will find in cheddar cheese

 

[mariovitali]

FYI @ppodhajski

ok so here is the analysis for FAD, same settings

FYI : baroreceptor topic is associated with OI

Tinnitus incidents would signal the beginning of my problems : Bad Mood, Constipation, Anhedonia, Impotence..you name it.

Look at a today's post : http://forums.phoenixrising.me/index.php?threads/ringing-in-ears.14388/page-3#post-635640

@Gondwanaland do you see the oxalates in the results?

Interestingly dolichol is also there (used for N-Linked Glycosylation) discussed in the beginning of this Thread.

I guess i have a lot of reading to do.

 

[mariovitali]

@ppodhajski

It seems that ER Stress also generates ROS :

ER stress is also a major source for the production of reactive oxygen species (ROS). This can occur via activation of protein disulfide isomerase (PDI), an enzyme which catalyzes disulfide bridge formation and in the process generates ROS. ROS are known to promote insulin resistance and inflammation (6,10). Thus, the ER may be a proximal site that senses nutritional excess and translates it into metabolic and inflammatory responses.

Link : http://diabetes.diabetesjournals.org/content/58/3/518.full


So it appears that there is a two-way association between ER and ROS

 

[mariovitali]

More :

Link :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565273/

Note PDI, FAD, ERO1 above :

PDI = Protein Disulfide Isomerase
FAD = Flavin Adenine Dinucleotide
ERO1 = ER oxidoreductin

PDI is a 57-kDa protein that resides in the endoplasmic reticulum (ER) of eukaryotic cells. There, PDI catalyzes the formation, reduction, and isomerization of disulfide bonds in newly synthesized proteins (25). Independent of its catalytic activity, PDI exhibits chaperone activity by inhibiting the aggregation of unfolded proteins (6, 71) and is a member of at least two multimeric enzyme complexes: prolyl 4-hydroxylase (45, 69) and microsomal triglyceride transfer protein (51, 89).

Link : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814249/

@ppodhajski Well done my friend! It appears that FAD acts as a cofactor for proper PDI functioning (?) which in turn aids proper Protein folding.

We will need to look more into this to make sure. Really trying hard to understand all this TBH

 

[ppodhajski]

More :


View attachment 12405


Link :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565273/

Note PDI, FAD, ERO1 above :

PDI = Protein Disulfide Isomerase
FAD = Flavin Adenine Dinucleotide
ERO1 = ER oxidoreductin




Link : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814249/

@ppodhajski Well done my friend! It appears that FAD acts as a cofactor for proper PDI functioning (?) which in turn aids proper Protein folding.

We will need to look more into this to make sure. Really trying hard to understand all this TBH

Yes, exactly. This is the nature and nurture of our disorders. Think of the ROS produced outside of the ER as nurture (environment) and the inside as our Nature (genetics)

 

[Gondwanaland]

do you see the oxalates in the results?

Pieces falling into place here. I noticed a remarkable ovelap of oxalate issues and anemia when I went thru them, and of course it wasn't a coincidence. What intrigued me is that I never read a recommendation to supplement with B2 when reading about oxalates

 

[mariovitali]

Biotin starvation causes mitochondrial protein hyperacetylation and partial rescue by the SIRT3-like deacetylase Hst4p.
Madsen CT1, Sylvestersen KB1, Young C1, Larsen SC1, Poulsen JW1, Andersen MA2, Palmqvist EA3, Hey-Mogensen M4, Jensen PB4, Treebak JT2, Lisby M5,Nielsen ML1.
Author information

Abstract
The essential vitamin biotin is a covalent and tenaciously attached prosthetic group in several carboxylases that play important roles in the regulation of energy metabolism. Here we describe increased acetyl-CoA levels and mitochondrial hyperacetylation as downstream metabolic effects of biotindeficiency. Upregulated mitochondrial acetylation sites correlate with the cellular deficiency of the Hst4p deacetylase, and a biotin-starvation-induced accumulation of Hst4p in mitochondria supports a role for Hst4p in lowering mitochondrial acetylation. We show that biotin starvation and knockout of Hst4p cause alterations in cellular respiration and an increase in reactive oxygen species (ROS). These results suggest that Hst4p plays a pivotal role in biotin metabolism and cellular energy homeostasis, and supports that Hst4p is a functional yeast homologue of the sirtuin deacetylase SIRT3. Withbiotin deficiency being involved in various metabolic disorders, this study provides valuable insight into the metabolic effects biotin exerts on eukaryotic cells.

 

[Gondwanaland]

Biotin starvation causes mitochondrial protein hyperacetylation and partial rescue by the SIRT3-like deacetylase Hst4p.

Wow Nature 2015 open access