Unfolded Protein Response and A Possible Treatment for CFS

[ppodhajski]

I agree that B2 is the way to go for Parkinson's disease, may I add some thoughts?

What if MAO and COMT are high because of the body's inability to use dopamine and therefore the need to break down the excess that isn't being used. The treatment using dopamine doesn't take into account why is not the dopamine that is already available being used. I agree that adding in more dopamine is not a good idea.

The article that says that a low protein diet actually says no red meat, and I am going to conjecture that it's because of the iron that red meat contains. The iron deposits in the substantia nigra in those with Parkinson's is a part of the problem, why it's there I don't know. But one of the reasons that B2 might be good for Parkinson's is that it helps to handle iron correctly, moving toxic stores out of the liver (and out of the brain?).

http://www.ncbi.nlm.nih.gov/pubmed/17465880

http://www.hindawi.com/journals/bri/2011/896474/

I first want to be be specific about language. The body uses dopamine as a neurotransmitter and at the same time it tries to metabolize it. It is "used up" when it is metabolized. The only reason I would say it is not " the body's inability to use dopamine" is that they find increased metabolites of dopamine in people with PD and they also see low levels of Dopamine.

I agree with the iron bit but the research on that is hard to figure out. It seem iron effects the dopamine receptors somehow but it is also used as a cofactor for making dopamine. There is more evidence fo riboflavin increasing MAO activity than there is for removing iron from the liver. Once iron is in the body it is hard to get out, that is why they have to bleed people who have hemochromatosis. But maybe that would be part of a PD treatment? It seems they have already linked hemochromatoisis to PD:
http://www.ncbi.nlm.nih.gov/pubmed/12902032

 

[mariovitali]

@ppodhajski

OK so how all of this info you provided is related to CFS? Do you have a thread -or a post- in which you have more information (as in which supplements to take/diet / any other intervention)?

 

[ppodhajski]

@ppodhajski

OK so how all of this info you provided is related to CFS? Do you have a thread -or a post- in which you have more information?

No posts, this is something I found early on before I came here. The first thing that stopped when I started all this was my CFS. I have one other person's genetics who has CFS and the similarities we share is with B2. She has bad MTHFR SNPs which also uses FAD as a cofactor. We also share RFK, BTD, CBS, MAO, COMT and GPX4 SNPs.

Fatigue is a feature of Parkinson's:
https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?fatigue
"One of Parkinson’s more insidious symptoms is fatigue. This is not your garden variety bone-tired. This is fatigue on a cellular level. Your body is working overtime to accomplish the simplest of tasks: Taking a shower, answering the phone, pouring orange juice. In addition, you may be coping with the combination"

Note to everyone who might jump on me for this: I am NOT saying B2 will cure everyone's CFS.

But getting deeper than that..I am not only interested on how CFS can appear based on genetics, but how all late onset diseases can appear and how we can use our personal genome to track them down and fix them. I tend to look less at diseases and more at symptoms. The reasons for fatigue in PD might be the same reasons for those with CFS.

 

[Violeta]

The only reason I would say it is not " the body's inability to use dopamine" is that they find increased metabolites of dopamine in people with PD and they also see low levels of Dopamine.

I see what you mean, I thought I had read there were actually high levels of dopamine in PD patients, but maybe it was high levels of metabolites.

All sources say there is decreased dopamine production in the substantia nigra due to neuron death, though. Does that fit in the picture?

 

[ppodhajski]

I see what you mean, I thought I had read there were actually high levels of dopamine in PD patients, but maybe it was high levels of metabolites.

All sources say there is decreased dopamine production in the substantia nigra due to neuron death, though. Does that fit in the picture?

Maybe it fits, as I understand it the nerve death is caused by the free radicals created from the breakdown of dopmaine. So it would be beneficial for there to be less dopamine, which is maybe the function of nerve death.

 

[Violeta]

Maybe it fits, as I understand it the nerve death is caused by the free radicals created from the breakdown of dopmaine. So it would be beneficial for there to be less dopamine, which is maybe the function of nerve death.

I am thinking the death of neuron cells might be the result of endoplasmic reticulum stress, and since there is excess iron found in the substantia nigra in Parkinson's patientes, the ER stress is induced by iron. Why the excess iron is there, though, I don't know. I think that's what I read was the cause of cell death in liver cells of people with hemachromatosis.

 

[ppodhajski]

I am thinking the death of neuron cells might be the result of endoplasmic reticulum stress, and since there is excess iron found in the substantia nigra in Parkinson's patientes, the ER stress is induced by iron. Why the excess iron is there, though, I don't know. I think that's what I read was the cause of cell death in liver cells of people with hemachromatosis.

So maybe we are just seeing some of the different pathways that can cause dopamine nerve death. This is why I only talk to people about their own specific genes instead of their illness.

 

[Violeta]

So maybe we are just seeing some of the different pathways that can cause dopamine nerve death. This is why I only talk to people about their own specific genes instead of their illness.

Yeah, you and mario are on the same wave length.

 

[mariovitali]

FYI @Violeta @ppodhajski @Gondwanaland @JaimeS


I just finished another round of analysis with some more Topics of interest added. Here is how the process looks at the software that i use :

Notice the node that is called "Math Formula" in the Yellow Background in the middle of the snapshot. This node can be edited so that different cutoff % values may be entered.

I will not get into details here but in a nutshell, the higher the percentage cutoff the more we zoom out of the problem (because there are fewer Topics that match). The smaller the cutoff the more zoom-in in the problem but we may lose the "Big Picture".

So lets begin with a very small cutoff criterion, namely


cuttoff > 0

So glutamate tops the list, ros (=Reactive Oxygen Species) then Dopamine, Phospholipids and Hepatocytes. What worries me is the entry ckd (=Chronic Kidney disease) further down the list


We now want to generalize a little bit more our results so we enter

cutoff > 0.1

Interestingly, Mitchondrial dysfunction moves toward the top of Topics


Let's generalize even more with a cutoff > 1%:

So we have recurring entries that have to do with ER Stress and Oxidative stress protection as we generalize. It is very interesting that Dopamine, Glutamate and ROS share the top positions during our "Zooming In"

Of course i am not suggesting that these results prove my theory.This tool is useful for making hypotheses only

 

[ppodhajski]

FYI @Violeta @ppodhajski @Gondwanaland @JaimeS


I just finished another round of analysis with some more Topics of interest added. Here is how the process looks at the software that i use :

View attachment 12363

Notice the node that is called "Math Formula" in the Yellow Background in the middle of the snapshot. This node can be edited so that different cutoff % values may be entered.

I will not get into details here but in a nutshell, the higher the percentage cutoff the more we zoom out of the problem (because there are fewer Topics that match). The smaller the cutoff the more zoom-in in the problem but we may lose the "Big Picture".

So lets begin with a very small cutoff criterion, namely

cuttoff > 0


So glutamate tops the list, ros (=Reactive Oxygen Species) then Dopamine, Phospholipids and Hepatocytes. What worries me is the entry ckd (=Chronic Kidney disease) further down the list


We know want to generalize a little bit more our results so we enter

cutoff > 0.1

Interestingly, Mitchondrial dysfunction moves toward the top of Topics

Let's generalize even more with a cutoff > 1%:

So we have recurring entries that have to do with ER Stress and Oxidative stress protection as we generalize. It is very interesting that Dopamine, Glutamate and ROS share the top positions during our "Zooming In"

Of course i am not suggesting that these results prove my theory.This tool is useful for making hypotheses only

Hypothesis is where it starts!

I find it interesting and important that glutamate was in the >0 cutoff. To me it is like a master signal the body uses to interface with the environment. Changes in glutamate also effect other neurotransmitters like dopamine and serotonin. Lowering dietary glutamates in my diet was one of the early pre-genetic changes I made that helped me a lot.

Looking at glutamate release and its transporters and receptors might be the next place to start. IS there any terms or things you need to plug into that program that I can help you look for?

 

[mariovitali]

@ppodhajski

Whatever you feel could be important just let me knwo and i will put it as input.

 

[ppodhajski]

@ppodhajski

Whatever you feel could be important just let me knwo and i will put it as input.

GABA, GAD1, NMDA, AMPA, kainate would be a start. I will look p the specific genes. (GAD1 is the only gene in that list)

 

[mariovitali]

GABA, GAD1, NMDA, AMPA, kainate would be a start. I will look p the specific genes. (GAD1 is the only gene in that list)

Okay i can wait so you can collect most of the Topics that you feel should be considered. I am saying this since each run takes about 7 hours so it would be better to have ready most topics prior the 7-hour run.

So take your time and when you have a list that you feel is pretty much whatever you have in mind please let me know and i will add it

 

[Gondwanaland]

I lost track of this thread, it is just too much for me to catch up now, but I would like to add the following:

Once people have Parkinson's they should lower protein AND take B2 until glutathione levels are restored. And once symptoms are resolved they should stop the B2.

Indeed, my uncle who has PD and very high ferritin (should limit meat intake) + megaloblastic anemia (should take B2).

 

[mariovitali]

@Gondwanaland

Well, basically i finished one more round of data analysis and it appears that Glutamate and Dopamine pop up which i believe is interesting. I will also be adding more Topics under consideration -for analysis -with the help of @ppodhajski .

So when you say about eating less meat once people have Parkinson'w why is that so? Because of Iron or the Protein content?

Oh and i found this, take a look and please let me know what you think (FYI @Violeta too) :

Loss of stress response as a consequence of viral infection: implications for disease and therapy

<SNIP>

CHRONIC FATIGUE SYNDROME
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis, is a condition with no specific etiology, but which has been associated with a host of viral and bacterial infections. Examples include EBV, described previously, and xenotropic murine leukemia virus-related virus, which recently received international press when key papers implicating the latter virus were retracted. These events serve to emphasize the difficulties encountered in associating CFS with a distinct pathogen.

We propose that CFS is not the result of a specific infection but rather a more general response of the body to infection. In particular, infectious impairment of the stress response, as the examples we have described herein suggest, could make subjects vulnerable to even minor stresses and injury. Indeed, subjects with CFS are not resilient to life stresses: a strikingly minimal stress like walking five blocks can leave a person with CFS feeling exhausted for several days. In studies comparing subjects with CFS to healthy control subjects, the stress protein response to exercise is significantly blunted. A study comparing serum Hsp27 and Hsp70 of CFS patients versus control subjects before and after an incremental exhaustive bicycle session found lower baseline Hsp 70 levels in the CFS group compared to the control group. Hsp27 and Hsp70 also failed to rise as high and as fast in the CFS group as in their healthy control counterparts (Jammes et al. 2009). A more recent study of CFS patients divided subjects into those that had postinfection CFS and those that did not. Hsp27 and Hsp70 levels failed to rise with exercise in subjects with infection-associated CFS, and in fact decreased from baseline—which may explain why CFS subjects often complain of exhaustion after moderate exercise (Jammes et al. 2011). Furthermore, CFS muscle biopsies contain mitochondria with functional and morphological defects consistent with an impaired intracellular stress defense (Myhill et al. 2009). Finally, studying aging subjects, Mets and colleagues have reported that monocyte and lymphocyte Hsp27 correlates positively with fatigue resistance (Beyer et al.2012).

While the etiology of CFS is presently regarded as multifactorial, prior infections—particularly viral infections—are likely major CFS triggers. In support of an infectious culprit, a study of CFS versus control subjects observed elevated titers of PKR protein and interferon, with minimal overlap of values with the control group (Vojdani et al. 2007). Elevated interferon titers were also detected in veterans ill with chronic fatigue associated with the Gulf War (Zhang et al. 1999). Interferon administration itself produces fatigue and has been used as model to study CFS (personal communication, J. Jones, CDC)

If CFS symptoms reflect an impaired Hsp state, then improving the Hsp response should improve the condition. Indeed, a nutraceutical product (ADAPT-232 forte), which combines extracts from three herbs (Eleutherococcus senticosus, Schizandra chinensis, and Rhodiola rosea), raises Hsps in response to exercise. This same agent is effective in reducing fatigue and improving performance in a placebo-controlled trial of patients with CFS (Panossian et al. 2009).

In case you are wondering why not many people know about this nutraceutical product/ If it was working we should know by now etc , Then i could probably think it's because they haven't used a multi-agent approach (namely use TUDCA, NAG, Selenium etc)

 

[ppodhajski]

@Gondwanaland

Well, basically i finished one more round of data analysis and it appears that Glutamate and Dopamine pop up which i believe is interesting. I will also be adding more Topics under consideration -for analysis -with the help of @ppodhajski .

So when you say about eating less meat once people have Parkinson'w why is that so? Because of Iron or the Protein content?

Oh and i found this, take a look and please let me know what you think (FYI @Violeta too) :

In case you are wondering why not many people know about this nutraceutical product/ If it was working we should know by now etc , Then i could probably think it's because they haven't used a multi-agent approach (namely use TUDCA, NAG, Selenium etc)

The neurotransmitters do not just control our mood, they control our immune system as well. This is why I focus on them so much.

http://www.ncbi.nlm.nih.gov/pubmed/25202009
A cytosolic relay of heat shock proteins HSP70-1A and HSP90β monitors the folding trajectory of the serotonin transporter.

http://www.intrinsicactivity.org/2014/2/S1/A1.9/index.html
Cytosolic heat shock proteins as key players in serotonin transporter folding

 

[Violeta]

http://www.ncbi.nlm.nih.gov/pubmed/25202009
A cytosolic relay of heat shock proteins HSP70-1A and HSP90β monitors the folding trajectory of the serotonin transporter.

Interesting, made me wonder if viruses recruit hsp and found this.

This is in a plant, mind you, but it's a start. That might explain a lot.

http://www.ncbi.nlm.nih.gov/pubmed/23894631

And this, with respect to hsp 70 and Epstein Barr virus from here: http://www.pnas.org/content/101/46/16286.full


Cell-encoded proteins are surprisingly major components of the mature EB virion tegument and are likely important for virion morphogenesis and infection. β-Actin was one of the most abundant tegument proteins and cofilin, tubulin, Hsp90, and Hsp70 were also readily detected. Capsids likely accumulate these proteins as mediators of morphogenesis. High-level presence in mature virions may also indicate a role in virion stability or ingress.

 

[Violeta]

@Gondwanaland

Well, basically i finished one more round of data analysis and it appears that Glutamate and Dopamine pop up which i believe is interesting. I will also be adding more Topics under consideration -for analysis -with the help of @ppodhajski .

So when you say about eating less meat once people have Parkinson'w why is that so? Because of Iron or the Protein content?

Oh and i found this, take a look and please let me know what you think (FYI @Violeta too) :





In case you are wondering why not many people know about this nutraceutical product/ If it was working we should know by now etc , Then i could probably think it's because they haven't used a multi-agent approach (namely use TUDCA, NAG, Selenium etc)

@mariovitali See if the paragraphs in your post are from the paper that this is from. I clicked on the citation number and it took me to this paper.

"Unlike eukaryotes and bacteria, viruses do not have heat shock proteins (Hsps) and rely on host Hsps for viral protein folding. As a result, processes that regulate host stress proteins are likely targets of strategic manipulation by both viruses and infected hosts.

Some viruses take advantage of a host's activated cellular stress response and are able to increase replication when Hsps are high. Several viruses in fact stimulate a major increase in Hsps toward this end, such as human papillomavirus (Song et al. 2010), adenovirus (Glotzer et al. 2000; Madara et al. 2005), polyomaviruses, and dengue viruses (Reyes-Del Valle et al. 2005). Other viruses, however, suffer a reduction in replication when host Hsps are high, such as human immunodeficiency virus (HIV) and influenza A, where Hsp70 inhibits viral gene expression and replication
Unlike eukaryotes and bacteria, viruses do not have heat shock proteins (Hsps) and rely on host Hsps for viral protein folding. As a result, processes that regulate host stress proteins are likely targets of strategic manipulation by both viruses and infected hosts.

Some viruses take advantage of a host's activated cellular stress response and are able to increase replication when Hsps are high. Several viruses in fact stimulate a major increase in Hsps toward this end, such as human papillomavirus (Song et al. 2010), adenovirus (Glotzer et al. 2000; Madara et al. 2005), polyomaviruses, and dengue viruses (Reyes-Del Valle et al. 2005). Other viruses, however, suffer a reduction in replication when host Hsps are high, such as human immunodeficiency virus (HIV) and influenza A, where Hsp70 inhibits viral gene expression and replication."

So whether you want to increase hsp 70 or not would depend on which virus you have.

 

[mariovitali]

@Violeta

It is from the same paper. The paper is here : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468676/

Look at the red paragraph here :

In addition to influenza A, other viral infections that are impaired by high Hsp expression—and which may therefore be sensitive to Hsp-raising agents—are caused by rhinovirus (Conti et al. 1999), rotavirus (Pavlovic et al. 1992), poliovirus (Conti et al. 1996), vesicular stomatitis virus (Rossi et al. 1996), Sindbis virus (Mastromarino et al. 1993), leukemia virus type 1 (D'Onofrio et al. 1994), and HIV1 (Kumar et al. 2011). To have agents that could treat diseases as ubiquitous as the common cold, as fatal as HIV, or as high impact as influenza pandemics would be a boon to mankind. Could an Hsp inducer be administered when type 1 diabetes is first diagnosed, and thereby limit beta cell destruction? On a similar note, Parkinson’s disease symptoms have been observed following seasonal influenza (Toovey et al. 2011). As it is known that Hsps have a protective role in limiting the impact of Parkinson’s (Aridon et al. 2011), Hsp-inducing medications could limit the ultimate downstream impacts of influenza infections on health. It is worth noting, however, that while raising Hsps may be protective in the case of some viral infections, in other cases, increasing Hsps could, theoretically, augment viral replication.

So maybe the reason for not having symptoms while being sick, is the fact that HSPs are elevated. I must admit that i do not know the mechanics of how HSPs and ER Stress works so i wish there could someone here with a better understanding.

Let me repeat that i believe that the regimen proposed here could have a protective role for diseases such as Diabetes, Alzheimer's and even aging. I will post references for this.

I am also still trying to explain why my hearing frequency response range has improved after being at the regimen.

 

[mariovitali]

@Valentijn

Could you comment in the following paper?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468676/

Also could you give us your comments/corrections on this Thread and what do you think for the theory that Protein Misfolding is a key aspect -so i am not suggesting that it is the cause- of CFS?

My intention is to make all necessary corrections in the beginning of the Thread : For example changing "fully recovered " to "being symptom-free" and corrections to the SNPs discussed on another Thread as soon as i get the relevant knowledge on the subject. I do get carried away -i must admit that- having gotten my life back after so many years.

Please also notice that i try to use words such

"it appears"
"Is associated with"
"My theory"
"I believe"

throughout the Thread (or at least i am trying to) due to having a statistical background. Of course i am also aware that whatever analysis was done is based on my personal data/observations therefore i cannot make any claims. I am also fully aware of topics such as "Cherry picking", Data Dredging, etc.


So i knew apriori that using Data Science under these circumstances has inherent flaws BUT this doesn't mean that we can use it to generate potentially interesting hypotheses


Would you be willing to give to the regimen a try at some point?



Thanks in advance!