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Unfolded Protein Response and A Possible Treatment for CFS

mariovitali

mariovitali

Senior Member
Messages
1,214
@Gondwanaland

There is no need to drop NAG. What i would generally suggest is that you slowly add Supplements and keep a log of the symptoms as you are adding them.

Since i found what works for me, I am now trying to find the absolute necessary subset of supplements that keep me symptom-free by dropping one by one and waiting for 10 days to see whether symptoms return. If not then i will move to drop a second such as P5P, etc.
 
ppodhajski

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
Gondwanaland said:
Very interesting synchronicity. We are talking about biotin at the oxalate thread.

And I was about to ask about calcium's role with so much choline supplementation.

And I was thinking to start making bone broth as a way to have a glycine intake. Glycine as a supplement can get converted into oxalates, but I think I need to up my collagen synthesis.

So now I am unsure to take NAG or not. @ppodhajski what were your criteria concerning it?
Click to expand...

Simple. It is not a cofactor so I do not supplement with it.

SHMT is the enzyme that intraconverts serine and glycine and uses P5P as a cofactor. I think if you have enough B6 your body will make what it needs.
http://www.uniprot.org/uniprot/P34896

No SHMT genes in 23andme. :(

shmt-reaction.jpg


However that is just one pathway. Here are more.

csm_GLY_SYNTH_Path_ENG_3_e2cc2b3734.gif
 
Violeta

Violeta

Senior Member
Messages
2,945
Violeta said:
@mariovitali , you just have to make sure you are cycling the nadp to nadph. Here's how that happens.

The major source of NADPH in animals and other non-photosynthetic organisms is thepentose phosphate pathway.

However, there are several other lesser-known mechanisms of generating NADPH, all of which depend on the presence of mitochondria. The key enzymes in these processes are:NADP-linked malic enzyme, NADP-linked isocitrate dehydrogenase, NADP-linkedglutamate dehydrogenase and nicotinamide nucleotide transhydrogenase.[1] The isocitrate dehydrogenase mechanism appears to be the major source of NADPH in fat and possibly also liver cells.[2] Also, in mitochondria, NADH kinase produces NADPH and ADP, using NADH and ATP as substrate
Click to expand...

I just found this with respect to NADP>>NADPH and riboflavin.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22938/

Three-dimensional structure of NADPH–cytochrome P450 reductase: Prototype for FMN- and FAD-containing enzymes

Cytochrome P450-mediated microsomal electron transport is responsible for oxidative metabolism of both endogenous compounds, including fatty acids, steroids, and prostaglandins, and exogenous compounds ranging from therapeutic drugs and environmental toxicants to carcinogens.
 
Violeta

Violeta

Senior Member
Messages
2,945
Violeta said:
I just found this with respect to NADP>>NADPH and riboflavin.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22938/

Three-dimensional structure of NADPH–cytochrome P450 reductase: Prototype for FMN- and FAD-containing enzymes

Cytochrome P450-mediated microsomal electron transport is responsible for oxidative metabolism of both endogenous compounds, including fatty acids, steroids, and prostaglandins, and exogenous compounds ranging from therapeutic drugs and environmental toxicants to carcinogens.
Click to expand...

Does this mean anything to anyone?

Both CPR and microsomal cytochromes P450 are integral membrane proteins, and CPR is one of only two known mammalian enzymes containing both FMN and FAD as prosthetic groups, the other being various isoforms of nitric-oxide synthase (NOS).
 
S

skwag

Senior Member
Messages
222
I've passed the 10 day mark in my trial of mariovitali's suggested supplements. I'm currently taking

3x250 mg Tudca
3x1400 mg NAG
3x235 mg choline ( as choline bitartrate)
3x750 mg inositol
100 mcg selenium

along with my usual routine of the deadlock quartet and basics.

I have had some improvement in some symptoms. Lower back pain has decreased significantly. Noise intolerance has also nearly vanished. I think NAG is responsible here. I doubled my dose of NAG starting on day 8 and the noise intolerance diminished even further. There is a slight sedating effect to it though.

In general I'm feeling better, but there has been no improvement in OI symptoms. More specifically, my heart rate is still rising over 30 bpm when I am upright and standing still.

I've noticed more 'tingly' sensations in my hands and feet. I'm not sure if this is a good or a bad thing. Could be nerves coming online or shutting down.

I'll continue to update.
 
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mariovitali

mariovitali

Senior Member
Messages
1,214
@skwag

Okay some comments which hopefully will be useful.

I should have made more clear on the first post that we have a pool of supplements that may work synergistically.
These are the following :

TUDCA, Taurine, NAG, Curcumin, Resveratrol, Vitamin C, Vitamin D3, Choline/Alpha GPC, Inositol and Selenium.

These should be used in addition of any Methylation regimen. I suggested (but not in the first post unfortunately) that these supplements are added one by one so that possible benefits (or lack of) are more easily found.

Looking at your posts it appears that you got an immediate (?) benefit from Choline/Inositol supplementation. What i would do is to slowly add after this, one supplement -say TUDCA- wait for 10 days or so, evaluate the results and then add Taurine wait for 10 days, then Selenium, etc.

So you must find which subset of those supplements that ameliorate ER Stress are beneficial to you. I will have to update the first post so that this step of the regimen is clear.

Regarding the symptoms : Some of them will take months to subside. Of course i am saying this based on my personal experience only.

Thank you and Please keep us updated. Good Luck!



EDIT : @all : my intention is to give at the regimen suggested by ppodhajski a try. To do this i will have to wait until the supplements arrive (20 days) but i will let you know as soon as i start. FYI i already started taking Biotin (which is part of ppodhajski's suggestions)
 
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mariovitali

mariovitali

Senior Member
Messages
1,214
@Gondwanaland

All that i could understand regarding Biotin is that oxalates impair its absorption (?)

I also used my software to see which Topics co-occur with oxalates :



Screen Shot 2015-09-05 at 14.28.40.png


insp-3 = inositol triphosphate receptor
trpv = transient receptor potential channels
ckd = chronic kidney disease

Of interest is the association between magnesium deficiency with oxalates as well.
 
Violeta

Violeta

Senior Member
Messages
2,945
Last edited:
adreno

adreno

PR activist
Messages
4,841
Can't remember if this was posted earlier:

In this study, we investigated the development of endoplasmic reticulum (ER) stress after traumatic brain injury (TBI) and the efficacy of post-TBI administration of docosahexaenoic acid (DHA) in reducing ER stress. TBI was induced by cortical contusion injury in SpragueDawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered intraperitoneally at 5 min after TBI, followed by a daily dose for 3–21 d. TBI triggered sustained expression of the ER stress marker proteins including phosphorylated eukaryotic initiation factor-2, activating transcription factor 4, inositol requiring kinase 1, and C/EBP homologous protein in the ipsilateral cortex at 3–21 d after TBI. The prolonged ER stress was accompanied with an accumulation of abnormal ubiquitin aggregates and increased expression of amyloid precursor protein (APP) and phosphorylated tau (p-Tau) in the frontal cortex after TBI. The ER stress marker proteins were colocalized with APP accumulation in the soma. Interestingly, administration of DHA attenuated all ER stress marker proteins and reduced the accumulation of both ubiquitinated proteins and APP/p-Tau proteins. In addition, the DHA-treated animals exhibited early recovery of their sensorimotor function after TBI. In summary, our study demonstrated that TBI induces a prolonged ER stress, which is positively correlated with abnormal APP accumulation. The sustained ER stress may play a role in chronic neuronal damage after TBI. Ourfindings illustratethat post-TBI administration of DHA hastherapeutic potentials in reducing ER stress, abnormal protein accumulation, and neurological deficits.
Click to expand...
Docosahexaenoic Acid Reduces ER Stress and Abnormal Protein Accumulation and Improves Neuronal Function Following Traumatic Brain Injury
 
mariovitali

mariovitali

Senior Member
Messages
1,214
@adreno

Thank you for the link, i will download all relevant PubMed articles regarding DHA and use them for my Data Mining analysis.


@adreno, @Valentijn

It would really be helpful if you could read the following paper (more specifically Sections 2.3 - 2.5) :

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


The paper discusses the relationship of ER Stress, Oxidative Stress and Mitochondrial Dysfunction among other things. Unfortunately i do not have the necessary knowledge to fully understand it so any additional help would be much appreciated.

I think that a major mistake that was made here (from me that is) was the fact that important pieces of information have been left out, namely ROS, Oxidative Stress, Mitochondrial Dysfunction and the Relation of all these to ER Stress.


Thank you in advance!

 
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Violeta

Violeta

Senior Member
Messages
2,945
ROS isn't the oxidant, is it?

I think metals are the oxidant. Here's something about cadmium, but I would bet that iron is even more common. As in oxidative stress.

http://www.ncbi.nlm.nih.gov/pubmed/20130962

The oxidative stress: endoplasmic reticulum stress axis in cadmium toxicity
 
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mariovitali

mariovitali

Senior Member
Messages
1,214
@Violeta,

Thanks for the links, from what i've read there exist both Endogenous and Exogenous ROS. So Cadmium and pollutants are just one part of the story
 
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