Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

@Valentijn @Violeta @Gondwanaland @ahmo @skwag @leela @jop @Tunguska

I am tagging you all because this is very important.


For the past two weeks i have noticed that my Heart was beating faster. I have a two floor apartment and so i have to use the stairs quite frequently. I noticed that getting to the top floor became more difficult and i had to breathe more heavily.

My normal BPM is usually 62 and this has increased by 23 BPM on average. But what got me curious/worried was the shortness of Breath.

The culrprit was NAC. I then find this which says that NAC may cause Pulmonary Hypertension :


http://www.sciencedaily.com/releases/2007/09/070904175353.htm


This means that for me, NAC is out. I will put that to the PDF i am preparing.


@Valentijn I think that you are taking NAC as part of your regimen. I searched for Pulmonary function on the forum and i found a post from you and about an abnormal test you had regarding pulmonary function (?)

FYI : Using an oximeter i found that my reading was 94%...on the lowest normal range. I know that an Oxymeter has limitations. Has anyone taken readings with an Oxymeter? How much Oxygen saturation have you found?


And another thing. Dr Ben Lynch of MTHFR.NET now begins talking not just about MTHFR but for the importance of Liver, Phosphatidylcholine, Bile Acids and Creatine :


http://chriskresser.com/what-influences-methylation-an-interview-with-dr-ben-lynch/


For me he is spot on. I had delayed speech as a kid and have really hard time to put on muscle. I looked at my GAMT gene (discussed in the Interview) , i have no problems but my creatine levels are low perhaps. Will research that more.

 

[Valentijn]

@Valentijn I think that you are taking NAC as part of your regimen. I searched for Pulmonary function on the forum and i found a post from you and about an abnormal test you had regarding pulmonary function (?)

My pulmonary function has tested completely normal since developing ME. But we seem to have different diagnoses, so I wouldn't expect us to react similarly to common supplements.

I'd also point out that NAC has been tested long-term in HIV patients, with no substantial side-effects. Though anyone prone to cysteine-based kidney stones should of course avoid NAC.

 

[jop]

Thanks @mariovitali. It seems that some of us react negatively to just about anything.

I'm interested in the liver ideas because of the hammering mine has had with previous illness. My enzyme tests look ok though.

I've been thinking about your data mining approach a bit but too tired to post more now.

Hope you recover from the NAC experiment soon.

 

[jump44]

Hey guys been awhile just thought id update.

been following the regimine for a few months. I would say It gave me about a 20-30% overall improvement in symptoms. Im thankful for that.

I saw inosine being discussed a few posts up. I Just started immunovir per my doctor for my reactivated EBV and low nk cell count etc. Anyways I am only taking a half tablet and its my 3rd day but it has already cleared my brain up better than anything Ive tried to this point. also has given me a noticeable energy boost. Idk how this plays into your theory @mariovitali, but I thought I would report it here. Perhaps in my case the immune system is a key player along with the liver. Anyways good to see this thread is still ticking, its super helpful. I will keep reporting the furhter into my immunovir/ldn treatment I get. I am continuing with Tudca, choline/inositol, some methylation, and selenium/fmn.

 

[ahmo]

thanks for the heads-up @mariovitali I don't use NAC. I haven't had the energy to post my detox profile yet, have not forgotten. Life has intervened. soon.

 

[mariovitali]

@jump44

The active ingredient of Immunovir is Isoprinosine. From searching PubMed there are quite a few entries for Immunomodulation after Liver Injury/ Cirrhosis.

Immune modulating effect of isoprinosine in patients with post-alcoholic liver cirrhosis].
[Article in German]
Boroń-Kaczmarska A1, Boroń P, Puch U, Hryniewicz A, Bobrowska E.
Author information

Abstract
Immunomodulating effect of isoprinosine was estimated in group of 10 patients with postalcoholic liver cirrhosis and compared with another group of 10 patients with postinflammatory liver cirrhosis with infection of hepatitis B virus. Disturbances of immunologic reactivity in the patients with postalcoholic liver cirrhosis mainly concerned increased immunoglobulin G, A concentrations in the blood serum, decreased percentage values of lymphocytes T and their subpopulations (lymphocytes T4 and T8) and increased percentage of lymphocytes B. Disturbances of the examined indices of the immunologic reactivity in the group of patient with postinflammatory liver cirrhosis concerned increased concentrations of circulating immunologic complexes, immunoglobulins A and M in the blood serum and decreased percentage of lymphocytes T and their subpopulation. Treatment with isoprinosine resulted in different immunologic effect in the examined patients concerning mainly increased concentrations of circulating immunologic complexes in the blood serum and increased percentage values of lymphocytes T, T4, T8, B in the course of postalcoholic liver cirrhosis. Patients with postinflammatory liver cirrhosis treated with isoprinosine mainly showed decreased concentrations of circulating immunologic complexes, immunoglobulins A, M the blood serum, increased percentage values of lymphocytes T4 and T8.

Please also see : "The Liver as an immunological organ"


http://onlinelibrary.wiley.com/stor...6p&s=cb2d649ac31ac12c416f1d6ebd46440f9bcf6d24

In other words, the Hypothesis is that Immune dysfunction originates from Liver injury and Oxidative/ER Stress which is uncontrolled.


Could you have a look at your Bile Acid levels?

 

[mariovitali]

Hey guys been awhile just thought id update.

been following the regimine for a few months. I would say It gave me about a 20-30% overall improvement in symptoms. Im thankful for that.

I saw inosine being discussed a few posts up. I Just started immunovir per my doctor for my reactivated EBV and low nk cell count etc. Anyways I am only taking a half tablet and its my 3rd day but it has already cleared my brain up better than anything Ive tried to this point. also has given me a noticeable energy boost. Idk how this plays into your theory @mariovitali, but I thought I would report it here. Perhaps in my case the immune system is a key player along with the liver. Anyways good to see this thread is still ticking, its super helpful. I will keep reporting the furhter into my immunovir/ldn treatment I get. I am continuing with Tudca, choline/inositol, some methylation, and selenium/fmn.

@jump44 How much TUDCA are you taking? 500 mg?

Also are you still taking Shilajt and LDN?

 

[mariovitali]

I finished a new Classification Analysis, wishing to identify potentially interesting hypotheses regarding the symptoms of CFS, PFS, Post-Accutane syndrome, etc.

Using a classifier called "Random Forests" i get an F-Measure (F1) of 0.84 for those that are interested. Unfortunately Random Forests do not tell us a lot of things regarding how they make their predictions but they can tell us which features are part of the solution (=differentiate Symptoms vs No-Symptoms in our case).

Note : The data that was used for the analysis were created using highly experimental methods. I do not wish to make any claims.

Here is the snapshot. it lists attributes in their order of importance :

As you can see, Oxidative stress Markers are on the top of the most important attributes. Notice how Choline deficiency, Taurine, Glutamate, iNOS, Solute Carriers (discussed by @ppodhajski), Isoprostane (Biomarker of Oxidative stress) and TBARS are also there (TBARS is used for measuring the damage done by ROS).

 

[jump44]

@jump44 How much TUDCA are you taking? 500 mg?

Also are you still taking Shilajt and LDN?

500mg of TUDCA most days/250 on some. The shilajit is in the Ubiquinol formula from life extension that I take. I believe its 200mg so not a huge amount.. Yes I am up to 1.5mg of ldn per night now as well.

 

[mariovitali]

OK Great... as discussed please let me know when you have your DNA Data available.

Consider also taking Taurine (i take just 300 mg) and see how you feel. TUDCA is typically given at 15-20 mg per Kilogram body weight so you could try increasing the dose and evaluate.

 

[jump44]

Thanks @mariovitali .. I do take Taurine as well usually every other day, its a 500 mg pill w 10mg of B6.. Id love to increase the TUDCA dosage its just damn expensive and Im only working part time right now so tryin to make the bottles last longer. Also you guys mentioned activated bs earlier. I have taken the drs best activated B complex 3 times now and once it made me feel good the other two times I had a weird depression descend on me the day after taking it.. ANy ideas on that? so weird. Most people would probably take that and either not feel anything or have more energy.

 

[Tunguska]

About NAC, on other forums, more paranoid people than us are concerned about its anti mucous activity and some negative blood brain barrier effects found on animals. I only take it in increased sickness and chronic use no longer gave me any benefit, rather a dumbening effect.

About TUDCA, the best effect I've had thus far and consistent is, especially when combined with coconut oil, it noticeably increases blood flow and perceptible body temperature (offsetting choline). Hence the possibility its effects have to do with improved thyroid receptors or whatnot.

 

[Gondwanaland]

especially when combined with coconut oil, it noticeably increases blood flow and perceptible body temperature (offsetting choline). Hence the possibility its effects have to do with improved thyroid receptors or whatnot.

I got that effect from coconut oil only FWIW

 

[mariovitali]

@Tunguska, @Gondwanaland

What you said about Coconut Oil appeared interesting. So what i normally do is to use this as a query to my Software :

*********************************Topic : coconut oil ******************************************
omega3.csv : 0.44 %
choline_deficiency.csv : 0.39 %
hmgcoa.csv : 0.30 %
tocotrienol.csv : 0.20 %
steatohepatitis.csv : 0.13 %
tbars.csv : 0.13 %
bile_acid.csv : 0.12 %
cyp7a1.csv : 0.12 %
resistant_starch.csv : 0.11 %
phosphatidylcholine.csv : 0.11 %
redox_homeostasis.csv : 0.11 %
oxidation.csv : 0.10 %
acetyl_coa_carboxylase.csv : 0.10 %
l_carnitine.csv : 0.08 %
phosphatidylserine.csv : 0.08 %
hydrolysis.csv : 0.08 %
triiodothyronine_levels.csv : 0.07 %
curcumin.csv : 0.07 %
cyp2e1.csv : 0.07 %
caloric_restriction.csv : 0.07 %
d_aminoacid_oxidase.csv : 0.06 %
rxr.csv : 0.06 %
cortisol_levels.csv : 0.06 %
ginkgo.csv : 0.06 %
dolichol.csv : 0.06 %
acetyl-coa.csv : 0.05 %
sirt1.csv : 0.05 %
thermoregulation.csv : 0.05 %
isotretinoin.csv : 0.05 %
cyp1b1.csv : 0.05 %
reactive_metabolites.csv : 0.05 %
rar.csv : 0.05 %
choline.csv : 0.05 %
phospholipid_human.csv : 0.05 %
pyrogen.csv : 0.05 %
lpa.csv : 0.05 %
udpgluc.csv : 0.05 %
vcam-1.csv : 0.04 %
catalase.csv : 0.04 %
resveratrol.csv : 0.04 %
nafld.csv : 0.04 %
glutathione_stransferase.csv : 0.04 %
niacin.csv : 0.04 %
coenzymeq10.csv : 0.04 %
inositol.csv : 0.03 %
pantothenic_acid.csv : 0.03 %
freet3.csv : 0.03 %
glucose-6-phosphatase.csv : 0.03 %
oxidative_stress_markers.csv : 0.03 %
selenium_deficiency.csv : 0.03 %
neuroinflammation.csv : 0.02 %
nac.csv : 0.02 %
isoprostane.csv : 0.02 %
hepatocytes.csv : 0.02 %
l-cysteine.csv : 0.02 %
gsh.csv : 0.02 %
magnesium_deficiency.csv : 0.02 %
3betahsd.csv : 0.02 %
glucuronidation.csv : 0.02 %
nadh_dehydrogenase.csv : 0.02 %
serotonin_levels.csv : 0.02 %
oxidative_stress_protection.csv : 0.02 %
butyrate.csv : 0.02 %
n-acetyltransferase.csv : 0.02 %
calcium_homeostasis.csv : 0.02 %
taurine.csv : 0.02 %
selenium.csv : 0.02 %
glucocorticoid_receptor.csv : 0.02 %
nrf2.csv : 0.02 %
iron_deficiency.csv : 0.02 %
il_10.csv : 0.02 %
urolithiasis.csv : 0.02 %
methionine.csv : 0.02 %
flavoprotein.csv : 0.01 %
glycolysis.csv : 0.01 %
detoxification.csv : 0.01 %
p450.csv : 0.01 %
cyp1a1.csv : 0.01 %
nadph.csv : 0.01 %
testosterone_production.csv : 0.01 %
conjugation.csv : 0.01 %
cholestasis.csv : 0.01 %
ros.csv : 0.01 %
endothelial_nos.csv : 0.01 %
vitamin_k.csv : 0.01 %
liver_injury.csv : 0.01 %
h2o2.csv : 0.01 %
insulin_resistance.csv : 0.01 %
bilirubin.csv : 0.01 %
uric_acid.csv : 0.01 %
gluten.csv : 0.01 %
nk_cell.csv : 0.01 %
molybdenum.csv : 0.01 %
ige.csv : 0.01 %
cox-2.csv : 0.01 %
inosine.csv : 0.01 %
probiotics.csv : 0.01 %
tlr.csv : 0.01 %
hydroxysteroid_dehydrogenase.csv : 0.01 %
gut.csv : 0.01 %
inflammatory_response.csv : 0.01 %
biotin.csv : 0.01 %
vitamin_d3.csv : 0.01 %
p450oxidoreductase.csv : 0.01 %
glutamate.csv : 0.01 %
hepatotoxicity.csv : 0.01 %
anorexia.csv : 0.01 %
liver_disease.csv : 0.01 %
dexamethasone.csv : 0.01 %
crohns_disease.csv : 0.01 %
hypoxia.csv : 0.01 %
norepinephrine.csv : 0.01 %
human_proteinuria.csv : 0.01 %
hba1c.csv : 0.01 %

Note how may results toward the top have to to do with Choline, Redox homeostasis and Bile Acids. I only now begin to understand the importance of Bile Acids and Coconut oil is spot on . I believe that the reason lies to the fact that Coconut Oil is rich in Medium-Chain Fatty Acids. Here is why :

Medium-chain triglycerides (MCTs) are triglycerides whose fatty acids have an aliphatic tail of 6–12 carbon atoms.[1]

The fatty acids found in MCTs are called medium-chain fatty acids (MCFAs). Like all triglycerides, MCTs are composed of a glycerol backbone and three fatty acids. In the case of MCTs, 2 or 3 of the fatty acid chains attached to glycerol are medium-chain in length.

Rich sources for commercial extraction of beneficial MCTs include palm kernel oil and coconut oil.


<SNIP>

MCTs passively diffuse from the GI tract to the portal system (longer fatty acids are absorbed into the lymphatic system) without requirement for modification like long-chain fatty acids or very-long-chain fatty acids. In addition, MCTs do not require bile salts for digestion. Patients who have malnutrition, malabsorption or particular fatty-acid metabolism disorders are treated with MCTs because MCTs do not require energy for absorption, use, or storage.

https://en.wikipedia.org/wiki/Medium-chain_triglyceride


So Coconut Oil does not require Bile Acids for its absorption which as a result puts less burden to the Enterohepatic system.

 

[Gondwanaland]

@mariovitali I became intolerant to coconut oil. (LPS? Salicylates?)
http://selfhacked.com/2014/03/14/mct-oil-may-create-food-allergies/ (something about NAC here as well)

 

[wastwater]

I kind of do word matching and was lead to these points of interest.
CADASIL a rare genetic disorder
Notch signalling pathway
And there is a paper on phonix rising from about 2012 about choline
cAMP choline connections just Internet search for that
Botulism/tetanus can effect choline
Unfortunately I have no idea if any of this is of interest what it means or what it relates to

 

[mariovitali]

@Gondwanaland Thanks for the link, really interesting


@wastwater i do not see any connection with CADASIL. Regarding Choline yes, well spotted.

 

[mariovitali]

Just a small update :

As disucssed, I started working with some people who are willing to follow the regimen in its entirety and have all the necessary blood tests (mainly Liver panel and Total Bile Acids).


I continue looking for creating a Predictive Model which might explain what is going on : The latest predictive model achieves accuracy of 0.91. Please see it below :

The chart shows the important parameters that differentiate the existence/absence of Symptoms on the dataset that was analyzed.




PDHC is Pyruvate Dehydrogenase Complex. It appears that Liver Disease is by far the most important factor. Note also acetylcholine, uric acid,probiotics,excitotoxicity, IgA, Cortisol and norepinephrine appear to be important elements.


I will post again as soon as i have updates from the people that follow the regimen. So far, ALL of them have used either Antibiotics or Accutane or Finasteride or Ciprofloxacin or -that's a new one which will be added to the list- Methotrexate or they got a viral disease such as EBV.

 

[Violeta]

@mariovitali , do you know uric acid's part in the picture? For example, what does it cause, how does one deal with it?

 

[mariovitali]

@Violeta


I think this :

Association between serum uric acid level and chronic liver disease in the United States.
Afzali A1, Weiss NS, Boyko EJ, Ioannou GN.
Author information

Abstract
Elevated serum uric acid (UA) levels strongly reflect and may even cause oxidative stress, insulin resistance, and metabolic syndrome, which are risk factors for the progression of liver disease. We sought to determine whether serum UA levels are associated with the development of cirrhosis or the presence of elevated serum liver enzymes. We used cohort data from the first National Health and Nutrition Examination Survey (NHANES I) to determine whether the baseline serum UA level was associated with the incidence of hospitalization or death due to cirrhosis among 5518 participants during a mean follow-up of 12.9 years (range = 4-21 years) after the exclusion of the first 4 years of follow-up. We also used cross-sectional data from NHANES 1988-1994 (n = 10,993) and NHANES 1999-2006 (n = 6186) to determine whether the serum UA level was associated with elevated serum alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT), two markers of hepatic necroinflammation. Compared to persons in the lower third of the distribution of serum UA (<4.8 mg/dL), those in the top third (>6 mg/dL) had a higher risk of cirrhosis-related hospitalization or death [adjusted hazard ratio (AHR) = 2.8, 95% confidence interval (CI) =1.3-5.7], whereas the risk was not substantially increased in persons within the middle third (serum UA level = 2.6-4.8 mg/dL, AHR = 1.3, 95% CI = 0.6-2.7). A higher serum UA level was associated with greater mean serum ALT and GGT levels and a greater probability of elevated serum ALT and GGT.

CONCLUSION:
The serum UA level is associated with the development of cirrhosis and the presence of elevated serum liver enzymes after adjustments for important causes and risk factors of chronic liver disease.