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Unfolded Protein Response and A Possible Treatment for CFS

Discussion in 'General Treatment' started by mariovitali, May 3, 2015.

  1. mariovitali

    mariovitali Senior Member

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    This post was last updated on July 27th, 2015

    Please note : Should you decide to follow the regimen, you do it at your own risk.


    Dear All,

    After many years of Brain Fog, Psychological Problems, Orthostatic Intolerance, Thyroid Problems, Testosterone Problems, i am totally recovered.

    Since i was not getting any help from Doctors and my Health was deteriorating, i decided to take things in my own hands. I started logging whatever was happening to me, what i was eating, what supplements i used, how was the weather, etc. Then i used special techniques (aka Data Science) to identify the common characteristics of Good Days vs Bad Days, analyze thousands of Pubmed Research Articles and find the root cause of my problems.

    Quite possibly, a key Element behind our problems has to do with Endoplasmic Reticulum (ER) stress, Misfolded Proteins and the the subsequent Unfolded Protein Response (UPR). Anything that impairs proper folding of Proteins within the ER ultimately leads to UPR and the Majority of our problems. At the end of the post you can find relevant References regarding why Methylation problems, Tetrahydrobiopterin Production Impairement, Celiac Disease, N-Linked Glycosylation impairment (among others), all create Stress within the ER and then signal a UPR.



    Some Causes for Misfolded Proteins / ER Stress (i will be updating the list as necessary) :

    a) Methylation problems
    b) Choline Deficiency
    c) Celiac Disease (Gluten Intolerance)
    d) Impaired BH4 (Tetrahydrobiopterin) Production & Phenylketonuria
    e) Impaired N-Linked Glycosylation (e.g from Statins , HmG-CoA Inhibitors)
    f) Pathogens (Credit to @@adreno - see his post below)
    g) Impaired Calcium Homeostasis
    h) Methamphetamine Use (Possibly)
    i) Sedentary Lifestyle
    j) Insulin Resistance
    k) Obesity

    l) High Cortisol from Stress and Weather Changes (Credit to@@Ema - see her post about Weather Changes and how it could be affecting us below)

    m) Environmental Toxins (Credit to @@JPV - see his post below )
    Now imagine the following scenario : There exists a bucket which is filled by any of the above causes with water. If you do not act either by avoiding filling the bucket with water and/or by making sure that some of the water is thrown at regular intervals then the bucket will eventually overfill. And this means trouble.

    In other words, if you have ANY of the above stressors, your "Bucket" is being filled and you must stop this. My theory is that this is the problem behind the Methylation Support Regimen that was proposed by Fredd / Rich Van Konynenburg. They dealt with one aspect of ER Stress only (namely Methylation problems and Increased Homocysteine which causes ER Stress). But if you have more than one Stressor going around then you will not have a full recovery.

    The key elements of the proposed regimen are using any agent/supplement/actions to prevent Protein Misfolding and Endoplasmic Reticulum Stress and at the same time avoid actions that induce Protein Misfolding.

    To help proper Protein Folding and ameliorate ER Stress the following Actions/Supplements are recommended :

    -Methylation Protocol (If you have Methylation problems you must follow it according to your Gene mutations)

    -Choline supplementation : Choline deficiency is very common and should be addressed because it leads to NAFLD (Non-alcoholic liver disease) and ER Stress. You must be aware of possible SNPs on the following genes :


    rs3733890(Risk A)
    rs2461823 (Risk C) NAFLD Disease
    Rs7643645 (Risk G) NAFLD Disease
    rs7946 (Risk T) (PEMT)
    rs4244593 (Risk G) (PEMT)
    rs2236225 (Risk A) (MTHFD1)
    rs9001 (Risk G) (CHDH)


    If you have several SNPs in the genes listed above, then you should supplement with Choline up to 700 mg per day and see how you feel.

    -TUDCA : ameliorates Misfolded Proteins/ER Stress

    -Taurine : Ameliorates ER Stress

    -Vitamin C : Boosts BH4 functionality in case you have impaired production. I have reduced Tetrahydrobiopterin production therefore i use Vitamin C to increase it. Phenylketonuria creates Endoplasmic Reticulum Stress and Unfolded Protein Response

    Key Genes :


    GCH1
    rs10483639( Risk C)
    rs3783641(Risk A)
    rs8007267(Risk T)
    rs12147422 -(Risk C)
    rs3783637 - (Risk T)
    rs3783641 - (Risk A)
    rs41298442 - (Risk T)
    rs4411417 - (Risk C)
    rs752688 - (Risk T)
    rs841 - (Risk A)
    rs998259 - (Risk T)
    rs7147286 - (Risk A)

    PAH Gene

    rs10860936 (Risk C)
    rs1722387 (Risk C)
    rs1522305 (Risk C)
    rs1522296 (Risk A)
    rs772897 (Risk C)
    rs1522307 (Risk G)
    rs11111419 (Risk T)



    -Selenium : Deficiency/Over-supplementation increases ER Stress. Induces HSP70, Prevents Protein Misfolding. Note that P5P (=Active form of Vitamin B6, Part of Methylation support regimen) is essential for proper Selenium metabolism.

    -Curcumin: Ameliorates ER Stress by boosting HSP70 (Heat Shock Protein). NOTE : High Curcumin intake (=In Supplement form) acts as a DHT Inhibitor.

    -Vitamin D3 : Ameliorates ER Stress, Induces HSP70 but it can be problematic to some people because it increases Calcium Absorption which could cause Symptoms if your Calcium Homeostasis is impaired.

    -Resveratrol : Induces HSP70. Note that many Resveratrol supplements contain Vitis Vinifera extract which is a potent HmG-CoA Inhibitor (Statin drugs are also HmG-CoA Inhibitors).

    -N-Acetylglucosamine (NAG) : Could play a role in controlling ER Stress. DO NOT take NAG and sweets or anything else that increases Glucose levels at the same time.


    Note : Foods high in Cholesterol and Glucose increase HmG-CoA activity which is beneficial for us but it is not suggested that you increase HmG-CoA by having Foods high in Cholesterol and Sugar!

    -Caloric Restriction (But don't go overboard) : Induces HSP70. Note however that severe drop of Insulin Level (Hypoglycemia) stops HmG-CoA production which for us could be a problem. Probably a good practice is to not eat anything for a day apart from drinking water. Check with your doctor that this is ok for you to do.

    -Calcium : Ensure that you have normal calcium levels. Calcium is VERY critical for proper handling of Endoplasmic Reticulum Stress but it can be a double-edged sword if Calcium homeostasis is not functioning properly. In this case, supplementing with Calcium will worsen your symptoms. It is recommended that you first supplement with Magnesium (Calcium Antagonist) and see how you feel.




    STAY AWAY From :

    P450 Inhibitors : Grapefruit, BioPerine, Quercetin, Capers (High in Quercetin). Caution : A lot of Supplements use Bioperine for increased absorption. Check Labels!

    HSP70 Inhibitors : Quercetin, Capers (High in Quercetin),Myricetin, Luteolin.

    Gluten sources (If you are Gluten intolerant) : Induces Oxidative Stress

    MSG Sources / Phenylalanine Sources : Parmesan, Whey Protein, Aspartame of any kind

    HmG-CoA Inhibitors : Statins, D-Limonene, L-Carnitine, Orange Juice, too much Olive Oil (Oleic Acid), Olives,Vitis Vinifera extract.

    N-Linked Glycosylation Inhibitors/Disruptors : Statins, Thapsigargin, Tunicamycin, Brefeldin A, DHT Inhibitors (e.g Finasteride/Propecia, Saw Palmetto, Green Tea)

    Oxidative Stress avoidance : Intense workouts, Extreme Weather changes (not much you can do about this), Psychological Stress, Testosterone Induction (Testosterone boosting creates Oxidative Stress)

    Other foods /supplements :Ashwagandha, ENADA/NADH, Ginkgo Biloba, Royal Jelly, Oats (not sure why i didn't feel good with those)



    My Regimen :

    -Methylation Support : Dibencozide (Adenosylcobalamin) , P5P (apart from Methylation, important also for proper Selenium Metabolism), Metafolin
    -ER Stress support : TUDCA, Curcumin (i either use turmeric powder sprinkled in salads or use Mustard). Some olive oil is used for better absorption.
    -Vitamin C
    -Selenium
    -NAG
    -Complete Elimination of Alcohol because of TUDCA Supplementation.
    -Avoidance of P450 Inhibitors, DHT Inhibitors, HSP70 Inhibitors, etc

    My current regimen :


    08:00
    Metafolin 2000 mcg
    Dibencozide 1/4 tablet
    Mucuna Dopa 100 mg
    N-Acetylglucosamine 700 mg
    Taurine 500 mg

    10:00
    Choline 350 mg


    12:00
    P5P 50 mg
    Selenium 100 mcg
    TUDCA 250 mg


    16:00
    5-HTP 50 mg
    Taurine 500 mg
    N-Acetylglucosamine 700 mg


    20:00
    Vitamin C 500 mg
    5-HTP 50 mg
    Choline 350 mg

    23:00
    NAG 700 mg


    24:00
    TUDCA 250 mg


    ALCOHOL IS NOT ALLOWED WHILE YOU USE TUDCA.


    I would also appreciate your feedback should you decide to do this regimen. Also, Please try to see if Weather Changes are affecting you and let me know.You will have side effects BEFORE the weather front hits you. For my symptoms there was a clear pattern of Side Effects being associated with Abrupt Weather Changes such as Temperature Drop, Barometric Pressure Drop and Wind picking up with Temperature Dropping abruptly being the worst.

    It appears that weather induces Protein Misfolding and as a consequence Stress within the Endoplasmic Reticulum which our bodies cannot handle.



    This is the complete list of Side Effects i experienced for more than 7 years :

    Depression & Suicidal Thoughts
    Poor Memory
    Early Morning Insomnia
    "Brain Fog" - Inability to think clearly
    Impaired Speech
    Low Energy
    Social Anxiety
    Dysphagia
    Constipation
    Urticaria
    Orthostatic Intolerance
    Tinnitus
    Sudden Hearing Loss
    Hypothyroidism
    Secondary Hypogonadism
    Numbness in Extremities
    Bradycardia
    Cardiac Arrhythmias
    Restless Leg Syndrome
    High Cholesterol
    Pain on Neck, Waist, Elbows areas
    Impotence
    Anorgasmia

    A user called "trynottoworry" first discussed the importance of Unfolded Protein Response in trying to identify what happens with the Post-Finasteride Syndrome. My problems originated right after quiting Finasteride (Propecia) for Hair loss. I believe that Chronic Fatigue Syndrome, Post-Finasteride Syndrome and cases of people with Permanent Side effects from Drug 'Accutane' share all the same mechanism.

    I will be editing this first post with new information/things to avoid. Please visit http://solvepfs.com and look at the Thread called SRD5A3/Mevalonate if you want to know more.

    Good Luck




    REFERENCES


    The factors that cause improper folding of Proteins are :

    -Hyperhomocysteinemia (HHcy). This is where MTHFR Mutation and Methylation comes in.

    http://www.ncbi.nlm.nih.gov/pubmed/15243582


    Next, we look at Celiac disease (CD):

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045209


    -A Third reason : improper Tetrahydrobiopterin Production, leads to Phenylketonuria which could be a Protein Misfolding Disease :


    http://www.ncbi.nlm.nih.gov/pubmed/20937381

    Upon looking my 23andme data for problems in Tetrahydrobiopterin (BH4) production, i found a mutations to gene GCH1 which results in impaired BH4 Production although not as serious as other genes that cause Phenylketonuria.

    Please also see this Thread :http://forums.phoenixrising.me/inde...imiting-enzyme-for-bh4-relation-to-nos.19570/

    If you have this mutation you could possibly help things by supplementing with a cAMP Stimulator, Forskolin but we do not know if you can co-administer TUDCA along with Forskolin :

    http://www.ncbi.nlm.nih.gov/pubmed/7521513


    Choline deficiency leads to NAFLD and ER Stress :

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601486/


    -User 'trynottoworry' discussing the Unfolded Protein Response as a consequence of Finasteride intake :


    http://www.hairlosstalk.com/interact/archive/index.php/t-53968.html


    NAG and ER Stress :http://www.researchgate.net/publica...ance_protein_quality_control_and_prolong_life



    Sedentary Lifestyle, Obesity impairs HSP Production, creates ER Stress :

    http://www.hspsanddiabetes.com/HooperHooper_CSC.pdf

    Regimen consists of Methylation/ BH4 Support, ER Stress and improving Proper Protein Folding within the Cell through induction of Chaperones. Supplements : TUDCA, N-Acetylglucosamine, Taurine, Choline, Selenium, Dibencozide, P5P, Metafolin, Vitamin C

    Disclaimer: I am not a medical professional, and what I say reflects conclusions from self experimentation
     
    Last edited by a moderator: Jul 27, 2015
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  2. adreno

    adreno Learned helplessness

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    More about tudca :

    http://examine.com/supplements/Tauroursodeoxycholic Acid/
     
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  3. Ema

    Ema Senior Member

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    Would it be a bad idea to take TUDCA and cholestyramine together?
     
  4. mariovitali

    mariovitali Senior Member

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  5. Ema

    Ema Senior Member

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    Here's more:

    So that seems to indicate that it would work synergistically with something like cholestyramine...helping to increase the amount of bile produced and shuttled through the gallbladder so cholestyramine could have even more opportunity to bind up the biotoxins as they come through.

    But I'm not at all sure about this.

    Especially in light of this:

    Would have been handy if they'd bothered to mention what those important interactions actually are...there are no such interactions listed on the interaction checker at drugs.com.

    This article suggests that it impairs absorption:

    Who knows what that interval actually is? And does it also apply to TUDCA?

    Also that UDCA is an inducer of the CYP4503A4 system which also metabolizes many other drugs and steroid hormones like cortisol:

     
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  6. adreno

    adreno Learned helplessness

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    Tudca is also quite expensive. Perhaps taurine could work as a cheaper surrogate (although not quite as effective)?

    @mariovitali, what is HmG-CoA (some intermediate in ketosis?), and why is that important?
     
    Last edited: May 3, 2015
  7. mariovitali

    mariovitali Senior Member

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    HmG-CoA is needed for proper Mevalonate Pathway function. Most Statins function by inhibiting HmG-CoA. As a result you lower Cholesterol but Mevalonate Pathway is a very important one since production of key neurosteroids and steroids is affected.

    Regarding Taurine you are right, it can also work in the same way although most studies that i've found discuss about TUDCA and its ability to limit Protein Misfolding and UPR.

    Unfortunately i do not know if we have a way to measure which of these compounds (TUDCA, Selenium, Resveratrol, Taurine, Vitamin D3, BH4) works better.
     
    Last edited: May 3, 2015
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  8. alice111

    alice111 Senior Member

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    This is very interesting! I just recently learned that a lack of sleeps makes a person feel "worse" (even healthy people) because it results in folded proteins.. So makes sense that this could be a big component of the illness. I had been pondering this, and up came your post!
     
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  9. Ema

    Ema Senior Member

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    I have this symptom too and I hate it. For me though, it's caused by low cortisol since weather fronts cause an increase in cortisol. I'm on replacement for adrenal insufficiency and I often have to stress dose for storms. When I'm properly covered with steroid, I don't notice the fronts.
     
  10. alex3619

    alex3619 Senior Member

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    I began talking about protein misfolding in CFS about 2000. Peroxynitrate can indirectly cause issues. A big one is that reduced glutathione is required for proper folding, and we are often deficient.
     
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  11. mariovitali

    mariovitali Senior Member

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    I will never forget what happened the night i had my initial crash. I was taking Finasteride and decided to quit it. Finasteride possibly generates problem on N-Glycosylation through downregulation of SRD5A3 (this also impairs proper Protein Folding). I was on diet at that time and decided to eat lots of Protein through consuming Egg Whites.

    I broke into Hives and had Tinnitus, Joint Pains, Difficulty swallowing,Impotence and Red Spots in my palms. The Doctors couldn't understand what was happening but now i know : Egg whites contain a lot of Phenylalanine. By taking Finasteride and at the same time being BH4 deficient i triggered a severe Unfolded Protein Response.

    It took me months to get well and i was taking antihistamines for Hives for more than a year. I thought this was over but then, as years passed by, problems started again. For me, a Tinnitus incident would signal an Unfolded Protein Response. Then as time passed by, more problems started appearing like Brain Fog, Inability to Sleep, Thyroid problems. I was a real mess.
     
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  12. adreno

    adreno Learned helplessness

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    Last edited: May 4, 2015
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  13. mariovitali

    mariovitali Senior Member

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    Now this can be interesting. Please have a look at the following list :

    The first String in the list has the format xyz.csv and then you have a number as percentage.

    The xyz is actually a research subject in PubMed. So for example, the first file is upr.csv and it contains 5153 entries of PubMed articles regarding Unfolded Protein response.

    Next we have er_stress.csv which is a file that contains 11088 entries of PubMed articles regarding Endoplasmic Reticulum Stress.

    The percentage you are seeing next to the file, contains the proportion (in %) that the phrase "misfolded proteins" was found to each file.

    It appears that the subject that contains the largest percentage of mentions on Misfolded Proteins is HSP70, then Calcium Homeostasis.


    Now, let's find out about HSP70 itself :


    It appears that HSP70 and Curcumin are discussed more frequently together within the chosen Subjects in PubMed. Of course we do not know the context of these mentions but after some reading i've found that Curcumin induces HSP70 and the same applies for Resveratrol.
     
    Last edited: May 4, 2015
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  14. chipmunk1

    chipmunk1 Senior Member

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    Discovery[edit]
    Members of the Hsp70 family are strongly upregulated by heat stress and toxic chemicals, particularly heavy metals such as arsenic, cadmium, copper, mercury, etc. Hsp70 was originally discovered by FM Ritossa in the 1960s when a lab worker accidentally boosted the incubation temperature of Drosophila (fruit flies). When examining the chromosomes, Ritossa found a "puffing pattern" that indicated the elevated gene transcription of an unknown protein.[4][5] This was later described as the "Heat Shock Response" and the proteins were termed the "Heat Shock Proteins" (Hsps).

    Structure[edit]

    Hsp70 proteins can act to protect cells from thermal or oxidative stress. These stresses normally act to damage proteins, causing partial unfolding and possible aggregation. By temporarily binding to hydrophobic residues exposed by stress, Hsp70 prevents these partially denatured proteins from aggregating, and allows them to refold. Low ATP is characteristic of heat shock and sustained binding is seen as aggregation suppression, while recovery from heat shock involves substrate binding and nucleotide cycling,

    Upregulation in stress[edit]
    Production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to toxins (ethanol, arsenic, trace metals, and ultraviolet light, among many others),starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants), or water deprivation. As a consequence, the heat shock proteins are also referred to as stress proteins and theirupregulation is sometimes described more generally as part of the stress response.[12]

    The mechanism by which heat-shock (or other environmental stressors) activates the heat shock factor has been determined in bacteria. During heat stress outer membrane proteins (OMPs) do not fold and cannot insert correctly into the outer membrane. They accumulate in the periplasmic space. These OMP's are detected by DegS, an inner membrane protease, that passes the signal through the membrane to the sigmaE transcription factor.[13] However, some studies suggest that an increase in damaged or abnormal proteins brings HSPs into action.


     
    Last edited: May 4, 2015
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  15. adreno

    adreno Learned helplessness

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    I can say that curcumin helps a little, but not much. Resveratrol helps, but the inhibition of angiotensin is bad news for my OI. Creatine was just horrible. Taurine seems to help, but again can worsen OI. D3 doesn't seem to do anything good either.

    In all, there's nothing on that list of supplements that has helped me significantly.
     
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  16. mariovitali

    mariovitali Senior Member

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    So you have Orthostatic Intolerance? Have you checked your Nitric Oxide levels?

    Although these compounds are frequently discussed together, these associations tell us nothing about what induces HSP70 more (ie Curcumin or Resveratrol or....)

    Did you use Curcumin in Supplement form (Meriva) or as a powder sprinked in Food?
     
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  17. adreno

    adreno Learned helplessness

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    Haven't checked NO. Erections are fine, I suppose that wouldn't be so if I had a problem with NO. Although there are several forms of NO, so it's all a bit complicated.

    I've tried curcumin mostly in different supplement formulations.

    I like your way of doing research, but there is no guarantee that the researchers on PubMed has made the correct (or optimal) associations. Lots of important stuff just hasn't been researched.
     
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  18. wastwater

    wastwater Senior Member

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    Due to my genetics I almost certainly have mismade or badly made proteins.
     
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  19. August59

    August59 Daughters High School Graduation

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    I believe that Dr. Baraniuk's study and Dr. Natelson's study on spinal fluid both indicated "misfolded proteins" unique to ME/CFS patients.

    If I can find them again I'll link them.
     
  20. mariovitali

    mariovitali Senior Member

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    http://link.springer.com/article/10.1186/1471-2377-5-22





    @August59 Spot on, Thank you!
     
    Last edited: May 5, 2015
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