mariovitali
Senior Member
- Messages
- 1,214
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
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
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