Unfolded Protein Response and A Possible Treatment for CFS

[Violeta]

@Sam7777 , what is the brand of kefir that you use?

Thanks

 

[Sam7777]

I *Think* this. But I'd have to double check with a family member.
http://www.amazon.com/gp/product/B0..._m=ATVPDKIKX0DER&pf_rd_r=1NHQNZKJGVKVYSHS2PFT

 

[op2pig]

Any success stories out there, regarding this protocol?

 

[mariovitali]

@op2pig

This protocol is -unfortunately- a bit complicated to say the least, since so many things have changed.


Unfortunately i did not have any more DNA Data coming in but i will update as soon as i have new data.


My update is as follows :


I completely stopped TUDCA and Alpha GPC without crashing..so far so good. Needless to say that this is the first time that after stopping TUDCA and Alpha GPC i remain completely symptom-less. Regarding Methylation protocol i take Metafolin, B12, FMN only two times a week, not more.

I begin to realise the importance of simple things like Lemon juice and Beet Roots for having Bile move around more efficiently. Also something that may be particularly beneficial for us is Ferulic Acid (FYI @Bdeep86) which is a cholagogue.


For this reason my regimen is as follows :

Breakfast (i wake up at 07:00) : Salad with Beets (one Medium beet) and Juice from a Half slice of Lemon and sprinkled Olive Oil

10:00 Vitamin B1+B5 and 500 mg of Taurine (for Bile Acid Conjugation)

11:00 Oats with as less milk as possible and pieces of Blueberries and a little bit of Honey.

13:00 Lunch taken with a capsule of Bile Acid factors from Jarrows

17:00 Salad with Beets (one Medium beet) and Juice from a Half slice of Lemon and sprinkled Olive Oil

19:00 Dinner with one Bile acid factors capsule if it contains Fat or the portion is large.


That's it.

 

[op2pig]

Thanks Mario- fascinating. What was the total duration of time that you took TUDCA for in total?

 

[mariovitali]

Thanks Mario- fascinating. What was the total duration of time that you took TUDCA for in total?

10 months i think

 

[Bdeep86]

@op2pig

This protocol is -unfortunately- a bit complicated to say the least, since so many things have changed.


Unfortunately i did not have any more DNA Data coming in but i will update as soon as i have new data.


My update is as follows :


I completely stopped TUDCA and Alpha GPC without crashing..so far so good. Needless to say that this is the first time that after stopping TUDCA and Alpha GPC i remain completely symptom-less. Regarding Methylation protocol i take Metafolin, B12, FMN only two times a week, not more.

I begin to realise the importance of simple things like Lemon juice and Beet Roots for having Bile move around more efficiently. Also something that may be particularly beneficial for us is Ferulic Acid (FYI @Bdeep86) which is a cholagogue.


For this reason my regimen is as follows :

Breakfast (i wake up at 07:00) : Salad with Beets (one Medium beet) and Juice from a Half slice of Lemon and sprinkled Olive Oil

10:00 Vitamin B1+B5 and 500 mg of Taurine (for Bile Acid Conjugation)

11:00 Oats with as less milk as possible and pieces of Blueberries and a little bit of Honey.

13:00 Lunch taken with a capsule of Bile Acid factors from Jarrows

17:00 Salad with Beets (one Medium beet) and Juice from a Half slice of Lemon and sprinkled Olive Oil

19:00 Dinner with one Bile acid factors capsule if it contains Fat or the portion is large.


That's it.

I will look into ferosulic acid, it would make sense that is why Gamma Oryzanol increases bile. I just checked and wanted to mention as a quick side note that jarrow bile acid co factors has some tudca in it.

 

[mariovitali]

@Bdeep86

Bile Acid Factors from Jarrows does not contain TUDCA.

TUDCA = TauroURSODeoxycholic Acid.

Bile Acid Factors contains : Taurocholic, Taurodeoxycholic and taurochenodeoxycholic acid

Are you sure you saw Tauro-Urso-Deoxycholic acid?

 

[Bdeep86]

@Bdeep86

Bile Acid Factors from Jarrows does not contain TUDCA.

TUDCA = TauroURSODeoxycholic Acid.

Bile Acid Factors contains : Taurocholic, Taurodeoxycholic and taurochenodeoxycholic acid

Are you sure you saw Tauro-Urso-Deoxycholic acid?

You are correct, my apologies. Thats great you haven't crashed yet, maybe tudca allowed for re-regulation of BA synthesis?

 

[mariovitali]

@Bdeep86 No worries, to be honest i was about to look for it, i thought they've added it to their original formula

 

[mariovitali]

All,

I think that this is an important message so i am mentioning users that hopefully will be interested :

@ahmo @Violeta @Bdeep86 @op2pig @Sam7777 @Valentijn @arty0mk @skwag @jump44 @Sidereal @whodathunkit

I collected and analysed 23 DNA Sample so far. Please see a snapshot of the xlsx file i used.

@Kina i am not able to upload the .xlsx file. Could you tell me what format may i upload? It is a formatted file so people here can see the data in a more efficient way

From what i see so far :


Heterozygous SNPs (=13-15 Occurrences) : CYP1B1,COMT,BHMT,CHDH,GAD1,NAT2,NAT8,ATF6,MSRA,APOE
Homozygous (=9-11 Occurrences) : TXNRD3, NDUFS7
Heterozygous+Homozygous (=16-18 Occurrences) : COMT,BHMT,CHDH,NR1H4,NAT8,ATF6,NDUFS7,JAG1,TXNRD3,ATF6,MSRA,MYO9B,rs12612347,PEMT,GRIK5

Equal to MAX SNPs (=18 Occurrences) : CHDH,NR1H4,NDUFS7,MYO9B,rs12612347

rs12612347 needs further inspection

Genome-wide association analysis in primary sclerosing cholangitis.
Karlsen TH1, Franke A, Melum E, Kaser A, Hov JR, Balschun T, Lie BA, Bergquist A, Schramm C, Weismüller TJ, Gotthardt D, Rust C, Philipp EE, Fritz T,Henckaerts L, Weersma RK, Stokkers P, Ponsioen CY, Wijmenga C, Sterneck M, Nothnagel M, Hampe J, Teufel A, Runz H, Rosenstiel P, Stiehl A, Vermeire S,Beuers U, Manns MP, Schrumpf E, Boberg KM, Schreiber S.
Author information

Abstract
BACKGROUND & AIMS:
We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers.

METHODS:
A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls).

RESULTS:
The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes.

CONCLUSIONS:
Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.

CHDH has to do with Choline deficiency :

• The protein encoded by this gene is a choline dehydrogenase that localizes to the mitochondrion. Variations in this gene can affect susceptibility to choline deficiency. A few transcript variants have been found for this gene, but the full-length nature of only one has been characterized to date. [provided by RefSeq, Dec 2010]

NR1H4 :

NR1H4 (Nuclear Receptor Subfamily 1, Group H, Member 4) is a Protein Coding gene. Diseases associated with NR1H4 include intrahepatic cholestasis and atp8b1 deficiency. Among its related pathways are Metabolism andRegulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha). GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and receptor activity. An important paralog of this gene is NR1I2.

NDUFS7 :

• This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]

MYO9B :

MYO9B (Myosin IXB) is a Protein Coding gene. Diseases associated with MYO9B include celiac disease 4 and celiac disease. Among its related pathways are Immune System and Signaling by GPCR. GO annotations related to this gene include protein homodimerization activity and GTPase activator activity. An important paralog of this gene is MYO7A.

 

[Valentijn]

I collected and analysed 24 DNA Sample so far.

Prevalence rates in ME or other patients isn't useful data in isolation. It must be compared to the rates in the general population. That data can be found by searching for the rs numbers at dbSNP: http://www.ncbi.nlm.nih.gov/SNP/

 

[mariovitali]

@Valentijn

Our different Point of views has been well documented in this Thread.

I believe that we must look at Genes in a Multivariate way (so certain combinations of frequent SNPs may have a completely different phenotype) as opposed to looking individual Genes (and their SNPs) way which your way of thinking suggests.

 

[Valentijn]

I believe that we must look at Genes in a Multivariate way (so certain combinations of frequent SNPs may have a completely different phenotype) as opposed to looking individual Genes (and their SNPs) way which your way of thinking suggests.

The issue isn't multiple SNPs and/or genes versus single ones, but rather the lack of a basis to believe that these specific combinations of SNPs can cause problems.

If you want to compare your "patient" group to a "control" group for those combinations, openSNP has hundreds of 23andME data sets for individuals which anyone can download and process. But since all of the SNPs you're interested in are very common, the combinations are probably equally prevalent in both groups.

 

[mariovitali]

The issue isn't multiple SNPs and/or genes versus single ones, but rather the lack of a basis to believe that these specific combinations of SNPs can cause problems.

If you want to compare your "patient" group to a "control" group for those combinations, openSNP has hundreds of 23andME data sets for individuals which anyone can download and process. But since all of the SNPs you're interested in are very common, the combinations are probably equally prevalent in both groups.

I discussed the lack of Controls on previous messages in this Thread (and actually said that this is a serious problem).

Unfortunately we do not know the Phenotypes of these individuals, which means that we may have among these "controls" individuals with CFS, PFS, Post-accutane Syndrome, Gulf-war Syndrome, Post-Lyme disease Syndrome etc.

So, it needs much more careful design as the one you are suggesting (in my opinion of course)

 

[Valentijn]

Unfortunately we do not know the Phenotypes of these individuals, which means that we may have among these "controls" individuals with CFS, PFS, Post-accutane Syndrome, Gulf-war Syndrome, Post-Lyme disease Syndrome etc.

People can fill out questionnaires when submitting their 23andMe data to openSNP. Many do not, but it's easy to see which ones have done so. There are options for both CFS and fatigue, if I recall correctly. So it's a matter of looking for the people who have said they don't have those symptoms.

 

[ndavisportland]

How did you come up with that protocol? I can't find a doctor to work with.

@whodathunkit

I know that this Thread is huge, probably i will have to make a new Thread i guess, since the information presented in the first Page is somewhat outdated.

My regimen looks like this :


08:00 Dibencozide, FMN, Metafolin
10:00 Alpha GPC, Manganese, Biotin, pantothenic Acid
12:00 TUDCA, Selenium P5P, Ubiquinol
16:00 TMG (Betaine)
23:00 Alpha GPC

Not only i have no sides but i also beginning to change as a person...yes i know this sounds crazy but bear with me. It seems to me that my "ups" and "downs" are not there any more. I had these for many years...you know i was mostly getting negatively affected by things happening to my life.

...Not anymore and -believe me- this is not just about Serotonin being low or anything like it. I think this is more profound. My Gums had Periodontitis for years. Now my Gums have a Pink color which i haven't seen for a decade or even more. I do not get any incidences of Sinus pains, conjunctivitis etc.

Regarding the SNP list this has changed quite a bit (i will PM you).

 

[CCC]

I've been following this thread with interest - thank you so much for persisting.

I'd also be interested to know the biochemistry for this regimen (below). It's not far off where we have gotten to separately (with lecethin instead of alpha-GPC, and without TUCDA).

And the timing - it's quite a schedule you have there.

How did you come up with that protocol? I can't find a doctor to work with.

My regimen looks like this :


08:00 Dibencozide, FMN, Metafolin
10:00 Alpha GPC, Manganese, Biotin, pantothenic Acid
12:00 TUDCA, Selenium P5P, Ubiquinol
16:00 TMG (Betaine)
23:00 Alpha GPC

 

[mariovitali]

@CCC @ndavisportland

Basically (in my case) it is about supporting the Krebs Cycle (FMN, Biotin, Pantothenic acid) and also making sure that Liver and Bile functioning is supported (Alpha GPC, TUDCA, TMG). Ubiquinol was added because of my Homozygous NDUFS7 SNPs.

Lemon juice might be also beneficial in the morning since citric acid also boosts Krebs Cycle.

Dibencozide + Metafolin are added for Methylation support.

 

[mariovitali]

IMPORTANT PLEASE READ

I have a very important update. In the past month or so i began having some strange symptoms which i never had. These were :

-Nausea
-Body chills
-Tears in my right eye without a reason
-Intestinal Bloating
-Loss of Appetite

Of course all the above were hardly noticeable, but as time passed by they became worse.

The past 5 days i hardly had any food and some water and lost 6 pounds...this was really scary. Luckily, i then found References that High Acetylcholine Levels may lead to these symptoms.


So i completely stopped Alpha GPC and TMG and my Symptoms have subsided. Yesterday i was able to eat and drink again.


To my amazement, prior to a very windy day (and being completely symptom free) i started having symptoms of High Acetylcholine again. They subsided when the wind (South Direction) has stopped.You will recall that i made numerous reference regarding the weather patterns and my Symptoms.

So it appears that whatever i had (Let's call it CFS) is a disruption of Acetylcholine activity.

There is also this post :

http://forums.phoenixrising.me/inde...acetylcholine-toxicity-the-cause-of-cfs.9757/


It also appears that Acetylcholine is also required for Bile Functioning :


https://books.google.com/books?id=ytWBLAy1FGQC&pg=PA852&lpg=PA852&dq=acetylcholine gallbladder&source=bl&ots=0aR_vzLgCh&sig=1N9K0BxWF-ZJ4PtyOlzLxMqlejE&hl=en&sa=X&ved=0ahUKEwie57Tl4_HLAhVLhSwKHeB6BjkQ6AEITDAI#v=onepage&q=acetylcholine gallbladder&f=false


I also had a call from a person having myopathy. He told me that after 10 years of mediocre Living he feels he is completely cured. All he does is Drinking Lemon juice every day for supporting the Krebs cycle. He said that he will have to wait to see Blood results first, but the fact that he feels normal again is in its own sense amazing.