• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To register, simply click the Register button at the top right.

Unfolded Protein Response and A Possible Treatment for CFS

Messages
15,786
What i specifically wanna know Val is what you believe is causing methylation disorders.
I believe that Yasko and her supplement-selling business has largely invented methylation disorders. I haven't see much proof that they exist on anywhere near the scale which would be indicated by many of the claims.

How is a methylation disorder scientifically defined? How is it diagnosed? What are the actual effects? Is there research showing that it's common at anywhere near the levels which some people report here?

It's mostly just assumptions at this point, many of which (regarding SNPs at least) are clearly wrong.
 

Violeta

Senior Member
Messages
2,843
@Sam7777 , I read about methylation issues other places before I found Phoenix Rising, and methylation blocks were considered the issue. The four possible blocks mentioned were metals, pathogens, drugs, and hormones. I'm not sure if this is what you are talking about or not, but their idea of fixing methylation problems was removing those blocks.

I have tried to go back and find the sites where I had read that but could no longer locate them.

Have you read Chris Masterjohn's articles on fatty liver and methylation?

Also, B2 deficiency as a root of methylation problems not only because of it's role in methylation but also it's role in removing metal stores from the liver.
 

mariovitali

Senior Member
Messages
1,214
@Valentijn is that so?

-What about the SNPs regarding CYP7A1?
-What about the SNPs regarding NAT2?

So in other words, these SNPs do not really tell us anything? Is this what you are saying?
 
Messages
15,786
So in other words, these SNPs do not really tell us anything? Is this what you are saying?
Specific SNPs tell us something, sometimes. Usually they tell us that they don't have an impact. Sometimes they don't tell us anything because there hasn't been any research yet.

If there hasn't been any research yet, we can't guess if they have an impact or not, nor the direction of any potential impact. If anything, the odds would favor individual unresearched SNPs having no impact.
 

mariovitali

Senior Member
Messages
1,214
@Valentijn

Let's keep it simple, so let's stick to CYP7A1 for now : Are you saying that polymorphisms found on CYP7A1 Genes are irrelevant to Bile Acid homeostasis?

I am asking you a very specific question, you are kindly asked to provide a very specific answer.
 
Messages
15,786
Let's keep it simple, so let's stick to CYP7A1 for now : Are you saying that polymorphisms found on CYP7A1 Genes are irrelevant to Bile Acid homeostasis?

I am asking you a very specific question, you are kindly asked to provide a very specific answer.
No, you are not asking a specific question. Which SNPs are you referring to on CYP7A1?

The answer would be both "yes" and "no" and "probably not" as the question stands. Some variants presumably have been shown to have an impact on that gene, even more have presumably been shown to have no impact, and the vast majority haven't been studied.

You cannot say that because some SNPs have an impact, all SNPs therefore have an impact. It's not just a baseless assumption - it is completely wrong.
 

mariovitali

Senior Member
Messages
1,214
@Valentijn

So the following doesn't mean a thing according to your thinking?


Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients.
Inamine T1, Higa S, Noguchi F, Kondo S, Omagari K, Yatsuhashi H, Tsukamoto K, Nakamura M.
Author information

Abstract
BACKGROUND:
Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression.

METHODS:
A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC.

RESULTS:
In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele.

CONCLUSION:
These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC.


and how about this regarding FXR (=NR1H4)?


Bile acid receptors and nonalcoholic fatty liver disease.
Yuan L1, Bambha K1.
Author information

Abstract
With the high prevalence of obesity, diabetes, and other features of the metabolic syndrome in United States, nonalcoholic fatty liver disease (NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis (NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor (TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.
 
Last edited:

roller

wiggle jiggle
Messages
775
what a thriller ;)

i need to go to bed, so here is the plot:
in addition to the disease X ppl with those SNPs may develop some trouble with the bile.
the study doesnt say the bile-issue may come out of the blue?

they may also develop some 50 other things.

so? yawn...

perhaps, one day, when 'science' puts the pieces together this info can be of value?
 

mariovitali

Senior Member
Messages
1,214
@roller

I don't know if you had the chance to read the Thread and my signature but after (now 8) years of having the following symptoms :


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 (SSHL)
Hypothyroidism
Secondary Hypogonadism
Numbness in Extremities
Bradycardia
Cardiac Arrhythmias
Restless Leg Syndrome
Periodontitis


I am completely Symptom-free (EDIT : Never felt better in my life!)




THANK GOD i didn't wait for "Research"....
 

ahmo

Senior Member
Messages
4,805
Location
Northcoast NSW, Australia
I regards to all the ongoing symptoms I'd had for 13 years, I, too, am symptom-free, and feel better than at most any other time in my life. I wish I could say the same about my levels of energy for physical and mental activity. But my quality of life, my sense of well being following from 4 years of healing, including diet, detox, and methylation, including Yasko, are incomparable from the mess I was in before I found a pathway forward.
 
Last edited:

Sam7777

Senior Member
Messages
115
Im suspicious of any arguement purely based on labeling someones entire career an attempt to push supplements. I dont really even take Cutlers libel towards Shade serious. Its ego mostly. Yasko seems sincere even if some things dont pan out. Good intentions usually fall short. Being right isnt easy but at least trying is. At this point Im rather sick of the whole "pharma drug pusher" "quack supplement pusher" narrative. If only reality were so simple.
 
Messages
15,786
Im suspicious of any arguement purely based on labeling someones entire career an attempt to push supplements.
My argument is based purely on Yasko frequently being completely wrong about her claims. Pushing supplements is merely a possible explanation for her failure to correct her errors, which seems plausible given the expenses of buying her treatments for the problems which do not exist. The alternative explanation would be complete incompetence.
 

mariovitali

Senior Member
Messages
1,214
@Valentijn


Unfortunately you still haven't answered how it is possible that an algorithm predicts Slow vs Intermediate vs Fast Acetylators by modelling the interaction of several NAT2 Genes. I would appreciate if you can tell me how/if Research (the way that you perceive Research that is) has an answer on that.


Let me also remind you the Sensitivity and Specificity (i assume you know what that is) of the Predictive Model :


Screen Shot 2016-02-10 at 11.01.43.png


May i also remind that according to what you believe there appears to be no interaction between Genes and a Phenotype, it is just individual Genes that are important to disease...Correct?

@all

I realized that i hadn't "Glycine" as a Topic to the Data that i analyze. Big Mistake (and you will see why)

So I continue to Research more into Bile Acids, Farnesoid X Receptor and why CoA (among others) comes up as an important feature.

So i find this :


5β-Reduced Steroids and Human Δ4-3-Ketosteroid 5β-Reductase (AKR1D1)

<SNIP>

Recently, δ-aminolevulinate synthase, the rate limiting enzyme of porphyrin-heme synthesis, has also been identified as a gene regulated by FXR, indicating a role of bile acids and their precursors in regulating hepatic heme biosynthesis [19]. The secondary bile acid, lithocholic acid activates PXR [20] and the vitamin D receptor [21, 22]. PXR in turn regulates the expression of CYP3A4, which encodes the major drug and xenobiotic catabolizing P450 isozyme in human liver. The secondary bile acid, ursodeoxycholic acid activates the glucocorticoid receptor and exerts immunomodulatory effects [23–25]. Bile acids also activate several signaling pathways including the c-Jun NH2- terminal kinase (JNK) 1/2 pathway (to feedback inhibit bile acid biosynthesis) [8], the protein kinase B (AKT) pathway (to regulate glucose metabolism) [8, 26], FXR, short heterodimer partner (SHP), liver X receptor (LXR), and the sterol regulatory element- binding protein (SREBP)-1c pathway (to regulate lipid metabolism) [8, 27], the extracellular-signal-regulated kinases (ERK) pathway (to prevent apoptosis) [28, 29], and the epidermal growth factor receptor (to modulate intestinal permeability) [30]. A recently identified G protein-coupled bile acid receptor (TGR5) [31] further expands the function of bile acids and their roles in energy metabolism [32], inflammation [33, 34], and gallbladder contractility [35]. Bile acids also affect cardiac function by regulating vascular tone and myocardial contractility, but the underlying mechanism for this remains largely unknown [36].

So we have some new topics being introduced to this Thread:

1) delta-aminolevulinate Synthase
2) Porphyrin-Heme Synthesis


Then we see this : (Thanks to @aquariusgirl)


Glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies

Metal chelation and inactivation of cytochrome P450 (CYP) enzymes (which contain heme) play important roles in the adverse effects of glyphosate on humans. A recent study on rats showed that both males and females exposed to Roundup® had 50% reduction in hepatic CYP enzyme levels compared with controls.[156] CYP enzyme dysfunction impairs the liver’s ability to detoxify xenobiotics. A large number of chemicals have been identified as being porphyrinogenic.[77] Rossignol et al.[242] have reviewed the evidence for environmental toxicant exposure as a causative factor in autism, and they referenced several studies showing that urinary excretion of porphyrin precursors to heme is found in association with autism, suggesting impaired heme synthesis. Impaired biliary excretion leads to increased excretion of heme precursors in the urine, a biomarker of multiple chemical sensitivity syndrome.[77] We later discuss the ability of glyphosate to disrupt bile homeostasis, which we believe is a major source of its toxic effects on humans


So The importance of Manganese (which is also discussed in the paper shown above) should be also looked at. But once again we see the Bile acids coming up.

Did you notice also "Porphyrinogenic"? OK, so now Check out these posts :

FYI @jump44


http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-40#post-641899

A Thread for Porphyria

http://forums.phoenixrising.me/index.php?threads/porphyria.8679/#post-512032


FYI @Violeta

http://forums.phoenixrising.me/inde...heavy-metal-chelation.1694/page-5#post-409426


and here


http://forums.phoenixrising.me/inde...h-chronic-fatigue-syndrome.42698/#post-691230

Of course, i would kindly ask from @Valentijn once again to comment on this and make a comment for the Research involved.


Regarding Glycine, check out ALA-Synthase (Aminolevulinic Acid Synthase) and Porphyrias :

https://en.wikipedia.org/wiki/Porphyrin#/media/File:Heme-Synthesis-Chemical-Details-Mirror.svg

ALAS1 is the rate-limiting enzyme of heme synthesis and is subject to various stimuli to adapt to ever-changing demands of the cell for heme. More than 80% of hepatic heme synthesis is required for incorporation of heme into cytochrome P450, the enzyme essential for detoxifying drugs and xenobiotics but also responsible for the synthesis and metabolism of endogenous substances such as steroid hormones, cholesterol, and bile acids.25 Cytochrome P450 CYP3A4 accounts for the metabolism of more than 50% of prescribed drugs and is a prerequisite for the hydroxylation and therefore detoxification of endogenous bile acids. The corresponding gene has also been identified as a direct target of FXR only recently.13 This finding and the identification of other FXR target genes involved in the elimination and metabolism of bile acids, such as UDP-glucuronosyltransferases,26 sulfotransferases,27 or transport proteins, such as multidrug-resistant protein 2,28 illustrate the central role of FXR in coordinating detoxification processes of potentially toxic bile acids. Because functional CYP3A4 contains heme as a prosthetic group, a sufficient supply of the hepatocytes with heme is required whenever bile acids accumulate. In this context, this study proposes a new model of coordinated induction of apocytochrome CYP3A4 and heme synthesis by bile acid–activated FXR.


http://onlinelibrary.wiley.com/doi/10.1002/hep.21879/full


PS : @Valentijn If you do not feel ok with me asking you things, please let me know and i will stop immediately. I do expect though that i have the ability in this Forum to mention you and the things that you say.
 
Last edited:
Messages
15,786
@mariovitali

We can engage in discussing individual SNPs when your hypothesis has either been corrected to comply with the scientifically-developed principles of genetics, or when you have successfully proven that all of that science is somehow wrong. Until then, you are wasting both your time and mine by deflecting into a discussion of specific genes.
 
Last edited:

aquariusgirl

Senior Member
Messages
1,732
Aha ...check this out ...based on this my mito or electron transport chain or TCA stack/ formula would be
Biotin proper copper & glycine

http://m.jn.nutrition.org/content/137/1/25.full

And checkout this throwaway line:

However, as expected from copper's role in complex IV, the recovery of complex IV was more efficient when copper and biotin were both added to the medium (data not shown).
 

Sam7777

Senior Member
Messages
115
Again look at the 150 references on metabolic detoxification- youll see so much of it relates to phase 1 2 & 3 processes in the titles and abstracts. I beleive this is a broad issue which methlyation is a piece of the puzzle. Bile metabolism is surely very involved in how well these enzymes and proteins function.
http://www.lifeextension.com/protocols/metabolic-health/metabolic-detoxification/page-refs

For reference as well (bearing in mind mercury toxic people cant just willy nilly take uncontrolled doses of r lipoic or nac because of redistribution

Life Extension Suggestions
N-acetyl cysteine: 600 mg one to three times daily
Green Tea extract; standardized to EGCG: 725 mg daily
Quercetin: 250 – 500 mg daily
B Vitamin Complex: Per label instructions
Magnesium: 300 – 600 mg daily
Broccoli extract; standardized to glucosinolates: 400 mg once or twice daily, with meals
I3C (Indole-3-carbinol): 80 – 160 mg daily
SAMe: 400 mg two to three times daily. Take with co-factors B12, B6 and folic acid.
Milk Thistle extract; standardized to silymarin and silibinins: 750 mg daily.
R-lipoic acid: 240 – 480 mg daily
Calcium-D-glucarate: 140 – 300 mg daily
Trans-Resveratrol: 250 mg daily
Curcumin: 400 mg daily, with meals
Chlorophyllin: 100 mg three times per day with food.
Artichoke extract: 500 mg daily
Probiotics: Per label instructions
 
Last edited:

Sam7777

Senior Member
Messages
115
At least I was very excited about this thread because I know how many issues with liver pain and poor bile and craving choline supplements I have. Im hoping more people try this because it does point in a peculiar direction. I find it very peculiar how so many pots sufferers have histamine issues and how dr driscolls eds slash histamime supplements are just acetylcholineesterase inhibitors and digestive enzymes. Mind you I just started homemade kefir and my histamine issues have gone down and bile flow is better. Choline deficiences and cholestasis and histamine issues and weak cyp enzymes weak phase two etc seem related. I hope more people will look at this thread. Maybe make a new thread with a concise suggestion for people here?
 
Messages
13
I believe that Yasko and her supplement-selling business has largely invented methylation disorders. I haven't see much proof that they exist on anywhere near the scale which would be indicated by many of the claims.

How is a methylation disorder scientifically defined? How is it diagnosed? What are the actual effects? Is there research showing that it's common at anywhere near the levels which some people report here?

It's mostly just assumptions at this point, many of which (regarding SNPs at least) are clearly wrong.

@Valentijn
I've been lurking on PR for several months after developing severe PEM last summer, this was after several years of poor health.

Searching through the forum here I came across Freddd's protocol, Mario's protcol, and a post you made where you said NAC helped you sleep (I also suffer from severe insomnia).

Being in a desperate situation, on the verge of no longer being able to work, I took a shotgun approach and combined all of these protocols, I realize this is NOT the right way to go about this, and could potentially be dangerous, but desperate times call for desperate measures. I did do a lot of research on the supplements involved to understand any hazards that might exist, and decided the risks were worth it for me. Long story short is that I am sleeping better and my PEM has largely disappeared. So I feel that something I did helped me.

I know from reading this thread that you feel Mario's protocol is BS, I can also see from this post that you think methylation disorders are BS.

So I'm wondering if you think that freddd's protocol is worthless? or is your objection more that there is no scientific explanation to support the idea of methylation disorders?

I'm am trying to determine if the fact that I am feeling better now is primarily due to the placebo effect, or if any of the supplements I am taking are actually helping me. My plan going forward is to start dropping supplements as I run out and see how I feel.