Unfolded Protein Response and A Possible Treatment for CFS

[Gondwanaland]

@ppodhajski from what I have been learning from your highly informative posts (can't thank you enough), my husband can't supplement with B2 successfully because he is "-" for MAO-A... He gets extremely depressed and gets extremely unpleasant dreams from it. wooo finally putting 2 and 2 together (hopefully)!

 

[Violeta]

@ppodhajski

Yes i see your point with ER Stress, totally agree


OK let's look at FAD then :




FAD matches even with a very small percentage to many Topics. Very interesting...

When I read the B2 I Love You thread, one of my first thoughts was, "B2 is the best kept secret!"

How can any one vitamin help with so many different things, and then have that few hits?

http://ajcn.nutrition.org/content/77/6/1352.full

 

[mariovitali]

OK this may be a problem for me. I noticed that FMN had a hit for 5 alpha reductase (5-AR)

So i look at PubMed and :

Mechanism of 4-ene-steroid 5 alpha-reductase proton transfer in androgen target tissues.
Cooke GM, Robaire B.
Abstract
The conversion of testosterone to 5 alpha-dihydrotestosterone, catalysed by 4-ene-steroid 5 alpha-reductase (3-oxo-5 alpha-steroid: NADP+ 4-ene-oxidoreductase EC 1.3.1.22) requires NADPH. In the present study, the role of flavins and Co-enzyme Q in this proton transfer was investigated for the first time in any male androgen target tissue. Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) inhibited epididymal nuclear 4-ene-steroid 5 alpha-reductase activity non-competitively with respect to the substrate testosterone. However, neither the oxidized nor reduced forms of Co-enzyme Q affected the Kmapp or the Vmaxapp and the reduced form was unable to support catalytic activity in the absence of NADPH. Further investigation of the effects of flavins revealed that the inhibition was caused by an elevation of NADP+ in the incubations and that the incorporation of a NADPH generating system abolished the inhibition. Therefore, neither flavins nor Co-enzyme Q directly affected the 4-ene-steroid 5 alpha-reductase activity. Further evidence to support this conclusion was obtained when several inhibitors of electron transfer reactions failed to inhibit 4-ene-steroid 5 alpha-reductases from rat epididymides, prostate and seminal vesicles. These findings show that, in male rat androgen target tissues, the conversion of testosterone to 5 alpha-dihydrotestosterone does not require intermediates of electron transfer reactions. We propose that the reduction proceeds by the direct transfer of protons from NADPH to testosterone.

Basically all of us that had problems from Finasteride was because its 5-AR inhibition

 

[Violeta]

OK this may be a problem for me. I noticed that FMN had a hit for 5 alpha reductase (5-AR)

So i look at PubMed and :





Basically all of us that had problems from Finasteride was because its 5-AR inhibition

That's really difficult to understand, but this sentence stood out to me:

Further investigation of the effects of flavins revealed that the inhibition was caused by an elevation of NADP+ in the incubations and that the incorporation of a NADPH generating system abolished the inhibition. Therefore, neither flavins nor Co-enzyme Q directly affected the 4-ene-steroid 5 alpha-reductase activity."

 

[ppodhajski]

@ppodhajski from what I have been learning from your highly informative posts (can't thank you enough), my husband can't supplement with B2 successfully because he is "-" for MAO-A... He gets extremely depressed and gets extremely unpleasant dreams from it. wooo finally putting 2 and 2 together (hopefully)!

Yes! Others I know who have fast MAO genes also get depressed quickly on FMN. I can take 4 a day and it levels me out because my MAO are So ++++++++++

I think your husdand might be a NAD type.

I see FAD and NAD as the yin and yang of the body.

 

[JaimeS]

@Gondwanaland
In case you are wondering why not many people know about this nutraceutical product/ If it was working we should know by now etc , Then i could probably think it's because they haven't used a multi-agent approach (namely use TUDCA, NAG, Selenium etc)

Or because some of us have horrible reactions to Selenium (so @Hip noted) and to Rhodiola, long-term (so I noted). Hip was recommending (not medically, just throwing it out there, of course) that higher doses of selenium were helpful. Some had great results, but many not so much. You'd have to talk to @Hip about that.

Regarding Rhodiola, I've discussed my reaction extensively, so I'll make it quick: it gave me so much energy and focus that I felt fantastic: I thought, my God, this is what normal people feel like all the time! BUT - and it's a big but - the effect was transitory. Not only did I begin to feel uncomfortably jittery and lose the ability to sleep, but eventually that feeling of super-productive well-being dissipated, then inverted. I crashed, hard. No matter what dose I took, there appeared to be two states: well-being ---> hyperactivity or completely ineffective. If I took it three days in a row, too, the efficacy totally disappeared. Taking more didn't give me any additional energy at all.

Rhodiola appears to 'push' a metabolic cycle of some kind, but for those of us with low reserves, eventually you 'run out' - of what? I'm not sure. I'll go with 'serotonin-like chemicals' for now, because serotonin-y things give me that same jittery feeling and are followed by a crash, and because there's evidence of serotinergic action in Rhodiola rosea.

-J

 

[ppodhajski]

That's interesting. And yes, they do seem to be opposites.

NAD is produced in vivo from tryptophan and seems to be controled by factors that effect the IDO enzyme. IDO uses iron as a cofactor as well

The preferred route (95%) of tryptophan metabolism is down the Kynurenine Pathway. And there is "Evidence for a key role of the peripheral kynurenine pathway in the modulation of anxiety- and depression-like behaviours in mice: focus on individual differences"

http://www.ncbi.nlm.nih.gov/pubmed/21167857

My THEORY is that people who are stressed (psychological, environmental) are the type who get depressed (NAD Type) or get Anxiety (FAD Type). There might be a third which fluctuates (Bipolar). This is just something I am floating around in my head.

More on the KYM pathway
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021918/

 

[ppodhajski]

Or because some of us have horrible reactions to Selenium (so @Hip noted) and to Rhodiola, long-term (so I noted). Hip was recommending (not medically, just throwing it out there, of course) that higher doses of selenium were helpful. Some had great results, but many not so much. You'd have to talk to @Hip about that.

Regarding Rhodiola, I've discussed my reaction extensively, so I'll make it quick: it gave me so much energy and focus that I felt fantastic: I thought, my God, this is what normal people feel like all the time! BUT - and it's a big but - the effect was transitory. Not only did I begin to feel uncomfortably jittery and lose the ability to sleep, but eventually that feeling of super-productive well-being dissipated, then inverted. I crashed, hard. No matter what dose I took, there appeared to be two states: well-being ---> hyperactivity or completely ineffective. If I took it three days in a row, too, the efficacy totally disappeared. Taking more didn't give me any additional energy at all.

Rhodiola appears to 'push' a metabolic cycle of some kind, but for those of us with low reserves, eventually you 'run out' - of what? I'm not sure. I'll go with 'serotonin-like chemicals' for now, because serotonin-y things give me that same jittery feeling and are followed by a crash, and because there's evidence of serotinergic action in Rhodiola rosea.

-J

THIS is why I only use vitamin cofactors, and even with those you have to know WHY you are taking it. I have never taken a cofactor that made me feel better and then made me feel worse. It either made me feel worse or better.

I see cofactors as facilitating pathway flow and drugs as forcing and trying to replace them.

It is my extremely strong opinion that if you take supplements without undertstanding your Nutrigenomic profile you can end up doing bad things, like making yourself more likely to have cancer. Selenium is a good example of that. If you stimulate GPX you will get rid of too much H2O2 which plays a role in cancer apoptosis. http://www.researchgate.net/profile...nd_therapy/links/54efac580cf2495330e27e9f.pdf

 

[JaimeS]

THIS is why I only use vitamin cofactors, and even with those you have to know WHY you are taking it.

On paper, Rhodiola is the perfect herb for us (or at least me). Unfortunately, all the research in the world can't substitute for experimentation - because research does not have all the answers.

-J

 

[mariovitali]

@ppodhajski @JaimeS

I only take 100 mcg of Selenium. I also discuss that too much Selenium is not good for us in the first post of the thread.

 

[JaimeS]

@mariovitali - I take 125-mcg as part of an antioxidant supplement. But Hip was talking about a larger dose.

And, as stated re: the Rhodiola, the dosage did not appear to matter.

The herbs you've mentioned are adaptogens. That means they tend to be gentle nudgers of the hormones and/or neurotransmitters. Theoretically, they should be exactly what will help us. Au contraire - they seem to be great for helping the average healthy person keep in balance, but not so great for us.

The first chronic fatigue-r I ever saw as a clinician had a horrible reaction to both licorice (known for its glucocorticoids) and ginseng (even American ginseng, which is a little gentler.) I didn't understand it at the time, but it certainly seems to be a pattern with us: when it comes to anything that messes with cortisol or serotonin, it seems we have to be very cautious.

Regarding the cortisol, though, I'm beginning to think that's because of its immunosuppressive qualities. In my case, the reaction is so instant, though - but maybe that's just the way of it.

-J

 

[mariovitali]

Or because some of us have horrible reactions to Selenium (so @Hip noted) and to Rhodiola, long-term (so I noted). Hip was recommending (not medically, just throwing it out there, of course) that higher doses of selenium were helpful. Some had great results, but many not so much. You'd have to talk to @Hip about that.

Regarding Rhodiola, I've discussed my reaction extensively, so I'll make it quick: it gave me so much energy and focus that I felt fantastic: I thought, my God, this is what normal people feel like all the time! BUT - and it's a big but - the effect was transitory. Not only did I begin to feel uncomfortably jittery and lose the ability to sleep, but eventually that feeling of super-productive well-being dissipated, then inverted. I crashed, hard. No matter what dose I took, there appeared to be two states: well-being ---> hyperactivity or completely ineffective. If I took it three days in a row, too, the efficacy totally disappeared. Taking more didn't give me any additional energy at all.

Rhodiola appears to 'push' a metabolic cycle of some kind, but for those of us with low reserves, eventually you 'run out' - of what? I'm not sure. I'll go with 'serotonin-like chemicals' for now, because serotonin-y things give me that same jittery feeling and are followed by a crash, and because there's evidence of serotinergic action in Rhodiola rosea.

-J

Haha yes this post of mine had a bit of an attitude @JaimeS . Thank you for bringing me back to reality!

 

[JaimeS]

Haha yes this post of mine had a bit of an attitude @JaimeS . Thank you for bringing me back to reality!

...? I'm sorry if mine had a finger-shaking flavor to it, mv!

 

[mariovitali]

...? I'm sorry if mine had a finger-shaking flavor to it, mv!

Naah, deserved every bit of it really.

I honestly learn so much from all of you Guys so all of your comments and knowledge are *much* appreciated.

 

[ppodhajski]

@mariovitali - I take 125-mcg as part of an antioxidant supplement. But Hip was talking about a larger dose.

And, as stated re: the Rhodiola, the dosage did not appear to matter.

The herbs you've mentioned are adaptogens. That means they tend to be gentle nudgers of the hormones and/or neurotransmitters. Theoretically, they should be exactly what will help us. Au contraire - they seem to be great for helping the average healthy person keep in balance, but not so great for us.

The first chronic fatigue-r I ever saw as a clinician had a horrible reaction to both licorice (known for its glucocorticoids) and ginseng (even American ginseng, which is a little gentler.) I didn't understand it at the time, but it certainly seems to be a pattern with us: when it comes to anything that messes with cortisol or serotonin, it seems we have to be very cautious.

Regarding the cortisol, though, I'm beginning to think that's because of its immunosuppressive qualities. In my case, the reaction is so instant, though - but maybe that's just the way of it.

-J

Cortisol stimulates IDO and the kyneurnine pathway

 

[Ema]

Cortisol isn't just immunosuppressive though. In some cases, it's actually an immune stimulant through the production of SOD. It's much more complicated and likely dose dependent.

I've always had good luck with licorice especially. Other adaptogens didn't seem to provoke much of an effect unfortunately.

 

[ppodhajski]

Cortisol isn't just immunosuppressive though. In some cases, it's actually an immune stimulant through the production of SOD. It's much more complicated and likely dose dependent.

I've always had good luck with licorice especially. Other adaptogens didn't seem to provoke much of an effect unfortunately.

Cortisol is not an immune stimulant under any conditions. If you think otherwise please cite you r source.

 

[Ema]

Cortisol is not an immune stimulant under any conditions. If you think otherwise please cite you r source.

I explained already...cortisol stimulates macrophages to produce SOD which is a critical part of the adaptive immune system response. The net effect is stimulation of the immune system. It's why cortisol naturally rises in times of illness.

If the high levels of cortisol go on for too long or are way beyond the physiological amounts, then it can become immunosuppressive, sure. But try fighting an infection without *enough* cortisol. It doesn't work out well. Biological functions are rarely black and white.

PubMed is your friend if you need cites. There's plenty on cortisol/CRH and SOD.

 

[ppodhajski]

I explained already...cortisol stimulates macrophages to produce SOD which is a critical part of the adaptive immune system response. The net effect is stimulation of the immune system. It's why cortisol naturally rises in times of illness.

If the high levels of cortisol go on for too long or are way beyond the physiological amounts, then it can become immunosuppressive, sure. But try fighting an infection without *enough* cortisol. It doesn't work out well. Biological functions are rarely black and white.

PubMed is your friend if you need cites. There's plenty on cortisol/CRH and SOD.

SOD activity lowers ROS and that lowers coritsol, low SOD raises cortisol.

http://www.ncbi.nlm.nih.gov/pubmed/17279464

If you cannot cite your sources and make me do it I have to assume you can't do it. I cannot find one study that says cortosol raises SOD levels.

 

[ahmo]

My simple-minded responses (from a bear with very little brain)

But when it comes to any other "disease", it would be good to find out what virus is involved, because if it's any of the diseases that involve viruses that use hsp in their replication process, you need to find a workaround. There are, I believe, other ways to work around the issue. For example, avoiding heat stress!

Heat stroke is what precpitated my collapse w/ ME. 2003 European summer heat wave.

Wondering if you also had/have tinnitus?

Very interesting to read of the antibody connection. My tinnitus was a nightmare. Within a week of quitting gluten, it had decreased by at least 50%. Later I found an adrenal connection. When my adrenals cleared, the remaining tinnitus cleared. Now, when it returns, I know my adrenals are stressed.

NO uses FAD and FMN as well....
...all of these things also create oxidative stress. If we see in out genetics where our weaknesses are in either creating too much ROS or not getting rid of them quickly enough we can supplement accordingly.

Almost a year ago I began trying to implement martin Pall's NO protocol, antioxidants. FMN decreased my need for antioxidants. And the 3 forms I recently added seem to have really shifted me into a higher state of well being, stamina. So well, it's time to see if I can push my energy boundaries.

I see cofactors as facilitating pathway flow and drugs as forcing and trying to replace them.