Unfolded Protein Response and A Possible Treatment for CFS

[adreno]

Agitation.

Meds suck. And believe me, I've tried my share of them. WRT antihistamines, ebastine gives me liver pain/congestion, fexofenadine as you say agitation and cetirizine drowsiness. The only one I seem to tolerate is loratadine and that one is useless for allergies.

 

[Sidereal]

Meds suck. And believe me, I've tried my share of them. WRT antihistamines, ebastine gives me liver pain/congestion, fexofenadine as you say agitation and cetirizine drowsiness. The only one I seem to tolerate is loratadine and that one is useless for allergies.

I hate meds. I take nothing most of the time. Whenever I think a symptom is bad, the side effect of the drug used to treat it turns out to be worse.

 

[mariovitali]

Well, i went asking for it..

Last night i suffered Sensorineural Hearing Loss for at least 11 hours on my right ear. This has happened to me before 3 times i think.

The reasons :

-I stopped taking Vitamin C, Resveratrol and TUDCA 5 days ago
-I ate meat after a long time (15 days) which means my Phenylalanine levels were low (which is good) until yesterday where Phenylalanine levels suddenly increased after meat consumption.

Upon 1 hour of ingesting meat, i experienced pain in my neck area and half an hour later i slowly started loosing my hearing. The thing is, that with this kind of Hearing Loss it is not certain that you will get your hearing back. So i will definitely make sure this never happens again.

This incidence leads me to believe even more that BH4 Production is a key issue for me and the same i believe holds for many CFS Sufferers.

 

[JPV]

I stopped taking Vitamin C, Resveratrol and TUDCA 5 days ago

It probably wasn't a good idea to stop taking these supplements, if they are working for you. Especially Resveratrol and TUDCA. They seem to be the most active ones that you're taking.

I guess you thought they cured your condition and you didn't need them anymore. That usually isn't the case. You're probably addressing an imbalance with these supplements and will likely need to take them for the rest of your life.

And not to put a hamper on your success, but there are countless stories on this forum about people finding regimens that bring relief only to find that they relapse days, weeks, months or years later. You need to be vigilant about maintaining your health and can't take things for granted. If something works, I wouldn't mess with it too much.

 

[adreno]

Upon 1 hour of ingesting meat, i experienced pain in my neck area and half an hour later i slowly started loosing my hearing. The thing is, that with this kind of Hearing Loss it is not certain that you will get your hearing back. So i will definitely make sure this never happens again.

So you'll never eat meat again?

 

[mariovitali]

@JPV You are right, i will make sure i will follow whatever works. It's just that i don't feel at ease taking all of these supplements.

@adreno
I think it was the combination of what i did : Stopped Vitamin C which protects BH4 levels (Resveratrol also boosts BH4 Production which i also stopped taking) and at the same time i wasn't eating meat which means that there was not too much Phenylalanine going around to trigger a "crash". So when i introduced meat then there was a spike of Phenylalanine with not too much BH4 around so ONOO was created instead and as a consequence, ER Stress.

What i am going to do is start Vitamin C and TUDCA for a week then slowly re-introduce meat and hopefully things will go well as they did before. Resveratrol will have to wait as it lowers E2 and quite possibly Low E2 means low BH4.

 

[Tunguska]

..and the list goes on.

At some point I had Thyroid problems and somewhat elevated total Cholesterol. My Endo told me that i should stop eating Foods High in Cholesterol, Exercise and lose weight.

So, i decided to change my Lifestyle as follows :

a) Eliminate Foods High in Cholesterol
b) Go to Gym 3 times a day
c) Eliminate too much Sugar and Carbohydrates from my Diet and focus on eating Protein and Vegetables
d) Taking Whey Protein after Gym
e) When i wanted something sweet i would have Sugarless Chewing Gum (with Aspartame)

It was at that particular time (apart from when i stopped taking Propecia for my hairloss) when i saw my Health deteriorating with Tinnitus incidents hitting me almost every day. Let's see why :


a) Foods high in Cholesterol and Sugar boost HmG-CoA activity which is beneficial for us. When i decided to change my diet (=eliminate Sugar and too much Cholesterol) i also stopped HmG-CoA activity, which made me feel worse.

b) Intense Exercise and Resistance Training increases Oxidative Stress.

c) Whey Protein possibly overloaded my Body with Proteins that could not be properly folded (?)

d) Aspartame further impaired my problematic BH4 Production due to my GCH1 Mutation

So This lifestyle resulted in feeling even more fatigued! I was trying to say this to Doctors and they wouldn't believe me. Instead when i was eating Food high in Cholesterol, Sweets/Cakes and wasn't exercising i was feeling great!

It all now makes sense.

This is all too much for me at the moment but to say a lot of your story is familiar. I had accutane years ago. Low carb is intolerable. Carnitine is slightly negative. Cutting dietary cholesterol is bad, or at least what you lose with it. Too much whey or dairy is bad. I noticed that my whey (whey in general) was specially high in lysine and low arginine, might be part of why (lowers NO). However sunlight was positive combined with nutrients (increases NO). I had tinnitus following fluoroquinolone poisoning but it's fixed. I'm not going anywhere with this.

 

[mariovitali]

@Tunguska

IMO The best thing to do is to assess your Methylation status (MTHFR, CBS, BH4) and pay particular attention to MTHFR and BH4 Mutation and first deal with these.

Then you could start adding slowly the supplements shown here probably starting with TUDCA and then Curcumin.

Also, follow the Thread regarding Clostridium Butyricum, the gut appears to be very important.

I am also currently looking to specific CYPs which could also be important. I will update the first post as soon as i find out more.

Good Luck

 

[JPV]

Here's another angle that has come up on the forum recently...

Tauroursodeoxycholic acid, a bile acid, promotes blood vessel repair by recruiting vasculogenic progenitor cells.

In addition, TUDCA decreased cellular senescence by reducing levels of p53, p21, and reactive oxygen species and increased nitric oxide. Transplantation of TUDCA-primed senescent EPCs in hind limb ischemia significantly improved blood vessel regeneration, as compared with senescent EPCs. Our results suggested that TUDCA promoted neovascularization by enhancing the mobilization of stem/progenitor cells from bone marrow, their differentiation into EPCs, and their integration with preexisting endothelial cells.

 

[mariovitali]

@JPV Thank you for this. FYI @Gondwanaland

I will post in the next couple of hours on the Clostridium Butyricum Thread some things i discovered that encompass Unfolded Proteins, Choline supplementation, a by-product of Choline called TMAO (Thrimethylamine-N-Oxide) and Butyrate. The interesting thing about TMAO is that it is pro-atherogenic (=not good) but is also a potent chaperone that prevents Protein Misfolding.

I stopped TUDCA and all i did was to supplement with Choline with no symptoms

 

[adreno]

Carnitine also produces TMAO. And it reduces ER stress:

http://www.ncbi.nlm.nih.gov/pubmed/25220073

 

[mariovitali]

@JPV @Sidereal @Gondwanaland @alicec @Hip

First things first : These are all just hypotheses



This is an output from the tool i am using to research CFS. Note how Misfolded proteins, N-Acetylglucosamine, Dolichols, Vitamin K2 and Phosphatidylcholine are part of the results :

[uric_acid, n-acetylglucosamine]: 70 ==> [choline_deficiency]: 70 <conf (1)> lift (2.19) lev (0.15) conv (38.08)
[uric_acid, misfolded_proteins]: 67 ==> [choline_deficiency]: 67 <conf (1)> lift (2.19) lev (0.14) conv (36.45)
[uric_acid, dolichol]: 66 ==> [choline_deficiency]: 66 <conf (1)> lift (2.19) lev (0.14) conv (35.91)
[n-acetylglucosamine, l_carnitine]: 75 ==> [choline_deficiency]: 75 <conf (1)> lift (2.19) lev (0.16) conv (40.8)
[n-acetylglucosamine, selenium_deficiency]: 72 ==> [choline_deficiency]: 72 <conf (1)> lift (2.19) lev (0.15) conv (39.17)
[n-acetylglucosamine, pqq]: 67 ==> [choline_deficiency]: 67 <conf (1)> lift (2.19) lev (0.14) conv (36.45)
[vitamin_k2, acetyl-coa]: 68 ==> [choline_deficiency]: 68 <conf (1)> lift (2.19) lev (0.14) conv (37)
[vitamin_k2, phosphatidylcholine]: 66 ==> [choline_deficiency]: 66 <conf (1)> lift (2.19) lev (0.14) conv (35.91)
[vitamin_k2, n-acetylglucosamine]: 63 ==> [choline_deficiency]: 63 <conf (1)> lift (2.19) lev (0.13) conv (34.28)
[uric_acid]: 97 ==> [choline_deficiency]: 87 <conf (0.9)> lift (1.97) lev (0.16) conv (4.8)
[n-acetylglucosamine]: 87 ==> [choline_deficiency]: 78 <conf (0.9)> lift (1.97) lev (0.15) conv (4.73)
[vitamin_k2]: 86 ==> [choline_deficiency]: 77 <conf (0.9)> lift (1.96) lev (0.14) conv (4.68)

Then i found this :


Effect of vitamin K2 on cortical and cancellous bone mass and hepatic lipids in rats with combined methionine-choline deficiency.
Iwamoto J1, Seki A, Sato Y, Matsumoto H, Takeda T, Yeh JK.
Author information
Abstract
The present study examined changes of cancellous and cortical bone in rats with combined methionine-choline deficiency (MCD). In addition, the effects of vitamin K2 on cortical and cancellous bone mass and hepatic lipids were investigated in rats with MCD. Six-week-old male Sprague-Dawley rats were randomized into three groups of ten, including an age-matched control (standard diet) group, an MCD diet group, and an MCD diet+vitamin K2 (menatetrenone at 30mg/kg/d orally, 5 times a week) group. After the one-month experimental period, histomorphometric analysis was performed on cortical and cancellous bone from the tibial diaphysis and proximal metaphysis, respectively, while histological examination of the liver was performed after staining with hematoxylin and eosin and Oil Red O. MCD rats displayed weight loss, diffuse and centrilobular fatty changes of the liver, and a decrease of the cancellous bone volume per tissue volume (BV/TV) and percent cortical area (Ct Ar) as a result of decreased trabecular, periosteal, and endocortical bone formation along with increased trabecular and endocortical bone resorption. Administration of vitamin K2 to rats with MCD attenuated weight loss, accelerated the decrease of cancellous BV/TV due to an increase of bone remodeling, and ameliorated the decrease of percent Ct Ar by increasing periosteal and endocortical bone formation. Vitamin K2 administration also prevented MCD-induced diffuse fatty change of the liver. These findings suggest a beneficial effect of vitamin K2 on cortical bone mass and hepatic lipid metabolism in rats with MCD. The loss of cancellous bone mass could possibly have been due to re-distribution of minerals to cortical bone.


Perhaps you should start eating Spinach because it contains both dolichol and contains high levels of Vitamin K and also making sure you eat some Choline food sources so that TMAO can be boosted. As a result, ER Stress is controlled through proper Protein Misfolding (but not too much because TMAO is atherogenic).


Regarding TMAO :


Forcing thermodynamically unfolded proteins to fold.
Baskakov I1, Bolen DW.
Author information
Abstract
A growing number of biologically important proteins have been identified as fully unfolded or partially disordered. Thus, an intriguing question is whether such proteins can be forced to fold by adding solutes found in the cells of some organisms. Nature has not ignored the powerful effect that the solution can have on protein stability and has developed the strategy of using specific solutes (called organic osmolytes) to maintain the structure and function cellular proteins in organisms exposed to denaturing environmental stresses (Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D., and Somero, G. N. (1982) Science 217, 1214-1222). Here, we illustrate the extraordinary capability of one such osmolyte, trimethylamine N-oxide (TMAO), to force two thermodynamically unfolded proteins to fold to native-like species having significant functional activity. In one of these examples, TMAO is shown to increase the population of native state relative to the denatured ensemble by nearly five orders of magnitude. The ability of TMAO to force thermodynamically unstable proteins to fold presents an opportunity for structure determination and functional studies of an important emerging class of proteins that have little or no structure without the presence of TMAO.



and finally this, from this forum where N-Acetylglucosamine and Turmeric are used :


Completely eliminated my severe anxiety symptoms with three supplements!

• The first and most potent anti-anxiety supplement is N-acetyl-glucosamine (NAG), taken at a dose of 700 mg twice daily; the dose can be reduced once daily after a few weeks. NAG should not be confused with glucosamine sulfate, as the latter will not work for this anti-anxiety purpose. Note that NAG is shellfish derived. Do not take NAG if you are on the blood thinner Warfarin (see here).

 

[Gondwanaland]

Perhaps you should start eating Spinach because it contains both dolichol and contains high levels of Vitamin K

Spinach contains vit K1 and a healthy gut is needed to convert it into K2. Spinach is among the culprits of my present joint/bone pain flare. I am seeing the world through oxalates from now on.

 

[adreno]

I have an aversion to leafy greens. I wonder if that means I don't need /tolerate them. When I've tried those green superfoods drinks, I've always felt worse.

 

[mariovitali]

@adreno @Gondwanaland

Yes, oxalates is indeed a problem for many people and so Spinach is out of the question in these cases.

Have you checked the genes i mentioned needed for Choline production/metabolism? Have you found any mutations?

 

[adreno]

Have you checked the genes i mentioned needed for Choline production/metabolism? Have you found any mutations?

Could you list them here, and also which are the risk alleles?

 

[Gondwanaland]

I have an aversion to leafy greens. I wonder if that means I don't need /tolerate them. When I've tried those green superfoods drinks, I've always felt worse.

I think you would benefit from paying a visit to the Trying Low Oxalates Yahoo group and browsing through the files.
I was hoping to never have to go back to that forum platform, but this is life

 

[mariovitali]

@adreno

Here they are :


PEMT

rs7946
rs4244593

MTHFD1
rs2236225
rs2236224

CHDH
rs9001

 

[adreno]

@adreno

Here they are :


PEMT

rs7946
rs4244593

MTHFD1
rs2236225
rs2236224

CHDH
rs9001

Thanks, but which are the risk alleles?

 

[Sparrowhawk]

If you are oxalate intolerant one could just supplement K2 directly, right?