Unfolded Protein Response and A Possible Treatment for CFS

Hip

Hip

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mariovitali said:
I mean symptoms such as tinnitus, orthostatic intolerance, brain fog, etc.

I had none of these symptoms whenever had a typical viral infection (which had symptoms of fever, throat pain, stuffed nose, cough etc)
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Generally speaking, ME/CFS patients do not experience any remission from their ME/CFS symptoms when they catch a cold. Interestingly, the majority of ME/CFS in fact become almost immune to catching colds, perhaps only catching a cold once every year or so. This immunity is probably due to a constant overactivation of certain parts of the immune system, with this state of hyper immune vigilance protecting against catching cold viruses. Rich Van Konynenburg had a theory about what causes this apparent hyper immune vigilance in ME/CFS.

Conversely, a small minority of ME/CFS patients seem catch colds all the time, and often these make their ME/CFS symptoms worse, and worse for some weeks or even months afterwards. It takes these people a long time to get over a cold.



There are two conditions that are known to dramatically improve during a cold, and these are: attention deficit disorder (ADD / ADHD) and autism. There is a phenomenon called the fever effect, where people with ADHD or autism will often experience significant reduction in their symptoms when they have a fever as a result of catching an infection.

Since fever is controlled by the locus coeruleus (LC) in the brain, the theory is that the fever effect might be caused by effects resulting from the activation of the LC.

The LC is found in the brainstem, and brainstem abnormalities have been found in ME/CFS. So LC activation may modulate brainstem activity, leading to improvements in symptoms.
 
Hip

Hip

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@mariovitali
Thanks for that explanation of your software.

So let me see if I have understood it:

First of all, you send a series of automated queries to the PubMed database, using key words that cover all the important topics related ME/CFS, PFS, and the various symptoms, comorbid conditions, biological systems, and drug/supplement treatments related to ME/CFS or FPS.

Each time the key word is found in the title or abstract of a paper, you download the text of that title/abstract, and save it in a file which is conveniently named the same as the key word.

So that is the set up stage, and once you have set up all these files containing these downloaded abstracts, then you use a second piece of software to search through these files every time you want to check the associations of a given search term related to ME/CFS or PFS (that search term could be an ME/CFS symptom, a drug or supplement, or a term relating to human biology and biochemistry).

When this second piece of software runs, the more times the search term is found in one of the key word files of dowloaded abstracts, the more significant is the connection between that search term and the key word.

In this way, when you are researching a particular search term in the context of ME/CFS and PFS, you can quickly discover the topics of highest significance that are linked to the search term.

Have I got this right?



One small thing that I do not understand: in your example above, when you searched using the search term "TUDCA", in your results, you had for the tudca.csv key word file of downloaded abstracts a 49.53 % hit rate. However, shouldn't this hit rate be 100%, because in that key word file, every abstract will contain the word "TUDCA".
 
mariovitali

mariovitali

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Hip said:
@mariovitali
Thanks for that explanation of your software.

So let me see if I have understood it:

First of all, you send a series of automated queries to the PubMed database, using key words that cover all the important topics related ME/CFS, PFS, and the various symptoms, comorbid conditions, biological systems, and drug/supplement treatments related to ME/CFS or FPS.

Each time the key word is found in the title or abstract of a paper, you download the text of that title/abstract, and save it in a file which is conveniently named the same as the key word.

So that is the set up stage, and once you have set up all these files containing these downloaded abstracts, then you use a second piece of software to search through these files every time you want to check the associations of a given search term related to ME/CFS or PFS (that search term could be an ME/CFS symptom, a drug or supplement, or a term relating to human biology and biochemistry).

When this second piece of software runs, the more times the search term is found in one of the key word files of dowloaded abstracts, the more significant is the connection between that search term and the key word.

In this way, when you are researching a particular search term in the context of ME/CFS and PFS, you can quickly discover the topics of highest significance that are linked to the search term.

Have I got this right?



One small thing that I do not understand: in your example above, when you searched using the search term "TUDCA", in your results, you had for the tudca.csv key word file of downloaded abstracts a 49.53 % hit rate. However, shouldn't this hit rate be 100%, because in that key word file, every abstract will contain the word "TUDCA".
Click to expand...

First of all : Yes you got it absolutely right :)

..and you asked a Good Question.


The following is an abstract that exists in the file TUDCA.csv :

Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins. In insulin resistant adipocytes, various dysfunctional/damaged molecules, organelles, proteins, and end-products accumulate. However, the role of autophagy (in particular, whether autophagy is activated or not) is poorly understood. In this study we found that in adipose tissue of insulin resistant mice and hypertrophic 3T3-L1 adipocytes autophagy was suppressed. Also in hypertrophic adipocytes, autophagy-related gene expression, such as LAMP1, LAMP2, and Atg5 was reduced, whereas gene expression in the inflammatory-related genes, such as MCP-1, IL-6, and IL-1beta was increased. To find out whether suppressed autophagy was linked to inflammation we used the autophagy inhibitor, 3-methyladenine, to inhibit autophagy. Our results suggest that such inhibition leads to an increase in inflammatory gene expression and causes endoplasmic reticulum (ER) stress (which can be attenuated by treatment with the ER stress inhibitor, Tauroursodeoxycholic Acid). Conversely, the levels of inflammatory gene expression were reduced by the activation of autophagy or by the inhibition of ER stress. The results indicate that the suppression of autophagy increases inflammatory responses via ER stress, and also defines a novel role of autophagy as an important regulator of adipocyte inflammation in systemic insulin resistance.
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It contains the words "Tauroursodeoxycholic acid" but not "TUDCA" but this is essentially the same Topic. PubMed is searched with the Keyword TUDCA and returns all relevant abstracts (even if these do not contain the exact keyword that was queried.

Obviously, this means that i have to use yet another type of processing called Information Extraction to change keywords to Topics as in :

Tauroursodeoxycholic acid / TUDCA = Topic "TUDCA"
Methylentetrahydrofolate Reductase = Topic MTHFR


and so on..
 
Hip

Hip

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@Violeta
Mario is saying that when he catches a cold virus or similar infection, his FPS symptoms (which are not viral symptoms) disappear.
 
mariovitali

mariovitali

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Violeta said:
How often have you had those viral symptoms, and did you have those viral symptoms previous to taking finasteride?
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Assuming that viral symptoms = Fever, cough, throat pain, etc then yes i had those prior Finasteride use.

The symptoms that i didn't have prior Finasteride where the typical CFS Symptoms such as Brain Fog, Orhtostatic Intolerance, Hypothyroidism, Insomnia, etc.


There could be another mechanism though. It could be the case that the reason for which CFS Sufferers are not getting sick easily is ROS.

Our bodies use ROS to destroy pathogens/viruses so if we assume that our bodies do not handle Oxidative Stress well (which means that ROS are increased) then any pathogen cannot find the proper environment to thrive.

Just a thought.
 
B

brenda

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UK
Hi @mariovitali

I am interested in your protocol so would you mind looking at my genes:

rs3733890 A or G AG risk A


rs2461823 C or T CC risk C


rs7643645 A or G AA risk G



rs7946 C or T CT risk T



rs4244593 G or T GT risk G


rs2236225 A or G AA risk A


rs9001 G or T TT risk G

GCH1

rs10483639 C or G GG risk C


rs3783641 A or T TT risk A


rs8007267 C or T CC risk T


rs12147422 C or T TT risk C


rs3783637 C or T CC riskT


rs3783641 A or T TT risk A


rs41298442 C or T TT risk T


rs4411417 C or T TT risk C


rs752688 C or T CC risk T


rs841 A or G GG riskA


rs998259 C or T CT risk T


rs7147286 A or G GG risk A

PAH Gene

rs10860936 C or T CC risk C


rs1722387 C or T CC risk C


rs1522305 C or G GG risk C


rs1522296 A or G AA risk A


rs772897 C or G CC risk C


rs1522307 A or G GG risk G


rs11111419 A or T AA risk T

I have given up eggs recently so have ordered choline bit. I am guessing I am a candidate for your protocol. Thanks. I take vit c, selenium, mg, small dose activated b's, CoQ10.
 
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mariovitali

mariovitali

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Hi @brenda

You have SNPs that could increase your risk for Non-alcoholic Fatty liver disease (NAFLD). Quite possibly you do not handle Phenylalanine well. If you had Phenylketonuria i am sure you'd know by now.

Avoid any Phenylalanine sources (Egg whites, too much protein, Chewing Gum with Aspartame /sources of Phenylalanine) due to PAH and GCH1 SNPs.

You could talk to your GP about the possibility of NAFLD and if you can have it checked. Choline will probably be beneficial to you. Start with 300 mg per day and see how you feel. Then up the dose to 700 mg but not more than that.

Supplement with high-dose Metafolin (e.g 2000 mcg) and Vitamin C (1 gram)
 
B

brenda

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Location
UK
Hi @mariovitali

Thanks. My liver enzymes are usually a bit raised with no alcohol. I eat a very clean diet. No meds. Lyme disease. I take 1 gm vit c but cannot tolerate anything but the smallest dose of folate. Sick all my life but put it down to mercury poisoning at 6 months old.
 
mariovitali

mariovitali

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brenda said:
Hi @mariovitali

Thanks. My liver enzymes are usually a bit raised with no alcohol. I eat a very clean diet. No meds. Lyme disease. I take 1 gm vit c but cannot tolerate anything but the smallest dose of folate. Sick all my life but put it down to mercury poisoning at 6 months old.
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Ok Brenda now i have a better picture.

Please make sure that you supplement with Choline. You seem to be a good candidate for TUDCA as well which is a liver protectant.

Perhaps if your liver condition gets better you will be able to tolerate Metafolin.
 
B

brenda

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Location
UK
@mariovitali

Thanks. One of my children showed signs of Phenylketonuria now that i have read about it - delayed physical development, ezcema, ADHD, small head. I am amazed as I have puzzled about this since he was very young (33 now)
 
whodathunkit

whodathunkit

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I'd like to start taking NAG but have resisted because I have insulin resistance and higher-than-ideal blood sugars and glucosamine sulfate seems to aggravate that.

Does anyone know if NAG would or would not have the same effect? Searching around on Google and PubMed didn't really net me anything of use.
 
mariovitali

mariovitali

Senior Member
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1,214
@whodathunkit ,

I believe there shouldn't be any problem but you should monitor your blood glucose levels just to be on the safe side :


Though preliminary evidence suggested glucosamine supplementation could cause insulin resistance, follow up studies conclude that glucosamine supplementation does not affect glucose metabolism.
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http://examine.com/supplements/glucosamine/


and

There has also been a concern that glucosamine might increase the amount of insulin in the body. Too much insulin might lead to high blood pressure and high levels of cholesterol and other blood fats called triglycerides. While animal research seems to confirm that glucosamine can increase cholesterol, researchers haven’t found this effect in people. In fact, research findings to date show that glucosamine does not seem to increase blood pressure or raise cholesterol levels in people over age 45 who take glucosamine sulfate for up to 3 years.
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http://www.webmd.com/vitamins-supplements/ingredientmono-619-n-acetyl glucosamine.aspx?activeingredientid=619&activeingredientname=n-acetyl glucosamine
 
whodathunkit

whodathunkit

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1,160
Thanks, @mariovitali...I found a bit of conflicting evidence, too. Glucosamine sulfate does seem to increase my sugars a bit. Perhaps it's a case by case basis.

I was hoping for some info specific to NAG, but maybe there isn't anything or it's buried so we won't find it. Nobody seems to make a distinction between the two forms. Maybe there isn't much difference in the way the body handles them...?
 
whodathunkit

whodathunkit

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Thanks, @mariovitali. I just bought some anyway. Ironically (or perhaps not), I was lecturing someone else in another thread about buying too many supplements and here I go again. :lol: BUT...I've been wondering about this for a while, because of its effect on the digestive tract. Your posts have kind of pushed me over the edge. ;)

And maybe it will be okay. I've taken a supp with NAG in it and I don't think it had any effect, but that product doesn't have much NAG relative to the amount taken, and it's a little pricey. I'll just check my sugars regularly and see how it goes. They're kind of all over the map anyway, but much better than in the past, so if I see a marked upward trend I'll know what the problem is.
 
Violeta

Violeta

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