Unfolded Protein Response and A Possible Treatment for CFS

[Gondwanaland]

Oh boy, that's terrible! I wonder if there is a way to undo the damage! I don't know how cipro causes damage, maybe somebody else does. Terrible that the medicines are causing so much damage!

It's a magnesium mugger. The rashes could be from histamine build-up from lowered magnesium

 

[Valentijn]

So far 2 same SNPs at CYP1B1 and CYP2D6. Can you tell us what kind of Symptoms you have and how you got CFS?

In the case of rs1135840 on CYP2D6, that's because the allele frequency of the supposedly "risky" allele is 60%. 36% of the world population is +/+, and another 48% are +/-.

 

[mariovitali]

In the case of rs1135840 on CYP2D6, that's because the allele frequency of the supposedly "risky" allele is 60%. 36% of the world population is +/+, and another 48% are +/-.

You are right @Valentijn, i completely forgot to look at the Frequencies.

Thank you for pointing this out.

 

[Violeta]

Yeah it caused me a lot of problems. I was on it for a couple months for suspected prostatitis. I definitely felt joint pain when I was taking it and some achilles pain. Like I said I think up until that point my cfs type symptoms were at least manageable, everything seemed to get way worse after that for me. If you google it you can find a ton of horror stories about people taking cipro and other fluoroquiniolone antibiotics and being severely damaged by them. In fact I think they come with a black box warning now, doctors used to pass them out like candy, and maybe still do. My Dad took some and after 3 days ended up in the hospital with a bizarre rash and other crazy stuff. I would highly advise against anyone taking them unless it was a life/death infection or something, its pretty much a poison.

I just read that cipro causes fluoride toxicity. Interesting that borax helps with fluoride toxicity, and prostate issues, not sure which ones.

 

[mariovitali]

Combating Oxidative Stress in ME/CFS

Over the past decade, ME Research UK-funded researchers at the University of Dundee have uncovered a range of biological abnormalities in ME/CFS patients (see below), including high levels of apoptotic (dying) white blood cells and increased arterial stiffness. Their main finding, however, has been that people with ME/CFS have high levels of reactive oxygen molecules, which can harm blood vessels and muscles. These molecules are formed in the body during biological processes that use oxygen, such as exercise. In healthy people they are counter-balanced by antioxidants that detoxify the oxygen molecules to prevent damage, but sometimes an imbalance can lead to increased ‘oxidative stress’ and an increased risk of cardiovascular disease.

It is important to discover the origin of these molecules, so that ways of counteracting oxidative stress-related cardiovascular damage can be developed. For this reason, the research team in Dundee has received funding from ME Research UK to investigate the role of ‘nuclear factor erythroid-derived 2’ (Nrf2). This is an extremely important regulatory protein in the body, and is now believed to be a master activator of the body’s natural defence against oxidative stress. When reactive oxygen species are generated, Nrf2 is activated, stimulating the body’s antioxidant pathways and thereby providing a buffer against oxidative stress.


<SNIP>


If low Nrf2 levels are found to play a central role in the increased oxidative stress found in ME/CFS patients, stimulation of Nrf2 could become an important treatment strategy, as there are currently no specifically effective treatments for the illness. The findings may also have broader implications for studies of Nrf2-targetted treatments in other conditions characterised by elevated oxidative stress, such as cancer, diabetes and liver disease.

Regarding Nrf2 :


http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-55#post-655459



Link of Post :


http://www.prohealth.com/library/showarticle.cfm?libid=20285

 

[mariovitali]

Dear All,


Please find attached a document that tries to put the whole Theory of this Thread in one place.

@Gondwanaland , @skwag, @Violeta, @jump44, @Hip, @Ema

I would really appreciate your Feedback since you know what this Thread is all about.

Of course feedback and corrections from any one else are more than welcome..

 

[Valentijn]

Please find attached a document that tries to put the whole Theory of this Thread in one place.

On the one hand i do not have the necessary knowledge to know what exactly constitutes a Pathogenic vs a Nonpathogenic SNP.

You can find it by looking up the SNP on http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs= . If it's pathogenic, the page for it will say "Pathogenic" near the top, and there will be a purple box in the map view.

However, my belief/hypothesis is that we are -presently- in no position to know what problems could be potentially caused by the combination of several Pathogenic and non-pathogenic SNPs of interest.

But that would be complete guess work, which is completely implausible when there are billions of SNPs to "potentially" do something and "potentially" interact.

 

[mariovitali]

@Valentijn

We already been through this before and i am happy that our conversation is being documented here.
I also clearly state in the document that whatever is discussed is a Hypothesis based on observations only from myself. This makes things *very* problematic but it does not mean that the Hypothesis may not be indeed true.


The section where i write about Pathogenic and Non-Pathogenic SNPs will be removed, Thank you for pointing this out.

I also asked you previously in the Thread the following Question, i would really appreciate if you answer it this time.

-If many people (say 100) begin feeling much better on the regimen to the point that they feel almost normal, would you consider following this regimen yourself?

Yes or No?

 

[Violeta]

Yeah it caused me a lot of problems. I was on it for a couple months for suspected prostatitis. I definitely felt joint pain when I was taking it and some achilles pain. Like I said I think up until that point my cfs type symptoms were at least manageable, everything seemed to get way worse after that for me. If you google it you can find a ton of horror stories about people taking cipro and other fluoroquiniolone antibiotics and being severely damaged by them. In fact I think they come with a black box warning now, doctors used to pass them out like candy, and maybe still do. My Dad took some and after 3 days ended up in the hospital with a bizarre rash and other crazy stuff. I would highly advise against anyone taking them unless it was a life/death infection or something, its pretty much a poison.

Cipro may cause fluoride toxicity, but the main damage that it can do is more likely due to this:

Allylamines inhibit squalene epoxidase, and squalene epoxidase is an enzyme in the mevalonate pathway.

 

[skwag]

Hi @mariovitali ,

As you probably know, I agree with @Valentijn that your emphasis on SNP's is premature. There are exceptions however. For example, the research behind some of the SNP's related to choline status does show that some of us would do well to make sure we get enough choline. The suggestions related to biotin also seem well supported, but I haven't looked into it myself. On the other hand, many of the other recommendations based on SNP's have little or no research to back them up.

If you want to continue your focus on SNP's, I think you have to be more careful to distinguish which things are based on research, and which things are speculation.

. Unfortunately you do not understand key things which i am not going to discuss further... simply because you do not understand.

This is out of bounds. I feel gross when the thread starts deteriorating like this. It makes me not want to participate. I wish all sides would try to be more diplomatic.

 

[mariovitali]

@skwag

Question : Do you agree with the possibility that a combination of several Non-Pathogenic SNPs (e.g in Choline metabolism) may lead to problems? Do you agree that this possibility may well exist?

I am sure that you have seen numerous times that i immediately acknowledge my lack of knowledge and mistakes and i ask anyone that can help to do just that.

The -bitter- Truth is that we do not have the data or the resources to make hypotheses in a proper way. Until Research on CFS advances we are left to our own devices. This is the unfortunate Truth.

My truth is that after 7 years of repeated failures with tens of supplements something happened and my Condition changed. Yes, it could be a random thing but maybe it's not. This is what we are trying to see in this Thread.

I will stop here, simply because i do not want this Thread to deteriorate as you said. And that's the only reason.

 

[skwag]

Question : Do you agree with the possibility that a combination of several Non-Pathogenic SNPs (e.g in Choline metabolism) may lead to problems? Do you agree that this possibility may well exist?

Of course, I agree. The question is how likely is it that any such particular set of SNP's will prove to be pathogenic.

 

[mariovitali]

Of course, I agree. The question is how likely is it that any such particular set of SNP's will prove to be pathogenic.

Exactly. And this the answer i was hoping to see from you.

Now, to answer your question : The truth is that i do not know

However ....the fact that i followed a regimen that targets these Gene Functions and that made me feel completely normal after having so many Symptoms for so many years could be a starting point for making a hypothesis.

And this is what this Thread is all about.


I hope you are feeling better and I am looking forward to your Update.

 

[skwag]

Trial Update Day 70

This will be my last full blown 10 day update, as I feel my experimentation is diverging from the ER stress protocol laid out by Mario. I will of course update if I experience any major changes or have any revelations.

In the following, changes from my last update will be in bold.

I'm currently taking,

• 3x1400 mg NAG
• 0 mg TUDCA: discontiniued on day 51
  
• 0 mg FMN ( B2 ) : discontinued on day 48: I had tried FMN before and found no benefit over the B2 I get in a b-complex. The same appears to be true now.
  
• 100 mcg selenium
• 2x250 mg citicoline: reduced from 3x250
  
• 2x300 mg alpha GPC: reduced from 3x300
  
• 1x500 mg choline (as choline L-bitartrate) : reduced from 5x500 mg
  
• 3x750 mg inositol :
  
• 1x100 mg Pantothenic Acid ( B5 ) : reduced from 3x300 mg
• 2x150 mg Pantethine : reduced from 2x300mg
• 3x100 mg Paba : new addition
• 2x450 mg Rutin : new addition
• 2x1000 mg Vit C : new addition, I had already been getting 300 mg Vit C as part of my B complex

along with methylation and mineral supplements. I have also been on the autoimmune paleo diet for 54 days.

Improvements:

• 50% lightening of sun damge/ liver spots on forearm ( onset one year ago )
• decreased urinary frequency. Now I go every 2-3 hours vs every hour
• lighter urine color
• better urinary flow ( probably due to less prostate inflammation )
• 60% improvement in folloculitis on arms and legs ( onset one year ago ) :
  
• 90% improvement in noise intolerance : down from 100%
• 95% improvement in headaches.
  
• 95% improvement in lower back pain ( onset one year ago ): up from 70%
  
• 40% improvement in energy levels: up from 33%
  
• 60% improvement in groin pull injury (onset 5 months ago, little improvement over previous 4 months )
• 50% improvement in nasal congestion :

No change:

• eye floaters ( onset one year ago )
• skin texture/ wrinkling ( onset one year ago )
• POTS: Poor man's tilt table test results: 30-35 bpm

At nearly three weeks after stopping TUDCA, I feel like I am continuing to slowly improve. It is really impossible to say how much of an effect TUDCA had. What I can say at the moment is that my recently achieved improvements are not dependent on ongoing TUDCA supplementation. It appears Mario and I differ in this respect.

I have given up on choline mega-dosing as a means to improve OI/POTS. It simply did not work for me. I have cut down on the choline significantly and will continue to taper it down. I will not stop it completely, as I suspect I was short on choline before starting this trial, and that the choline supplementation has helped me greatly.

10 days ago, I was hopeful that Pantethine had eliminated my remaining noise intolerance. A couple days after that update, I had a few episodes of noise intolerance once again. I still believe Pantethine may be useful in this respect, but it is not the complete cure I had naively hoped for.

Two new supplements I have been trialing are Paba and Rutin. Rutin, a bioflavanoid, is said to strengthen capillaries and perhaps other parts of the vascular system. I also found a paper which claimed Rutin was a selective vasoconstrictor. So maybe it could be helpful in some types of OI. Within a few days of taking it, I noticed my lower legs and feet were not as sore from standing. I also could see that the size of the veins on my hands were greatly reduced. I did not, however, notice the same thing with the veins on my ankles and feet. I have also not noticed any reduction in standing heart rate. We'll see what happens.

I cannot identify any direct effect or improvement due to Paba. However, 3 days after starting it, I had a bout of angular chelitis ( cracks in the corners of the mouth/lips ). This has always been a sign of folate deficiency for me, and it did go away after upping my methylfolate. Is this a good sign or a bad sign? Again, we'll see.

Just to state the obvious: I am much better off than I was 70 days ago. The improvement in the symptoms that I've tracked bears that out. So, thanks to @mariovitali and everyone who has contributed here.

 

[Valentijn]

Exactly. And this the answer i was hoping to see from you.

When you're talking about billions of SNPs, the odds of any random combination being relevant is so close to zero that it had effectively might as well be zero.

Taking basic genetic courses is not a full time job. One course can be taken at a time, and the introductory ones especially do not take a lot of time. I managed a couple of them even while housebound with ME and while on antibiotics which made me even sicker than usual. It should be quite manageable with your current good health.

As I said, it does mean more time and effort, and accordingly a further delay for your hypothesis. However, it would be of great benefit to your hypothesis. If you are as invested in your hypothesis as I think you are, it should be worth the extra work.

 

[mariovitali]

When you're talking about billions of SNPs, the odds of any random combination being relevant is so close to zero that it had effectively might as well be zero.

Right, so that means -according to your way of thinking- that we should stop any Research under way at the moment. FYI i am not talking just about "Random" SNPs here : I talk specifically about :

-Liver Function
-Gut Function (new)
-Redox Genes
-ROS Handling
-ER Stress Genes (including ER Signaling)
-P450 Enzymes
-Bile Acid Synthesis and Circulation (new)

Taking basic genetic courses is not a full time job. One course can be taken at a time, and the introductory ones especially do not take a lot of time. I managed a couple of them even while housebound with ME and while on antibiotics which made me even sicker than usual. It should be quite manageable with your current good health.

Of course not, but once again you are not looking at the whole picture. I have a Full time job (actually i work sometimes 12 hours a day and 4-6 hours on Weekends). Add to this the Software i am building to generate the Hypotheses (which i am sure you've seen) plus other things i am doing relevant to CFS/PFS 'Generation of Hypotheses'. Please Note that i haven't mentioned anything about me "Researching CFS". Add to this the time it takes me answering and trying to help. Seeing @skwag saying that he feels much better is a good start. The same applies for @jump44.

As I said, it does mean more time and effort, and accordingly a further delay for your hypothesis. However, it would be of great benefit to your hypothesis. If you are as invested in your hypothesis as I think you are, it should be worth the extra work.

I couldn't agree more with this. However, what i was hoping for is to have an actual expert here (not someone from taking Coursera courses).

A Coursera course does not make you an expert. Period. I am not aiming this to you of course. Becoming a Medical Professional takes Years of Studying. Do you accept that?

To perform Research we have to have a Hypothesis (which i am putting here) and the proper environment and methodology to either Accept or Reject this Hypothesis.

FYI : There is one additional factor that may be important : Bile Acid Circulation.

@skwag @jump44

If you can please try adding a Standardized Artichoke extract to your regimen and see if you benefit from it.

Pharmacological Studies of Artichoke Leaf Extract and Their Health Benefits.
Salem MB1, Affes H, Ksouda K, Dhouibi R, Sahnoun Z, Hammami S, Zeghal KM.
Author information

Abstract
Artichoke (Cynara scolymus) leaf extract was one of the few herbal remedies which the clinical and experimental trials have complemented each other. Both experimental and clinical effects have been verified through extensive biomedical herbal remedy research. Specifically, antioxidant, choleretic, hepatoprotective, bile-enhancing and lipid-lowering effects have been demonstrated, which corresponded with its historical use. Ongoing research seems to indicate that artichoke indeed have medicinal qualities. Most significant appears to be its beneficial effect on the liver. In animal studies, liquid extracts of the roots and leaves of artichoke have demonstrated an ability to protect the liver, with possibly even to help liver cells regenerate. Although research is not yet conclusive, scientists were optimistic that its long-standing use in humans for digestive and bowel problems was indeed justified. It may also play a role in lowering cholesterol and thus help to prevent heart disease. Boiled wild artichoke reduced postprandial glycemic and insulinemic responses in normal subjects but has no effect on metabolic syndrome patients. This article intended to review the wide ranging pharmacological effects of artichoke leaf extract.

and

Choleretic activity and biliary elimination of lipids and bile acids induced by an artichoke leaf extract in rats.
Saénz Rodriguez T1, García Giménez D, de la Puerta Vázquez R.
Author information

Abstract
The therapeutic properties of artichoke (Cynara scolymus L.) preparations have been known since ancient times. The traditional use of artichoke leafextract (ALE) in gastroenterology is mainly based upon its strong antidyspeptic actions which are mediated by its choleretic activity. The aim of this study was to investigate the effects of ALE on bile flow and the formation of bile compounds in anaesthetised Wistar rats after acute and repeated (twice a day for 7 consecutive days) oral administration. A significant increase in bile flow was observed after acute treatment with ALE as well as after repeated administration. The choleretic effects of ALE were similar to those of the reference compound dehydrocholic acid (DHCA). Total bileacids, cholesterol and phospholipid were determined by enzymatic assays. There was a strong ALE-induced increase in total bile acid concentration over the entire experiment. With the highest dose (400 mg/kg), a significant increase was obtained after single and repeated administration. The bileacids-increased effects of ALE were much more pronounced than those of reference (DHCA). No significant differences in cholesterol and phospholipid content could be found.

 

[Valentijn]

Right, so that means -according to your way of thinking- that we should stop any Research under way at the moment. FYI i am not talking just about "Random" SNPs here : I talk specifically about :

So you're talking about random SNPs on specific genes. That's still effectively completely random. And that's not just "my way of thinking". It's science.

I couldn't agree more with this. However, what i was hoping for is to have an actual expert here (not someone from taking Coursera courses).

Take one of those Coursera courses, and you'll have access to those actual experts. They'll be the teachers, and you can interact with them and the other students via the course forums.

A Coursera course does not make you an expert. Period. I am not aiming this to you of course. Becoming a Medical Professional takes Years of Studying. Do you accept that?

When did I claim I was an expert? My claim is that your admitted lack of knowledge in the area perhaps is creating a fatal flaw in your hypothesis. And if you gain some knowledge of genetics, you can make a great deal of progress.

 

[mariovitali]

@Valentijn

OK, you've made your point and i tried to make mine as well. As i said previously : My Point of view (and way of thinking) is documented here and so is yours.


Let's just not derail this Thread anymore.

 

[mariovitali]

Just ran an analysis on PubMed entries regarding CFS itself, however the query to PubMed was asking for PubMed entries as follows :

"Chronic" or "Fatigue" or "Syndrome"

The code extracts statistically significant Phrases using Pointwise Mutual Information (PMI) and Chi-Square


Please have a look at the entries shown on red rectangles : several Topics appear that are discussed here.

(Click on Pictures)

Shown on yellow rectangle above is the Phrase Biliary Cirrhosis. So i collected all PubMed entries regarding Biliary Cirrhosis :


Here is the same analysis for Biliary Cirrhosis PubMed entries :

Notice that 'Fatigue" is one of the words that appear. Also notice :

-Cytochrome P450
-Lymph Nodes
-Heat Shock
-Ursodeoxycholic Acid

I then ran a co-occurrence analysis for Symptoms associated with Biliary Cirrhosis

Notice the terms :

-Asymptomatic
-Fatigue
-Pruritus
-Cognitive
-Autonomic


I am in no way suggesting that CFS originates from Liver disease but i believe that Liver is a Key component of the problem. What i would like to suggest is to *definitely* rule out any Liver issues. Notice that one of the words found was ASYMPTOMATIC.

Regarding NAFLD :

Liver biopsy is of unquestioned value in determining the presence of steatosis, distinguishing steatosis from steatohepatitis, and assessing the degree of fibrosis. Because the diagnostic accuracy of noninvasive diagnostic tools is low, histology is the most reliable means to grade the severity of the disease and thus estimate prognosis. Biopsy is also helpful in ruling out an alternative diagnosis. In addition to establishing the cause and severity of disease, histology permits the monitoring of disease progression and the response to therapy, because aminotransaminase levels can decrease during the course of the disease regardless of whether fibrosis progresses or improves. A histologic scoring system (NAFLD activity score) has been proposed to aid with diagnosis and monitoring of the disease.

http://www.clevelandclinicmeded.com.../hepatology/nonalcoholic-fatty-liver-disease/

Note also that Liver Biopsy is the unquestionable way to diagnose Biliary Cirrhosis.


Again : Please check your Liver function thoroughly.

 

[skwag]

Biliary Cirrhosis

There are a number of SNPs which increase the risk of biliary cirrhosis:

rs7574865 (risk T)
rs6441286 (risk G)
rs7774434 (risk C)
rs9303277 (risk T)
rs3745516 (risk A)
rs10488631 (risk C)
rs4979462 (risk T)

From the above list, rs10488631 and [URL='http://www.snpedia.com/index.php/rs7574865']rs7574865[/URL] are also associated with a host of autoimmune diseases.
I found these SNPs by searching in Promethease for "cirrhosis".