Inflammation increases pyruvate dehydrogenase kinase 4 (PDK4) expression via the JNK pathway

[nanonug]

So only if the liver is not up to scratch in detoxifying LPS will this toxin enter the systemic circulation. So for those who think translocation of LPS plays a role in ME/CFS, presumably this implies that there must an impairment in liver deacetylation in ME/CFS which allows LPS into the systemic circulation.

@mariovitali is of the opinion that liver injury has something to do with SEID. I've seen him make this case several times already. A recent post from him about liver injury is here: https://forums.phoenixrising.me/ind...olic-trap-for-me-cfs.58606/page-6#post-972037

 

[Hip]

@mariovitali is of the opinion that liver injury has something to do with SEID.

Yes, his machine learning algorithm came up with the liver X receptor (LXR) as a mechanism that may be involved in ME/CFS.

 

[Hip]

At 14:00 minutes into this video it shows a 100% genetic expression match of ME/CFS to Systemic inflammatory response syndrome (SIRS). Which is the same response as in sepsis.

That discovery really deserves a thread of its own; according to Cort's article, both Dr Wenzhong Xiao and Prof Montoya found ME/CFS looks like systemic inflammatory response syndrome (SIRS).

Though it should be pointed out that SIRS does not have to have an infectious origin; in the Wikipedia article, it says conditions like ischemia and hemorrhage can also cause SIRS.

Sepsis is a particular form of SIRS caused by the presence and proliferation of bacteria in the blood; but you can also have SIRS without any infection present.

Given that ischemia can cause SIRS, one might speculate that the energy metabolism blockages found in ME/CFS (which perhaps might in simulate the lack of oxygen under ischemic conditions) could be the cause of the SIRS-like state of ME/CFS.

 

[ljimbo423]

That discovery really deserves a thread of its own; according to Cort's article, both Dr Wenzhong Xiao and Prof Montoya found ME/CFS looks like systemic inflammatory response syndrome (SIRS).

I wasn't aware that Montoya thought ME/CFS looked like SIRS but I'm glad he does.

Though it should be pointed out that SIRS does not have to have an infectious origin; in the Wikipedia article, it says conditions like ischemia and hemorrhage can also cause SIRS.

Yes, that's true.

I don't know if you have seen my recent posts about how a high dose of coq10 has stopped my flu-like flares (not PEM) from exercising. I was getting them every 2-3 weeks and they would last 2-5 days, usually putting me in bed for those days. Since starting the high dose coq10, 3 months ago, I haven't had one.

My feeling is the coq10 is improving mito. function and that improved mito. function is stopping the flares. There seems to be a clear correlation of mito dysfunction and the immune system, hence the flu-like flares stopping from the coq10.

I've done some research on this and mito dysfunction can cause an up-regulated immune system and an up-regulated immune system can cause mito dysfunction from oxidative stress, ROS/RNS etc.

There appears to be some kind of a feed-forward loop, where they each feed each other. I just thought I would pass this on, I find it incredibly intriguing. Maybe this ties into the SIRS theory somehow?

Jim

 

[mariovitali]

@Hip @nanonug

Just to make some points which may be of interest :

1) I've recently sent to @Janet Dafoe (Rose49) a confirmation that Machine Learning Algorithms score "Sepsis" as Highly relevant to ME/CFS. "Sepsis" is the second most highly relevant Topic after "Liver Disease".

2) On February 5th 2018 i shared a Video with @Janet Dafoe (Rose49) where Network Analysis identifies the following areas as being relevant to ME/CFS :

-Liver (Liver Injury, Steatohepatitis, etc)
-Inflammation
-ER Stress and Unfolded Protein Response (UPR)

Here is a snapshot of the same video at approximately 5 minutes, 28 seconds (see JNK, Inflammatory response among the topics chosen by Network Analysis) showing the Inflammation Segment of the Network:

3) Some weeks ago i shared with Janet a 33-page document which explains the "Multiple Pathways Hypothesis" with the latest findings from Machine Learning. Among them is Catalase.I am pasting the following snapshot from within the document which i believe is relevant to this discussion (Notice LPS, JNK, Nf-Kb pathway). Note that this excerpt was taken from a Book called "Molecular Pathology of Liver Disease" :

EDIT :

@Hip
I believe that the "Bile" mentioned here is also very important :

Finally, if LPS crosses the gut mucosa, it is directed via the portal vein to the liver, where major detoxification processes occur by deacetylation and excretion through the bile. If this disposal process is not sufficient, LPS enters the systemic circulation, where it is handled by numerous transport proteins that clear it back to the liver for further excretion.

-What would happen if for some reason Bile Acid Metabolism is impaired?

-Why do quite a few cases of ME/CFS Patients i know where found to have Total Bile Acids (=Serum TBA) elevated?

 

[nanonug]

Catalase

I'm almost done with a bottle of GliSODin and will try some Jiaogulan afterwards to see what happens.

EDIT: It seems sulforaphane has similar actions to jiaogulan and given that I already have this on hand, I'll replace GliSODin with sulforaphane instead.

 

[Hip]

I don't know if you have seen my recent posts about how a high dose of coq10 has stopped my flu-like flares (not PEM) from exercising. I was getting them every 2-3 weeks and they would last 2-5 days, usually putting me in bed for those days. Since starting the high dose coq10, 3 months ago, I haven't had one.

I think flu-like symptoms is included under post-exertional malaise, although not everyone gets these symptoms as part of their PEM.

My feeling is the coq10 is improving mito. function and that improved mito. function is stopping the flares.

Dr Sarah Myhill uses Q10 for treating ME/CFS because she thinks it helps mitochondrial function. There are a couple of studies, here and here, which found Q10 benefits ME/CFS. She also uses D-ribose in patients with group B mitochondrial dysfunction.

 

[ljimbo423]

I think flu-like symptoms is included under post-exertional malaise, although not everyone gets these symptoms as part of their PEM.

The reason I separate the flu-like symptoms from the PEM is that my PEM is just like clockwork. It comes on 48 hours after physical exertion and is gone 24 hours later. It has worked like that for years.


The flu-like flares can come on anywhere from the day of exertion to 3-4 days later and last up to 5 days. It does appear to be some kind of PEM, yet it's very different. I have yet to figure out what is causing the big difference in these two types of PEM.

Good to know coq10 is also helping my heart.

Dr Sarah Myhill uses Q10 for treating ME/CFS because she thinks it helps mitochondrial function. There are a couple of studies, here and here, which found Q10 benefits ME/CFS. She also uses D-ribose in patients with group B mitochondrial dysfunction.

At first glance I appear to fall into both group A and B. I have tried Ribose but it only works for a week or two then stops.

Jim

 

[kangaSue]

Here's a thought to consider around increased intra-abdominal pressure.

I was looking for any information I could find about the effects of left renal compression and ended up at some papers on Pre-eclampsia. This condition could be viewed as a model for a chronic form of sepsis where increased intra-abdominal pressure is at the core of the problem and results in having increased intestinal permeability too.
https://www.sciencedirect.com/science/article/pii/S0306987714002722

Now bloating commonly occurs in IBS and has been found to involve increased intra-abdominal pressure, albeit accidently.
https://www.ncbi.nlm.nih.gov/pubmed/20019454

Is it possible then that those with ME/CFS have a problem with increased intra-abdominal pressure, and maybe over and above other populations with IBS too? It's not an aspect of ME/CFS that I have seen any mention of before.

Measurement of bladder pressure via an indwelling urinary catheter is a simple and effective way of indirectly measuring intra-abdominal pressure.

 

[wastwater]

On Wenzhong Xiao slide I noticed IL-2 at the bottom of diagram
4q27 is IL-2 location and so is axenfeld rieger syndrome
Side effects of IL-2 would present like ME maybe
And was sky high in oslers web

 

[nandixon]

That discovery really deserves a thread of its own; according to Cort's article, both Dr Wenzhong Xiao and Prof Montoya found ME/CFS looks like systemic inflammatory response syndrome (SIRS).

In his talk from February (transcript here), I think Prof Montoya is indicating that the mRNA gene expression data that had appeared to indicate essentially a 100% match with systemic inflammatory response syndrome (SIRS/sepsis) has been found to have a problem. His statement sort of flew under the radar because he didn't actually refer to SIRS by name but I'd been waiting for that study to be published for at least a couple years now and was wondering what the delay was and so happened to notice it. Prof Montoya said:

So this cohort of 200 patients and 400 healthy controls, they have undergone cytokines.

We have issues with the gene expression, so we're going to redo the study of the gene expression.

We were very unhappy with the data.

There were serious issues in that data.

If the problem is a fundamental one relating to methodology/technology then Dr Xiao’s data may have a similar problem.

Perhaps I'm misunderstanding what's being referred to, though. @Cort, have you heard anything about the issues Prof Montoya mentioned?

 

[Hip]

If the problem is a fundamental one relating to methodology/technology then Dr Xiao’s data may have a similar problem.

Also, as touched upon in my above post, given that ischemia (which involves lack of oxygen) is a known cause of SIRS, possibly the energy metabolism blockages (eg in aerobic glycolysis) found in ME/CFS could be the reason for the SIRS gene expression in ME/CFS, as these blockages may simulate a lack of oxygen.

On first reading about the match between ME/CFS and SIRS gene expression it looks very exciting as it suggests there might be some sepsis going on in ME/CFS, but my guess is that this match might also be explained by an energy metabolism blockage simulating a lack of oxygen, and have nothing to do with sepsis.

 

[wastwater]

I wonder in the ME family cases which genetic points are showing as relevant

 

[FMMM1]

In his talk from February (transcript here), I think Prof Montoya is indicating that the mRNA gene expression data that had appeared to indicate essentially a 100% match with systemic inflammatory response syndrome (SIRS/sepsis) has been found to have a problem. His statement sort of flew under the radar because he didn't actually refer to SIRS by name but I'd been waiting for that study to be published for at least a couple years now and was wondering what the delay was and so happened to notice it. Prof Montoya said:




If the problem is a fundamental one relating to methodology/technology then Dr Xiao’s data may have a similar problem.

Perhaps I'm misunderstanding what's being referred to, though. @Cort, have you heard anything about the issues Prof Montoya mentioned?

That's interesting.
At the September 2017 OMF Symposium Dr Xiao presented data presented from a gene expression study which showed that the closes match was to Sepsis (SIRS).

I've watched part of Professor Montoya's video presentation. I assume that the section you are referring to is approx 24 minutes (from the start) where Prof Montoya expresses serious concern about the gene expression data. I'd be interested in knowing what the problem was/is e.g. some parts of the genome are very difficult to sequence (e.g. HLA). Possibly someone like Cort will know what the issue is. The problem with the gene expression data would be more concerning if they weren't comfortable with owing up to a potential problem. That seems to have been a fundamental issue in science in recent years. They're good scientists, i.e. Dr Xiao and Ron Davis +++, I'm confident that they will review the data and their assessment of that data.

I checked Ron Davis's presentation at the Invest in ME Conference in London (June 2018). I had noticed that he was suggesting that it could be similar to sleeping sickness. Kind of strengthens the case for trying out suramin i.e. the sleeping sickness drug. Also they are developing a test for these parasites (trypanosome PCR markers). It's amazing that they can now develop a test for this in a relatively short period of time. I assume that all it takes is the right people and the money.

Montoya mentions in the video that the data indicates that HLA & KIR genes appear to determine your risk of getting ME/CFS and also the severity of the illness. Check out the 2018 NIH grant, to Ron Davis and Mike Snyder, for HLA and KIR sequencing. I assume that this data was used to support the successful application.