Emerge Australia ME/CFS International Research Symposium March 12-15, 2019

[SlamDancin]

@Diwi9 I know it will be uploaded later but I missed the first talk, was mTORC1 found to be upregulated?

 

[Diwi9]

@Diwi9 I know it will be uploaded later but I missed the first talk, was mTORC1 found to be upregulated?

I believe so. The data showed that Complex 5 was downregulated, leading to upregulation of Complexes 1-4 in a compensatory manor. The mitochondrial membranes also showed protein "leaking" to compensate for the lack of electrons coming from Complex 5. Hope I'm explaining this okay, I'm a science novice.

 

[Diwi9]

Videos will be uploaded to Vimeo here: https://vimeo.com/emergeaustralia

 

[SlamDancin]

Interesting! Also looks like TRPM3 is important especially in cells with cilia (as the presentation pointed out there are lots of these everywhere in the body). I’m starting to become confident that cilia are dysfunctional in ME/CFS.

Cilia regulate TRPM3 signaling in renal epithelial cells

 

[Diwi9]

Interesting! Also looks like TRPM3 is important especially in cells with cilia (as the presentation pointed out there are lots of these everywhere in the body). I’m starting to become confident that cilia are dysfunctional in ME/CFS.

Cilia regulate TRPM3 signaling in renal epithelial cells

Yes, multisystemic (CNS, GI, Cardiovascular). Hmm, sounds familiar.

 

[ScottTriGuy]

The last speaker mentioned there was a '3 day washout before CD24s returned to homeostasis if you like'.

I wonder if that has anything to do with PEM? It takes me about 3 days to 'recover' from over exertion.

I missed the mTOR presentation too, so will have to take a look at that. The stuff about AMPK may be related to mTOR as well.

 

[SlamDancin]

@Diwi @ScottTriGuy

Well I must say guys, as a wannabe researcher, I am encouraged that we've seen problems relating to mTOR/AMPK/Cilia (Ca+) signaling just as I expected.

I also happened to catch that the AhR was one of the 11 genes differentially regulated in the Broderick work.
FKBP5 and Glucocorticoid excess, and the low/high estrogen states, along with the metabolic reprogramming seen, fits with many of the theories I've thrown around on here.

Very very interesting and hopeful stuff guys.

By the way, I discovered today that IDO directly activates AMPK and AhR to metabolically reprogram ATP synthesis and Free Fatty Acid Oxidation.

IDO decreases glycolysis and glutaminolysis by activating GCN2K, while it increases fatty acid oxidation by activating AhR, thus preserving CD4+ T‑cell survival and proliferation.

The results indicate that IDOdecreased glycolysis and glutaminolysis by activating GCN2K, resulting in activation of AMP‑activated protein kinase (AMPK). In parallel with AMPK activation, IDO‑induced activation of aryl hydrocarbon receptor increased the expression of all carnitine palmitoyltransferase I isoenzymes, leading ultimately to increased free fatty acid oxidation and preservation of CD4+ T‑cell survival and proliferation. Thus, contrary to what is generally hypothesized, in a normal environment containing fatty acids, the immunosuppressive effect of IDO may not be due to a decrease in CD4+ T‑cell survival and proliferation, since IDO supplies the required energy for cell survival and proliferation by increasing free fatty acid oxidation.

Also interesting, and confounding, but possibly setting up a potential feedback loop, I found that new Berberine alkaloid derivatives have been studied in cancer due to their IDO1 inhibitory effects. Check out how it works;

Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation.

So apparently, AMPK can both be induced by IDO1 or inhibit IDO1 by activation.
The drug I'm most interested in right now is Metformin, which inhibits Mito Complex 1 but also activates AMPK and inhibits mTORC1. Metformin seems to be protective in both low and high AMPK activated situations, further compounding to the complexity.

 

[Diwi9]

@SlamDancin - Search "Metformin" on PR. It has been discussed. I did not know it inhibits Complex 1. I'm actually really impressed with the Aussies. For the last few years, we've gotten headlines...but not hardcore publications. It's clear they are on to something and perhaps this was the basis for the Australian government funding this conference. I know part of the OMF team is over there and @ChrisArmstrong recently joined OMF. I hope their participation in this conference will join more Aussie researchers in the OMF team because their work is starting to connect. Also, I hope that all of this study data impacts the NIH conference next month. There is so much work that should be funded.

 

[Diwi9]

The current pediatric studies in Melbourne makes me hopeful that children are being treated more seriously, and not being dismissed with "CBT" and GET.

 

[Mel9]

I was really impressed by the Queensland researchers.

It would be good if they could give us a simplified possible model.

Profs Sonya Marshall-Gradisnik and Donald Staines idea that something has gone wrong with the TRP3 ion channels makes sense to me.

TRP channels respond to threats, including temperature, allergens, infection and tortion or , stretch (eg. Exercise)

Given that TRP3 is found in cells throughout the body, but there are more of them in brain, spinal column, pancreas, eyes, GI tract, this might explain a lot of our symptoms.

E.g.: The crashes we experience may involve the pancreas.

i was interested in the co-location of TRP3with the acetylcholine receptors too as many of us respond to Mestinon.

 

[Diwi9]

i was interested in the co-location of TRP3with the acetylcholine receptors too as many of us respond to Mestinon.

Yes, I too have had a positive response to Mestinon. Hope this is a true target for treatment research.

 

[SlamDancin]

Has anyone here tried Phenylephrine?

It possibly* works to bypass any problems with getting glucose to the muscles during exercise and also has been found to correct CBFv (cerebral blood flow velocity) in CFS patients.

If I’m not mistaken adrenergic (I have high levels of antibodies towards a1 and less so for a2) and muscarinic acetylcholine receptors work as a team.

I’m taking Phe and it seemingly helps POTS and exercise tolerance (though I just started walking again after exhaustive physical therapy to correct kyphotic scoliosis which was impacting my breathing and blood/CSF/lymph flow).

 

[Diwi9]

Some info posted from @JaimeS, you have to click on the Twitter post to get the full thread:

https://twitter.com/i/web/status/1105675713133240320

 

[Diwi9]

Has anyone here tried Phenylephrine?

Not regularly, but pseudophedrine got me through grad school when I was in a milder state (did grad school on a part-time basis because of health). I could only take a low dose. I thought it was helping my allergies, because that was all I had been diagnosed with at the time. After graduation when I returned to full-time work, I relapsed to a worsened state.

 

[SlamDancin]

@Diwi9 Actually Pseuodoepehdrine doesn’t agonize the alpha1 adrenergic receptor like Phenylephrine, and it doesn’t have the same effect on blood perfusion.

Totally different drug actually. I don’t want to start throwing around recommendations willy nilly but just so you know, it may help even if Pseudo doesn’t!!

 

[Diwi9]

@Diwi9 Actually Pseuodoepehdrine doesn’t agonize the alpha1 adrenergic receptor like Phenylephrine, and it doesn’t have the same effect on blood perfusion.

Totally different drug actually. I don’t want to start throwing around recommendations willy nilly but just so you know, it may help even if Pseudo doesn’t!!

I think that pseudophedrine may have been helping with vasoconstriction. I'm now on desmopressin and midodrine.

 

[SlamDancin]

I think that pseudophedrine may have been helping with vasoconstriction. I'm now on desmopressin and midodrine.

Do you have POTS too?

Midodrine should act like Phenylephrine, nice. Desmopressin is a good drug too. Have they helped?

 

[Diwi9]

Yes, I have POTS too. Both medications have helped. I'm also on metoprolol and pyridostigmine...those have been big winners. I've even reduced my metoprolol since pyridostigmine. Because of forum rules, we are veering off-topic. I'm happy to further discuss my treatment, but unless it's directly related to Emerge, we should take this to a new thread or private message...

 

[sb4]

@SlamDancin I recently was interested in metformin due to complex 1 inhibition however a quick search of these forums was enough to put me off. Seems a fair amount of CFS encounted worsened PEM/lactic acid problems which is a known issue witrh the drug.

 

[Gemini]

Are there now two threads giving summaries; maybe we ought to put them together; someone pls do this.

Sent a merge request to Moderators @perrier. Thanks.