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WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

almost

almost

Senior Member
Messages
138

Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?​

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This, maybe?
https://deepblue.lib.umich.edu/bits.../ars.2007.1782.lowlink.pdf_v03.pdf;sequence=1

Both oxidative and endoplasmic nreticulum stress should be dealt with.
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Now if we just knew how to do that, things might improve for some.

The endoplasmic reticulum (ER) and mitochondria are physically connected to form dedicated structural domains known as mitochondria-associated ER membranes (MAMs), which participate in fundamental biological processes, including lipid and calcium (Ca2+) homeostasis, mitochondrial dynamics and other related cellular
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680862/
 
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Forummember9922

Forummember9922

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170
Today there was some buzz on twitter to be grateful for RE potential developments in the Itaconate Shunt model. A mentioning of ER on one of Phairs videos on youtube. around 29:14 when he illustrates the loop.

To piggy back off DataDragon, Inez, and Judee’s previous post,
  • Recent research has shown that ER stress can influence the production of itaconate in macrophages. Specifically, during ER stress, there is an upregulation of a protein called IRE1α, which can enhance the production of itaconate.
 
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mariovitali

mariovitali

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Now if we just knew how to do that, things might improve for some.
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I think we can. All that is needed is to provide the right antioxidants along with ER Stress amelioration , quite possibly via TUDCA.

I would also add Calcium metabolism regulation
 
almost

almost

Senior Member
Messages
138
I would tend to agree @mariovitali . That 'all' is the complex part.

I am working through your thread on ER stress. Your hypothesis seems to move around a bit. Would you provide a latest executive summary on that thread as of today? That would be helpful.

One of the things that drove me crazy in the thread was all the abstract dumping in posts with no links to the study/article that one can then explore and validate. This one is a great example, and relevant to the topic at hand here. Where did what is quoted in that post ('Combating Oxidative Stress in ME/CFS') come from? I'd like to read it. The link at the bottom doesn't provide the article, if that was the one intended to do so. If it isn't linked or is behind a paywall it really isn't useful. If you would provide a working link, I would appreciate it, and we could all benefit. Thank you.
 
almost

almost

Senior Member
Messages
138
Thank you @mariovitali .

I swear I searched for the article I referenced above several times, as its title and teaser were very attractive. Never found it or got a hit . . . until now. My bad. Don't know what I did differently, and it wasn't high on the results list, but here it is: Combating Oxidative Stress in ME/CFS.

Alas, of course, there wasn't a magic recipe to eliminate oxidative stress, but there was some additional info I thought was interesting:
This group has received a number of grants from ME Research UK in the past 13 years. In a step-by-step progression involving both adults and young people with the illness, the group has discovered:
  • Unusual sensitivity of blood flow to acetylcholine (a neurotransmitter) – Link
  • Increased levels of isoprostanes (a gold standard marker of oxidative stress in the bloodstream) – Link
  • An unexpected increase in dying (apoptotic) white blood cells, consistent with an activated inflammatory process or persistent infection – Link . . . .
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Forummember9922

Forummember9922

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D

datadragon

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404
Location
USA
It would be interesting to know which medication this is.
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An experimental drug, called salubrinal, known to reduce ER stress. After this treatment, WASF3 levels decreased in the cells, more mitochondrial energy complexes formed, and energy production improved.

From the article:

Further laboratory studies led the team to a protein called WASF3. This protein, which was boosted in response to cellular stress, disrupted the cells’ energy production. Blocking WASF3 allowed mitochondria to produce energy at normal levels. The team then showed that extra WASF3 in the cells interfered with formation of the structures that mitochondria use to produce energy.

To better understand the role of WASF3, the team engineered mice to produce excess WASF3. They found that, similar to people with post-exertional malaise, muscles in these mice were slow to recover after exercise. The mice also showed a 50% reduction in their ability to run on a treadmill, even though their muscle strength was comparable to mice without extra WASF3.

To see if WASF3 dysfunction might be involved in ME/CFS, the team compared muscle tissue samples taken from 14 people with ME/CFS to samples from 10 healthy volunteers. They found substantially higher levels of WASF3 in most of the people with ME/CFS.

This dysfunctional increase in WASF3 seemed to be linked to impairment of a cellular signaling pathway called the ER stress pathway. When the team treated human muscle cells with a compound known to increase ER stress, they saw a corresponding harmful increase in WASF3.

The researchers treated cells from the initial study participant with an experimental drug, called salubrinal, known to reduce ER stress. After this treatment, WASF3 levels decreased in the cells, more mitochondrial energy complexes formed, and energy production improved.

https://www.nih.gov/news-events/nih...ein-may-be-linked-exercise-intolerance-me-cfs

Also can look at this post regarding some of the many downstream effects of inflammation/infection and NLRP3 over activation related to WASF3/ER Stress https://forums.phoenixrising.me/thr...ose-protein-high-dose-zinc.90738/post-2442998

ER Stress leads to NLRP3 inflammasome activation also as mentioned earlier which feeds into many of those other downstream effects:

12974_2021_2137_Fig1_HTML.jpg
 
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jaybee00

Senior Member
Messages
593
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Violeta

Violeta

Senior Member
Messages
2,996
datadragon said:
High Copper seems it dramatically increased the expression levels of Grp78, CRT, and ATF4, resulting in ER stress (GRP78 increases WASF3) https://pubmed.ncbi.nlm.nih.gov/27502587/ https://link.springer.com/article/10.1007/s11356-023-27924-z https://www.sciencedirect.com/science/article/abs/pii/S0304389421018677 while any loss of bioavailable (usable) copper at the same time due to the lowering of Zinc and Vitamin A (and subsequently ceruloplasmin production) during inflammation and infection is going to result in disruption of mitochondrial function.
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This in the past has been an important angle, bioavailability of copper vs toxic copper.

Thank you for the studies, @datadragon.

Organization in my mind is looking like this:

Things that cause ER stress Things that ER stress cause Things that relieve ER stress


Edit in: Pinpoint and try to avoid causes of ER and oxidative stress.


Things that cause oxidative stress Things that oxidative stress cause Things that relieve oxidative stress
 
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Dude

Dude

Senior Member
Messages
190
jaybee00 said:
No it’s not salubrinal! Salubrinal is not a good pharma candidate. See here.

“An EC50 of 15 micromolar is generally considered not good enough for drug development. ”

From here

https://www.alzforum.org/news/research-news/salubrinal-rescue-new-compound-fights-er-stress

It’s Relyvrio—an ALS drug TUDCA plus NaPB.
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Am I stupid or can you easily put together this relyvrio yourself using freely available nutritional supplements? Is it sodium phenylbutyrate?
 
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