Cytokine Storm In COVID-19 / Sepsis Due To "cancer Metabolism" (Warburg Effect)

haidut

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A great study illustrating the crucial effects of metabolism even in "non-metabolic" conditions like COVID-19. We already have evidence that increased PUFA peroxidation is one of the causes behind the (often lethal) cytokine storm in viral diseases, including COVID-19. However, the direct mechanism through which immune cells such as phagocytes "go berserk" and increase release of inflammatory cytokines (that cause multiple organ failure and death) is not well-understood. The study below provides a neat explanation demonstrating that viral disease is metabolically not very different from diabetes, cancer, CVD, etc. Namely, when there is an increased energetic demand placed on the cells of a specific system for a prolonged period of time, the cells in that system will start "abandoning" OXPHOS in favor of more primitive but faster method of energy production (e.g. aerobic glycolysis) and in the process generate a lot of oxidative stress and tissue damage. Inhibiting the excessive glycolysis is apparently highly therapeutic for the cases of immune overreaction in COVID-19 patients and demonstrates that "deranged" cells can quickly return back to normal if their metabolism is improved. The process is in principle valid for any other disease (viral or not) where a cytokine storm is present. This raises serious questions as to why the reversal back to normal can apparently happen quite easily in "deranged" immune cells, but we are told by doctors it cannot happen in "deranged" cancer cells. The study below has no problem comparing the "deranged" immune and "deranged" cancer cells and discussing reversibility. So, I think my readers already know (or can easily guess) the answer to that (fake) riddle. :):

Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic Analysis
"...The pathogenesis of a COVID-19 respiratory infection, in a major way, is related to what is referred to as the cytokine storm [cytokine storm syndrome (CSS, hypercytokinemia, etc.], i.e., it is a hyper-inflammatory response. During this response, an explosive production of proinflammatory cytokines such as TNF-α IL-1β, and others occurs, greatly exaggerating the generation of molecule-damaging reactive oxygen species (free radicals) [1]. In severe cases, the cytokine storm is responsible for the most obvious signs of a COVID-19 infection including fever, lung injury which causes cough and shortness of breath (and the long-term complication, lung fibrosis) and in death. A causative factor related to the hyper-inflammatory state of immune cells is their ability to dramatically change their metabolism. Similar to cancer cells in many solid tumors, immune cells such as macrophages/monocytes under inflammatory conditions abandon mitochondrial oxidative phosphorylation for ATP production in favor of cytosolic aerobic glycolysis (also known as the Warburg effect) [2]. This switch is driven by the transcription factor HIF-1α (hypoxia inducible factor-1α) and the serine/threonine kinase, mTOR (mammalian target of rapamycin) and other proteins. The change to aerobic glycolysis allows immune cells to become highly phagocytic, accelerate ATP production, intensify their oxidative burst and to provide the abundant metabolic precursors required for enhanced cellular proliferation and increased synthesis and release of cytokines (Fig. 1 )."
 

ziton

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Thanks for this, haidut. I read the linked article, but am confused, as it recommends supplemental melatonin as a treatment to overcome a COVID-19 infection, whereas I thought supplementing melatonin wasn't a good thing as it supposedly inhibits progesterone production but stimulates estrogen production. Have I missed something?
 

Soren

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Would this mean something like ethyl pyruvate or acetoacetate would be therapeutic for treating the cytokine storm?
 

Soren

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I think I found my answer in another thread...

So Pyrucet, with ethyl acetoacetate, probably also raises levels of dehydroascorbic acid in the body.

Antiviral effects of dehydroascorbic acid
"In the present study, dehydroascorbic acid inhibited the multiplication of viruses of three different families: herpes simplex virus type 1 (HSV-1), influenza virus type A and poliovirus type 1."
There was a strong effect with flu, a moderate effect with herpes, and a weak effect with polio.
"dehydroascorbic acid showed even stronger antiviral activity" than did ascorbic acid.

So Pyrucet might also be beneficial in treating flu and herpes.
 

Perry Staltic

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The best way IMO to avoid the covid cytokine storm is to not go to the hospital where ritual intubation is practiced. Mechanical ventilation activates inflammatory cascades via barotrauma and biotrauma that can cause an out-of-control immune response and excessive inflammation. So being on a ventilator is a virtual guarantee of exacerbated lung inflammation and possible cytokine storm leading to thrombosis, multiple organ failure and death. To go down the rabbit hole, web search "mechanical ventilation" + inflammation.

 

Perry Staltic

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the direct mechanism through which immune cells such as phagocytes "go berserk" and increase release of inflammatory cytokines (that cause multiple organ failure and death) is not well-understood.

That's largely due to them always ignoring the role they play in creating or exacerbating that inflammation.
 
Last edited:

LeeLemonoil

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This still reads like a „sensible“ move by immune cells. They produce more ROS to the destroy the Virus, create more „reinforcement“ of themselves and create ample ATP to sustain that.
Yes, they damage the host tissue in the process.

What makes the immune system work efficiently apart from OXPHOS?

And is OXPHOS-immunity sufficient to combat the virus?
Is it necessary after all to combat the virus? I think it is unless you want it to replicate indefinitely.
So what makes certain immune cells that are functional under OXPHOS succeed? What do they do differently? Different cytokines release? Longer duration?
 
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