Thread by @GrimaldesJ

#Immunometabolism
PART 1

The general course of events during infections (Sars-CoV2) leading to "cytokine storm" can look like this:

1. Cells undergo damage, senescence, or become infected with a virus.
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2. Those cells release damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), which activate receptors in the immune system.
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3. DAMPs, like HBGM1, signal the production of the inflammatory response.
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4. HBGM1 binds to TLR2 / TLR4 / RAGE receptors to begin mobilizing pro-inflammatory cytokines.
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5. Activation of the NF-kB / NLRP3 inflammasomes ensues.
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6. Release of pro-inflammatory cytokines IL-1, IL-6, IL-1B, IL-18, IL-17, IL-22, and others occurs.
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7. Initiation of cytokine storm and pyropoptosis, which describes a highly inflammatory programmed cell death, damaging other tissues.
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8. Reduction of T and B lymphocytes and their function due to pro-inflammatory cytokines.
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9. Increased susceptibility to viral replication and spreads throughout the body.
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10. Monocytes and macrophages become infected with the virus, activating more pro-inflammatory genes and compromising immune function.
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11. The number of circulating neutrophils and extracellular neutrophil traps increases, causing organ damage and injury.
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12. As the cytokine storm continues, the body's immune organs and cells are continually damaged further, further weakening the ability to resist the virus, eventually leading to sequential organ failure or death.

frontiersin.org/articles/10.33…

PART 2

There is a wide range of outcomes among people who have been infected with Sars-CoV2, ranging from a mild cough and fever to severe pneumonia, organ failure, and death.

Comorbidities, immune disorders, and age appear to be the greatest predictors of severity of covid19.

✅ "Hyperglycemia and diabetes mimic the same # HMBG1 response by increasing the expression of #RAGE and creating oxidative stress." Anything that inhibits RAGE and improves glycemic control will reduce HMBG1 expression and its pro-inflammatory effects.

Therefore, there is a big difference in the course of events between mild and severe Covid results.
-Covid LEVE: immune system works well, active TCD8 cells + IFN type 1➡️ reduced viral replication + lack of inflammation ➡️ lack of cytokine storm ➡️ patient recovered.

-Covid SEVERE: immunosenescence + senescent cells➡️ dysfunctional CD8 + IFN type 1 cells ➡️ cells more susceptible to viral infection➡️ cytokine storm ➡️ ARDS / Thrombi / FOM / sepsis➡️death.

✅ HMBG1 is considered a drug target for hyperinflammatory conditions,

its inhibition can improve inflammation and prevent cytokine storm onset. Other targets are TLR-2 / TLR-4, IL, LPS, and cytokines.
frontiersin.org/articles/10.33…

#Immunometabolism
PART 3

✅ NUTRACEUTICALS that can inhibit:
HMGB1, TLR4, LPS, NLRP3 inflammasome, RAGE, NF-kB and the cytokine storm.

1. NICOTINAMIDE RIBOSIDE (vitamin B3: NAD +), inhibits HMGB1
pubmed.ncbi.nlm.nih.gov/29803807/

2. GLICIRRICIN, direct antagonist of HMGB1,

benefits in vitro against Sars-CoV1.
pubmed.ncbi.nlm.nih.gov/28363255/

3. FERULIC ACID, reduces HMGB1, IL-6 and IL-8, also MIP2.
pubmed.ncbi.nlm.nih.gov/29901427/

4. GINSENG, reduces LPS and HMGB1.
pubmed.ncbi.nlm.nih.gov/30630344/

5. GREEN TEA, reduces LPS, HMGB1 / RAGE and stimulates autophagy.
ncbi.nlm.nih.gov/pmc/articles/P…

6. DOCOSAHEXAENOIC ACID (DHA), reduces LPS, TLR-4, HMGB1, macrophage accumulation and inhibits ACE.
pubmed.ncbi.nlm.nih.gov/26940787/

7. CHLOROQUINE, DEXAMETASONE, GOLD SODIUM TRIOMALATE, reduce HMGB1
pubmed.ncbi.nlm.nih.gov/20386869/

8. HYDROXICLOROQUINA, inhibiting endosomal NADPH oxidase complex, reducing HMGB1.
pubmed.ncbi.nlm.nih.gov/32373993/

Romulo Daniel Grimaldes Jiménez, MD
Internal Medicine
July 01, 2021

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