# Mechanistic therapy on Notch-3 signaling, N-acetyl-cysteine prophylaxis and treatment in pulmonary fibrosis (# sequelacovid19) and other complications. #Immunometabolic
Proteins of the Notch family are cell surface receptors that TRANSDUCE SIGNALS BETWEEN NEIGHBORING CELLS. The Notch signaling pathway is evolutionarily highly conserved, including many aspects of vascular development.
The interaction of Notch receptors with ligands leads to the cleavage of the Notch intracellular domain (NICD) which then translocates to the nucleus and activates the transcription factor CBF1 / JBP-Jkappa, regulating downstream gene expression.
Not signaling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1-4) have been identified that regulate various cellular processes.
Of these, # Notch3 IS ALMOST EXCLUSIVELY EXPRESSED IN THE CELLS OF THE SMOOTH VASCULAR MUSCLE (#CMLV), where it PARTICIPATES critically in VASCULAR DEVELOPMENT AND DIFFERENTIATION.
Under pathological conditions, Notch3 regulates the VSMC shift between the contractile and synthetic phenotypes.
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✅The severity of COVID-19 disease, especially in the elderly and patients with comorbidities, is characterized by hypercytokinemia, an exaggerated immune response associated with an uncontrolled and excessive release of pro-inflammatory cytokine mediators (cytokine storm).
1. The immunomodulatory capacity of flavonoids, carried out by the regulation of inflammatory mediators, the inhibition of endothelial activation, the NLRP3 inflammasome, the toll-like receptors (TLR)
2. Or the bromodomain-containing protein 4 (BRD4), and the activation erythroid-derived nuclear factor 2 (Nrf2), could be beneficial in regulating cytokine storm during SARS-CoV-2 infection.
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.
⬇️ 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.
⬇️ 5. Activation of the NF-kB / NLRP3 inflammasomes ensues.
⬇️ 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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