Abstract
Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication. We examined gene expression levels by GeneChip microarray and by RNA-seq assays. We found that the potent Nrf2-activating composition PB125® downregulates ACE2 and TMPRSS2 mRNA expression in human liver-derived HepG2 cells. ACE2 is a surface receptor and TMPRSS2 activates the spike protein for SARS-CoV-2 entry into host cells. Furthermore, in endotoxin-stimulated primary human pulmonary artery endothelial cells, we report the marked downregulation by PB125 of 36 genes encoding cytokines. These include IL-1-beta, IL-6, TNF-α, the cell adhesion molecules ICAM-1, VCAM-1, and E-selectin, and a group of IFN-γ-induced genes. Many of these cytokines have been specifically identified in the “cytokine storm” observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm.
Highlights
Nrf2 is a transcription factor encoded in humans by the NFE2L2 gene
To examine the effects of PB125 on genes that are induced by endotoxin exposure and which may contribute to the cytokine storm, we examined a model of pro-inflammatory lipopolysaccharide (LPS)-treated human pulmonary arterial endothelial cells, with and without treatment with PB125
SERPINE1 a normal plasma component and known entrygene), into a human cell depends on expression of ACE2 for binding and potent inhibitor on TMPRSS2 for proteolytic activation of the spike protein [27], we examined the effects of PB125 on of TMPRSS2 [30]
Summary
Nrf is a transcription factor encoded in humans by the NFE2L2 gene. It has been called by many the “master regulator of cellular redox homeostasis” [1] as well as the “guardian of healthspan”and “gatekeeper of species longevity” [2]. Oxidative stress is a common theme among the key features associated with the aging process, collectively referred to as the “hallmarks of aging”, as it disrupts proteostasis [10], alters genomic stability [11], alters susceptibility to viral and microbial infections [12], and leads to cell death.
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