7-4- Nrf2 and COVID-19
A putative mechanism may be proposed (Figure 5). SARS-CoV-2 downregulates ACE2 inducing an increased insulin resistance associated with oxidative stress through the AT1R pathway. This may explain risk factors for severe COVID-19.
Fermented vegetables are often made from cruciferous (Brassica) vegetables that release glucoraphanin converted by the plant or by the gut microbiome into sulforaphane which activates Nrf2 and subsequently reduces insulin intolerance by its potent antioxidant activities. Fermented vegetables contain a high content of Lactobacillus that can activate Nrf2 and impact on the microbiome. 114Sulforaphane and LAB both therefore have the ability to reduce insulin resistance.
Other putative actions on COVID-19 severity may be postulated. The down-regulation of ACE2 reduces the Ang-1,7 anti-oxidant activity that was found to activate Nrf2. 115,116 Nrf2 protects against hallmarks of severe COVID-19. It has anti-fibrotic effects on various organs including the lungs, 117 protects against lung injury and acute respiratory distress syndrome,118 and endothelial damage, 75 . Finally, Nrf2 can block IL-6 in different models of inflammation119 and might play a role in the COVID-19 cytokine storm.
These different mechanisms may explain the importance of fermented cabbage in preventing the severity of COVID-19. It is clear that other nutrients, vitamin D 120 and many different foods act on NRF2 and that mechanisms other than Nrf2 may be operative.
It is not yet known whether sulforaphane and/or LAB may act on the infectivity of SARS-CoV-2. Disulfide bonds can be formed under oxidizing conditions and play an important role in the folding and stability of some proteins. The receptor-binding domain of the viral spike proteins and ACE2 have several cysteine residues. Using molecular dynamics simulations, the binding affinity was significantly impaired when all of the disulfide bonds of both ACE2 and SARS-CoV/CoV-2 spike proteins were reduced to thiol groups. This computational finding possibly provides a molecular basis for the differential COVID-19 cellular recognition due to the oxidative stress.121
It is likely that foods with anti-oxidant activity can interact with COVID-19 and that fermented or cruciferous vegetables represent one of the possible foods involved. If some foods are found to be associated with a prevention of COVID-19 prevalence or severity, it may be of interest to study their LAB and/or sulforaphane composition in order to eventually find some common mechanisms and targets for therapy.
May dietary modifications change the course of COVID-19?