Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies

Abstract

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.

SARS-CoV-2 Infection and Oral Health: Therapeutic Opportunities and Challenges

“…NRF2 deficiency is known to upregulate ACE-2, whereas its activator oltipraz reduces ACE2 levels, suggesting that NRF2 activation might reduce the availability of ACE-2 for SARS-CoV-2 entry into the cell [ 57 ]. The upregulation of NRF2 signaling inhibits the overproduction of IL-6, pro-inflammatory cytokines and chemokines as well as limiting the activation of NFĸB [ 58 ]. Glycogen synthase kinase 3 beta (GSK-3β) has been reported to be elevated in adipose tissue of insulin-resistant obese rodent models and in skeletal muscle of diabetic patients [ 59 ].…”

Spices to Control COVID-19 Symptoms: Yes, but Not Only…

“…Nrf2 is the most potent antioxidant in humans [ 20 , 21 ] and can downregulate the oxidative stress from the AT 1 R axis as well as in the ER [ 7 , 22 ]. In particular, the upregulation of Nrf2 signalling inhibits the overproduction of IL-6, proinflammatory cytokines, and chemokines.…”

“…Many foods have antioxidant properties, and many mechanisms may be involved. However, the activation of Nrf2 may be of primary importance [ 7 , 30 , 31 ]. Differences in COVID-19 death rates among countries may partly be associated with Nrf2 and Nrf2-interacting nutrients like spices and raw or fermented vegetables that could reduce COVID-19 severity [ 2 , 3 , 4 ] (shown in Table 1 ).…”

“…Spices and aromatic herbs have potent antibacterial and antiviral activities [ 35 , 36 , 37 ]. Spices can also interact with many other mechanisms in COVID-19 including the entry of SARS-CoV-2 into the cell and autophagy processes [ 7 , 38 ].…”

“…Among the spices with a beneficial effect on human health, allicin, capsaicin, curcumin, gingerol, mustard oil, piperine, and quercetin glucosides are the major ones [ 6 ]. Most of them have an antioxidant activity through different mechanisms including the direct or indirect activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [ 7 ], and all are TRP (transient receptor potential) agonists. However, spices may interact with SARS-CoV-2 by other mechanisms [ 8 ].…”