Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

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

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, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) 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

N2-Phenyl-9-(hydroxyalkyl)guanines and related compounds are substrates for Herpes simplex thymidine kinases

Herpes simplex virus (HSV) types 1 and 2 thymidine kinases (TK) are responsible for phosphorylation of antiherpes acyclonucleosides such as acyclovir (ACV) and 9-(4-hydroxybutyl)guanine (HBG). Related compounds, the N2-phenyl-9-(hydroxyalkyl)guanines, are devoid of direct antiviral activity, but potently inhibit the viral TKs and block viral reactivation from latency in vivo. The similarity in structure between the acyclonucleosides and TK inhibitors raised the question of the relevance of phosphorylation of certain of the latter analogs in their mechanisms of action. Using recombinant TKs and HPLC analysis of reaction mixtures, we report that the lead TK inhibitor N2-phenyl-9-(4-hydroxybutyl)guanine (HBPG) and its pentyl homolog (HPnPG) are excellent substrates for the enzymes, approaching the efficiency with which the natural substrate thymidine is phosphorylated, and significantly better than ACV or HBG. Other 9-hydroxyalkyl congeners are substrates for the enzymes, but with much poorer efficiency. HBPG triphosphate was a poor inhibitor of HSV DNA polymerase, the target of acyclonucleoside triphosphates, suggesting that phosphorylation of HBPG is not important in its mechanism of blocking viral reactivation in vivo. The fact that HBPG is an efficient substrate is consistent, however, with its binding mode based both on molecular modeling studies and x-ray structure of the HBPG:TK complex

First dual AK​/GSK-​3β inhibitors endowed with antioxidant properties as multifunctional, potential neuroprotective agents

The manuscript deals with the design, synthesis and biological evaluation of novel benzoxazinone-based and indole-based compounds as multifunctional neuroprotective agents. These compounds inhibit human adenosine kinase (hAK) and human glycogen synthase kinase 3 beta (hGSK-3β) enzymes. Computational analysis based on a molecular docking approach underlined the potential structural requirements for simultaneously targeting both proteins' allosteric sites. In silico hints drove the synthesis of appropriately decorated benzoxazinones and indoles (5a-s, and 6a-c) and biochemical analysis revealed their behavior as allosteric inhibitors of hGSK-3β. For both our hit 4 and the best compounds of the series (5c,l and 6b) the potential antioxidant profile was assessed in human neuroblastoma cell lines (IMR 32, undifferentiated and neuronal differentiated), by evaluating the protective effect of selected compounds against H2O2 cytotoxicity and reactive oxygen species (ROS) production. Results showed a strong efficacy of the tested compounds, even at the lower doses, in counteracting the induced oxidative stress (50 μM of H2O2) and in preventing ROS formation. In addition, the tested compounds did not show any cytotoxic effect determined by the LDH release, at the concentration range analyzed (from 0.1 to 50 μM). This study allowed the identification of compound 5l, as the first dual hAK/hGSK-3β inhibitor reported to date. Compound 5l, which behaves as an effective antioxidant, holds promise for the development of new series of potential therapeutic agents for the treatment of neurodegenerative diseases characterized by an innovative pharmacological profile