Abstract
The role of the ACE2 enzyme in the COVID-19 infection is 2-fold, with opposing implications for the disease development. 1. The membrane bound angiotensin converting enzyme 2 (ACE2) serves as the entry point of COVID-19 2. Conversely, it supports an anti-inflammatory pathway. This led to the controversy of the impact of medications, which influence its expression. ACE2 is part of the wider renin-angiotensin-aldosterone system (RAAS) and is upregulated via compounds, which inhibits the classical ACE, thereby plasma aldosterone and aldosterone receptor (MR) activation. MR activation may therefore protect organs from binding the COVID-19 by reducing ACE2 expression. Glycyrrhizin (GL) is a frequent component in traditional Chinese medicines, which have been used to control COVID-19 infections. Its systemically active metabolite glycyrrhetinic acid (GA) inhibits 11beta hydroxysteroid dehydrogenase(11betaHSD2) and activates MR in organs, which express this enzyme, including the lungs. Does this affect the protective effect of ACE2? Importantly, GL has anti-inflammatory properties by itself via toll like receptor 4 (TLR4) antagonism and therefore compensates for the reduced protection of the downregulated ACE2. Finally, a direct effect of GL or GA to reduce virus transmission exists, which may involve reduced expression of type 2 transmembrane serine protease (TMPRSS2), which is required for virus uptake. Glycyrrhizin may reduce the severity of an infection with COVID-19 at the two stages of the COVID-19 induced disease process, 1. To block the number of entry points and 2. provide an ACE2 independent anti-inflammatory mechanism.
Highlights
In the absence of primary prevention by immunization and a specific treatment for COVID19 rationale treatment strategies may be available
Glycyrrhizin may reduce the severity of an infection with COVID-19 at the two stages of the COVID-19 induced disease process, 1
What is the role of soluble vs. membrane bound angiotensin converting enzyme 2 (ACE2)? May there be a role of soluble ACE2 to protect membrane occupancy? This has recently been proposed on the basis of findings in cell culture experiments [41]
Summary
In the absence of primary prevention by immunization and a specific treatment for COVID19 rationale treatment strategies may be available. An influence on interferone secretion has been described: glycyrrhiza extract leads to an increased secretion of interferon 1ß in upper and lower respiratory tract cells [20] similar to the effect of GL and GA in mice, as determines in serum samples [37]; GL reduces death in mice infected with a lethal dose of influenza virus via an interferon G and T-cell dependent way [38] These antiinflammatory mechanisms may be of importance in the CNS [39, 40] and may protect against neurological and psychiatric consequences of a COVID-19 infection.
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