Several compounds have been investigated for their potential efficacy against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogenic agent that triggered the ongoing coronavirus disease 2019 (COVID-19) pandemic. A recent PLoS One study explored the activity of glycyrrhizin, an herbal compound, against SARS-CoV-2.
Study: Glycyrrhizin through licorice intake modulates ACE2 and HMGB1 levels—A pilot study in healthy individuals with implications for COVID-19 and ARDS. Image Credit: Scisetti Alfio / Shutterstock.com
Glycyrrhizin is a licorice alkaloid from the licorice root associated with certain antiviral and anti-inflammatory properties. In addition, this compound is considered responsible for the healing activity of this root, which has been extensively used to treat coughs, colds, and respiratory infections, particularly by traditional Chinese medicine (TCM) practitioners.
Glycyrrhizin could reduce the entry of SARS-CoV-2 into the host cell, as with other viruses, by inhibiting the activity of the angiotensin-converting enzyme 2 (ACE2) host cell receptor. In addition, this compound also reduces the activity of the inflammatory alarmin high-mobility group box 1 (HMGB1).
The current study reports the effect of glycyrrhizin ingestion on ACE2 and HMGB1 expression in health. Furthermore, the researchers describe changes in HMGB1 expression in patients with acute respiratory distress syndrome (ARDS) associated with COVID-19.
The current study included 20 healthy individuals and 23 hospitalized patients; four had mild COVID-19, seven had COVID-19 with ARDS, and the remaining had non-COVID-19 ARDS. All patients were given 50 g of sweets containing 3% licorice root extract.
Patients were followed up on days three and seven for HMGB1 and electrolyte levels, and ACE2 levels in peripheral blood mononuclear cells (PBMCs).
What did the study show?
The researchers observed a reduction in ACE2 levels in PBMC membranes following licorice intake for seven days, from 1.3 at baseline to 0.6 by day seven. This decline in ACE2 level reached 70% in two patients, while the levels decreased by a third or more in half of the cohort.
On days three and seven, HMGB1 levels also reduced from 7.1 μg/L to 6.4 and 5.9 μg/L, respectively. Half of the samples declined by 15% or more.
In ARDS patients, with a median age of 66 years, the initial HMGB1 levels were comparable, irrespective of the etiology, with a median of 19.6 μg/L and 33.6 μg/L in ARDS-COVID-19 and ARDS without COVID-19, respectively. This indicates an increase from baseline levels in healthy individuals by 2.5- and six-fold, respectively.
Mild COVID-19 patients also exhibited increased HMGB1 levels comparable to that of ARDS patients at 18.7 μg/L. This could be due to the high proportion of patients with diabetes mellitus in this group, as this is independently associated with raised HMGB1 levels.
HMGB1 levels in non-COVID ARDS patients showed a wide range of values, with the lowest being 23-fold less than the highest. There were no changes in the blood pressure following licorice ingestion.
In the current study, the 50% reduction in ACE2 expression following seven days of licorice intake could support the use of licorice for treating SARS-CoV-2 infection.
Glycyrrhizin is likely responsible for licorice root extract's pharmacological activity. This compound has been used throughout history to treat respiratory infections, which may be attributed to, at least in part, its inhibitory effect on ACE2-mediated viral entry into respiratory cells.
In vitro experiments have shown the ability of glycyrrhizin to prevent the replication of SARS-CoV and SARS-CoV-2, both of which depend on ACE2 for cell entry. This could implicate a double mechanism of action by glycyrrhizin, in which the agent both directly inhibits viral replication and reduces ACE2 expression.
Computer simulations showed glycyrrhizin capable of binding ACE2, thus blocking the receptor from binding the virus to ultimately prevent infection.
Glycyrrhizin is also associated with anti-inflammatory activity, with neutrophils exhibiting reduced oxidative activity and lower cytokine production. Conversely, HMGB1 enhances the severity of inflammation due to its effect on cytokine release.
By the demonstrable effect of licorice on HMGB1 levels, due to its binding by glycyrrhizin that subsequently prevents its activation by phosphorylation, the alkaloid could help mitigate or prevent disease progression in COVID-19. This study represents the first experimental evidence of this anti-HMGB1 effect of glycyrrhizin in humans.
The most significant reduction in HMGB1 levels occurred in those with the highest levels at the beginning of the study.
Both ACE2 and HMGB2 expression were reduced with licorice intake. This aligns with previous observations that HMGB1 treatment of alveolar cells increases the expression of ACE2.
The five-fold rise in HMGB1 levels previously reported in patients with severe COVID-19 compared to those with mild disease is due to it being a damage-associated molecular pattern (DAMP) molecule released by cells following injury or infection to activate the immune system and induce inflammation.
It is, therefore, a potential biomarker and therapeutic target in situations with an overwhelming immune response.”
Notably, the results of this study were achieved with relatively low doses of licorice. Further research is needed to demonstrate the clinical utility of these observations in treating viral diseases, including COVID-19.
- Buder, F., Selejan, S., Hohl, M., et al. (2022). Glycyrrhizin through liquorice intake modulates ACE2 and HMGB1 levels—A pilot study in healthy individuals with implications for COVID-19 and ARDS. PLoS ONE. doi:10.1371/journal.pone.0275181.