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Review 1: "Prophylactic treatment of Glycyrrhiza glabra mitigates COVID-19 pathology through inhibition of pro-inflammatory cytokines in the hamster model and NETosis"

This preprint demonstrates the use of Glycyrrhiza glabra for mitigation of COVID-19 pathology in hamsters. Reviewers find the study reliable, but highlight the need to extend the study to a clinically relevant setting, and pinpoint the exact GG extract ingredients responsible.

Published onJun 24, 2022
Review 1: "Prophylactic treatment of Glycyrrhiza glabra mitigates COVID-19 pathology through inhibition of pro-inflammatory cytokines in the hamster model and NETosis"
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Prophylactic treatment of <i>Glycyrrhiza glabra</i> mitigates COVID-19 pathology through inhibition of pro-inflammatory cytokines in the hamster model and NETosis
Description

AbstractSevere coronavirus disease (COVID-19) is accompanied with acute respiratory distress syndrome & pulmonary pathology, and is presented mostly with inflammatory cytokine release, dysregulated immune response, skewed neutrophil/ lymphocyte ratio, and hypercoagulable state. Though vaccinations have proved effective in reducing the COVID-19 related mortality, the limitation of use of vaccine against immunocompromised, comorbidity, and emerging variants remains a concern. In the current study we investigate for the first-time the efficacy of Glycyrrhiza glabra (GG) extract, a potent immunomodulator, against SARS-CoV-2 infection in hamsters. Prophylactic treatment with GG showed protection against loss in body weight and 35-40% decrease in lung viral load along with reduced lung pathology in the hamster model. Remarkably, GG reduced the mRNA expression of pro-inflammatory cytokines and Plasminogen activator inhibito-1 (PAI-1). In-vitro, GG acted as potent immunomodulator by reducing Th2 and Th17 differentiation and IL-4 and IL-17A cytokine production. In addition, GG also showed robust potential to suppress ROS, mtROS and NETs generation in a concentration dependent manner in both human polymorphonuclear neutrophils (PMNs) and murine bone marrow derived neutrophils (BMDNs). Taken together, we provide evidence for the protective efficacy of GG against COVID-19 and its putative mechanistic insight, which might be developed as a future immunomodulatory approach against various pathologies with high cytokine production, aberrant neutrophil activation including coronavirus infection.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

In this manuscript named “Prophylactic treatment of Glycyrrhiza glabra mitigates COVID-19 pathology through inhibition of pro-inflammatory cytokines in the hamster model and NETosis”, Zaigham Abbas Rizvi et al. study the effects of herbal extracts from the plant Glycyrrhiza glabra (GG; licorice) on SARS-CoV-2 infection in the Syrian hamster model of COVID-19, and show reduced lung pathology in GG-pretreated animals. Corroborating these findings, GG treatment also influences T cell differentiation, cytokine expression in vitro, and generation of NETs and ROS in ex vivo neutrophils. Although the immune-modulatory properties of GG extract ingredients are well-documented, the effects of GG extract on SARS-CoV-2 pathology had not been studied in vivo. The data presented support the authors' claims, yet some questions remain: In this manuscript, GG extract is only studied prophylactically in the hamster model. Additionally, animals were sacrificed after 4 days. A therapeutic setting combined with a longer follow-up period would be a more clinically relevant study design, resembling the clinical course of COVID-19 patients. This would be an interesting addition to the current study. Herbal extracts contain a multitude of pharmaceutically active compounds, which may or may not contribute to the effects demonstrated in the manuscript. Pinpointing which (combination of) GG extract ingredients are responsible for the observed effect may be essential for its further development, and requires additional investigation. The Results section refers to Figure 3C, mentioning that the expression of IFNγ was significantly reduced in the GG group. However, Figure 3C shows a clear upregulation of IFNγ in the GG group compared to the infected and untreated groups. Currently, the figure legends do not correspond to the provided figures (starting from Figure 5), or refer to supplementary figures instead. Some figure legends are missing, or refer to the wrong panels. This makes the manuscript tiresome to read and review.

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