Repurposing Astragalus Polysaccharide PG2 for Inhibiting ACE2 and SARS-CoV-2 Spike Syncytial Formation and Anti-Inflammatory Effects.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health. In an effort to develop novel anti-coronavirus therapeutics and achieve prophylactics, we used gene set enrichment analysis (GSEA) for drug screening and identified that Astragalus polysaccharide (PG2), a mixture of polysaccharides purified from Astragalus membranaceus, could effectively reverse COVID-19 signature genes. Further biological assays revealed that PG2 could prevent the fusion of BHK21-expressing wild-type (WT) viral spike (S) protein and Calu-3-expressing ACE2. Additionally, it specifically prevents the binding of recombinant viral S of WT, alpha, and beta strains to ACE2 receptor in our non-cell-based system. In addition, PG2 enhances let-7a, miR-146a, and miR-148b expression levels in the lung epithelial cells. These findings speculate that PG2 has the potential to reduce viral replication in lung and cytokine storm via these PG2-induced miRNAs. Furthermore, macrophage activation is one of the primary issues leading to the complicated condition of COVID-19 patients, and our results revealed that PG2 could regulate the activation of macrophages by promoting the polarization of THP-1-derived macrophages into an anti-inflammatory phenotype. In this study, PG2 stimulated M2 macrophage activation and increased the expression levels of anti-inflammatory cytokines IL-10 and IL-1RN. Additionally, PG2 was recently used to treat patients with severe COVID-19 symptoms by reducing the neutrophil-to-lymphocyte ratio (NLR). Therefore, our data suggest that PG2, a repurposed drug, possesses the potential to prevent WT SARS-CoV-2 S-mediated syncytia formation with the host cells; it also inhibits the binding of S proteins of WT, alpha, and beta strains to the recombinant ACE2 and halts severe COVID-19 development by regulating the polarization of macrophages to M2 cells.

How Chinese Herbal Medicine Prevents Epidemics: From Ancient Pestilences to COVID-19 Pandemic.

The ongoing coronavirus disease 2019 (COVID-19) pandemic calls for effective control and prevention. Chinese medicine (CM) has developed systematic theories and approaches for infectious disease prevention over 2000 years. Here, we review and analyze Chinese herbal medicines (CHM) used in infectious disease prevention from ancient pestilences to modern epidemics and pandemics to share cumulative preventive medical experience. A total of 829 formulas, including 329 herbs from 189 ancient books, 131 formulas with 152 herbs, and 13 Chinese patent medicines (CPM) from 30 official Chinese prevention programs used in ancient epidemics, SARS, influenza and COVID-19 prevention, were reviewed and analyzed. Preventive CHM mainly has four functions and can be taken orally or applied externally. CHM that kill pathogens (Realgar [Xionghuang], Cyrtomium Fortunei J. Sm[Guanzhong]) were commonly used externally for disinfection in ancient prevention while CHM tonifying Qi (Astragali Radix [Huangq], Glycyrrhizae Radix et Rhizoma [Gancao]) are used for modern prevention. Taking CHM that expel pathogens (Realgar [Xionghuang], Lonicerae Japonicae Flos[Jinyinhua]) and CHM eliminating dampness (Atractylodis Rhizoma [Cangzhu], Pogostemonis Herba[Guanghuoxiang]) have been commonly used from ancient times to COVID-19. Damp toxins are a common characteristic of infectious diseases such as SARS and COVID-19. Thus, taking CHM expelling damp toxins and tonifying Qi are the main methods for SARS and COVID-19 prevention. CHM with different approaches have been widely used in infectious disease prevention from ancient times to the present. Multiple CM prevention methods may provide new perspectives for future pandemics.

Single-cell RNA sequencing reveals the sustained immune cell dysfunction in the pathogenesis of sepsis secondary to bacterial pneumonia.

Sepsis is a leading cause of mortality in intensive care unit worldwide, it's accompanied by immune cell dysfunction induced by multiple factors. However, little is known about the specific alterations in immune cells in the dynamic pathogenesis of sepsis secondary to bacterial pneumonia. Here, we used single cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) in a healthy control and two patients with sepsis secondary to bacterial pneumonia, including acute, stable and recovery stage. We analyzed the quantity and function of immune cells. During disease course, interferon gamma response was upregulated; T/NK cell subtypes presented activation and exhaustion properties, which might be driven by monocytes through IL-1ß signaling pathways; The proportion of plasma cells was increased, which might be driven by NK cells through IFN signaling pathways; Additionally, interferon gamma response was upregulated to a greater degree in sepsis secondary to pneumonia induced by SARS-COV-2 compared with that induced by influenza virus and bacteria.

Debt Rollover Risk, Credit Default Swap Spread and Stock Returns: Evidence from the COVID-19 Crisis

This paper studies how the COVID-19 shock affects the CDS spread changes and abnormal stock returns of U.S. firms with different levels of debt rollover risk. We use the COVID-19 crisis as a quasi-natural experiment of adverse cash flow shock that increases the default risk of firms facing an immediate liquidity shortfall. We find that the COVID-19 shock significantly increased the CDS spread and decreased the shareholder value for firms facing higher debt rollover risk. The effect is stronger for non-financial firms, for firms that are financially constrained, and for firms that are highly volatile. Moreover, we find that firms with immediate refinancing needs suffered more than firms with distant refinancing needs during the COVID-19 shock, which further confirms that firms’ debt rollover risk is indeed a key factor that drives the heterogenous reactions to the shock. The paper provides fresh insights into the role of firms’ debt rollover risk during the COVID-19 health crisis.