Oridonin Inhibits SARS-CoV-2 by Targeting Its 3C-Like Protease.

The current COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enormous threat to public health. The SARS-CoV-2 3C-like protease (3CLpro), which is critical for viral replication and transcription, has been recognized as an ideal drug target. Herein, it is identified that three herbal compounds, Salvianolic acid A (SAA), (-)-Epigallocatechin gallate (EGCG), and Oridonin, directly inhibit the activity of SARS-CoV-2 3CLpro. Further, blocking SARS-CoV-2 infectivity by Oridonin is confirmed in cell-based experiments. By solving the crystal structure of 3CLpro in complex with Oridonin and comparing it to that of other ligands with 3CLpro, it is identified that Oridonin binds at the 3CLpro catalytic site by forming a C-S covalent bond, which is confirmed by mass spectrometry and kinetic study, blocking substrate binding through a nonpeptidomimetic covalent binding mode. Thus, Oridonin is a novel candidate to develop a new antiviral treatment for COVID-19.

Astragaloside IV promotes the angiogenic capacity of adipose-derived mesenchymal stem cells in a hindlimb ischemia model by FAK phosphorylation via CXCR2.

BACKGROUND: Therapeutic angiogenesis by transplantation of autologous/allogeneic adipose stem cells (ADSCs) is a potential method for the treatment of critical limb ischemia (CLI). However, the therapeutic efficiency is limited by poor viability, adhesion, migration and differentiation after cell transplantation into the target area. Astragaloside IV (AS-IV), one of the main active components of Astragalus, has been widely used in the treatment of ischemic diseases and can promote cell proliferation and angiogenesis. However, there is no report on the effect of AS-IV on ADSCs and its effect on hindlimb ischemia through cell transplantation. PURPOSE: The purpose of this study was to elucidate that AS-IV pretreatment enhances the therapeutic effect of ADSC on critical limb ischemia, and to characterize the underlying molecular mechanisms. METHODS: ADSCs were obtained and pretreated with the different concentration of AS-IV. In vitro, we analyzed the influence of AS-IV on ADSC proliferation, migration, angiogenesis and recruitment of human umbilical vein endothelial cells (HUVECs) and analyzed the relevant molecular mechanism. In vivo, we injected drug-pretreated ADSCs into a Matrigel or hindlimb ischemia model and evaluated the therapeutic effect by the laser Doppler perfusion index, immunofluorescence, and histopathology. RESULTS: In vitro experiments showed that AS-IV improved ADSC migration, angiogenesis and endothelial recruitment. The molecular mechanism may be related to the upregulation of CXC receptor 2 (CXCR2) to promote the phosphorylation of focal adhesion kinase (FAK). In vivo, Matrigel plug assay showed that ADSCs pretreated with AS-IV have stronger angiogenic potential. The laser Doppler perfusion index of the hindlimbs of mice in the ADSC/AS-IV group was significantly higher than the laser Doppler perfusion index of the hindlimbs of mice of the ADSC group and the control group, and the microvessel density was significantly increased. CONCLUSION: Our results demonstrate that AS-IV pretreatment of ADSC improves their therapeutic efficacy in ameliorating severe limb exclusion symptomology through CXCR2 induced FAK phosphorylation, which will bring new insights into the treatment of severe limb ischemia.