In December 2019, a novel coronavirus SARS-CoV-2, causing the disease COVID-19, spread from Wuhan throughout China and has infected people over 200 countries. Thus far, more than 3,400,000 cases and 240,000 deaths have occurred worldwide, and the coronavirus pandemic continues to grip the globe. While numbers of cases in China have been steadying, the number of infections outside China is increasing at a worrying pace. We face an urgent need to control the spread of the COVID-19 epidemic, which is currently expanding to a global pandemic. Efforts have focused on testing antiviral drugs and vaccines, but there is currently no treatment specifically approved. Traditional Chinese medicine (TCM) is grounded in empirical observations and the Chinese people use TCM to overcome these sorts of plagues many times in thousands of years of history. Currently, the Chinese National Health Commission recommended a TCM prescription of Qing-Fei-Pai-Du-Tang (QFPDT) in the latest version of the “Diagnosis and Treatment guidelines of COVID-19” which has been reported to provide reliable effects for COVID-19. While doubts about TCM still exist today, this review paper will describe the rationalities that QFPDT is likely to bring a safe and effective treatment of COVID-19.
Interleukin (IL)‐37 diminishes a variety of inflammatory responses through ligation to its receptor IL‐1R8/Sigirr. Sigirr is a Toll like receptor/IL‐1R family member. We have shown that Sigirr is not stable in response to IL‐37 treatment. IL‐37‐induced Sigirr degradation is mediated by the ubiquitin‐proteasome system, and the process is reversed by a deubiquitinase, USP13. However, the molecular mechanisms by which USP13 regulates Sigirr stability have not been revealed. In this study, we investigate the roles of glycogen synthesis kinase 3β (GSK3β) in Sigirr phosphorylation and stability. IL‐37 stimulation induced Sigirr phosphorylation and degradation, as well as activation of GSK3β. Inhibition of GSK3β attenuated IL‐37‐induced Sigirr phosphorylation, while exogenous expressed GSK3β promoted Sigirr phosphorylation at threonine (T)372 residue. Sigirr association with GSK3β was detected. Amino acid residues 51–101 in GSK3β were identified as the Sigirr binding domain. These data indicate that GSK3β mediates IL‐37‐induced threonine phosphorylation of Sigirr. Further, we investigated the role of GSK3β‐mediated phosphorylation of Sigirr in Sigirr degradation. Inhibition of GSK3β attenuated IL‐37‐induced Sigirr degradation, while T372 mutant of Sigirr was resistant to IL‐37‐mediated degradation. Furthermore, inhibition of Sigirr phosphorylation prevented Sigirr internalization and association with USP13, suggesting GSK3β promotes Sigirr degradation through disrupting Sigirr association with USP13.
Background COVID-19 infections could be complicated by acute respiratory distress syndrome (ARDS), increasing mortality risk. We sought to assess the methylome of peripheral blood mononuclear cells in COVID-19 with ARDS. Methods We recruited 100 COVID-19 patients with ARDS under mechanical ventilation and 33 non-COVID-19 controls between April and July 2020. COVID-19 patients were followed at four time points for 60 days. DNA methylation and immune cell populations were measured at each time point. A multivariate cox proportional risk regression analysis was conducted to identify predictive signatures according to survival. Results The comparison of COVID-19 to controls at inclusion revealed the presence of a 14.4% difference in promoter-associated CpGs in genes that control immune-related pathways such as interferon-gamma and interferon-alpha responses. On day 60, 24% of patients died. The inter-comparison of baseline DNA methylation to the last recorded time point in both COVID-19 groups or the intra-comparison between inclusion and the end of follow-up in every group showed that most changes occurred as the disease progressed, mainly in the AIM gene, which is associated with an intensified immune response in those who recovered. The multivariate Cox proportional risk regression analysis showed that higher methylation of the “Apoptotic execution Pathway” genes (ROC1, ZNF789, and H1F0) at inclusion increases mortality risk by over twofold. Conclusion We observed an epigenetic signature of immune-related genes in COVID-19 patients with ARDS. Further, Hypermethylation of the apoptotic execution pathway genes predicts the outcome. Trial registration: IMRPOVIE study, NCT04473131.
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