Integrated Analysis of microRNAs and Metabolomics in Rat’s Serum Reveals Multi-action Modes of Qingfei Paidu Decoction for COVID-19 Treatment

Abstract Background During the fight against coronavirus disease 2019 (COVID-19) in China, Qingfei Paidu decoction (QFPDD) has been widely applied to treat COVID-19 patients. Retrospective studies showed that QFPDD could improve clinical outcomes of COVID-19. Thus, it is necessary and interesting to explore the action mode of QFPDD for further application and development.MethodsSprague-Dawley (SD) rats were randomly divided into two groups, QFPDD (n=9) and control (n=10) groups. They were parallelly treated for 12 days with QFPDD and warm distilled water, respectively. At the endpoint, the microRNA (miRNA or miR) profiles in serum were detected to identify differently expressed miRNAs (DEMs). Then, the action mode of QFPDD were explored via review of potential roles of DEMs and functional enrichment analysis of their targets (e.g., GO enrichment and KEGG pathway analysis), especially focusing on the aspects of immunity, inflammation, virus infection and pulmonary fibrosis. Core genes were identified based on KEGG pathway analysis. Metabolomics were detected in serum and significantly changed metabolites (SCMs), especially the metabolic substrates and products of enzyme of core gene were identified as biomarkers to validate the regulation of DEMs to enzyme activity of core gene through metabolomic analysis and linear correlation analysis between SCMs and DEMs. Results23 DEMs were identified in the serum between QFPDD and control groups, with 1636 predicted genes. Reported evidence has showed that both the DEMs and their target genes involve regulation of immunity, inflammation, virus infection and pulmonary fibrosis. Phospholipase C, gamma 1 (Plcg1) was identified as a core gene and predicted to be upregulated attributed to downregulation of novel-89-mature. The levels of three SCMs, PC(P-18:1(11Z)/22:5(4Z,7Z,10Z,13Z,16Z)), PC(22:5(4Z,7Z,10Z,13Z,16Z)/P-18:0) and PC(16:1(9Z)/16:1(9Z)), which were the metabolic substrates of phospholipase C, were significantly reduced in QFPDD group, in addition, PC(P-18:1(11Z)/22:5(4Z,7Z,10Z,13Z,16Z)) and PC(22:5(4Z,7Z,10Z,13Z,16Z)/P-18:0) presented positively linear correlation with the expression level of novel-89-mature. The level of phosphorylcholine, a product of PCs metabolized by phospholipase C, was significantly elevated in QFPDD group. Conclusion QFPDD can induce modification of miRNAs profile, and subsequently multi-regulate the immunity, inflammation, virus infection and pulmonary fibrosis in vivo, playing an important role for the positive outcomes of COVID-19 patients treated by QFPDD in China.