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Combination therapy using Western and traditional Chinese medicines has shown notable effects on coronavirus disease 2019 (COVID-19). The He-Jie-Shen-Shi decoction (HJSS), composed of Bupleurum chinense DC., Scutellaria baicalensis Georgi, Pinellia ternata (Thunb.) Makino, Glycyrrhiza uralensis Fisch. ex DC., and nine other herbs, has been used to treat severe COVID-19 in clinical practice. The aim of this study was to compare the clinical efficacies of HJSS combination therapy and Western monotherapy against severe COVID-19 and to study the potential action mechanism of HJSS. From February 2020 to March 2020, 81 patients with severe COVID-19 in Wuhan Tongji Hospital were selected for retrospective cohort study. Network pharmacology was conducted to predict the possible mechanism of HJSS on COVID-19-related acute respiratory distress syndrome (ARDS). Targets of active components in HJSS were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and PharmMapper databases. The targets of COVID-19 and ARDS were obtained from GeneCards and Online Mendelian Inheritance in Man databases. The key targets of HJSS in COVID-19 and ARDS were obtained based on the protein–protein interaction network (PPI). Kyoto Encyclopedia of Genes and Genomes analysis (KEGG) was conducted to predict the pathways related to the targets of HJSS in COVID-19 and ARDS. A “herb-ingredient-target-pathway” network was established using Cytoscape 3.2.7. Results showed that the duration of the negative conversion time of nucleic acid was shorter in patients who received HJSS combination therapy. HJSS combination therapy also relieved fever in patients with severe COVID-19. Network pharmacology analysis identified interleukin (IL) 6, tumor necrosis factor (TNF), vascular endothelial growth factor A (VEGFA), catalase (CAT), mitogen-activated protein kinase (MAPK) 1, tumor protein p53 (TP53), CC-chemokine ligand (CCL2), MAPK3, prostaglandin-endoperoxide synthase 2 (PTGS2), and IL1B as the key targets of HJSS in COVID-19-related ARDS. KEGG analysis suggested that HJSS improved COVID-19-related ARDS by regulating hypoxia-inducible factor (HIF)-1, NOD-like receptor, TNF, T cell receptor, sphingolipid, PI3K-Akt, toll-like receptor, VEGF, FoxO, and MAPK signaling pathways. In conclusion, HJSS can be used as an adjuvant therapy on severe COVID-19. The therapeutic mechanisms may be involved in inhibiting viral replication, inflammatory response, and oxidative stress and alleviating lung injury. Further studies are required to confirm its clinical efficacies and action mechanisms.

Background: In this study, we preliminarily investigated the mechanism of Yin-Chai-Xiao-Du decoction for the treatment of COVID-19 by the method of network pharmacology. Methods: The potential targets and pathways of Yin-Chai-Xiao-Du decoction for the treatment of COVID-19 were examined using network pharmacology; the ingredient and active targets of Yin-Chai-Xiao-Du decoction were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and PharmMapper databases; the COVID-19-related targets were obtained from the online Mendelian inheritance in man, GeneCards, and GeneMANIA databases; the STRING database and Cytoscape were used to build a protein-protein interaction network, and a Network Analyzer tool was used to perform topology analysis to screen for the key ingredients and targets; the ClueGO and KOBAS 3.0 databases were for the enrichment analysis of gene function (Gene Oncology) and gene pathway (Kyoto Encyclopedia of Genes and Genomes); the herb-ingredient-target-pathway network diagram was constructed by Cytoscape. Results: The core herbs screened by the network pharmacological analysis were Jinyinhua (Lonicerae japonicae flos), Lianqiao (Forsythia suspensa), Chaihu (Bupleuri radix), Huangqin (Scutellariae radix), Yinchen (Herba Artemisiae Scopariae), Guanghuoxiang (Pogostemonis herba), Roudoukou (Semen myristicae) and Qinghao (Artemisiae annuae herba). A total of 293 active ingredients were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the key ingredients were quercetin, kaempferol, isorhamnetin, stigmasterol, beta-sitosterol, and luteolin. Yin-Chai-Xiao-Du decoction has 138 COVID-19-related targets, and the key targets were mitogen-activated protein kinase 3, interleukin-6, tumor necrosis factor, vascular endothelial growth factor A, and CC motif ligand 2. Kyoto Encyclopedia of Genes and Genomes analysis revealed 120 enriched gene pathways, and the key pathways were signaling by interleukins, immune system, cytokine signaling in the immune system, and the signaling pathways of interleukin-17, tumor necrosis factor, and relaxin. Conclusion: The core herbs of Yin-Chai-Xiao-Du decoction are Jinyinhua (Lonicerae japonicae flos), Lianqiao (Forsythia suspensa), Chaihu (Bupleuri radix), Huangqin (Scutellariae radix), Yinchen (Herba Artemisiae Scopariae), Guanghuoxiang (Pogostemonis herba), Roudoukou (Semen myristicae) and Qinghao (Artemisiae annuae herba). The key ingredients are quercetin, kaempferol, isorhamnetin, stigmasterol, and beta-sitosterol; the critical targets are luteolin, interleukin-6, mitogen-activated protein kinase 3, tumor necrosis factor, and CC motif ligand 2; and the core signaling pathways are those mediated by interleukin-17, tumor necrosis factor, and relaxin.