He-Jie-Shen-Shi Decoction as an Adjuvant Therapy on Severe Coronavirus Disease 2019: A Retrospective Cohort and Potential Mechanistic Study.

Haibo Hu,Shenghao Tu,Chuanbo Fan,Kun Wang,Li Wang,Zhaoshan Zhou,Huantian Cui,Ning Li,Juan Chen,Xuechao Lu,Ying Sun,Yongchun Li,Yanjun Du

doi:10.3389/fphar.2021.700498

Abstract

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.

Highlights

Since its outbreak in 2019, coronavirus disease 2019 (COVID-19) has become a global pandemic (Jin et al, 2020)
Atractylenolide III, saikosaponin A, saikosaponin D, lobetyolin, baicalin, pachymic acid, liquiritin, L-arginine, chlorogenic acid, geniposidic acid, cinnamic acid and alisol B-23-acetate were identified as the main components in He-Jie-Shen-Shi decoction (HJSS)
The typical based peak intensity (BPI) chromatograms and the characteristic fragment ions of these compounds were shown in Supplementary Figure S2 and Table S2 respectively (Supplementary meterial)

Summary

Introduction

Since its outbreak in 2019, coronavirus disease 2019 (COVID-19) has become a global pandemic (Jin et al, 2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, infects host cells by binding with angiotensin-converting enzyme 2 (ACE2) mainly in the respiratory system, thereby impairing it, as indicated by fever, coughing, shortness of breath, and chest tightness, among other symptoms (Farsalinos et al, 2020; Gao et al, 2020). Some patients with SARS-CoV-2 infection have exhibited multi-system symptoms including diarrhea, acute cardiac injury, abnormal renal function, and myalgia (Adapa et al, 2020; Asadi-Pooya et al, 2020; Nishiga et al, 2020; Villapol et al, 2020). Clinical studies have further shown that recovered patients can develop sequelae such as interstitial lung disease and hyposmia, which can have long-term impacts on the quality of life (Mihai et al, 2020; Meng et al, 2020)

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