Potential common mechanism of four Chinese patent medicines recommended by diagnosis and treatment protocol for COVID-19 in medical observation period.

The global epidemic has been controlled to some extent, while sporadic outbreaks still occur in some places. It is essential to summarize the successful experience and promote the development of new drugs. This study aimed to explore the common mechanism of action of the four Chinese patent medicine (CPMs) recommended in the Medical Observation Period COVID-19 Diagnostic and Treatment Protocol and to accelerate the new drug development process. Firstly, the active ingredients and targets of the four CPMs were obtained by the Chinese medicine composition database (TCMSP, TCMID) and related literature, and the common action targets of the four TCMs were sorted out. Secondly, the targets of COVID-19 were obtained through the gene-disease database (GeneCards, NCBI). Then the Venn diagram was used to intersect the common drug targets with the disease targets. And GO and KEGG pathway functional enrichment analysis was performed on the intersected targets with the help of the R package. Finally, the results were further validated by molecular docking and molecular dynamics analysis. As a result, a total of 101 common active ingredients and 21 key active ingredients of four CPMs were obtained, including quercetin, luteolin, acacetin, kaempferol, baicalein, naringenin, artemisinin, aloe-emodin, which might be medicinal substances for the treatment of COVID-19. TNF, IL6, IL1B, CXCL8, CCL2, IL2, IL4, ICAM1, IFNG, and IL10 has been predicted as key targets. 397 GO biological functions and 166 KEGG signaling pathways were obtained. The former was mainly enriched in regulating apoptosis, inflammatory response, and T cell activation. The latter, with 92 entries related to COVID-19, was mainly enriched to signaling pathways such as Coronavirus disease-COVID-19, Cytokine-cytokine receptor interaction, IL-17 signaling pathway, and Toll-like receptor signaling pathway. Molecular docking results showed that 19/21 of key active ingredients exhibited strong binding activity to recognized COVID-19-related targets (3CL of SARS-CoV-2, ACE2, and S protein), even better than one of these four antiviral drugs. Among them, shinflavanone had better affinity to 3CL, ACE2, and S protein of SARS-CoV-2 than these four antiviral drugs. In summary, the four CPMs may play a role in the treatment of COVID-19 by binding flavonoids such as quercetin, luteolin, and acacetin to target proteins such as ACE2, 3CLpro, and S protein and acting on TNF, IL6, IL1B, CXCL8, and other targets to participate in broad-spectrum antiviral, immunomodulatory and inflammatory responses.

Potential Mechanisms for Traditional Chinese Medicine in Treating Airway Mucus Hypersecretion Associated With Coronavirus Disease 2019.

BACKGROUND: The rapid development of coronavirus disease 2019 (COVID-19) pandemic has become a great threat to global health. Its mortality is associated with inflammation-related airway mucus hypersecretion and dysfunction of expectoration, and the subsequent mucus blockage of the bronchioles at critical stage is attributed to hypoxemia, complications, and even death. Traditional Chinese medicine (TCM) has rich experience in expectorant, including treatment of COVID-19 patients with airway mucus dysfunction, yet little is known about the mechanisms. This study is aiming to explore the potential biological basis of TCM herbal expectorant for treating COVID-19. OBJECTIVE: To get core herbs with high used frequency applications in the actions of expectoration by using association rule algorithm and to investigate the multitarget mechanisms of core herbs in expectorant formulae for COVID-19 therapies. METHODS: Forty prescriptions for expectorant were retrieved from TCM Formulae. The ingredient compounds and targets of core herbs were collected from the TCMSP database, Gene-Cards, and NCBI. The protein interaction network (PPI) was constructed by SRING, and the network analysis was done by Cytoscape software. Bioconductor was applied for functional enrichment analysis of targets. RESULTS: The core herbs of expectorant could regulate core pathways (MAP kinase activity, cytokine receptor binding, G-protein-coupled receptor binding, etc.) via interactions of ingredients (glycyrol, citromitin, etc.) on mucin family to eliminate phlegm. CONCLUSION: TCM herbal expectorant could regulate MAPK and cytokine-related pathways, thereby modulating Mucin-family to affect mucus generation and clearance and eventually retarding the deterioration of COVID-19 disease.

Herbal plants coordinate COVID-19 in multiple dimensions - An insight analysis for clinically applied remedies.

The use of multipronged measures, including traditional Chinese medicine (TCM), has greatly increased in response to the COVID-19 pandemic, and we found the use of TCM and is positively correlated with the regional cure rate in China (R=0.77, P<10-5). We analyzed 185 commonly administered TCM recipes comprised of 210 herbs nationwide to reveal mechanistic insight. Eight out of the 10 most commonly used herbs showed anti-coronavirus potential by intersecting with COVID-19 targets. Intriguingly, 17 compounds from the 5 most commonly used herbs were revealed to have direct anti-SARS-CoV-2 potential by docking with the two core structures [CoV spike (S) glycoprotein (6SVB) and CoV 3CL hydrolase (6LU7)]. Seven reported COVID-19 drugs served as positive controls; among them, retionavir (-7.828 kcal/mol) and remdesivir (-8.738 kcal/mol) performed best with 6VSB and 6LU7, respectively. The top candidate was madreselvin B (6SVB: -8.588 kcal/mol and 6LU7: -9.017 kcal/mol), an appreciable component of Flos Lonicerae. Eighty-six compounds from 22 unlisted herbs were further identified among 2,042 natural compounds, completing our arsenal for TCM formulations. The mechanisms have been implicated as multifactorial, including activation of immunoregulation (Th2, PPAR and IL10), suppression of acute inflammatory responses (IL-6, IL-1α/ß, TNF, COX2/1, etc.), enhancement of antioxidative activity (CAT and SOD1), and modulation of apoptosis (inhibited CASP3). It is of interest to understand the biological mechanisms of TCM recipes. We then analyzed 18 representative remedies based on molecular targets associated with 14 medical conditions over the disease course, e.g., pyrexia, coughing, asthenia, lymphopenia, cytokine storm, etc. The significant level of coherence (SLC) revealed, in part, the potential uses and properties of corresponding TCMs. Thus, herbal plants coordinate to combat COVID-19 in multiple dimensions, casting a light of hope before effective vaccines are developed.

Potential mechanisms of Chinese Herbal Medicine that implicated in the treatment of COVID-19 related renal injury.

Clinical studies have shown that renal injury in Corona Virus Disease 2019 (COVID-19) patients has been a real concern, which is associated with high mortality and an inflammation/apoptosis-related causality. Effective target therapy for renal injury has yet been developed. Besides, potential anti-COVID-19 medicines have also been reported to cause adverse side effects to kidney. Chinese Herbal Medicine (CHM), however, has rich experience in treating renal injury and has successfully applied in China in the battle of COVID-19. Nevertheless, the molecular mechanisms of CHM treatment are still unclear. In this study, we searched prescriptions in the treatment of renal injury extensively and the potential mechanisms to treat COVID-19 related renal injury were investigated. The association rules analysis showed that the core herbs includes Huang Qi, Fu Ling, Bai Zhu, Di Huang, Shan Yao. TCM herbs regulate core pathways, such as AGE-RAGE, PI3K-AKT, TNF and apoptosis pathway, etc. The ingredients (quercetin, formononetin, kaempferol, etc.,) from core herbs could modulate targets (PTGS2 (COX2), PTGS1 (COX1), IL6, CASP3, NOS2, and TNF, etc.), and thereby prevent the pharmacological and non-pharmacological renal injury comparable to that from COVID-19 infection. This study provides therapeutic potentials of CHM to combat COVID-19 related renal injury to reduce complications and mortality.