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BACKGROUND: Qimai Feiluoping decoction (QM), a Traditional Chinese Medicine formula, has been included in rehabilitation program for functional disorders of discharged COVID-19 patients. QM has been proved to effectively improve the clinical symptoms and imaging signs of PF in COVID-19 convalescent patients. PURPOSE: This study to explore the pharmacological effect of QM against PF from the perspectives of imaging, pathological staining, and molecular mechanisms, and identify possible active components. METHODS: Micro-CT imaging and immunohistochemical staining were investigated to verify the therapeutic effect of QM in the bleomycin (BLM)-induced PF mouse model. The 4D-label-free proteomics analysis of lung tissues was then conducted to explore the novel mechanisms of QM against PF, which were further validated by a series of experiments. The possible components of QM in plasma and lung tissues were identified with UHPLC/IM-QTOF-MS analysis. RESULTS: The results from micro-CT imaging and pathological staining revealed that QM treatment can inhibit BLM-induced lung injury, extracellular matrix accumulation and TGF-ß expression in the mouse model with PF. The 4D-label-free proteomics analysis demonstrated that the partial subunit proteins of mitochondrial complex I and complex II might be potential targets of QM against PF. Furthermore, QM treatment can inhibit BLM-induced mitochondrial ROS content to promote ATP production and decrease oxidative stress injury in the mouse and cell models of PF, which was mediated by the inhibition of mitochondrial complex I. Finally, a total of 13 protype compounds and 15 metabolites from QM in plasma and lung tissues were identified by UHPLC/IM-QTOF-MS, and liquiritin and isoliquiritigenin from Glycyrrhizae radix et rhizoma could be possible active compounds against PF. CONCLUSION: It concludes that QM treatment could treat PF by inhibiting mitochondrial complex I-mediated mitochondrial oxidated stress injury, which could offer new insights into the pharmacological mechanisms of QM in the clinical application of PF patients.
Subject(s)
COVID-19 , Pulmonary Fibrosis , Mice , Animals , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Bleomycin/toxicity , COVID-19/pathology , Lung/pathology , Oxidative StressABSTRACT
Background:The emergence of novel coronavirus pneumonia has seriously affected people's normal life and health. Cold-dampness epidemic prescription has a good effect in the prevention and treatment of novel coronavirus pneumonia. Methods:TCMSP, PubChem, Swiss Target Prediction, PharmMapper database and related literatures were used to retrieve and predict the main chemical components and corresponding targets of Traditional Chinese Medicine (TCM)TCM. GeneCard, OMIM, NCBI and TTD databases were used to collect disease targets. Uniprot disease database was used to standardize target names. Cytoscape3.8.2 software was used to establish the 'active components-action target' network. Protein interaction (PPI) network was established by using protein interaction database (STRING), and core genes were screened by CytoNCA plug-in of Cytoscape3.8.2 software.GO enrichment analysis and KEGG pathway enrichment analysis were carried out through DAVID network database, and Hiplot network platform was used for visualization. Molecular docking technology was used to verify the docking between core components and targets. Results:After preliminary screening, 102 effective components, 255 potential targets and 2230 COVID-19 disease targets were obtained, and it was speculated that the mechanism might be related to 177 pathways such as TNF signaling pathway, IL-17 signaling pathway and AGE-RAGE signaling pathway in diabetic complications. The absolute values of docking binding energy between active components such as quercetin, luteolin and wogonin and targets such as PTGS2, AR, TP53 and CASP3 were greater than 5.0 Kcal/mol, and the docking results were good. Conclusion:Cold-dampness epidemic prescription has the characteristics of multiple components, multiple targets and multiple pathways in the prevention and treatment of COVID-19, and may play a therapeutic role through anti-inflammatory, antiviral and immune regulation. © 2022 IEEE.
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Glycyrrhizae Radix et Rhizoma, a traditional Chinese medicine also known as Gan Cao (GC), is frequently included in clinical prescriptions for the treatment of pneumonia. However, the pharmacological components of GC for pneumonia treatment are rarely explored. Gan An He Ji oral liquid (GAHJ) has a simple composition and contains GC liquid extracts and paregoric, and has been used clinically for many years. Therefore, GAHJ was selected as a compound preparation for the study of GC in the treatment of pneumonia. We conducted an in vivo study of patients with pneumonia undergoing GAHJ treatments for three days. Using the intelligent mass spectrometry data-processing technologies to analyze the metabolism of GC in vivo, we obtained 168 related components of GC in humans, consisting of 24 prototype components and 144 metabolites, with 135 compounds screened in plasma and 82 in urine. After analysis of the metabolic transformation relationship and relative exposure, six components (liquiritin, liquiritigenin, glycyrrhizin, glycyrrhetinic acid, daidzin, and formononetin) were selected as potential effective components. The experimental results based on two animal pneumonia models and the inflammatory cell model showed that the mixture of these six components was effective in the treatment of pneumonia and lung injury and could effectively downregulate the level of inducible nitric oxide synthase (iNOS). Interestingly, glycyrrhetinic acid exhibited the strongest inhibition on iNOS and the highest exposure in vivo. The following molecular dynamic simulations indicated a strong bond between glycyrrhetinic acid and iNOS. Thus, the current study provides a pharmaceutical basis for GC and reveals the possible corresponding mechanisms in pneumonia treatment.
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Objective: To analyze the action mechanism of anti-Corona Virus Disease 2019(COVID-19)by Chinese herbal compound and propose a combination of Chinese medicine through network pharmacology and molecular docking. Method(s): Based on the Chinese medicine and Chinese medicine prescription for prevention and treatment of COVID-19, ADME properties(OB>=30%;DL>=0.18)was used for virtual screening;Potentially active molecules in protease Mpro and receptor ACE2 were screened by molecular docking(Binding Scores>4);Through the overlap ratio of active components and key targets, the suggestions on optimizing formula combination were provided. Result(s): 127 Chinese medicinal materials and 885 active components were obtained. The active components close to Lopinavie scores included squalene, shikonin, stigmasterol, etc. The traditional chinese medicinal materials with overlap rate of active molecules>=15% included Ephedrae Herba, Lonicerae Japonicae Flos, Scutellariae Radix, etc. The key Chinese herbal medicines with overlapping rate of key targets>=15% included Glycyrrhizae Radix et Rhizoma, Pinelliae Rhizoma, Curcumae Radix, etc. Conclusion(s): The combinations of Chinese herbal are proposed:(1)Ephedrae Herba, Armeniacae Semen Amarum, Glycyrrhizae Radix et Rhizoma, Curcumae Longae Rhizoma;(2)Lonicerae Japonicae Flos, Scutellariae Radix, Arnebiae Radix, Verbenae Herba;(3)Ephedrae Herba, Pinelliae Rhizoma, Curcumae Radix, Pseudostellariae Radix. Copyright © 2021, Central Station of Chinese Medicinal Materials Information, National Medical Products Administration. All right reserved.
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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.
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In recent years, with the frequent occurrence of viral diseases accompanied by high morbidity and mortality rates, there has been an increasing awareness of importance of antiviral drugs research. Traditional Chinese medicine contain biologically structurally diverse bioactive substances that provide important template structures for pharmaceutical research. Because of its novelty, multicomponent and multi-target characteristics, it is a valuable source for new drug development. The antiviral mechanisms of active components of traditional Chinese medicines include inhibition of viral replication, block binding of virus with receptor, directly killing virus, enhancement of the immune system and inhibition of cytokines/chemokines responses, etc. The active components of traditional Chinese medicine with antiviral active ingredients based on the mechanism of antiviral action were reviewed in this paper, in order to provide a basis for development of antiviral natural drugs to cope with the virus epidemic including the new variant of SARS-CoV-2 and other virus outbreaks that may occur in the future. © 2022 Editorial Office of Chinese Traditional and Herbal Drugs. All rights reserved.