New insights for infection mechanism and potential targets of COVID-19: Three Chinese patent medicines and three Chinese medicine formulas as promising therapeutic approaches / 中草药·英文版

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high pathogenicity and infectiousness has become a sudden and lethal pandemic worldwide. Currently, there is no accepted specific drug for COVID-19 treatment. Therefore, it is extremely urgent to clarify the pathogenic mechanism and develop effective therapies for patients with COVID-19. According to several reliable reports from China, traditional Chinese medicine (TCM), especially for three Chinese patent medicines and three Chinese medicine formulas, has been demonstrated to effectively alleviate the symptoms of COVID-19 either used alone or in combination with Western medicines. In this review, we systematically summarized and analyzed the pathogenesis of COVID-19, the detailed clinical practice, active ingredients investigation, network pharmacology prediction and underlying mechanism verification of three Chinese patent medicines and three Chinese medicine formulas in the COVID-19 combat. Additionally, we summarized some promising and high-frequency drugs of these prescriptions and discussed their regulatory mechanism, which provides guidance for the development of new drugs against COVID-19. Collectively, by addressing critical challenges, for example, unclear targets and complicated active ingredients of these medicines and formulas, we believe that TCM will represent promising and efficient strategies for curing COVID-19 and related pandemics.

Tissue distribution of Qingfei Paidu Decoction based on HPLC-MS/MS / 中国中药杂志

The tissue distribution of Qingfei Paidu Decoction was studied by HPLC-MS/MS in vivo. Hypersil GOLD C_(18) column(2.1 mm×50 mm, 1.9 μm) was used for gradient elution with acetonitrile as the mobile phase A and 0.1% formic acid solution as the mobile phase B. High-resolution liquid chromatography-mass spectrometry in both positive and negative ion scanning mode and multiple response monitoring(MRM) mode was employed to analyze the behaviors of the active components of Qingfei Paidu Decoction in diffe-rent tissues. The results showed that 19, 9, 17, 14, 22, 19, 24, and 2 compounds were detected in plasma, heart, liver, spleen, lung, kidney, large intestine, and brain, respectively. The compounds belonged to 8 groups, covering 14 herbs in the prescription. After administration with Qingfei Paidu Decoction, the compounds were rapidly distributed in various tissues, especially in the lung, liver, large intestine, and kidney. The majority of the compounds displayed secondary distribution. This study comprehensively analyzed the distribution rules of the main active components in Qingfei Paidu Decoction and provided a basis for the clinical application.

Establishment of Poly （I∶C）-induced Cytokine Storm Model in Mice and Intervention Effect of Artesunate and Qingfei Paidu Decoction / 中国实验方剂学杂志

ObjectiveTo observe the intervention effect of artesunate （ART） and Qingfei Paidu decoction （QFPD） on the mouse model of cytokine storm （CS） induced by viral mimic Poly （I∶C）. MethodEighty-four SPF male BALB/c mice were randomly divided into seven groups， with 12 mice in each group. Mice， except for those in the blank group （n=12）， were subjected to CS model induction by tail vein injection of Poly （I∶C） at 15 mg·kg-1， followed by drug treatments of low-dose ART （ART-l， 10 mg·kg-1）， medium-dose ART （ART-m， 20 mg·kg-1）， high-dose ART （ART-h， 40 mg·kg-1）， Qingfei Paidu Decoction （QFPD， 2.4 g·kg-1）， and dexamethasone （DXM， 10 mg·kg-1）. After 6 hours， lung tissues， bronchoalveolar lavage fluid （BALF）， spleen， lung， and peripheral blood were collected. The lung and spleen indexes were calculated and the number of inflammatory cells in BALF was detected. The pathological changes in lung tissues were observed by hematoxylin-eosin （HE） staining and the levels of tumor necrosis factor-α （TNF-α）， interferon-γ （IFN-γ）， interleukin-1β （IL-1β）， and IL-6 in BALF were detected by enzyme-linked immunosorbent assay （ELISA）. The expression of immune cells in BALF and peripheral blood was detected by flow cytometry. ResultThe analysis of lung and spleen indexes showed that compared with the blank group， the model group showed increased lung and spleen indexes to varying degrees （P<0.05）. Compared with the model group， the ART groups showed reduced spleen index （P<0.05） and the ART-l group showed reduced lung index （P<0.05）. Additionally， the QFPD group showed reduced lung and spleen indexes （P<0.05）. ELISA results showed that except for TNF-α， the levels of IFN-γ， IL-1β， and IL-6 in the model group increased compared with those in the blank group （P<0.05）. Compared with the model group， the ART-l group and the QFPD group showed reduced content of TNF-α （P<0.05）， and all groups with drug intervention showed reduced content of IFN-γ， IL-1β， and IL-6 （P<0.05）. The number of inflammatory cells in BALF showed a downward trend in the model group， and the number of cells increased in the groups with drug intervention except for the DXM group （P<0.05）. Flow cytometry showed that compared with the blank group， the model group showed decreased number of CD3 in the peripheral blood （P<0.05）， increased Ly-6G and F4/80 （P<0.05）， decreased expression of CD45， CD3， and F4/80 in BALF （P<0.05）， and increased expressions of Ly-6G （P<0.05）. Compared with the model group， the ART groups and QFPD group showed increased CD45 content in peripheral blood （P<0.05）， decreased Ly-6G and F4/80 content （P<0.05）， increased CD45 and F4/80 content in BALF （P<0.05）， and decreased expression of Ly-6G （P<0.05）. ConclusionART and QFPD have a good protective effect on Poly （I∶C）-induced CS in mice， and the mechanism is related to the effective intervention in immune cell disorder.

Significance of "Qingfei" and "Paidu" of Qingfei Paidu Decoction in Treatment of COVID-19 / 中国实验方剂学杂志

Traditional Chinese medicine （TCM） has played an important role in the prevention and treatment of novel coronavirus disease 2019 （COVID-19）. Qingfei Paidu decoction，as a general prescription of Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia from the sixth to eighth versions，has been proved effective clinically and is suitable for mild，moderate，severe，and critical patients. It can significantly improve clinical symptoms such as fever， cough，asthma，fatigue， etc. On the basis of the findings of relevant research papers，this paper summarized the TCM understanding of COVID-19， including etiology，pathogenesis， disease location， and treatment，and concluded that the disease is caused by the pestilential Qi，localized in the lungs， and can affect the five organs. It is mainly characterized by coldness，dampness，heat，toxicity，stasis，and deficiency. In response to the etiology and pathogenesis of the disease，the therapeutic principles at all stages are dominated by the elimination of pathogens and removal of toxicity. According to the stages of disease development，the treatment should combine the severity of the disease and the course of the disease with the TCM syndromes. Furthermore，from the clinical application of Qingfei Paidu decoction，this paper discussed the therapeutic intention of "Qingfei （clearing of lungs）" and "Paidu （removal of toxicity）". Qingfei Paidu decoction can clear the pathogenic toxin in the lungs and eliminate external pestilential Qi，which is in line with the therapeutic principles for this pandemic by regulating the triple energizer and protecting healthy Qi using both coldness and warmth to treat both the symptoms and the root cause. Additionally，the experimental research progress on Qingfei Paidu decoction and its modified prescriptions were summarized. As studied， this prescription can inhibit cytokine storm，moderate the overactive immune response，potentiate the immune function and anti-viral ability of the body，and exert its effect on COVID-19 with multiple components，multiple targets，multiple pathways， and multiple biological functions. In conclusion，Qingfei Paidu decoction，as a core prescription for the treatment of COVID-19，can rapidly contain the development of COVID-19， which has been confirmed in terms of TCM theory，clinical efficacy， and experimental research.

Identification and attribution of chemical constituents of Qingfei Paidu Decoction based on UHPLC-LTQ-Orbitrap-MS technology / 中国中药杂志

UHPLC-LTQ-Orbitrap-MS was developed for the identification of chemical constituents in Qingfei Paidu Decoction, which will clarify its material basis. ACQUITY UHPLC HSS T3 chromatography column(2.1 mm×100 mm, 1.8 μm) was used with 0.1% formic acid(B)-acetonitrile(A) as the mobile phase in gradient elution. The decoction was detected by high-resolution liquid chromatography-mass spectrometry equipped with an ESI ion source in positive and negative mode. Based on the accurate mass measurements, retention time, mass fragmentation patterns combined with comparison of reference and literature reports, a total of 87 major compounds including 43 flavonoids, 9 alkaloids, 4 triterpenoid saponins, 1 sesquiterpene, 2 coumarins, 10 phenolic acids and 18 other compounds were tentatively screened and characterized. UHPLC-LTQ-Orbitrap-MS was employed to comprehensively elucidate the chemical components in Qingfei Paidu Decoction, which basically covered 20 Chinese medicines except gypsum in Qingfei Paidu Decoction. These collective results provide a scientific basis for further research on the quality control standard of Qingfei Paidu Decoction.

Preliminary exploration of the mechanism of Qingfei Paidu decoction against novel coronavirus pneumonia based on network pharmacology and molecular docking technology / 药学学报

Traditional Chinese medicine (TCM) network pharmacology and molecular docking technology were applied to explore the mechanism of anti-coronavirus pneumonia (coronavirus disease 2019, COVID-19) of Qingfei Paidu decoction. The Chinese Pharmacopoeia (2015 edition) and Traditional Chinese Medicine Systems Pharmacology (TCMSP), OMIM (Online Mendelian Inheritance in Man), GeneCard, STRING, and others online databases are used for building a series of network, and selecting the core target and analyzing the signal pathway. Finally, we make molecular docking predictions for the important compounds. The results showed that the Qingfei Paidu decoction compound-pneumonia target network contained 292 compounds and 214 corresponding targets, and the core targets involved AKT1 (AKT serine/threonine kinase 1), IL6 (interleukin 6), MAPK8 (mitogen-activated protein kinase 8), MAPK1 (mitogen-activated protein kinase 1), and JUN (jun proto-oncogene). GO (Gene Ontology) function enrichment analysis yielded 858 GO entries, and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment screening yielded 122 related pathways, including hypoxia inducible factor-1 (HIF-1) and Toll-like receptor (TLRs) signaling pathways related to pneumonia, as well as T-cell receptor (TCR) signaling pathway related to lung injury protection. The molecular docking results showed that some core compounds of the Chinese herbal medicine of Qingfei Paidu decoction have a certain degree of affinity for 2019-novel coronavirus (2019-nCoV) main protease (3C-like protease, 3CLpro) and angiotensin-converting enzyme 2 (ACE2). In this paper, we preliminarily explored the potential therapeutic mechanism for Qingfei Paidu decoction to against COVID-19 and predicted the active ingredients. We hope that the results will help to the further study on the active ingredients and mechanism of Qingfei Paidu decoction to COVID-19.

Investigating Clinical Efficacy and Mechanism of Qingfei Paidu Decoction for Treatment of COVID-19 Based on Integrative Pharmacology / 中国实验方剂学杂志

Objective:Potential targets and pathways of Qingfei Paidu decoction（QFPD）for treating coronavirus disease-2019（COVID-19） were analyzed based on the integrative pharmacology，the efficacy and material basis was predicted.This study provide a reference for the development and clinical application of QFPD. Method:Based on the integrative pharmacology of traditional Chinese medicine（TCMIP V2.0），the key targets and pathways of the intervention of QFPD on COVID-19 were enriched，the interaction network of "formula-herb-disease-targets-pathways" was constructed to explored the molecular mechanism of QFPD for the treatment of COVID-19. Result:The research results show that key-targets such as cell tumor antigen p53（tp53），protein kinase B1（Akt1），Nuclear factor nuclear transcription factor-κB（NF-κB）p105 subunit（NFKB1），nuclear factor p65 subunit（RELA），human NF-κB inhibited protein α（NFKBIA），ect.Closely associated with lung damage.The pathways such as interleukin signaling，adrenoceptors，7 members of the family of c-type lectin domains A（CLEC7A）/inflammasome pathway，phosphoinositide-3-kinase（PI3K）/protein kinase B（Akt）inflammatory signaling pathway，tp53 regulates transcription of DNA repair ect. may be the key pathways related with QFPD's effect on the treatment of COVID-19 accompany with lung injury， fever， cough and other symptoms.The results show that QFPD has many clinical effects， such as anti-inflammatory， anti-virus， strengthening immunity， inhibit the development of pulmonary fibrosis， protecting heart and lungs， treating asthma， regulating gastrointestinal tract， etc.In addition， there is a good synergism between the original prescription and the combined prescription， and each original prescription has its own emphasiscan prevention and treatment of COVID-19. Conclusion:QFPD plays a role in balancing immunity and eliminating inflammation，and it can treat COVID-19 by multi-pathway，multi-channel，multi-target and multi-link.This study also provides a new idea for the research of prevention and treatment of modern infectious diseases by use the traditional Chinese medicine.

Analysis on Composition Mechanism of Qingfei Paidu Decoction from Pathogenesis of Cold Pestilence of COVID-19 / 中国实验方剂学杂志

Qingfei Paidu decoction has a remarkable clinical effect, which has been recommended by the Diagnosis and Treatment Plan of Novel Coronavirus Pneumonia (Trial Sixth Edition) of the National Health Commission and National Administration of Traditional Chinese Medicine. In this paper, the authors intend to explore the pathogenesis of cold pestilence of coronavirus disease-2019 (COVID-19) and composition mechanism of Qingfei Paidu decoction, and believe that this formula can be used to relieve internal and external pressure and regulate triple energizer with the functions of promoting lung Qi, dispelling evil and detoxification, moistening and dampening, and purging heat by removing water. This formula is suitable for the pathogenesis of COVID-19, including cold, dryness and dampness, and can effectively treat symptoms. Therefore, it should be widely used throughout the country to contain the spread of the epidemic.

Mechanism of decoction for treatment of COVID-19: analysis based on network pharmacology and molecular docking technology / 南方医科大学学报

OBJECTIVE@#To explore the target, signaling pathways and their biological functions of Decoction in the treatment of COVID-19 based on network pharmacology and molecular docking technology.@*METHODS@#The active components and target proteins in 21 drugs such as and in decoction were analyzed, and the signaling pathways and biological functions of the target proteins common with COVID-19 were screened by using TCMSP, Swiss Target Prediction, CooLGeN, GeneCards, DAVID and other databases. The network diagram of decoction was constructed using Gephi software.@*RESULTS@#We identified 163 active ingredients, including MOL004798, MOL000519, MOL004824, MOL000554, MOL010428, and MOL013443, from 18 drugs in decoction (such as , , , , and ). These ingredients activate renin-angiotensin system signaling pathway and apoptosis signaling pathway by regulating 10 protein targets (ACE, ACE2, AGTR1, FURIN, TNF, CASP3, CASP6, DPP4, MCL1 and POLD1) to execute 42 biological functions such as renin-angiotensin regulation of blood volume and systemic arterial blood pressure to treat COVID-19. The results of preliminary molecular docking showed that MOL000519 (from ), MOL000554 (from ), MOL004798 (from ), MOL004824 (from ), MOL010428 (from ), and MOL013443 (from ) had good affinity with SARS-CoV-2 3CL hydrolase to form complexes with stable conformations and high binding activity (binding energy ≤- 5 kJ/mol).@*CONCLUSIONS@# decoction can treat COVID-19 through its multiple medicinal ingredients that have multiple targets and involve multiple signaling pathways for different biological functions. Our finding provides reference for further investigation into the pharmacological mechanism of decoction in treating COVID-19.

Investigation of modulating effect of Qingfei Paidu Decoction on host metabolism and gut microbiome in rats / 中国中药杂志

This study is to explore the effect of Qingfei Paidu Decoction(QPD) on the host metabolism and gut microbiome of rats with metabolomics and 16 S rDNA sequencing. Based on 16 S rDNA sequencing of gut microbiome and metabolomics(GC-MS and LC-MS/MS), we systematically studied the serum metabolites profile and gut microbiota composition of rats treated with QPD for continued 5 days by oral gavage. A total of 23 and 43 differential metabolites were identified based on QPD with GC-MS and LC-MS/MS, respectively. The involved metabolic pathways of these differential metabolites included glycerophospholipid metabolism, linoleic acid metabolism, TCA cycle and pyruvate metabolism. Meanwhile, we found that QPD significantly regulated the composition of gut microbiota in rats, such as enriched Romboutsia, Turicibacter, and Clostridium_sensu_stricto_1, and decreased norank_f_Lachnospiraceae. Our current study indicated that short-term intervention of QPD could significantly regulate the host metabolism and gut microbiota composition of rats dose-dependently, suggesting that the clinical efficacy of QPD may be related with the regulation on host metabolism and gut microbiome.