A network pharmacology approach to explore the mechanism of action of Yiqi Fumai lyophilized injection in the treatment of novel coronavirus disease

Background:Shengmai decoction,which has been included in the diagnosis and treatment of coronavirus disease 2019(COVID-19),is effective in the early treatment of patients with severe COVID-19.Yiqi Fumai lyophilized injection(YQFM)is a modern Chinese medicine preparation of the Shengmai decoction.The mechanism of its intervention at the molecular level in the severe stage of COVID-19 remains unclear.Therefore,it is necessary to investigate the mechanism of YQFM in the treatment of patients with severe COVID-19.Methods:The corresponding target genes of the main active ingredients in YQFM and COVID-19 were obtained by using multiple databases and literature retrieval.A protein-protein interaction network was constructed,and enrichment analysis of the target was performed using Cytoscape 3.8.1.Lastly,the docking of all the identified compounds with angiotensin-converting enzyme II was confirmed by applying molecular docking technology.Results:YQFM has anti-inflammatory effects on RAW267.4 macrophages.The main active compounds of YQFM are all effective anti-inflammatory agents,and these active compounds also show beneficial physiological functions,such as anti-oxidation,anti-bacterial,and anticancer activities.Gene Ontology analysis showed enrichment in the following pathways:lipopolysaccharides,interleukins,NF-kappa B,interleukin-2 and others,revealing that YQFM may play a role in the treatment of patients with severe COVID-19 through these pathways.Conclusion:YQFM has multicomponent and multitarget characteristics,and it could reduce lung injury by inhibiting inflammatory reactions,promoting antiviral activities,and regulating immunity,among other functions,to treat patients with severe COVID-19.

Metabonomic analysis of hepatitis B virus-induced liver failure:identification of potential diagnostic biomarkers by fuzzy support vector machine

Hepatitis B virus （HBV）-induced liver failure is an emergent liver disease leading to high mortality. The severity of liver failure may be reflected by the profile of some metabolites. This study assessed the potential of using metabolites as biomarkers for liver failure by identifying metabolites with good discriminative performance for its phenotype. The serum samples from 24 HBV-indueed liver failure patients and 23 healthy volunteers were collected and analyzed by gas chromatography-mass spectrometry （GC-MS） to generate metabolite profiles. The 24 patients were further grouped into two classes according to the severity of liver failure. Twenty-five eommensal peaks in all metabolite profiles were extracted, and the relative area values of these peaks were used as features for each sample. Three algorithms, F-test, k-nearest neighbor （KNN） and fuzzy support vector machine （FSVM） combined with exhaustive search （ES）, were employed to identify a subset of metabolites （biomarkers） that best predict liver failure. Based on the achieved experimental dataset, 93.62% predictive accuracy by 6 features was selected with FSVM-ES and three key metabolites, glyeerie acid, cis-aeonitie acid and citric acid, are identified as potential diagnostic biomarkers.

Intestinal permeability of metformin using single-pass intestinal perfusion in rats

AIM： To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein （P-gp）. METHODS： The effective intestinal permeability of metformin was investigated using single-pass intestinal perfusion （SPIP） technique in male Waster rats. SPIP was performed in three isolated intestinal segments （duodenum, jejunum and ileum） at the same concentration of metformin （50 μg/mL） to test if the intestinal transport of metformin exhibited site- dependent changes, and in a same isolated intestinal segment （duodenal segment） at three different concentrations of metformin （10, 50, 200 μg/mL） to test if the intestinal transport of metformin exhibited concentration-dependent changes. Besides, P-gp inhibitor verapamil （400 μg/mL） was co-perfused with metformin （50 μg/mL） in the duodenum segment to find out if the intestinal absorption of metformin was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of metformin could be attributed to intestinal absorption. RESULTS： The effective permeability values （Peff） of metformin in the jejunum and ileum at 50μg/mL were significantly lower than those in the duodenum at the same concentration. Besides, Peff values in the duodenum at high concentration （200 μg/mL） were found to be significantly lower than those at low and medium concentrations （10 and 50 μg/mL）. Moreover the coperfusion with verapamil did not increase the Peff value of metformin at 50 μg/mL in the duodenum.CONCLUSION： Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The Peff value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported by P-gp in the gut wall. Furthermore metformin is neither a substrate nor an inducer of P-gp. Based on the Peff values obtained in the present study and using established relationships, the human fraction dose absorbed for metformin is estimated to be 74%-90% along human intestine.

Novel assays for quality evaluation of XueBiJing:Quality variability of a Chinese herbal injection for sepsis management

XueBiJing is an intravenous five-herb injection used to treat sepsis in China.The study aimed to develop a liquid chromatography-tandem mass spectrometry(LC-MS/MS)-or liquid chromatography-ultraviolet(LC-UV)-based assay for quality evaluation of XueBiJing.Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel.Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition,pharmacokinetics,and pharmacodynamics.A selectivity test(for“similarity of response”)was developed to identify and minimize interference by nontarget constituents.Then,an intercept test was developed to fulfill“linearity through zero”for each analyte(absolute ratio of intercept to C response,<2%).Using the newly developed assays,we analyzed samples from 33 batches of XueBiJing,manufactured over three years,and found small batch-to-batch variability in contents of the marker constituents(4.1%-14.8%),except for senkyunolide I(26.5%).

Relationship of quantitative structure and pharmacokinetics in fluoroquinolone antibacterials

AIM： To study the relationship between quantitative structure and pharmacokinetics （QSPkR） of fluorocluinolone antibacterials.METHODS： The pharmacokinetic （PK） parameters of oral fluoroquinolones were collected from the literature. These pharmacokinetic data were averaged, 19 compounds were used as the training set, and 3 served as the test set. Genetic function approximation （GFA） module of Cerius2 software was used in QSPkR analysis.RESULTS： A small volume and large polarizability and surface area of substituents at C-7 contribute to a large area under the curve （AUC） for fluoroquinolones. Large polarizability and small volume of substituents at N-1 contribute to a long half life elimination.CONCLUSION： QSPkR models can contribute to some fluoroquinolones antibacterials with excellent pharmacokinetic properties.

Progress in the study of antiplatelet and antithrombotic effects of salvia polyphenolic acid for injection

Salvia polyphenolic acid for injection is a new generation of Chinese medicine injectable,which is developed by extracting and separating the water-soluble phenolic acid active ingredients of Salvia divinorum by using modern advanced technology as raw material.Pharmacological research shows that salvia polyphenolic acid has anti-inflammatory,anti-oxidative stress,neurotrophic,regenerative and protective effects on ischemic brain injury and can reduce myocardial ischemic injury.In clinical practice,it is mainly used in the treatment of stroke(mild to moderate cerebral infarction)in the recovery period of fetish blood obstruction.In recent years,it has also been gradually extended to treating acute cerebral infarction and respiratory syndrome.Since its launch,the pharmacological effects and clinical applications of Danshen polyphenolic acid for injection are reviewed to provide research clues for further essential trials and reference basis for clinical promotion and application.

Research progress on pharmacological action and mechanism of injection Yiqi Fumai lyophilized injection in treating cardiomyopathy

The pharmacological studies of Yiqi Fumai lyophilized injection in cardiovascular system mainly include anti-cardiac failure,improvement of myocardial ischemia,improvement of myocardial hypertrophy and myocardial injury caused by ischemia and hypoxia.In recent years,a large number of studies have shown that Yiqi Fumai Lyophilized Injection has good protective effects on myocardial injury caused by ischemia and hypoxia by enhancing myocardial contractility and delaying ventricular remodeling.

A New Concept on Quality Marker for Quality Assessment and Process Control of Chinese Medicines

Chinese medicine （CM） is the most typical conventional therapy compared with any other traditional or alternative medicine systems. The active components of CMs are either primary or secondary metabolites generated by metabolic and biosynthetic enzymes in plants, protecting the plants from environmental stress. The characteristics of these metabolites are diverse, complicated and unique. In this paper, current approaches for quality assessment were extensively reviewed, a new concept of quality marker （Q-marker） was then proposed for CM quality assessment. Additionally, definition of the Q-marker, as well as the relevant methods, were discussed, on the basis of the biosynthetic pathways of secondary metabolites and source of biological active components. Study design of Q-marker is complex system for quality assessment and production process control of CM products with transitivity and traceability. Therefore, the system with characteristics of transmission and traceability is expected to be established for regulation of quality. Upon the concept which the transitivity and traceability in the quality assessment and production process control covered the entire process, such as raw materials, decoction slices, processing, extraction and production can be further enhanced. The transitivity and traceability will inevitably require close attention to ＂who, what, where, when, and why＂ details at each stage of Q-markers of CM production form raw materials to patent product. The establishing quality standards are enablers of many and various transitivity and traceability solutions, not a solution in them. It means that the transitivity and traceability system is readily link between products and across borders in quality. According to the thinking mode and methods of investigation on quality assessment of CM product, we focus on the entire process, in terms of safety and effectiveness and quality control. The standard preparation of CM or CM decoction is not only the basis for study of Q-marker, but also the basis for transmission and traceability of the quality of CM product.

Prediction of quality markers of traditional Chinese medicines based on network pharmacology

Network pharmacology is a powerful tool to reflect the pharmacologically active effects,mechanism of action and toxic activity of traditional Chinese medicines(TCMs).The ingredients of TCMs,associated with quality control of TCM products,are those fundamental chemicals that exhibit biological activities.A great amount of effort has been made by scientists in that field in order to improve the quality of TCMs,though the approaches to determine their quality and the TCM theory and compatibility rules remain ambiguous.Now some methods and technologies must be applied to predict and explore the quality marker(Q-marker)for quality control,as well as to clarify the factors affecting the quality of TCM,which may give new insight into rational ground of establishment of appropriate quality control and assessment system.In this review paper,authors focus on the prediction of quality markers of TCMs by network pharmacology based on three aspects:(1)from network medicine to network pharmacology,(2)complex network system of traditional Chinese medicine,and(3)predicting TCM quality markers based on network pharmacology.Authors proposed the research pattern on network pharmacology based on biological and medical networks,and further TCM network pharmacology based on substantial basis of TCM formulae,and the idea of"effect-ingredient-target-fingerprint"to predict and recognize the TCM Qmarker was the ultimate goal.In addition,authors yet noted how to make full use of the advantages of network toxicology to provide new ideas for the toxicity study of complex TCM systems and the prediction of TCM toxicity markers.

Network Pharmacology Bridges Traditional Application and Modern Development of Traditional Chinese Medicine

Traditional Chinese medicine （TCM） has developed over thousands of years and has accumulated abundant clinical experience, forming a comprehensive and unique medical system. Emerging evidence has begun to illustrate TCM as an area of important medical rediscoveries. This review article briefly introduced the concept, significance, and technology of network pharmacology based on network biology and systems biology. It focused on the theoretical system and potential prospect of TCM network applied in TCM research and development including predicting new drug targets, action mechanism, new drug discovery; evaluating pharmacodynamics, pharmacokinetics, safety, toxicology, quality control, and bioinformatics of drugs. We also discussed the opportunities and challenges in the development and application of network pharmacology in the modernization of TCM research.

Network toxicology and LC-MS-based metabolomics:New approaches for mechanism of action of toxic components in traditional Chinese medicines

Network toxicology combined with metabonomics is of great significance for the study of the toxic mechanism and prediction of toxicity of traditional Chinese medicines(TCMs).In this study,we reviewed the application of network toxicology based on LC-MS metabolomics,mainly in the study of toxic components and the toxicity mechanism of TCMs,which provides new ideas and methods for the further study of the toxicity mechanism of TCMs.

Rapid Analysis and Identification of Absorbed Components and Their Metabolites of Yuanhu Zhitong Dropping Pill in Rat Plasma and Brain Tissue Using UPLC-Q-TOF/MS with Multivariate Statistical Analysis

Objective To establish an effective approach for rapid and comprehensive analysis on the absorbed and metabolic components in rats after ig administration of Yuanhu Zhitong Dropping Pill（YHZT）. Methods Based on the combination of UPLC-Q-TOF/MS and multivariate statistical analysis, the absorbed prototype constituents and their metabolites in rat plasma were rapidly analyzed and identified, and the components absorbed into brain were further identified by comparing the extracted ion chromatograms（EICs） of control and brain tissue samples of dosed rats. Results A total of 38 YHZT-related xenobiotic compounds were detected and identified as the potential bioactive constituents in rat plasma, including 24 absorbed prototype constituents and 14 metabolites. In particular, of all prototype constituents, 14 were also detected in rat brain tissue, indicating that they could penetrate the blood-brain barrier and enter into brain. Conclusion An effective method is established and applied to analyze the potential bioactive constituents in YHZT, which provides a pathway to further investigate the pharmacological pattern and mechanism of YHZT.

In Silico Molecular Docking Study of Repensine and Bentysrepinine against HBV DNA Polymerase

Bentysrepinine （Y101 ）, a derivative of repensine, is a novel di-peptide structure isolated from Dichondra repens. In vitro and in vivo tests exhibited that bentysrepinine markedly inhibited DNA-HBV and cccDNA activities. The binding mode of Y101 and repensine with DNA polymerase was driven by hydrophobic interactions. This might provide novel recognition of inhibitory effect of Y1 01 against HBV, though its inhibition mechanism needs to be validated by bio-assay at cellular level and of polymerase activity. Preliminary docking study suggested that Y101 might be able to inhibit HIV inverse transcriptase, also have the potential to interact with DNA polymerase and HCV NS5B polymerase.

Determination of Quality Markers is Basis for Establishing Quality Standard and Control of Chinese Herbal Medicines

The quality marker is a brand new concept not only for the quality assessment and control of TCMs but also for other herbal medicine systems which shares similar features of multiple components.It is also worth to mention that integration of traditional Chinese medicinal theory with such modern science as natural products chemistry,chromatographic analysis,network pharmacology,systems biology,is essential for the determination and validation of reasonable,scientific,and practical quality markers.

Pay attention to situation of SARS-CoV-2 and TCM advantages in treatment of novel coronavirus infection

Since the outbreak of the new coronavirus epidemic,novel coronavirus has infected nearly 100,000 people in more than 110 countries.How to face this new coronavirus epidemic outbreak is an important issue.Basic reproduction number(R0)is an important parameter in epidemiology;The basic reproduction number of an infection can be thought of as the expected number of cases directly generated by one case in a population where all individuals are susceptible to infection.Epidemiology dynamics is a mathematical model based on a susceptibility-infection-recovery epidemic model.Researchers analyzed the epidemiological benefits of different transmission rates for the establishment of effective strategy in prevention and control strategies for epidemic infectious diseases.In this review,the early use of TCM for light and ordinary patients,can rapidly improve symptoms,shorten hospitalization days and reduce severe cases transformed from light and normal.Many TCM formulas and products have wide application in treating infectious and non-infectious diseases.The TCM theoretical system of treating epidemic diseases with TCM and the treatment scheme of integrated Chinese and Western medicine have proved their effectiveness in clinical practice.TCM can cure COVID-19 pneumonia,and also shows that the role of TCM in blocking the progress of COVID-19 pneumonia.

Development and Application of Network Toxicology in Safety Research of Chinese Materia Medica

Network toxicology that is an important branch of the network pharmacology emerges on the basis of network biology. It refers to study on the toxicological features of a constructed network model which is used to analyze toxic substances and their interaction and regulation in biological systems, particularly investigate the toxic effects of drugs and/or compatibility of medicines on body, and clarify the mechanism of toxicity. Network toxicology currently develops rapidly in safety prediction of Chinese materia medica （CMM）. The application of network toxicology to safety and toxicology study on CMM is extremely beneficial to identify the toxic components and potential incompatibility of CMM. Since CMM is a complex system with multi-components, multi-targets, and multi-interactions, the network toxicology in safety prediction of CMM faces three great challenges, including integration studies of bioinformatics, innovation of methods, and tools and risk assessment in future development of the network toxicology in CMM research. In this paper, relevant database, approaches and tools that network toxicology utilized in the safety study of CMM were carefully reviewed. Based on the progress made, the scientific development and modernization of CMM will be greatly enhanced.

Panax japonicus and chikusetsusaponins: A review of diverse biological activities and pharmacology mechanism

Panax japonicus, which in the Tujia dialect is known as "Baisan Qi" and "Zhujieshen", is a classic "qi" drug of Tujia ethnomedicine and it has unique effects on disease caused by "qi" stagnation and blood stasis.This paper serves as the basis of further scientific research and development of Panax japonicus. The pharmacology effects of molecular pharmacology were discussed and summarized. P. japonicus plays an important role on several diseases, such as rheumatic arthritis, cancer, cardiovascular agents, and this review provides new insights into P. japonicus as promising agents to substitute ginseng and notoginseng.

Systems Biology Application in Research on Sustainable Utilization of Chinese Materia Medica Resources

This paper reviews the progress of systems biology applied to researching on sustainable utilization of Chinese materia medica （CMM） resources in the following aspects： identification and evaluation of CMM resources, analysis of biosynthesis and their regulation of active ingredients in medicinal plants, metabolic engineering and synthetic biology research of medicinal plants, and molecular breeding of medicinal plants. Development of systems biology is currently leading to extremely broad applications in the field of CMM resources, and systems biology wiil become a significant approach for the sustainable utilization of CMM resources.

Application and prospect of toxicity quality markers of Chinese materia medica based on metabolomics

In view of the problem that the quality evaluation indicators divorced from effectiveness and safety in Chinese materia medica（CMM）, Prof. Chang-xiao Liu et al have put forward a concept of quality markers（Q-markers） of CMM, which provided a new thought for improving the CMM quality control method. The toxicity Q-markers of CMM are described as follows, the early toxicity prediction of CMM, the discovery, formation and susceptibility research of toxicity Q-markers of CMM. Metabolomics is a systematic biology approach, closely related to the toxicity phenotype of organism, has unique advantages in toxicity Q-markers research. The toxicity Q-markers of CMM are explained from the following four aspects in this review： 1） the establishment of toxicity prediction model of CMM, which is based on metabolomics,pattern recognition, and other techniques; 2） the discovery of toxicity Q-markers of CMM based on metabolomic, which is meaning that the toxicity Q-markers are interpreted regarding to the chemical composition analysis of CMM, preliminary screening and verification of the toxicity Q-markers and toxicity mechanism research; 3） the research on the formation of toxicity Q-markers based on metabolomics,which is described from biosynthetic pathway analysis and the secondary metabolites analysis of toxicity Q-markers; and 4） the susceptibility study of toxicity Q-markers based on metabolomics, namely, the key targets, and metabolic pathways of toxicity Q-markers are explained according to the target organ toxicity susceptibility caused by CMM, and then the toxicity susceptibility mechanism of CMM is clarified. Therefore, the application of metabolomics helps to systematically and comprehensively discover the quality control indicators related to the CMM safety, which further provides a rational evidence for the clinical application of toxicity of CMM.

Medicinal Plant of Bletilla striata: A Review of its Chemical Constituents, Pharmacological Activities, and Quality Control

Bletilla striata belongs to the family Orchidaceae,and it is mainly distributed in East Asia.The tubers of B.striata have been utilized in Traditional Chinese Medicine for various ailments,such as hematemesis,tuberculosis,malignant ulcers,hemorrhoids,traumatic bleeding,and chapped skin.Phytochemical investigation on B.striata has resulted in the identification of 192 monomeric compounds,including bibenzyls,phenanthrene derivatives,triterpenoids and its saponins,steroids and its saponins,malic acid derivatives,and anthocyanins.Moreover,B.striata polysaccharide is another typical chemical constituent of this plant.Pharmacology studies have shown that the plant possesses wound healing,antimicrobial,anticancer,antioxidative,and antiviral activities.This review aims to provide the latest and comprehensive information on chemical constituents,pharmacological activities,and quality control of B.striata and to identify future research needs.