PREDICTION OF THE THERAPEUTIC EFFECTIVENESS OF NEW DRUGS FROM CLINICAL PHARMACOLOGY STUDIES

The development of new drugs for therapeutic purposes has become very expensive and time-consuming in American and European countries.It is estimated that on the average 50 to 100 million dollars and 10 or more years from the time of patenting are required to make a new drug available for general prescription. Every new drug needs to be charac-

Exploration of the molecular mechanism of Indigo Naturalis in the treatment of myelodysplastic syndromes through integrated pharmacological study

Background:Oral administration of indigo naturalis(IN)is used as a complementary and alternative medicine(CAM)regimen for the treatment of myelodysplastic syndromes(MDS).However,its mechanism of action has not been fully elucidated and needs to be further explored.Methods:By searching the traditional Chinese medicine system and analyzing platforms(TCMSP),bioinformatics analysis tool for the molecular mechanism of traditional Chinese medicine(BATMAN-TCM),and Swiss Target Prediction network database,the main active components and potential targets of IN were obtained.Based on this,a component-target network was established by Cytoscape 3.6.1 software.Differentially expressed genes(DGEs)in MDS were obtained from three GEO(Gene Expression Omnibus)gene chips.Then,the protein-protein interaction(PPI)network of DGEs was constructed and analyzed by STRING database and Cytoscape 3.6.1 software.In addition,Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)biological enrichment analysis were carried out using REVIGO and KEGG Orthology Based Annotation System(KOBAS)on DGEs,respectively.Identification of IN-MDS compound targets was performed by matching potential targets of active components with disease-related targets.The results of KEGG pathway enrichment analysis were combined with compound targets to screen key targets.In the end,molecular docking was performed by SYBYL-X2.1 to verify the key targets.Results:Nine active components of IN and 439 potential targets of IN were identified by analyzing TCMSP,BATMAN-TCM,and Swiss Target Prediction network databases.Three MDS disease-related gene microarray chips were obtained from the GEO databases:GSE4619,GSE19429,and GSE58831.Through this analysis,87 DEGs were finally obtained using the Venn diagram.A PPI network of DEGs was then constructed,in which 18 genes were upregulated and 69 genes were downregulated.After the GO enrichment results were de-redundant,the representative GO terms were obtained by using REVIGO semantic similarity measuremen.The KEGG biological pathway analysis using the KOBAS indicated that the Hippo signaling pathway is important in MDS.The Hippo signaling pathway involves four genes:AREG,LEF1,SMAD7,and TCF4.By matching and mapping DEGs with potential targets,six IN-MDS compound targets were obtained:PDE4B,PLAUR,ELANE,NR3C1,AREG,and LEF1.We found that AREG and LEF1 are consistent with the genes involved in the Hippo signaling pathway.Through molecular docking simulation,we found that the indican binds best to AREG and LEF1.Conclusion:Based on the integrated pharmacology model,the material basis of the efficacy and biological molecular mechanism of IN in the treatment of MDS was systematically studied,which provided a novel indication of the CAM regimen for the improvement of MDS management.

Pharmacological Studies of Meisoindigo: Absorption and Mechanism of Action

Meisoindigo, an indirubin derivative, is a new type of cancer chemotherapeutic agent. It exhibited higher activity against rodent tumors than indirubin itself. Experiments have shown the improved absorption of meisoindigo, compared to indirubin to be one of the major reasons for the enhancement of antitumor activity. Studies on the mechanism of meisoindigo action indicate that it strongly inhibits DNA biosynthesis in tumor cells. Strong inhibition of the drug on assembly of microtubule protein was also obtained. By means of FCM technique the effects of meisoindigo on mouse leukemia L1210 cell cycle were examined. Experimental results showed that under the action of meisoindigo the S phase cells accumulated and the traverse of the cells in G2 + M phase to G1 phase may also be blocked to some extent.

Research progress of Astragalus and Angelica

Astragalus angelica is a famous pair of Qi tonifying and blood enriching drugs.After compatibility,it can achieve the same effect,complement each other and promote each other.It can enhance human immunity,improve blood circulation,promote hematopoiesis,protect cardiovascular and cerebrovascular vessels,anti fibrosis,protect kidney,assist in the treatment of kidney syndrome,diabetes,children's cough,dizziness,improve cancer and other functions.In this paper,Astragalus Angelica pairs were systematically elaborated from its efficacy and material basis,pharmacological research and clinical application,and its further research was prospected,providing basis for the development of Astragalus Angelica pairs.

Identification and verification of effective components of Huanghuai for dysfunctional uterine bleeding based on network pharmacology and molecular docking

Objective:The Huanghuai(HH),which is made from the dried roots of Scutellaria baicalensis(Huangqin in Chinese) and the dried flowers and buds of Sophora japonica(Huaihua in Chinese),is a traditional Chinese formula used to treat dysfunctional uterine bleeding(DUB)(Benglou in Chinese) and proven to treat hemostasis effectively in our previous study.Network pharmacology and molecule docking were performed to study the underlying mechanism of Huanghuai(HH),and pharmacodynamic experiments were conducted to verify its curative effect.Methods:TCMSP,UniProt,GeneCards,STRING,DAVID databases,and Cytoscape 3.7.2 were utilized for the construction of a compound-target-pathway network.Docking the potential effective components with potential targets.The HPLC analysis of the potential effective components was performed.In vivo,the hot plate test model was used to study the analgesic activity,the egg white was used to study the swollen reaction in the sole in mice,and the hemostasis effect was studied by the capillary method,tail-breaking method and abortion uterus test.Results:The results showed that six compounds(acacetin,beta-sitosterol,wogonin,baicalein,kaempferol and quercetin) and four potential targets(PTGS2,AKT1,TP53 and TNF) in the compound-targetpathway network were the potential material basis for HH to treat DUB.It can be seen that the binding energy of the acacetin,wogonin,baicalein,beta-sitosterol,kaempferol and quercetin in HH docked with the receptor proteins PTGS2,AKT1,TP53,and TNF were far less than-5.0 kJ/mol,which means the molecules have low conformational energy,stable structure and high binding activity.And the result of HPLC analysis showed that acacetin,wogonin,baicalein,kaempferol and quercetin were the potential effective components of the hemostasis mechanism of HH,beta-sitosterol was removed due to low content.In vivo testing of the potential effective components,it revealed that the group of potential effective components identified by HPLC could increase the pain threshold,inhibit the swelling hind paws of mice induced by egg white,reduce the bleeding time and clotting time,reduce uterine bleeding,decrease the uterine weight,increase the content of Ca and ET-1,and reduce the content of NO in uterine homogenate tissue,and decrease of E_(2) and P content in uterine serum in aborted rats,whose efficacy was equal to HH.Conclusion:The results indicated that HH and potential active ingredient groups obtained from network pharmacology can treat DUB and play a hemostatic effect.The results obtained by network pharmacology have certain reliability.This study provides new indications for further mechanism research of HH on DUB and the development of HH or its components as an alternative therapy for patients with DUB.At the same time,the application of network pharmacology strategy may provide a powerful tool for exploring the mechanism of traditional Chinese medicine and discovering new biologically active ingredients.

A novel intravenous general anesthetic—emulsified isoflurane:from bench to bedside

Application of volatile anesthetics greatly alters modern medicine.There are obvious advantages of volatile anesthetics such as strong anesthetic potency,rapid onset and elimination through respiration system.Isoflurane is one of the most widely used volatile anesthetics in clinic.Emulsified isoflurane,the emulsion of isoflurane,is a novel intravenous general anesthetic.With the development of emulsified isoflurane in the past fifteen years,its utility has spread from intravenous general anesthesia to various fields including regional anesthesia,organ protection,as well as anesthetic pharmacological study.In this review,we will summarize literatures of emulsified isoflurane about its history,clinical application and future potential utility in the above mentioned fields.