The anti-hair loss mechanism of Aquilaria sinensis leaf extract(ASE)has been studied by using metabolomics and network pharmacology.Metabolomics was utilized to comprehensively identify the active constituents of ASE,...The anti-hair loss mechanism of Aquilaria sinensis leaf extract(ASE)has been studied by using metabolomics and network pharmacology.Metabolomics was utilized to comprehensively identify the active constituents of ASE,and the network pharmacology was used to elucidate their anti-hair loss mechanism,which was verified by molecular docking technology.572 active compounds were identified from the ASE by metabolomics methods,where there are 1447 corresponding targets and 492 targets related to hair loss,totaling 88 targets.20 core active substances were identified by constructing a network between common targets and active substances,which include vanillic acid,chorionic acid,caffeic acid and apigenin.The five key targets of TNF,TP53,IL6,PPARG,and EGFR were screened out by the PPI network analysis on 88 common targets.The GO and KEGG pathway enrichment analysis showed that the inflammation,hormone balance,cell growth,proliferation,apoptosis,and oxidative stress are involved.Molecular docking studies have confirmed the high binding affinity between core active compounds and key targets.The drug similarity assessment on these core compounds suggested that they have the potential to be used as potential hair loss treatment drugs.This study elucidates the complex molecular mechanism of ASE in treating hair loss,and provides a reference for the future applications in hair care products.展开更多
Objective Traditional Chinese medicine(TCM)constitutes a valuable cultural heritage and an important source of antitumor compounds.Poria(Poria cocos(Schw.)Wolf),the dried sclerotium of a polyporaceae fungus,was first ...Objective Traditional Chinese medicine(TCM)constitutes a valuable cultural heritage and an important source of antitumor compounds.Poria(Poria cocos(Schw.)Wolf),the dried sclerotium of a polyporaceae fungus,was first documented in Shennong’s Classic of Materia Medica and has been used therapeutically and dietarily in China for millennia.Traditionally recognized for its diuretic,spleen-tonifying,and sedative properties,modern pharmacological studies confirm that Poria exhibits antioxidant,anti-inflammatory,antibacterial,and antitumor activities.Pachymic acid(PA;a triterpenoid with the chemical structure 3β-acetyloxy-16α-hydroxy-lanosta-8,24(31)-dien-21-oic acid),isolated from Poria,is a principal bioactive constituent.Emerging evidence indicates PA exerts antitumor effects through multiple mechanisms,though these remain incompletely characterized.Neuroblastoma(NB),a highly malignant pediatric extracranial solid tumor accounting for 15%of childhood cancer deaths,urgently requires safer therapeutics due to the limitations of current treatments.Although PA shows multi-mechanistic antitumor potential,its efficacy against NB remains uncharacterized.This study systematically investigated the potential molecular targets and mechanisms underlying the anti-NB effects of PA by integrating network pharmacology-based target prediction with experimental validation of multi-target interactions through molecular docking,dynamic simulations,and in vitro assays,aimed to establish a novel perspective on PA’s antitumor activity and explore its potential clinical implications for NB treatment by integrating computational predictions with biological assays.Methods This study employed network pharmacology to identify potential targets of PA in NB,followed by validation using molecular docking,molecular dynamics(MD)simulations,MM/PBSA free energy analysis,RT-qPCR and Western blot experiments.Network pharmacology analysis included target screening via TCMSP,GeneCards,DisGeNET,SwissTargetPrediction,SuperPred,and PharmMapper.Subsequently,potential targets were predicted by intersecting the results from these databases via Venn analysis.Following target prediction,topological analysis was performed to identify key targets using Cytoscape software.Molecular docking was conducted using AutoDock Vina,with the binding pocket defined based on crystal structures.MD simulations were performed for 100 ns using GROMACS,and RMSD,RMSF,SASA,and hydrogen bonding dynamics were analyzed.MM/PBSA calculations were carried out to estimate the binding free energy of each protein-ligand complex.In vitro validation included RT-qPCR and Western blot,with GAPDH used as an internal control.Results The CCK-8 assay demonstrated a concentration-dependent inhibitory effect of PA on NB cell viability.GO analysis suggested that the anti-NB activity of PA might involve cellular response to chemical stress,vesicle lumen,and protein tyrosine kinase activity.KEGG pathway enrichment analysis suggested that the anti-NB activity of PA might involve the PI3K/AKT,MAPK,and Ras signaling pathways.Molecular docking and MD simulations revealed stable binding interactions between PA and the core target proteins AKT1,EGFR,SRC,and HSP90AA1.RT-qPCR and Western blot analyses further confirmed that PA treatment significantly decreased the mRNA and protein expression of AKT1,EGFR,and SRC while increasing the HSP90AA1 mRNA and protein levels.Conclusion It was suggested that PA may exert its anti-NB effects by inhibiting AKT1,EGFR,and SRC expression,potentially modulating the PI3K/AKT signaling pathway.These findings provide crucial evidence supporting PA’s development as a therapeutic candidate for NB.展开更多
The use of Chinese herbal medicines can replace antibiotics that cause drug-resistance problems,which are currently necessary for disease control.In this paper,a traditional Chinese medicine compound named Ephedra hou...The use of Chinese herbal medicines can replace antibiotics that cause drug-resistance problems,which are currently necessary for disease control.In this paper,a traditional Chinese medicine compound named Ephedra houttuynia granule for the treatment of Mycoplasma galliscepticum(MG)infection was prepared.Furthermore,its action mechanism was explored through network pharmacology.The optimal extraction and granulation processes of the compound were determined by high performance liquid chromatography(HPLC)method and L9 orthogonal test,and in the treatment experiment,Ephedra houttuynia granule showed a significant therapeutic effect on MG infection.In the study of network pharmacology,the results showed that the core targets of Ephedra houttuynia granule against MG infection were vascular endothelial growth factor(VEGFA),fos proto-oncogene(FOS),prepro-coagulation factor II(F2),etc.,the gene ontology/kyoto encyclopedia of genes and genomes(GO/KEGG)analysis results indicated that the signaling pathways of neuroactive ligand receptor interaction,cAMP,IL-17,T cell receptor,and tumor necrosis factor(TNF)might involve in anti-MG infection.In conclusion,this study would provide a new idea for elucidating the action mechanism of other diseases in veterinary clinic,which had a certain guiding significance.展开更多
OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(...OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(CCVDs)remains not comprehensive understanding.Hence,a network pharmacology-based method was suggested in this study to address this problem.METHODS This study was based on network pharmacology and bioinformatics analysis.Information on compounds in herbal medicines of triphala formula was acquired from public databases.Oral bioavailability as well as drug-likeness were screened by using absorption,distribution,metabolism,and excretion(ADME)criteria.Then,components of triphala,candidate targets of each component and known therapeutic targets of CCVDs were collected.Compound-target gene and compounds-CCVDs target networks were created through network pharmacology data sources.In addition,key targets and pathway enrichment were analyzed by STRING database and DAVID database.Moreover,we verified three of the key targets(PTGS2,MMP9 and IL-6)predicted by using Western blotting analysis.RESULTS Network analysis determined 132 compounds in three herbal medicines that were subjected to ADME screening,and 23 compounds as well as 65 genes formed the principal pathways linked to CCVDs.And 10 compounds,which actually linked to more than three genes,are determined as crucial chemicals.Core genes in this network were IL-6,TNF,VEGFA,PTGS2,CXCL8,TP53,CCL2,IL-10,MMP9 and SERPINE1.And pathways in cancer,TNF signaling path⁃way,neuroactive ligand-receptor interaction,etc.related to CCVDs were identified.In vitro experiments,the results indi⁃cated that compared with the control group(no treatment),PTGS2,MMP9 and IL-6 were up-regulated by treatment of 10μg·L^-1 TNF-α,while pretreatment with 20-80 mg·L^-1 triphala could significantly inhibit the expression of PTGS2,MMP9 and IL-6.With increasing Triphala concentration,the expression of PTGS2,MMP9 and IL-6 decreased.CON⁃CLUSION Complex components and pharmacological mechanism of triphala,and obtained some potential therapeutic targets of CCVDs,which could provide theoretical basis for the research and development of new drugs for treating CCVDs.展开更多
OBJECTIVE Depression is one of the prevalent and prominent complex psychiatric diseases and the number of depressed patients has been on the rise globally during the recent decades.Xiaoyaosan,as a famous Chinese herba...OBJECTIVE Depression is one of the prevalent and prominent complex psychiatric diseases and the number of depressed patients has been on the rise globally during the recent decades.Xiaoyaosan,as a famous Chinese herbal formula,has been widely used in depression patients for a long time. However,the therapeutic mechanisms remain uncertain because of difficulty of depression pathophysiology and the lack of bioinformatic approach to understand the molecular connection. METHODS In this thesis,we applied a network pharmacology approach to explain the potential mechanisms between Xiaoyaosan and depression involved in oral bioavailability screening,drug-likeness assessment,caco-2 permeability,blood-brain barrier target recognition and network analysis. RESULTS 66 active compounds in Xiaoyaosan formula with favorable pharmacokinetic profiles are predicted as active compounds for anti-depression treatment. Network analyses show that these 66 compounds target 40depression-associated proteins including especially HTR2A,NR 3C1,MAOB,XDH and CNR2. These proteins are mainly involved in the neuroactive ligand-receptor interaction,serotonergic synapse,cAMP signaling pathways and calcium signaling pathways. CONCLUSION The integrated network pharmacology method is an effective approach to illustrate the anti-depression mechanisms of herbs,and this in silico approach can be applied in drug discovery.展开更多
Oleanolic acid(OA)is a pentacyclic triterpenoid chemical component that exists in natural plants with a molecular formula of C30H48O3 and a molecular weight at 456.71 g·mol-1.OA is widespread in traditional Chine...Oleanolic acid(OA)is a pentacyclic triterpenoid chemical component that exists in natural plants with a molecular formula of C30H48O3 and a molecular weight at 456.71 g·mol-1.OA is widespread in traditional Chinese herbal medicine(Ligustri Lucidi Fructus,Achyranthis Bidentate Radix,Red Sage)and berries(blueberries,grapes).In recent years,because of the extensive pharmacological effects of OA,its advantages in disease treatment have become increasingly prominent and gradually attracted the attention of pharmaceutical researchers.OA has effective therapeutic effects on a series of chronic diseases such as inflammation,cancer,diabetes,and cardiovascular diseases through multiple signaling pathways and various targets.Especially in cancers,such as colorectal cancer,liver cancer,gastric cancer,lung cancer,breast cancer and other malignancies,OA presents substantial efficacy.However,its poor aqueous solubility,needy bioavailability,and unsatisfactory pharmacological activity excessively restrict its clinical application.More importantly,the improper utilization of OA can cause adverse reactions,toxic effects and even damage to organs in some specific situations.With the discovery of various pharmacological effects,the complex action mechanisms of OA,the continuous progress in structural modification of OA,as well as the synthesis of OA derivatives,its application is expanding gradually.Among numerous studies,there is a clear indication that OA and its derivatives,if fully developed,may provide an alternative and cheaper treatment for a variety of chronic diseases.However,the specific molecular mechanisms of OA and its derivatives as an alternative therapy and supplementary therapy for cancer,diabetes,cardiovascular disease and other chronic diseases remain to be clarified.Therefore,it is necessary to further study the pharmacokinetics,pharmacological activity,specific targets and related mechanisms of OA to lay a solid foundation for drug development and the application of OA in clinical settings.展开更多
Aim YiQiFuMai Powder Injection is a well-known traditional Chinese medicine formula that has been used extensively in clinical treatment of cardio-cerebral ischemic diseases in China. However, the mechanisms under-lyi...Aim YiQiFuMai Powder Injection is a well-known traditional Chinese medicine formula that has been used extensively in clinical treatment of cardio-cerebral ischemic diseases in China. However, the mechanisms under-lying its clinical efficacy remain unknown. In this study, a network pharmacology approach was employed to identify the YiQiFuMai Powder Injection＇s potential pathways and targets against cardio-cerebral ischemia. The target-path- way interaction network clustered the signaling pathways based on high degree nodes of the drug-target network. The potential protein targets presented in the highly scored clustered pathways were the key network hubs and concentrated on one or limited functional signaling pathways amenable to experimental verification. Twelve main functional annota- tion clusters and main signaling pathways for YiQiFuMai Powder Injection were established by Biocarta analysis, in- eluding the NF-KB signaling pathway, the MAPKinase signaling pathway and the mTOR-signaling pathway and so on. YiQiFuMai Powder Injection is hypothesized to target multiple proteins with a high degree and betweenness of net- work. In addition, the most related pathways were also confirmed in tumor necrosis factor-alpha （TNF-oL） induced human vascular endothelial cell line EA. hy926 by Western blot. This study elucidates the systematic network and pathway analysis of multi-targets in YiQiFuMai Powder Injection. The results provide the possible mechanisms for its mode of action against cardio-cerebral ischemic diseases and may also reveal new clues for its potential application in the inflammatory diseases or tumors.展开更多
Chinese Journal of Pharmacology and Toxicology(CJPT)started its publication in 1986.It is amonthly and distributed to readers both at home and abroad.This journal is collaboratiyely sponsored by the Chinese Pharmacolo...Chinese Journal of Pharmacology and Toxicology(CJPT)started its publication in 1986.It is amonthly and distributed to readers both at home and abroad.This journal is collaboratiyely sponsored by the Chinese Pharmacological Society,the Chinfese Society of Toxicology and BeijingInstitute of Pharmacology and Toxicology.This journal focuses on the presentation of the latestfindings in the fields of pharmacology and toxicology in order to promote academic exchangesworldwide and steer this sphere of research forward.展开更多
OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key target...OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key targets toward Alzheimer disease.Then,druglikeness,oral bioavailability and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for central nervous system diseases treatment.Finallly,we were attempted to predict the targets of constituents and find potential multi-target compounds from Nao De Sheng formula by combining the advantages of machine learning,molecular docking and pharmacophore mapping together.RESULTS Constituenttarget network,constituent-target-target network and targetbiological pathway network were built to explain the network pharmacology of the constituents in NaoD eS heng formula.CONCLUSION To the best of our knowledge,we were the first to study the mechanism of Nao De Sheng formula for potential efficacy for Alzheimer disease treatment by means of the virtual screening and network pharmacology methods.展开更多
OBJECTIVE To explore the potential molecular mechanism of Shenlian(SL)on myocardial ischemia(MI)on the basis of network pharmacology.METHODS Firstly,the main active ingredients of SL were screened in the Traditional C...OBJECTIVE To explore the potential molecular mechanism of Shenlian(SL)on myocardial ischemia(MI)on the basis of network pharmacology.METHODS Firstly,the main active ingredients of SL were screened in the Traditional Chinese Medicine Integrated Database,and the MI-associated targets were collected from the DisGeNET database.Then,we used compound-target and target-pathway networks to uncover the therapeutic mechanisms of SL On the basis of network pharmacology analysis results,we assessed the effects of SL in MI rat model and oxygen glu⁃cose deprivation model of H9c2 cells and validated the possible molecular mechanisms of SL on myocardial injury in vivo and in vitro.RESULTS The network pharmacology results showed that 37 potential targets were recognized,including TNF-α,Bcl-2,STAT3,PI3K,and MMP2.The pathways revealed that the possible targets of SL were involved in the reg⁃ulation of inflammation and apoptosis signaling pathway.Then,in vivo experiments indicated that SL significantly reduced the myocardial infarction size of MI rats.Serum CK-MB,cTnT,CK,LDH,and AST levels were significantly decreased by SL(P<0.05 or P<0.01).In vitro,SL significantly increased H9c2 cell viability.The levels of inflammation factors including TNF-αand MMP2 were significantly decreased by SL(P<0.05 or P<0.01).TUNEL and Annexin V/propidium iodide assays indicated that SL could significantly decrease the cell apoptotic rate in vivo and in vitro(P<0.05 or P<0.01).The remarkable upregulation of anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax protein level further confirmed this result.Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the PI3K-Akt and JAK2-STAT3 pathways were significantly enriched in SL.Compared with the model group,SL treatment significantly activated the PI3K-Akt and JAK2-STAT3 pathways in vivo and in vitro according to Western blotting analyses.CONCLU⁃SION SL could protect the myocardium from MI injury.The underlying mechanism may be related to the reduction of inflammation and apoptosis by activating the PI3K/Akt and JAK2/STAT3 pathways.展开更多
OBJECTIVE To explore mecha⁃nisms of imperatorin on regulating P-glycoprotein(P-gp)in blood-brain barrier(BBB)based on net⁃work pharmacology combined with in vitro experi⁃ment.METHODS Drug targets were predicted using ...OBJECTIVE To explore mecha⁃nisms of imperatorin on regulating P-glycoprotein(P-gp)in blood-brain barrier(BBB)based on net⁃work pharmacology combined with in vitro experi⁃ment.METHODS Drug targets were predicted using the Pharmapper and Swiss targets data⁃bases;disease targets were obtained through the Genecards database;intersections between drugs and disease targets were screened by Cytoscape software;the obtained core targets were used to construct protein-protein interaction(PPI)network,gene ontology(GO)functions,and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis.The effects of imperatorin(20,50,100μmol·L^(-1))on P-gp activity were monitored in hCMEC/D3 in vitro BBB model,and the effects of imperatorin on the expression of target proteins were verified using Western blot method.RESULTS 55 drug targets and 3102 disease targets were obtained from the network pharmacology screening,and 37 core targets were obtained after the combination.Enrichment analysis showed that core targets were closely related to chemical synaptic trans⁃mission regulation,neurotransmitter receptor activity,protein kinase regulation activity,G proteincoupled receptor signaling pathway,neural active ligand receptor interaction pathway,PI3K-Akt sig⁃naling pathway,VEGF signaling pathway,etc..In vitro experimental validation suggested that all tested concentration groups of imperatorin signifi⁃cantly reduced the activity and expression of P-gp,which were achieved by significantly downregu⁃lating the phosphorylation levels of PI3K and Akt,and repressing the expression of VEGFR2 pro⁃tein.CONCLUSION Network pharmacology was used to predict the core targets and signaling pathways of imperatorin on regulating P-gp in BBB and relevant validation was conducted through in vitro experiments,providing a refer⁃ence basis for further exploration of the mecha⁃nisms of imperatorin on regulating P-gp in BBB.展开更多
OBJECTIVE To investigate the regulatory effects of icariin(ICA)on cardiac micro⁃vascular endothelial cells(CMEC)after oxygenglucose deprivation reperfusion(OGD/R)injury.METHODS CMEC were subjected to OGD/R treatment t...OBJECTIVE To investigate the regulatory effects of icariin(ICA)on cardiac micro⁃vascular endothelial cells(CMEC)after oxygenglucose deprivation reperfusion(OGD/R)injury.METHODS CMEC were subjected to OGD/R treatment to construct a myocardial ischemiareperfusion model,and were divided into normal,model,low(10μmol·L^(-1)),medium(20μmol·L^(-1))and high(40μmol·L^(-1))ICA group,and high ICA+inhibitor group(40μmol·L^(-1)+20 nmol·L^(-1)).CCK-8 assay was used to assess the protective ability of ICA against CMEC,and cell migration assay and tube-formation assay were used to detect the migration and generation ability of CMEC.The TCMSP database,Swiss-Target database and literature mining methods were used to col⁃lect ICA-related targets,the GeneCards data⁃base was used to collect target genes related to myocardial ischemia/reperfusion,and Cytoscape 3.8.0 software was used to construct a"drug-tar⁃get-disease"network.The potential targets were imported into STRING 11.5 database to obtain the PPI network.GO and KEGG enrichment analyses were performed on the potential targets using the DAVID database.Molecular docking was performed using AutoDock-vina 1.1.2 soft⁃ware.Western blot detected the expression of related proteins.RESULTS After CMEC was subjected to OGD/R treatment,ICA had a protec⁃tive effect at 10^(-1)60μmol·L^(-1);the results of the cell migration assay showed that each group of ICA could promote the migratory effect of CMEC(P<0.01,P<0.01);and the results of tube-for⁃mation assay showed that each group of ICA could significantly promote the generation of branches(P<0.01)and the capillary length exten⁃sion(P<0.05).Network pharmacology collected a total of 23 ICA action targets,1500 disease tar⁃gets and 12 key targets.GO function enrichment analysis found 85 results.KEGG pathway enrich⁃ment analysis found 53 results,involving AGERAGE signaling pathway,sphingolipid signaling pathway and VEGF signaling pathway.Molecu⁃lar docking results showed that ICA had better binding with core targets PRKCB,PRKCA and PTGS2.Western blot results showed that ICA could regulate the expression of PRKCB,PRKCA and PTGS2 proteins.The results of cell migra⁃tion assay,tube-formation assay and protein expression were reversed after addition of PKC inhibitor.CONCLUSION The potential mecha⁃nism of action of ICA against myocardial isch⁃emia-reperfusion injury may be related to the reg⁃ulation of processes such as CMEC migration and angiogenesis,and it functions through the key target gene PKC.展开更多
OBJECTIVE To explore the key mechanism of Bazi Bushen capsule(BZBS)in delaying the senescence of mesenchymal stem cells(MSCs)through network pharmacology and in vitro experiments.METHODS Network pharmacology was used ...OBJECTIVE To explore the key mechanism of Bazi Bushen capsule(BZBS)in delaying the senescence of mesenchymal stem cells(MSCs)through network pharmacology and in vitro experiments.METHODS Network pharmacology was used to predict the mechanism targets of BZBS in delaying MSCs senescence.A MSCs senescence model induced by D-galactose(D-gal)was used to investigate the effect and mechanism of BZBS on MSCs senescence in vitro.RESULTS Network pharmacology analy⁃sis showed that BZSB could delay MSCs senes⁃cence.The experiment showed that BZBS could significantly improve the survival activity of the aged MSCs.It significantly reduced the positive rate ofβ-galactosidase staining and p16,p21 expression in aged MSCs,enhanced the ability of adipogenic differentiation and osteogenic differentiation,and increased expression of Nanog,OCT4 and SOX2 in senescent MSCs.CONCLU⁃SIONS Network pharmacology and in vitro cell experiments verified that BZBS could delay MSCs senescence.展开更多
Pulsatilla chinensis is a widely used traditional Chinese herb,which contains 56 types of chemical constituents,mainly including triterpenoid saponins,organic acids,coumarins and lignans.The largest portion of the ing...Pulsatilla chinensis is a widely used traditional Chinese herb,which contains 56 types of chemical constituents,mainly including triterpenoid saponins,organic acids,coumarins and lignans.The largest portion of the ingredients in Pulsatilla chinensis is the family of triterpenoid saponins,in which anemoside B4 is the major effective compound and indexing component.The main components of Pulsatilla chinensis can metabolize into a vast array of active products in vivo,which play vital roles in its biological activity.Mounting evidence reveals that Pulsatilla chinensis exerts a wide range of therapeutic activities,such as anti-cancer,immunoregulation,anti-inflammation and anti-schistosome,with fewer adverse reactions,via various signaling pathways and multiple targets.It was documented that the active ingredient of Pulsatilla chinensis can lessen the drug resistance and synergize the effects of other natural products including paclitaxel,as well as ameliorate the clinical efficacy of chemical drugs,such as adriamycin.However,Pulsatilla chinensis was also reported to be possibly the main cause of hemolysis and chronic liver injury.The efforts should be made to deeply investigate the pharmacological actions and underlying mechanisms of Pulsatilla chinensis,with a focus on the anti-cancer efficacy,and develop new drugs based on the components of Pulsatilla chinensis for future utilization in the clinical setting.展开更多
Objective To investigate the potential therapeutic targets and pharmacological mechanism of(-)-epigallocatechin-3-gallate(EGCG)based on network pharmacology and experimental verification.METHODS The druggability of EG...Objective To investigate the potential therapeutic targets and pharmacological mechanism of(-)-epigallocatechin-3-gallate(EGCG)based on network pharmacology and experimental verification.METHODS The druggability of EGCG was measured by the traditional Chinese medicine systems pharmacology(TCMSP)server,and potential targets of EGCG were identified by Pharm Mapper and Drug Repositioning and Adverse drug Reaction via Chemical-Protein Interactome(DRAR-CPI).The potential targets were imported into GeneMANIA database to obtain the protein-protein direct interaction network,and target physical interaction,co-expression,prediction,genetic interaction,and shared protein domains.The biological process,molecular functions,cellular components and KEGG signaling pathways of potential targets were analyzed using DAVID database.For further study,ethanol was used to establish a model of endothelial injury in vitro.The cell viability was assayed by MTT method,the cellular apoptosis was stained by Annexin V/PI,and the expression levels of Bcl-2,Bax and cleved-caspase-3 were tested by Western blotting.Then,JC-1 and nuclear translocation of NF-κB experiments were used to study the mitochondrial membrane potential and nuclear translocation.RESULTS The oral availability of EGCG was 55.09%(≥30%)and drug-like index was 0.77(≥0.18),which were considered pharmacokinetically active.17 potential targetable proteins of EGCG were predicted by Pharm Mapper and DRAR-CPI.Further research showed that 68.13%displayed similar co-expression characteristics,26.11%physical interactions,and 2.74%shared the same protein domain.The depth network analysis results showed that the biofunctions of EGCG were mainly by regulating glutathione derivative biosynthetic process,glutathione metabolic process,nitrogen compound metabolic process etc..via drug binding,catalytic activity,glutathione transferase activity,anion binding etc..in sarcoplasmic reticulum,spindle pole,microtubule cytoskeleton and cytoplasm.KEGG enrichment analysis showed that Glutathione metabolism,IL^(-1)7 signaling pathway,EGFR tyrosine kinase inhibitor resistance,PI3K-Akt signaling pathway and other pathways were involves in the biofunction of EGCG.The above analyses indicated that EGCG exerts its biofunction through antioxidant and anti-inflammatory mechanisms.The experimental results showed that ethanol 20.0 mmol·L^(-1) decreased cell viability,Bcl-2 expression,and increased cell apoptosis,the intracellular ROS,as well as the expression of Bax and cleaved-caspase-3 of human endothelial cells.However,treatment of the cells with EGCG can significantly alleviate ethanol induced endothelial cells injury.Further study showed that EGCG significantly alleviates ethanol induced mitochondrial depolarization and nuclear translocation of NF-κB.CONCLUSIONS EGCG exerts pharmacological efficacies on ethanol induced endothelial cell injury through multi-target,multi-function and multi-pathway mode.Protective effect of EGCG on ethanol induced cell injury was mainly through alteration of mitochondrial function and NF-κB translocation.Therefore,EGCG have great potential in protecting against endothelial dysfunction of the persons who are chronically abuse of ethanol.This study also provides a new understanding of EGCG in clinical application on cardiovascular and cerebrovascular diseases.展开更多
OBJECTIVE To predict the potential targets of hyperoside(Hyp)on improving ischemia/reperfusion injury by network pharmacology,and explore its possible mechanism combined with related literature.METHODS The action targ...OBJECTIVE To predict the potential targets of hyperoside(Hyp)on improving ischemia/reperfusion injury by network pharmacology,and explore its possible mechanism combined with related literature.METHODS The action targets of Hyp and ischemia/reperfusion injury were obtained by TCMSP,Swiss Target Prediction,Pharm Mapper,Similarity ensemble approach,Online Mendelian Inheritance in Man,DisGENT and database.The common targets of drugs and diseases were screened by Omishare and STRING database respectively,and the protein-protein interaction(PPI)network map was constructed.Then the interaction network between Hyp and disease targets was constructed by Cytoscape software and topological cross-linking analysis was carried out.Then the interaction network between Hyp and disease targets was constructed and cross-linked analysis was carried out by using Cytoscape software.The gene ontology(GO)of the core target was analyzed by David database,and then the related pathways of the core target were enriched by KEGG database.RESULTS A total of 54 GO enrichment processes were obtained by GO enrichment analysis of 44 common genes,including 38 biological processes(BP),15 cell composition(CC)processes,and 1 molecular functional(MF)process.43 items were obtained by signal pathway enrichment analysis in KEGG database.CONCLUSION It is suggested that the mechanism of Hyp may be related to PI3K-Akt,RAP1,RAS,VEGF and other signal transduction pathways.The above results laid a theoretical foundation for the study of the mechanism and clinical application of the treatment of ischemia/reperfusion injury.展开更多
Chinese Journal of Pharmacology and Toxicology(CJPT)started its publication in 1986.It is a monthly and distributed to readers both at home and abroad.This journal is collaboratively sponsored by the Chinese Pharmacol...Chinese Journal of Pharmacology and Toxicology(CJPT)started its publication in 1986.It is a monthly and distributed to readers both at home and abroad.This journal is collaboratively sponsored by the Chinese Pharmacological Society,the Chinese Society of Toxicology and Beijing Institute of Pharmacology and Toxicology.This journal focuses on the presentation of the latest findings in the fields of pharmacology and toxicology in order to promote academic exchanges worldwide and steer this sphere of research forward.In line with the principles of precision,展开更多
Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global atte...Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global attention in the medical field.Precision medicine aims at applying genetic information of individual diseases to guide his or her diagnosis and treatment.展开更多
There are two general approaches to drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alt...There are two general approaches to drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alternative is mechanism-based, a process that entails the in vitro screening of purified chemical compounds to identify those that interact specifically with a selected biological target, after which they are tested for therapeutic potential. A major difference between these approaches is the extent to which the principles of pharmacology are employed to demonstrate safety and efficacy and to enable improvements in the therapeutic properties of the product. As a thorough pharmacological analysis of the pharmacokinetics and pharmacodynamics of a test agent requires that it be a stable, single, purified substance, such testing is more difficult with unpurified samples containing multiple compounds as compared to single agents. A lack of pharmacological information compromises the clinical utility of a test substance by leaving open questions about its bioavailability, metabolism, and mechanisms of therapeutic actions and toxicities. Although drug discovery success has be achieved with both the empirically-driven and mechanism-based approaches, the proper application of pharmacological techniques in the drug discovery process maximizes efficacy, safety and the chance for regulatory approval. In addition, pharmacological data provides information needed for improving the therapeutic properties of an agent, enhancing its clinical utility, and extending the product lifespan.展开更多
Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conse...Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conserved thrombospondin family,THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions.Through dynamic interactions with various ECM components,THBS4 plays pivotal roles in cell adhesion,proliferation,inflammation regulation,and tissue remodeling,establishing it as a key modulator of microenvironmental organization.The transcription and translation of THBS4 gene,as well as the activity of the THBS4 protein,are tightly regulated by multiple signaling pathways and extracellular cues.Positive regulators of THBS4 include transforming growth factorβ(TGF-β),interferonγ(IFNγ),granulocyte-macrophage colony-stimulating factor(GM-CSF),bone morphogenetic proteins(BMP12/13),and other regulatory factors(such as B4GALNT1,ITGA2/ITGB1,PDGFRβ,etc.),which upregulate THBS4 at the mRNA and/or protein level.Conversely,oxidized low-density lipoprotein(OXLDL)acts as a potent negative regulator of THBS4.This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to diverse physiological and pathological stimuli.Functionally,THBS4 acts as a critical signaling hub,influencing multiple downstream pathways essential for cellular behavior and tissue homeostasis.The best-characterized pathways include:(1)the PI3K/AKT/mTOR axis,which THBS4 modulates through both direct and indirect interactions with integrins and growth factor receptors;(2)Wnt/β-catenin signaling,where THBS4 functions as either an activator or inhibitor depending on the cellular context;(3)the suppression of DBET/TRIM69,contributing to its diverse regulatory roles.These signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes.Substantial evidence links aberrant THBS4 expression to a range of pathological conditions,including neoplastic diseases,cardiovascular disorders,fibrotic conditions,neurodegenerative diseases,musculoskeletal disorders,and atopic dermatitis.In cancer biology,THBS4 exhibits context-dependent roles,functioning either as a tumor suppressor or promoter depending on the tumor type and microenvironment.In the cardiovascular system,THBS4 contributes to both adaptive remodeling and maladaptive fibrotic responses.Its involvement in fibrotic diseases arises from its ability to regulate ECM deposition and turnover.The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine.As a biomarker,THBS4 expression patterns correlate significantly with disease progression and patient outcomes.Therapeutically,targeting THBS4-mediated pathways offers novel opportunities for precision medicine approaches,including anti-fibrotic therapies,modulation of the tumor microenvironment,and enhancement of tissue repair.This comprehensive review systematically explores three key aspects of THBS4 research:(1)the fundamental biological functions of THBS4 in ECM organization;(2)its mechanistic involvement in various disease pathologies;(3)its emerging potential as both a diagnostic biomarker and therapeutic target.By integrating recent insights from molecular studies,animal models,and clinical investigations,this review provides a framework for understanding the multifaceted roles of THBS4 in health and disease.The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts.Given its unique position at the intersection of ECM biology and cellular signaling,THBS4 represents a promising frontier for the development of novel diagnostic tools and therapeutic strategies in precision medicine.展开更多
文摘The anti-hair loss mechanism of Aquilaria sinensis leaf extract(ASE)has been studied by using metabolomics and network pharmacology.Metabolomics was utilized to comprehensively identify the active constituents of ASE,and the network pharmacology was used to elucidate their anti-hair loss mechanism,which was verified by molecular docking technology.572 active compounds were identified from the ASE by metabolomics methods,where there are 1447 corresponding targets and 492 targets related to hair loss,totaling 88 targets.20 core active substances were identified by constructing a network between common targets and active substances,which include vanillic acid,chorionic acid,caffeic acid and apigenin.The five key targets of TNF,TP53,IL6,PPARG,and EGFR were screened out by the PPI network analysis on 88 common targets.The GO and KEGG pathway enrichment analysis showed that the inflammation,hormone balance,cell growth,proliferation,apoptosis,and oxidative stress are involved.Molecular docking studies have confirmed the high binding affinity between core active compounds and key targets.The drug similarity assessment on these core compounds suggested that they have the potential to be used as potential hair loss treatment drugs.This study elucidates the complex molecular mechanism of ASE in treating hair loss,and provides a reference for the future applications in hair care products.
文摘Objective Traditional Chinese medicine(TCM)constitutes a valuable cultural heritage and an important source of antitumor compounds.Poria(Poria cocos(Schw.)Wolf),the dried sclerotium of a polyporaceae fungus,was first documented in Shennong’s Classic of Materia Medica and has been used therapeutically and dietarily in China for millennia.Traditionally recognized for its diuretic,spleen-tonifying,and sedative properties,modern pharmacological studies confirm that Poria exhibits antioxidant,anti-inflammatory,antibacterial,and antitumor activities.Pachymic acid(PA;a triterpenoid with the chemical structure 3β-acetyloxy-16α-hydroxy-lanosta-8,24(31)-dien-21-oic acid),isolated from Poria,is a principal bioactive constituent.Emerging evidence indicates PA exerts antitumor effects through multiple mechanisms,though these remain incompletely characterized.Neuroblastoma(NB),a highly malignant pediatric extracranial solid tumor accounting for 15%of childhood cancer deaths,urgently requires safer therapeutics due to the limitations of current treatments.Although PA shows multi-mechanistic antitumor potential,its efficacy against NB remains uncharacterized.This study systematically investigated the potential molecular targets and mechanisms underlying the anti-NB effects of PA by integrating network pharmacology-based target prediction with experimental validation of multi-target interactions through molecular docking,dynamic simulations,and in vitro assays,aimed to establish a novel perspective on PA’s antitumor activity and explore its potential clinical implications for NB treatment by integrating computational predictions with biological assays.Methods This study employed network pharmacology to identify potential targets of PA in NB,followed by validation using molecular docking,molecular dynamics(MD)simulations,MM/PBSA free energy analysis,RT-qPCR and Western blot experiments.Network pharmacology analysis included target screening via TCMSP,GeneCards,DisGeNET,SwissTargetPrediction,SuperPred,and PharmMapper.Subsequently,potential targets were predicted by intersecting the results from these databases via Venn analysis.Following target prediction,topological analysis was performed to identify key targets using Cytoscape software.Molecular docking was conducted using AutoDock Vina,with the binding pocket defined based on crystal structures.MD simulations were performed for 100 ns using GROMACS,and RMSD,RMSF,SASA,and hydrogen bonding dynamics were analyzed.MM/PBSA calculations were carried out to estimate the binding free energy of each protein-ligand complex.In vitro validation included RT-qPCR and Western blot,with GAPDH used as an internal control.Results The CCK-8 assay demonstrated a concentration-dependent inhibitory effect of PA on NB cell viability.GO analysis suggested that the anti-NB activity of PA might involve cellular response to chemical stress,vesicle lumen,and protein tyrosine kinase activity.KEGG pathway enrichment analysis suggested that the anti-NB activity of PA might involve the PI3K/AKT,MAPK,and Ras signaling pathways.Molecular docking and MD simulations revealed stable binding interactions between PA and the core target proteins AKT1,EGFR,SRC,and HSP90AA1.RT-qPCR and Western blot analyses further confirmed that PA treatment significantly decreased the mRNA and protein expression of AKT1,EGFR,and SRC while increasing the HSP90AA1 mRNA and protein levels.Conclusion It was suggested that PA may exert its anti-NB effects by inhibiting AKT1,EGFR,and SRC expression,potentially modulating the PI3K/AKT signaling pathway.These findings provide crucial evidence supporting PA’s development as a therapeutic candidate for NB.
基金the National Natural Science Foundation of China(32273062,31973005)。
文摘The use of Chinese herbal medicines can replace antibiotics that cause drug-resistance problems,which are currently necessary for disease control.In this paper,a traditional Chinese medicine compound named Ephedra houttuynia granule for the treatment of Mycoplasma galliscepticum(MG)infection was prepared.Furthermore,its action mechanism was explored through network pharmacology.The optimal extraction and granulation processes of the compound were determined by high performance liquid chromatography(HPLC)method and L9 orthogonal test,and in the treatment experiment,Ephedra houttuynia granule showed a significant therapeutic effect on MG infection.In the study of network pharmacology,the results showed that the core targets of Ephedra houttuynia granule against MG infection were vascular endothelial growth factor(VEGFA),fos proto-oncogene(FOS),prepro-coagulation factor II(F2),etc.,the gene ontology/kyoto encyclopedia of genes and genomes(GO/KEGG)analysis results indicated that the signaling pathways of neuroactive ligand receptor interaction,cAMP,IL-17,T cell receptor,and tumor necrosis factor(TNF)might involve in anti-MG infection.In conclusion,this study would provide a new idea for elucidating the action mechanism of other diseases in veterinary clinic,which had a certain guiding significance.
基金National Natural Science Foundation of China(81603385)China Postdoctoral Science Foundation(2018M643843)+1 种基金Natural Science Foundation of Shaanxi Province(2017JM8056)Key Research and Development Foundation of Shaanxi province(2018SF-241)
文摘OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(CCVDs)remains not comprehensive understanding.Hence,a network pharmacology-based method was suggested in this study to address this problem.METHODS This study was based on network pharmacology and bioinformatics analysis.Information on compounds in herbal medicines of triphala formula was acquired from public databases.Oral bioavailability as well as drug-likeness were screened by using absorption,distribution,metabolism,and excretion(ADME)criteria.Then,components of triphala,candidate targets of each component and known therapeutic targets of CCVDs were collected.Compound-target gene and compounds-CCVDs target networks were created through network pharmacology data sources.In addition,key targets and pathway enrichment were analyzed by STRING database and DAVID database.Moreover,we verified three of the key targets(PTGS2,MMP9 and IL-6)predicted by using Western blotting analysis.RESULTS Network analysis determined 132 compounds in three herbal medicines that were subjected to ADME screening,and 23 compounds as well as 65 genes formed the principal pathways linked to CCVDs.And 10 compounds,which actually linked to more than three genes,are determined as crucial chemicals.Core genes in this network were IL-6,TNF,VEGFA,PTGS2,CXCL8,TP53,CCL2,IL-10,MMP9 and SERPINE1.And pathways in cancer,TNF signaling path⁃way,neuroactive ligand-receptor interaction,etc.related to CCVDs were identified.In vitro experiments,the results indi⁃cated that compared with the control group(no treatment),PTGS2,MMP9 and IL-6 were up-regulated by treatment of 10μg·L^-1 TNF-α,while pretreatment with 20-80 mg·L^-1 triphala could significantly inhibit the expression of PTGS2,MMP9 and IL-6.With increasing Triphala concentration,the expression of PTGS2,MMP9 and IL-6 decreased.CON⁃CLUSION Complex components and pharmacological mechanism of triphala,and obtained some potential therapeutic targets of CCVDs,which could provide theoretical basis for the research and development of new drugs for treating CCVDs.
文摘OBJECTIVE Depression is one of the prevalent and prominent complex psychiatric diseases and the number of depressed patients has been on the rise globally during the recent decades.Xiaoyaosan,as a famous Chinese herbal formula,has been widely used in depression patients for a long time. However,the therapeutic mechanisms remain uncertain because of difficulty of depression pathophysiology and the lack of bioinformatic approach to understand the molecular connection. METHODS In this thesis,we applied a network pharmacology approach to explain the potential mechanisms between Xiaoyaosan and depression involved in oral bioavailability screening,drug-likeness assessment,caco-2 permeability,blood-brain barrier target recognition and network analysis. RESULTS 66 active compounds in Xiaoyaosan formula with favorable pharmacokinetic profiles are predicted as active compounds for anti-depression treatment. Network analyses show that these 66 compounds target 40depression-associated proteins including especially HTR2A,NR 3C1,MAOB,XDH and CNR2. These proteins are mainly involved in the neuroactive ligand-receptor interaction,serotonergic synapse,cAMP signaling pathways and calcium signaling pathways. CONCLUSION The integrated network pharmacology method is an effective approach to illustrate the anti-depression mechanisms of herbs,and this in silico approach can be applied in drug discovery.
基金National Natural Science Foundation of China(81573813,81173598)Sichuan Provincial Admin⁃istration of Traditional Chinese Medicine of China(2021MS447)+1 种基金Excellent Talent Program of Chengdu University of Tra⁃ditional Chinese Medicine of China(YXRC2019002,ZRYY1917)and Open Research Fund of the State Key Laboratory of Southwestern Chinese Medicine Resources of China(2020XSGG006)。
文摘Oleanolic acid(OA)is a pentacyclic triterpenoid chemical component that exists in natural plants with a molecular formula of C30H48O3 and a molecular weight at 456.71 g·mol-1.OA is widespread in traditional Chinese herbal medicine(Ligustri Lucidi Fructus,Achyranthis Bidentate Radix,Red Sage)and berries(blueberries,grapes).In recent years,because of the extensive pharmacological effects of OA,its advantages in disease treatment have become increasingly prominent and gradually attracted the attention of pharmaceutical researchers.OA has effective therapeutic effects on a series of chronic diseases such as inflammation,cancer,diabetes,and cardiovascular diseases through multiple signaling pathways and various targets.Especially in cancers,such as colorectal cancer,liver cancer,gastric cancer,lung cancer,breast cancer and other malignancies,OA presents substantial efficacy.However,its poor aqueous solubility,needy bioavailability,and unsatisfactory pharmacological activity excessively restrict its clinical application.More importantly,the improper utilization of OA can cause adverse reactions,toxic effects and even damage to organs in some specific situations.With the discovery of various pharmacological effects,the complex action mechanisms of OA,the continuous progress in structural modification of OA,as well as the synthesis of OA derivatives,its application is expanding gradually.Among numerous studies,there is a clear indication that OA and its derivatives,if fully developed,may provide an alternative and cheaper treatment for a variety of chronic diseases.However,the specific molecular mechanisms of OA and its derivatives as an alternative therapy and supplementary therapy for cancer,diabetes,cardiovascular disease and other chronic diseases remain to be clarified.Therefore,it is necessary to further study the pharmacokinetics,pharmacological activity,specific targets and related mechanisms of OA to lay a solid foundation for drug development and the application of OA in clinical settings.
文摘Aim YiQiFuMai Powder Injection is a well-known traditional Chinese medicine formula that has been used extensively in clinical treatment of cardio-cerebral ischemic diseases in China. However, the mechanisms under-lying its clinical efficacy remain unknown. In this study, a network pharmacology approach was employed to identify the YiQiFuMai Powder Injection＇s potential pathways and targets against cardio-cerebral ischemia. The target-path- way interaction network clustered the signaling pathways based on high degree nodes of the drug-target network. The potential protein targets presented in the highly scored clustered pathways were the key network hubs and concentrated on one or limited functional signaling pathways amenable to experimental verification. Twelve main functional annota- tion clusters and main signaling pathways for YiQiFuMai Powder Injection were established by Biocarta analysis, in- eluding the NF-KB signaling pathway, the MAPKinase signaling pathway and the mTOR-signaling pathway and so on. YiQiFuMai Powder Injection is hypothesized to target multiple proteins with a high degree and betweenness of net- work. In addition, the most related pathways were also confirmed in tumor necrosis factor-alpha （TNF-oL） induced human vascular endothelial cell line EA. hy926 by Western blot. This study elucidates the systematic network and pathway analysis of multi-targets in YiQiFuMai Powder Injection. The results provide the possible mechanisms for its mode of action against cardio-cerebral ischemic diseases and may also reveal new clues for its potential application in the inflammatory diseases or tumors.
文摘Chinese Journal of Pharmacology and Toxicology(CJPT)started its publication in 1986.It is amonthly and distributed to readers both at home and abroad.This journal is collaboratiyely sponsored by the Chinese Pharmacological Society,the Chinfese Society of Toxicology and BeijingInstitute of Pharmacology and Toxicology.This journal focuses on the presentation of the latestfindings in the fields of pharmacology and toxicology in order to promote academic exchangesworldwide and steer this sphere of research forward.
基金The project supported by the Research Special Fund for the National Great Science and Technology Projects(2012ZX09301002,2012ZX09508104,2013ZX09402203)the International Col aboration Project(2011DFR31240)Peking Union Medical College Graduate Student Innovation Fund(2013-1007-18)
文摘OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key targets toward Alzheimer disease.Then,druglikeness,oral bioavailability and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for central nervous system diseases treatment.Finallly,we were attempted to predict the targets of constituents and find potential multi-target compounds from Nao De Sheng formula by combining the advantages of machine learning,molecular docking and pharmacophore mapping together.RESULTS Constituenttarget network,constituent-target-target network and targetbiological pathway network were built to explain the network pharmacology of the constituents in NaoD eS heng formula.CONCLUSION To the best of our knowledge,we were the first to study the mechanism of Nao De Sheng formula for potential efficacy for Alzheimer disease treatment by means of the virtual screening and network pharmacology methods.
文摘OBJECTIVE To explore the potential molecular mechanism of Shenlian(SL)on myocardial ischemia(MI)on the basis of network pharmacology.METHODS Firstly,the main active ingredients of SL were screened in the Traditional Chinese Medicine Integrated Database,and the MI-associated targets were collected from the DisGeNET database.Then,we used compound-target and target-pathway networks to uncover the therapeutic mechanisms of SL On the basis of network pharmacology analysis results,we assessed the effects of SL in MI rat model and oxygen glu⁃cose deprivation model of H9c2 cells and validated the possible molecular mechanisms of SL on myocardial injury in vivo and in vitro.RESULTS The network pharmacology results showed that 37 potential targets were recognized,including TNF-α,Bcl-2,STAT3,PI3K,and MMP2.The pathways revealed that the possible targets of SL were involved in the reg⁃ulation of inflammation and apoptosis signaling pathway.Then,in vivo experiments indicated that SL significantly reduced the myocardial infarction size of MI rats.Serum CK-MB,cTnT,CK,LDH,and AST levels were significantly decreased by SL(P<0.05 or P<0.01).In vitro,SL significantly increased H9c2 cell viability.The levels of inflammation factors including TNF-αand MMP2 were significantly decreased by SL(P<0.05 or P<0.01).TUNEL and Annexin V/propidium iodide assays indicated that SL could significantly decrease the cell apoptotic rate in vivo and in vitro(P<0.05 or P<0.01).The remarkable upregulation of anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax protein level further confirmed this result.Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the PI3K-Akt and JAK2-STAT3 pathways were significantly enriched in SL.Compared with the model group,SL treatment significantly activated the PI3K-Akt and JAK2-STAT3 pathways in vivo and in vitro according to Western blotting analyses.CONCLU⁃SION SL could protect the myocardium from MI injury.The underlying mechanism may be related to the reduction of inflammation and apoptosis by activating the PI3K/Akt and JAK2/STAT3 pathways.
基金Natural Science Foundation of Hebei Province(H2022206456)Natural Sci⁃ence Foundation of Hebei Province(H2021206449)+1 种基金Undergraduate Innovative Experiment Program of Hebei Medical University(USIP2022173)Undergraduate Innovative Experiment Program of Hebei Medical University(USIP2023107)。
文摘OBJECTIVE To explore mecha⁃nisms of imperatorin on regulating P-glycoprotein(P-gp)in blood-brain barrier(BBB)based on net⁃work pharmacology combined with in vitro experi⁃ment.METHODS Drug targets were predicted using the Pharmapper and Swiss targets data⁃bases;disease targets were obtained through the Genecards database;intersections between drugs and disease targets were screened by Cytoscape software;the obtained core targets were used to construct protein-protein interaction(PPI)network,gene ontology(GO)functions,and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis.The effects of imperatorin(20,50,100μmol·L^(-1))on P-gp activity were monitored in hCMEC/D3 in vitro BBB model,and the effects of imperatorin on the expression of target proteins were verified using Western blot method.RESULTS 55 drug targets and 3102 disease targets were obtained from the network pharmacology screening,and 37 core targets were obtained after the combination.Enrichment analysis showed that core targets were closely related to chemical synaptic trans⁃mission regulation,neurotransmitter receptor activity,protein kinase regulation activity,G proteincoupled receptor signaling pathway,neural active ligand receptor interaction pathway,PI3K-Akt sig⁃naling pathway,VEGF signaling pathway,etc..In vitro experimental validation suggested that all tested concentration groups of imperatorin signifi⁃cantly reduced the activity and expression of P-gp,which were achieved by significantly downregu⁃lating the phosphorylation levels of PI3K and Akt,and repressing the expression of VEGFR2 pro⁃tein.CONCLUSION Network pharmacology was used to predict the core targets and signaling pathways of imperatorin on regulating P-gp in BBB and relevant validation was conducted through in vitro experiments,providing a refer⁃ence basis for further exploration of the mecha⁃nisms of imperatorin on regulating P-gp in BBB.
基金National Natural Science Foundation of China(82030124)National Natural Science Foundation of China(82174015)Science and Technology Innovation Project of China Academy of Traditional Chinese Medicine(CI2021A04609)。
文摘OBJECTIVE To investigate the regulatory effects of icariin(ICA)on cardiac micro⁃vascular endothelial cells(CMEC)after oxygenglucose deprivation reperfusion(OGD/R)injury.METHODS CMEC were subjected to OGD/R treatment to construct a myocardial ischemiareperfusion model,and were divided into normal,model,low(10μmol·L^(-1)),medium(20μmol·L^(-1))and high(40μmol·L^(-1))ICA group,and high ICA+inhibitor group(40μmol·L^(-1)+20 nmol·L^(-1)).CCK-8 assay was used to assess the protective ability of ICA against CMEC,and cell migration assay and tube-formation assay were used to detect the migration and generation ability of CMEC.The TCMSP database,Swiss-Target database and literature mining methods were used to col⁃lect ICA-related targets,the GeneCards data⁃base was used to collect target genes related to myocardial ischemia/reperfusion,and Cytoscape 3.8.0 software was used to construct a"drug-tar⁃get-disease"network.The potential targets were imported into STRING 11.5 database to obtain the PPI network.GO and KEGG enrichment analyses were performed on the potential targets using the DAVID database.Molecular docking was performed using AutoDock-vina 1.1.2 soft⁃ware.Western blot detected the expression of related proteins.RESULTS After CMEC was subjected to OGD/R treatment,ICA had a protec⁃tive effect at 10^(-1)60μmol·L^(-1);the results of the cell migration assay showed that each group of ICA could promote the migratory effect of CMEC(P<0.01,P<0.01);and the results of tube-for⁃mation assay showed that each group of ICA could significantly promote the generation of branches(P<0.01)and the capillary length exten⁃sion(P<0.05).Network pharmacology collected a total of 23 ICA action targets,1500 disease tar⁃gets and 12 key targets.GO function enrichment analysis found 85 results.KEGG pathway enrich⁃ment analysis found 53 results,involving AGERAGE signaling pathway,sphingolipid signaling pathway and VEGF signaling pathway.Molecu⁃lar docking results showed that ICA had better binding with core targets PRKCB,PRKCA and PTGS2.Western blot results showed that ICA could regulate the expression of PRKCB,PRKCA and PTGS2 proteins.The results of cell migra⁃tion assay,tube-formation assay and protein expression were reversed after addition of PKC inhibitor.CONCLUSION The potential mecha⁃nism of action of ICA against myocardial isch⁃emia-reperfusion injury may be related to the reg⁃ulation of processes such as CMEC migration and angiogenesis,and it functions through the key target gene PKC.
基金Natural Science Foundation of Hebei Province(H2022106065)Scientific Research Program of Hebei Provincial Administration of Traditional Chinese Medicine(2023172)。
文摘OBJECTIVE To explore the key mechanism of Bazi Bushen capsule(BZBS)in delaying the senescence of mesenchymal stem cells(MSCs)through network pharmacology and in vitro experiments.METHODS Network pharmacology was used to predict the mechanism targets of BZBS in delaying MSCs senescence.A MSCs senescence model induced by D-galactose(D-gal)was used to investigate the effect and mechanism of BZBS on MSCs senescence in vitro.RESULTS Network pharmacology analy⁃sis showed that BZSB could delay MSCs senes⁃cence.The experiment showed that BZBS could significantly improve the survival activity of the aged MSCs.It significantly reduced the positive rate ofβ-galactosidase staining and p16,p21 expression in aged MSCs,enhanced the ability of adipogenic differentiation and osteogenic differentiation,and increased expression of Nanog,OCT4 and SOX2 in senescent MSCs.CONCLU⁃SIONS Network pharmacology and in vitro cell experiments verified that BZBS could delay MSCs senescence.
基金National Natural Science Foundation of China(8157381381173598)+3 种基金Sichuan Provincial Admin⁃istration of Traditional Chinese Medicine of China(2021MS447)Excellent Talent Program of Chengdu University of Tra⁃ditional Chinese Medicine of China(YXRC2019002ZRYY1917)and Open Research Fund of the State Key Laboratory of Southwestern Chinese Medicine Resources of China(2020XSGG006)。
文摘Pulsatilla chinensis is a widely used traditional Chinese herb,which contains 56 types of chemical constituents,mainly including triterpenoid saponins,organic acids,coumarins and lignans.The largest portion of the ingredients in Pulsatilla chinensis is the family of triterpenoid saponins,in which anemoside B4 is the major effective compound and indexing component.The main components of Pulsatilla chinensis can metabolize into a vast array of active products in vivo,which play vital roles in its biological activity.Mounting evidence reveals that Pulsatilla chinensis exerts a wide range of therapeutic activities,such as anti-cancer,immunoregulation,anti-inflammation and anti-schistosome,with fewer adverse reactions,via various signaling pathways and multiple targets.It was documented that the active ingredient of Pulsatilla chinensis can lessen the drug resistance and synergize the effects of other natural products including paclitaxel,as well as ameliorate the clinical efficacy of chemical drugs,such as adriamycin.However,Pulsatilla chinensis was also reported to be possibly the main cause of hemolysis and chronic liver injury.The efforts should be made to deeply investigate the pharmacological actions and underlying mechanisms of Pulsatilla chinensis,with a focus on the anti-cancer efficacy,and develop new drugs based on the components of Pulsatilla chinensis for future utilization in the clinical setting.
基金National Natural Science Foundation of China(82100488)Key Research and Development Pro⁃gram Project of Shaanxi Province(2021SF-071)and National Training Program of Innovation and Entrepreneurship for Students of China(201910716019,201910716020,202110716027)。
文摘Objective To investigate the potential therapeutic targets and pharmacological mechanism of(-)-epigallocatechin-3-gallate(EGCG)based on network pharmacology and experimental verification.METHODS The druggability of EGCG was measured by the traditional Chinese medicine systems pharmacology(TCMSP)server,and potential targets of EGCG were identified by Pharm Mapper and Drug Repositioning and Adverse drug Reaction via Chemical-Protein Interactome(DRAR-CPI).The potential targets were imported into GeneMANIA database to obtain the protein-protein direct interaction network,and target physical interaction,co-expression,prediction,genetic interaction,and shared protein domains.The biological process,molecular functions,cellular components and KEGG signaling pathways of potential targets were analyzed using DAVID database.For further study,ethanol was used to establish a model of endothelial injury in vitro.The cell viability was assayed by MTT method,the cellular apoptosis was stained by Annexin V/PI,and the expression levels of Bcl-2,Bax and cleved-caspase-3 were tested by Western blotting.Then,JC-1 and nuclear translocation of NF-κB experiments were used to study the mitochondrial membrane potential and nuclear translocation.RESULTS The oral availability of EGCG was 55.09%(≥30%)and drug-like index was 0.77(≥0.18),which were considered pharmacokinetically active.17 potential targetable proteins of EGCG were predicted by Pharm Mapper and DRAR-CPI.Further research showed that 68.13%displayed similar co-expression characteristics,26.11%physical interactions,and 2.74%shared the same protein domain.The depth network analysis results showed that the biofunctions of EGCG were mainly by regulating glutathione derivative biosynthetic process,glutathione metabolic process,nitrogen compound metabolic process etc..via drug binding,catalytic activity,glutathione transferase activity,anion binding etc..in sarcoplasmic reticulum,spindle pole,microtubule cytoskeleton and cytoplasm.KEGG enrichment analysis showed that Glutathione metabolism,IL^(-1)7 signaling pathway,EGFR tyrosine kinase inhibitor resistance,PI3K-Akt signaling pathway and other pathways were involves in the biofunction of EGCG.The above analyses indicated that EGCG exerts its biofunction through antioxidant and anti-inflammatory mechanisms.The experimental results showed that ethanol 20.0 mmol·L^(-1) decreased cell viability,Bcl-2 expression,and increased cell apoptosis,the intracellular ROS,as well as the expression of Bax and cleaved-caspase-3 of human endothelial cells.However,treatment of the cells with EGCG can significantly alleviate ethanol induced endothelial cells injury.Further study showed that EGCG significantly alleviates ethanol induced mitochondrial depolarization and nuclear translocation of NF-κB.CONCLUSIONS EGCG exerts pharmacological efficacies on ethanol induced endothelial cell injury through multi-target,multi-function and multi-pathway mode.Protective effect of EGCG on ethanol induced cell injury was mainly through alteration of mitochondrial function and NF-κB translocation.Therefore,EGCG have great potential in protecting against endothelial dysfunction of the persons who are chronically abuse of ethanol.This study also provides a new understanding of EGCG in clinical application on cardiovascular and cerebrovascular diseases.
基金National Natural Science Foundation of China(81170148)and Major Project of Natural Science Foundation of the Department of Education of Anhui Province(KJ2019ZD32)。
文摘OBJECTIVE To predict the potential targets of hyperoside(Hyp)on improving ischemia/reperfusion injury by network pharmacology,and explore its possible mechanism combined with related literature.METHODS The action targets of Hyp and ischemia/reperfusion injury were obtained by TCMSP,Swiss Target Prediction,Pharm Mapper,Similarity ensemble approach,Online Mendelian Inheritance in Man,DisGENT and database.The common targets of drugs and diseases were screened by Omishare and STRING database respectively,and the protein-protein interaction(PPI)network map was constructed.Then the interaction network between Hyp and disease targets was constructed by Cytoscape software and topological cross-linking analysis was carried out.Then the interaction network between Hyp and disease targets was constructed and cross-linked analysis was carried out by using Cytoscape software.The gene ontology(GO)of the core target was analyzed by David database,and then the related pathways of the core target were enriched by KEGG database.RESULTS A total of 54 GO enrichment processes were obtained by GO enrichment analysis of 44 common genes,including 38 biological processes(BP),15 cell composition(CC)processes,and 1 molecular functional(MF)process.43 items were obtained by signal pathway enrichment analysis in KEGG database.CONCLUSION It is suggested that the mechanism of Hyp may be related to PI3K-Akt,RAP1,RAS,VEGF and other signal transduction pathways.The above results laid a theoretical foundation for the study of the mechanism and clinical application of the treatment of ischemia/reperfusion injury.
文摘Chinese Journal of Pharmacology and Toxicology(CJPT)started its publication in 1986.It is a monthly and distributed to readers both at home and abroad.This journal is collaboratively sponsored by the Chinese Pharmacological Society,the Chinese Society of Toxicology and Beijing Institute of Pharmacology and Toxicology.This journal focuses on the presentation of the latest findings in the fields of pharmacology and toxicology in order to promote academic exchanges worldwide and steer this sphere of research forward.In line with the principles of precision,
文摘Since President Obama announced the Precision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a world-wide hotspot and drawn global attention in the medical field.Precision medicine aims at applying genetic information of individual diseases to guide his or her diagnosis and treatment.
文摘There are two general approaches to drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alternative is mechanism-based, a process that entails the in vitro screening of purified chemical compounds to identify those that interact specifically with a selected biological target, after which they are tested for therapeutic potential. A major difference between these approaches is the extent to which the principles of pharmacology are employed to demonstrate safety and efficacy and to enable improvements in the therapeutic properties of the product. As a thorough pharmacological analysis of the pharmacokinetics and pharmacodynamics of a test agent requires that it be a stable, single, purified substance, such testing is more difficult with unpurified samples containing multiple compounds as compared to single agents. A lack of pharmacological information compromises the clinical utility of a test substance by leaving open questions about its bioavailability, metabolism, and mechanisms of therapeutic actions and toxicities. Although drug discovery success has be achieved with both the empirically-driven and mechanism-based approaches, the proper application of pharmacological techniques in the drug discovery process maximizes efficacy, safety and the chance for regulatory approval. In addition, pharmacological data provides information needed for improving the therapeutic properties of an agent, enhancing its clinical utility, and extending the product lifespan.
文摘Thrombospondin 4(THBS4;TSP4),a crucial component of the extracellular matrix(ECM),serves as an important regulator of tissue homeostasis and various pathophysiological processes.As a member of the evolutionarily conserved thrombospondin family,THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions.Through dynamic interactions with various ECM components,THBS4 plays pivotal roles in cell adhesion,proliferation,inflammation regulation,and tissue remodeling,establishing it as a key modulator of microenvironmental organization.The transcription and translation of THBS4 gene,as well as the activity of the THBS4 protein,are tightly regulated by multiple signaling pathways and extracellular cues.Positive regulators of THBS4 include transforming growth factorβ(TGF-β),interferonγ(IFNγ),granulocyte-macrophage colony-stimulating factor(GM-CSF),bone morphogenetic proteins(BMP12/13),and other regulatory factors(such as B4GALNT1,ITGA2/ITGB1,PDGFRβ,etc.),which upregulate THBS4 at the mRNA and/or protein level.Conversely,oxidized low-density lipoprotein(OXLDL)acts as a potent negative regulator of THBS4.This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to diverse physiological and pathological stimuli.Functionally,THBS4 acts as a critical signaling hub,influencing multiple downstream pathways essential for cellular behavior and tissue homeostasis.The best-characterized pathways include:(1)the PI3K/AKT/mTOR axis,which THBS4 modulates through both direct and indirect interactions with integrins and growth factor receptors;(2)Wnt/β-catenin signaling,where THBS4 functions as either an activator or inhibitor depending on the cellular context;(3)the suppression of DBET/TRIM69,contributing to its diverse regulatory roles.These signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes.Substantial evidence links aberrant THBS4 expression to a range of pathological conditions,including neoplastic diseases,cardiovascular disorders,fibrotic conditions,neurodegenerative diseases,musculoskeletal disorders,and atopic dermatitis.In cancer biology,THBS4 exhibits context-dependent roles,functioning either as a tumor suppressor or promoter depending on the tumor type and microenvironment.In the cardiovascular system,THBS4 contributes to both adaptive remodeling and maladaptive fibrotic responses.Its involvement in fibrotic diseases arises from its ability to regulate ECM deposition and turnover.The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine.As a biomarker,THBS4 expression patterns correlate significantly with disease progression and patient outcomes.Therapeutically,targeting THBS4-mediated pathways offers novel opportunities for precision medicine approaches,including anti-fibrotic therapies,modulation of the tumor microenvironment,and enhancement of tissue repair.This comprehensive review systematically explores three key aspects of THBS4 research:(1)the fundamental biological functions of THBS4 in ECM organization;(2)its mechanistic involvement in various disease pathologies;(3)its emerging potential as both a diagnostic biomarker and therapeutic target.By integrating recent insights from molecular studies,animal models,and clinical investigations,this review provides a framework for understanding the multifaceted roles of THBS4 in health and disease.The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts.Given its unique position at the intersection of ECM biology and cellular signaling,THBS4 represents a promising frontier for the development of novel diagnostic tools and therapeutic strategies in precision medicine.
