BACKGROUND Traditional Chinese medicine(TCM)is widely used as an important complementary and alternative healthcare system for cancer treatment in Asian countries.Network pharmacology,which utilizes various database p...BACKGROUND Traditional Chinese medicine(TCM)is widely used as an important complementary and alternative healthcare system for cancer treatment in Asian countries.Network pharmacology,which utilizes various database platforms and computer software to study the interactions between complex drug components in vivo,is particularly useful for studying the pharmacodynamic mechanisms of multi-pathway and multi-target Chinese medicines.AIM To explore the potential targets and function of Jianpi Yiwei Recipe treatment of gastric cancer(GC)through network pharmacology and molecular docking.METHODS Data on the components of Jianpi Yiwei Recipe(Radix Astragali,Radix Codonopsis,Agrimonia eupatoria,Atractylodes macrocephala Koidz.,Poria cocos,stirbaked rhizoma dioscoreae,Amomum villosum Lour.,fried Fructus Aurantii,pericarpium citri reticulatae,Rhizoma Pinelliae Preparata,and Radix Glycyrrhizae Preparata)were collected and screened by using the TCM systems pharmacology database and analysis platform(TCMSP).Then the targets of these compounds were predicted.GC-related targets were screened using the GeneCards database.Venn diagram was used to identify common targets.An active ingredient-core target interaction network and a protein-protein interaction(PPI)network were built.Moreover,we performed gene ontology(GO)functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses on the core targets and validated them by molecular docking.RESULTS TCMSP screening revealed 11 active components and 184 targets,whereas GeneCards found 10118 disease-related targets,with 180 shared targets between them.Topology analysis of the PPI network identified 38 targets,including ATK1,TP53,and tumor necrosis factor,as key targets for the treatment of GC by Jianpi Yiwei Recipe.Quercetin,naringenin,luteolin,etc.,may be the main active components of Jianpi Yiwei Recipe.GO enrichment analysis identified 2809,1218,and 553 functions related to biological process,molecular function,and cellular component,respectively.KEGG pathway enrichment analysis revealed 167 related pathways,mainly involved in cancer,endocrine resistance,and AGE-RAGE signaling in diabetic complication.Validation with molecular docking analysis showed docking of key active components with core targets.CONCLUSION Jianpi Yiwei Recipe plays a therapeutic role in GC through multiple components,targets,and pathways.These findings form a basis for follow-up exploration of Jianpi Yiwei Recipe in the treatment of GC.展开更多
Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesyla...Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesylate(PM),a highly selective HDAC I/II binhibitor,exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models,outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations.Different from panobinostat,bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses.The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte-and T cell-mediated immune responses.In a phase I trial(NCT05526313;N=29)of PM at doses up to 15 mg/m2,treatment-related Grade≥3 adverse events predominantly comprised hematologic toxicities:thrombocytopenia(75.9%),neutropenia(55.2%),leukopenia(41.4%),and lymphopenia(31.0%),with no dose-limiting toxicities observed.PM monotherapy achieved a disease control rate of 72.7%(8/11)and an objective response rate(ORR)of 9.1%(1/11)in r/r MM.Notably,r/r lymphoma patients showed an ORR of 61.6%(11/18),particularly reaching 63.6%(7/11)with 6 complete responses in diffuse large B-cell lymphoma(DLBCL).Treatment responders exhibited enhanced immune activation,with elevated CD3+CD8+T cells and increased cytokine levels,such as IFN-γand CXCL10.Overall,PM is safe and moderately effective in MM,but highly effective in lymphoma.Additionally,PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment.These findings support further openlabel,multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM,as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.展开更多
文摘BACKGROUND Traditional Chinese medicine(TCM)is widely used as an important complementary and alternative healthcare system for cancer treatment in Asian countries.Network pharmacology,which utilizes various database platforms and computer software to study the interactions between complex drug components in vivo,is particularly useful for studying the pharmacodynamic mechanisms of multi-pathway and multi-target Chinese medicines.AIM To explore the potential targets and function of Jianpi Yiwei Recipe treatment of gastric cancer(GC)through network pharmacology and molecular docking.METHODS Data on the components of Jianpi Yiwei Recipe(Radix Astragali,Radix Codonopsis,Agrimonia eupatoria,Atractylodes macrocephala Koidz.,Poria cocos,stirbaked rhizoma dioscoreae,Amomum villosum Lour.,fried Fructus Aurantii,pericarpium citri reticulatae,Rhizoma Pinelliae Preparata,and Radix Glycyrrhizae Preparata)were collected and screened by using the TCM systems pharmacology database and analysis platform(TCMSP).Then the targets of these compounds were predicted.GC-related targets were screened using the GeneCards database.Venn diagram was used to identify common targets.An active ingredient-core target interaction network and a protein-protein interaction(PPI)network were built.Moreover,we performed gene ontology(GO)functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses on the core targets and validated them by molecular docking.RESULTS TCMSP screening revealed 11 active components and 184 targets,whereas GeneCards found 10118 disease-related targets,with 180 shared targets between them.Topology analysis of the PPI network identified 38 targets,including ATK1,TP53,and tumor necrosis factor,as key targets for the treatment of GC by Jianpi Yiwei Recipe.Quercetin,naringenin,luteolin,etc.,may be the main active components of Jianpi Yiwei Recipe.GO enrichment analysis identified 2809,1218,and 553 functions related to biological process,molecular function,and cellular component,respectively.KEGG pathway enrichment analysis revealed 167 related pathways,mainly involved in cancer,endocrine resistance,and AGE-RAGE signaling in diabetic complication.Validation with molecular docking analysis showed docking of key active components with core targets.CONCLUSION Jianpi Yiwei Recipe plays a therapeutic role in GC through multiple components,targets,and pathways.These findings form a basis for follow-up exploration of Jianpi Yiwei Recipe in the treatment of GC.
基金funded by the Sichuan Province“14th Five-Year Plan”Life and Health Major Science and Technology Project(2022ZDZX0027)Key Project of Chengdu(2021-YF08-00002-GX)+3 种基金the Incubation Program for Clinical Trials of West China Hospital(19HXFH030)the National Natural Science Foundation of China(82104211)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23020,ZYJC21007)National Key Research and Development Program of China(2022YFC2502600,2022YFC2502603).
文摘Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesylate(PM),a highly selective HDAC I/II binhibitor,exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models,outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations.Different from panobinostat,bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses.The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte-and T cell-mediated immune responses.In a phase I trial(NCT05526313;N=29)of PM at doses up to 15 mg/m2,treatment-related Grade≥3 adverse events predominantly comprised hematologic toxicities:thrombocytopenia(75.9%),neutropenia(55.2%),leukopenia(41.4%),and lymphopenia(31.0%),with no dose-limiting toxicities observed.PM monotherapy achieved a disease control rate of 72.7%(8/11)and an objective response rate(ORR)of 9.1%(1/11)in r/r MM.Notably,r/r lymphoma patients showed an ORR of 61.6%(11/18),particularly reaching 63.6%(7/11)with 6 complete responses in diffuse large B-cell lymphoma(DLBCL).Treatment responders exhibited enhanced immune activation,with elevated CD3+CD8+T cells and increased cytokine levels,such as IFN-γand CXCL10.Overall,PM is safe and moderately effective in MM,but highly effective in lymphoma.Additionally,PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment.These findings support further openlabel,multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM,as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.
