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
Terminalia chebula(TC),a kind of Combretaceae,is a widely used herb in India and East Asia to treat cerebrovascular diseases.However,the potential mechanism of the neuroprotective effects of TC at the metabonomics lev...Terminalia chebula(TC),a kind of Combretaceae,is a widely used herb in India and East Asia to treat cerebrovascular diseases.However,the potential mechanism of the neuroprotective effects of TC at the metabonomics level is still not unclear.The present study focused on the effects of TC on metabonomics in stroke model.In our study,rats were divided randomly into Sham,Model,and TC groups.The TC group were intragastricly administered with TC for 7 d after middle cerebral artery occlusion(MCAO)operation.The sham and the model groups received vehicle for the same length of time.Subsequently,the neuroprotective effects of TC were examined by neurological defects evalua⁃tion,infarct volume assessment,and identification of biochemical indicators for antioxidant and anti-inflammatory activi⁃ties.Further,metabonomics technology was employed to evaluate the endogenous metabolites profiling systematically.Consist to results of biochemical and histopathological assays,pattern recognition analysis showed a clear separation of the Model and the Sham group,indicating a recovery impact of TC on the MCAO rats.Moreover,12 potential biomarkers were identified in MCAO Model group,involved in energy(lactic acid,succinic acid,and fumarate),amino acids(leucine,alanine,and phenylalanine)and glycerophospholipid[PC(16∶0/20∶4),PC(20:4/20:4),LysoPC(18:0)and LysoPC(16:0)]metabolism,and other types of metabolism(arachidonic acid and palmitoylcarnitine).Notably,we found that metabolite levels of TC group were partially reversed to normal.In conclusion,TC could ameliorate MCAO rats by intervening with energy metabolism(glycolysis and TCA cycle),amino acid metabolism,glycerophospholipid metabolism and other types of metabolism.展开更多
OBJECTIVE To explore the mechanism of action of Danshen-Gegen on coronary heart disease.METHODS First using network pharmacology,according to oral bioavailability and drug-like properties,taking Danshen-Gegen as the r...OBJECTIVE To explore the mechanism of action of Danshen-Gegen on coronary heart disease.METHODS First using network pharmacology,according to oral bioavailability and drug-like properties,taking Danshen-Gegen as the research object,obtaining its active ingredients and targets in the pharmacological analysis platform of Chinese medicine system,using TTD,DrugBank and Disgenet database to obtain coronary heart disease targets,the active componentcoronary heart disease target network was constructed by CytosCape3.6.1 software,and the target protein interaction network was constructed by String database,Finally,GO and KEGG enrichment analysis was performed on the target in the DAVID database.RESULTS 61 active ingredients were screened from Danshen-Gegen,and 68 targets related to coronary heart disease were selected.GO analysis showed that Danshen-Gegen is involved in many biological processes such as transcription and inflammation of RNA polymeraseⅡpromoter.The target of treating coronary heart disease is mainly concentrated in extracellular space,plasma membrane and nucleus to treat coronary heart disease.The main effects of treatment of coronary heart disease are zinc ion binding,cytokine activity and sequence-specific DNA binding.The results of KEGG analysis showed that the regulation of Danshen-Gegen includes signaling pathways such as HIF-10,PI3K-Akt,TNF and Jak-STAT.CONCLUSION The combination of Danshen-Gegen has 61 active ingredients to play a role in the treatment of coronary heart disease through 68 targets and Jak-STAT,PI3K-Akt and other signaling path⁃ways.The results of this study provide a reference for further study of the pharmacological effects of Danshen-Gegen.展开更多
OBJECTIVE To investigate the neuroprotective effects and exact mechanisms of myrrh extract following cerebral ischemic stroke.METHODS Male rats were randomly divided into three groups:sham group,middle cerebral artery...OBJECTIVE To investigate the neuroprotective effects and exact mechanisms of myrrh extract following cerebral ischemic stroke.METHODS Male rats were randomly divided into three groups:sham group,middle cerebral artery occlusion(MCAO)group and myrrh group.Morphological changes were assessed after 7 d of myrrh treatment.Microarray analysis with circulating mRNA was performed to identify differential gene expression profile,gene ontology and pathway enrichment analyses were carried out to predict the gene function.Gene co-expression and pathway networks were constructed to identify the potential targets.The markers of oxidative stress,inflammatory reaction and ferroptosis in the cerebral cortex were detected by ELISA assays.The identified hub pathways and genes were validated by western blotting,immunofluorescence and immunohistochemistry analyses.Neurons were exposed to transient oxygen-glucose deprivation(OGD)to model ischemia-like conditions.siRNA-TXNIP were transfected in OGD-induced neurons to explore the mechanism.RESULTS Myrrh extract significantly alleviated neurological deficits,infarct volume and histo⁃pathological damage in MCAO rats.A total of 2200 differentially expressed genes were identified among the three groups.Oxidation-reduction process,inflammatory response,ferroptosis were enriched as the significant gene ontology items.NOD-like receptor signaling were identified as the hub pathway based on the pathway relation network.TXNIP and NLRP3 were screened as the potential targets by a time sequence profile analysis.The levels of IL-1β,IL-18,TNF-α,MDA and TFR in brain tissues were increased while the CAT,SOD,GSH-px and GPX4 levels were significantly decreased in MCAO group.As expected,myrrh extract greatly reversed these changes.The similarly results were also observed in OGD treated neuron cells.The elevated expressions of TXNIP and NLRP3 induced by OGD were success⁃fully inhibited by myrrh treatment.Knockdown of TXNIP significantly alleviated OGD-induced ROS accumulation and oxidative stress,but the antioxidative effect of myrrh was impaired when TXNIP was absent in neuron cells.In addition,knockdown of TXNIP significantly decreased the expression of NLRP3 and increased the expression of GPX4 in OGDinduced neuron cells.However,myrrh treatment scarcely changed the expressions of NLRP3 and these ferroptosis markers in siRNA-TXNIP pretreated cells,compared with the siRNA-TXNIP alone treatment group.Therefore,these data demonstrated that the neuroprotective effect of myrrh extract was dependent on TXNIP-NLRP3 axis.CONCLU⁃SION Thatmyrrh extract exerts neuroprotective property through alleviated ROS-mediated ferroptosis by regulating the TXNIP/NLRP3 axis in ischemic stroke.Myrrh extract could be considered as a promising candidate for the treatment of ischemic stroke.展开更多
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.
基金National Natural Science Foundation of China(8160338581673631+4 种基金8150100381601149)Science Foundation of Shaanxi Province(2017JM8006)China Postdoctoral Science Foundation(2015M5804652017JQ8038)
文摘Terminalia chebula(TC),a kind of Combretaceae,is a widely used herb in India and East Asia to treat cerebrovascular diseases.However,the potential mechanism of the neuroprotective effects of TC at the metabonomics level is still not unclear.The present study focused on the effects of TC on metabonomics in stroke model.In our study,rats were divided randomly into Sham,Model,and TC groups.The TC group were intragastricly administered with TC for 7 d after middle cerebral artery occlusion(MCAO)operation.The sham and the model groups received vehicle for the same length of time.Subsequently,the neuroprotective effects of TC were examined by neurological defects evalua⁃tion,infarct volume assessment,and identification of biochemical indicators for antioxidant and anti-inflammatory activi⁃ties.Further,metabonomics technology was employed to evaluate the endogenous metabolites profiling systematically.Consist to results of biochemical and histopathological assays,pattern recognition analysis showed a clear separation of the Model and the Sham group,indicating a recovery impact of TC on the MCAO rats.Moreover,12 potential biomarkers were identified in MCAO Model group,involved in energy(lactic acid,succinic acid,and fumarate),amino acids(leucine,alanine,and phenylalanine)and glycerophospholipid[PC(16∶0/20∶4),PC(20:4/20:4),LysoPC(18:0)and LysoPC(16:0)]metabolism,and other types of metabolism(arachidonic acid and palmitoylcarnitine).Notably,we found that metabolite levels of TC group were partially reversed to normal.In conclusion,TC could ameliorate MCAO rats by intervening with energy metabolism(glycolysis and TCA cycle),amino acid metabolism,glycerophospholipid metabolism and other types of metabolism.
文摘OBJECTIVE To explore the mechanism of action of Danshen-Gegen on coronary heart disease.METHODS First using network pharmacology,according to oral bioavailability and drug-like properties,taking Danshen-Gegen as the research object,obtaining its active ingredients and targets in the pharmacological analysis platform of Chinese medicine system,using TTD,DrugBank and Disgenet database to obtain coronary heart disease targets,the active componentcoronary heart disease target network was constructed by CytosCape3.6.1 software,and the target protein interaction network was constructed by String database,Finally,GO and KEGG enrichment analysis was performed on the target in the DAVID database.RESULTS 61 active ingredients were screened from Danshen-Gegen,and 68 targets related to coronary heart disease were selected.GO analysis showed that Danshen-Gegen is involved in many biological processes such as transcription and inflammation of RNA polymeraseⅡpromoter.The target of treating coronary heart disease is mainly concentrated in extracellular space,plasma membrane and nucleus to treat coronary heart disease.The main effects of treatment of coronary heart disease are zinc ion binding,cytokine activity and sequence-specific DNA binding.The results of KEGG analysis showed that the regulation of Danshen-Gegen includes signaling pathways such as HIF-10,PI3K-Akt,TNF and Jak-STAT.CONCLUSION The combination of Danshen-Gegen has 61 active ingredients to play a role in the treatment of coronary heart disease through 68 targets and Jak-STAT,PI3K-Akt and other signaling path⁃ways.The results of this study provide a reference for further study of the pharmacological effects of Danshen-Gegen.
基金National Natural Science Foundation of China(8167363181603385)+2 种基金China Postdoctoral Science Foundation(2018M643843)Natural Science Foundation of Shaanxi Province(2017JM8056)Key Research and Development Foundation of Shaanxi province(2018SF-241)
文摘OBJECTIVE To investigate the neuroprotective effects and exact mechanisms of myrrh extract following cerebral ischemic stroke.METHODS Male rats were randomly divided into three groups:sham group,middle cerebral artery occlusion(MCAO)group and myrrh group.Morphological changes were assessed after 7 d of myrrh treatment.Microarray analysis with circulating mRNA was performed to identify differential gene expression profile,gene ontology and pathway enrichment analyses were carried out to predict the gene function.Gene co-expression and pathway networks were constructed to identify the potential targets.The markers of oxidative stress,inflammatory reaction and ferroptosis in the cerebral cortex were detected by ELISA assays.The identified hub pathways and genes were validated by western blotting,immunofluorescence and immunohistochemistry analyses.Neurons were exposed to transient oxygen-glucose deprivation(OGD)to model ischemia-like conditions.siRNA-TXNIP were transfected in OGD-induced neurons to explore the mechanism.RESULTS Myrrh extract significantly alleviated neurological deficits,infarct volume and histo⁃pathological damage in MCAO rats.A total of 2200 differentially expressed genes were identified among the three groups.Oxidation-reduction process,inflammatory response,ferroptosis were enriched as the significant gene ontology items.NOD-like receptor signaling were identified as the hub pathway based on the pathway relation network.TXNIP and NLRP3 were screened as the potential targets by a time sequence profile analysis.The levels of IL-1β,IL-18,TNF-α,MDA and TFR in brain tissues were increased while the CAT,SOD,GSH-px and GPX4 levels were significantly decreased in MCAO group.As expected,myrrh extract greatly reversed these changes.The similarly results were also observed in OGD treated neuron cells.The elevated expressions of TXNIP and NLRP3 induced by OGD were success⁃fully inhibited by myrrh treatment.Knockdown of TXNIP significantly alleviated OGD-induced ROS accumulation and oxidative stress,but the antioxidative effect of myrrh was impaired when TXNIP was absent in neuron cells.In addition,knockdown of TXNIP significantly decreased the expression of NLRP3 and increased the expression of GPX4 in OGDinduced neuron cells.However,myrrh treatment scarcely changed the expressions of NLRP3 and these ferroptosis markers in siRNA-TXNIP pretreated cells,compared with the siRNA-TXNIP alone treatment group.Therefore,these data demonstrated that the neuroprotective effect of myrrh extract was dependent on TXNIP-NLRP3 axis.CONCLU⁃SION Thatmyrrh extract exerts neuroprotective property through alleviated ROS-mediated ferroptosis by regulating the TXNIP/NLRP3 axis in ischemic stroke.Myrrh extract could be considered as a promising candidate for the treatment of ischemic stroke.
