Background:The traditional Chinese medicine Toosendan Fructus has certain hepatotoxicity,which is used after being processed by stir-frying to attenuate toxicity.However,there are few studies on its attenuating toxici...Background:The traditional Chinese medicine Toosendan Fructus has certain hepatotoxicity,which is used after being processed by stir-frying to attenuate toxicity.However,there are few studies on its attenuating toxicity mechanism.The effects of Toosendan Fructus on the activities of CYP450P1A2,CYP2E1 and CYP3A4 were studied in vivo and in vitro and the dose-toxicity mechanism of hepatotoxicity before and after stir-frying was explored to provide the basis for safe,rational use of Toosendan Fructus.Methods:The rat liver microsomes in vitro incubation method and in vivo pharmacokinetics were used to detect the concentrations of phenacetin,chlorzoxazone and dapsone in the liver microsomes in vitro incubation system and the rat plasma to study the effect of stir-frying of Toosendan Fructus on the activity of CYP450P1A2,CYP2E1,CYP3A4.Results:The results of pharmacokinetics in vivo showed that the AUC of phenacetin and dapsone in different groups was lower,and CL value was higher than those of the normal group.At the same dose,the AUC of stir-fried Toosendan Fructus was higher than that of the raw,while CL value was lower.For the same processed product,AUC value was high-dose>low-dose>middle-dose group,CL value was high-dose<low-dose<middle-dose.AUC and CL values of chlorzoxazone showed no difference from those of the normal group.The results of pharmacokinetics in vivo showed that Toosendan Fructus can induce the activity of CYP3A4 in a dose-dependent manner and the induction effect will decrease after stir-frying in vitro.Conclusion:The toxicity attenuation of Toosendan Fructus may be related to the decrease of induction effect after stir-frying.These results would provide the basis for safe,rational use of Toosendan Fructus.展开更多
Two new phenylpropanetriol glycosides, named as meliadanoside A (3 - methoxy- 5 - hydroxy-9- (1' - O-β-D-glucopyranosyl) - threo - phenylpropanetriol ) and meliadanoside B (4- hydroxy-7, 8- (2', 1' - O- ...Two new phenylpropanetriol glycosides, named as meliadanoside A (3 - methoxy- 5 - hydroxy-9- (1' - O-β-D-glucopyranosyl) - threo - phenylpropanetriol ) and meliadanoside B (4- hydroxy-7, 8- (2', 1' - O- β- D -glucopyranosyl) - phenylpropanetriol), were isolated from the water-soluble extract of the fruits of Meliatoosendan Sieb. et Zucc., along with threo-guaiacylglycerol. Their structures were elucidated by spectroscopic and chendcal analysis.展开更多
Two new limonoid-type triterpenoids, named 12-o-ethyl-l-deacetylnimbolinin B and 1-o-tigloyl-1-o-debenzoylohchinal, have been isolated from the fruit of Melia toosendan Sieb. et Zucc. Their structures were elucidated ...Two new limonoid-type triterpenoids, named 12-o-ethyl-l-deacetylnimbolinin B and 1-o-tigloyl-1-o-debenzoylohchinal, have been isolated from the fruit of Melia toosendan Sieb. et Zucc. Their structures were elucidated by spectral methods, including 2D-NMR spectra.展开更多
Two new limonoids,1α-tigloyloxy-3α-acetoxyl-7α-hydroxyl-12α-ethoxyl nimbolinin（1） and lα-benzoyloxy-3α-acetoxyl-7α- hydroxyl-12α-ethoxyl nimbolinin（2）,were isolated from the fruits of Melia toosendan.Their...Two new limonoids,1α-tigloyloxy-3α-acetoxyl-7α-hydroxyl-12α-ethoxyl nimbolinin（1） and lα-benzoyloxy-3α-acetoxyl-7α- hydroxyl-12α-ethoxyl nimbolinin（2）,were isolated from the fruits of Melia toosendan.Their structures were established on the basis of various NMR spectroscopic analyses,including 2D-NMR techniques（HSQC,HMBC,NOESY） and HR-ESI-MS.展开更多
Objective:Objective:To analyze and explore the key targets and molecular mechanisms of action of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity and the relationship between corresponding compound...Objective:Objective:To analyze and explore the key targets and molecular mechanisms of action of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity and the relationship between corresponding compounds based on network pharmacology.Methods:Using network pharmacology,a"traditional Chinese medicine-chemical composition-key target-pathway"analysis was conducted on Radix Paeoniae Alba for the treatment of Toosendan Fructus-induced hepatotoxicity.The possible mechanism of action was analyzed in terms of function.Results:The core targets,such as interleukin(IL)-6,tumor necrosis factor(TNF),heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator-activated receptor gamma(PPARG),prostaglandin-endoperoxide synthase 2(PTGS2),heme oxygenase 1(HMOX1),Jun proto-oncogene(JUN),caspase-3,estrogen receptor 1(ESR1),and aryl hydrocarbon receptor(AHR)were screened from the targets of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity.Biological process(BP)of toxic targets(BP terms)involved"response to drug;activation of cysteine-type endopeptidase activity involved in apoptotic process,”positive regulation of transcription.Cellular components(CC terms)mainly involved cytosol and membrane rafts.Molecular function(MF)terms included"protein homodimerization activity,"RNA polymerase II transcription factor activity and enzyme binding,etc."The Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway included the TNF signaling pathway,cancer pathways,and apoptosis.Conclusion:Radix Paeoniae Alba might alleviate Toosendan Fructus-induced hepatotoxicity through IL6,TNF,HSP90AA1,PPARG,PTGS2,HMOX1,and other targets,possibly via the activation of cysteine-type endopeptidase activity involved in these pathways.展开更多
Objective:To explore the potential mechanism of hepatotoxicity induced by Fructus Meliae Toosendan(FMT)through network pharmacology.Methods:The active components and targets of FMT were identified and screened by Trad...Objective:To explore the potential mechanism of hepatotoxicity induced by Fructus Meliae Toosendan(FMT)through network pharmacology.Methods:The active components and targets of FMT were identified and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database,PubChem Database and Swiss Target Prediction database,etc.Genecards,pharmGKB,and OMIM databases were used to collect relevant targets of hepatotoxicity,and intersect them with the targets of active ingredients to obtain the potential targets of hepatotoxicity caused by FMT.A compound-target network was constructed with Cytoscape 3.8.0 software.The String 11.0 database was used to construct the protein-protein interaction(PPI)network of the targets and to screen out the core targets.In addition,Gene Ontology(GO)terms and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted by R software,and then the pathways directly related to hepatotoxicity were integrated.Results:In this study,9 active ingredients of FMT and 265 targets were obtained.There are 533 hepatotoxicity-related targets,and 76 potential targets for hepatotoxicity caused by FMT,among which quercetin,melianone,and nimbolin A are the key active components for hepatotoxicity caused by FMT,and MYC,STAT3,JUN,and RELA were the core target proteins of FMT’s hepatotoxicity.There were 2353 GO entries(P<0.05),including 2181 Biological Process(BP),41 Cellular Component(CC)and 131 Molecular Function(MF).KEGG enrichment analysis revealed 165 pathways(P<0.05),of which Th17 cell differentiation,HIF-1 signaling pathway,PI3K-Akt signaling pathway were strongly correlated with the hepatotoxicity of FMT.Conclusion:Through network pharmacology,it was found that many potential components in azadirachia chinaberry may be involved in the regulation of apoptosis,excessive inflammatory response and mitochondrial dynamics through multi-target and multi-pathway,resulting in the generation of hepatotoxicity.展开更多
Two new limonoids, 12-ethoxynimbolinins G and H(compounds 1 and 2), and one known compound, toosendanin(Chuanliansu)(compound 3), were isolated from the bark of Melia toosendan. Their structures were elucidated by spe...Two new limonoids, 12-ethoxynimbolinins G and H(compounds 1 and 2), and one known compound, toosendanin(Chuanliansu)(compound 3), were isolated from the bark of Melia toosendan. Their structures were elucidated by spectroscopic analysis and X-ray techniques. The absolute configuration of toosendanin(3) was established by single-crystal X-ray diffraction. Compounds 1-3 were evaluated for their cytotoxicity against five tumor cell lines.展开更多
Objective： To investigate the anti-cancer effects of crude extract from Melia toosendan Sieb. et Zucc and its possible molecular mechanisms in vitro and in vivo. Methods： Transonic alcohol-chloroform extraction meth...Objective： To investigate the anti-cancer effects of crude extract from Melia toosendan Sieb. et Zucc and its possible molecular mechanisms in vitro and in vivo. Methods： Transonic alcohol-chloroform extraction method was used to extract toosendanin from the bark of Melia toosendan Sieb. et Zucc, and the content of toosendanin in the crude extract was measured by high performance liquid chromatography （HPLC）. Anti-cancer effects of crude extract from Melia toosendan Sieb. et Zucc were investigated in in vivo and in vitro studies. In the in vitro experiment, human hepatocellular carcinoma cell lines SMMC-7721 and Hep3B were co-incubated with toosendanin crude extract of different concentrations, respectively. In the in vivo experiment, BALB/c mice were subcutaneously inoculated with mouse hepatocellular carcinoma H22 cells and treated with crude extract. Results： HPLC revealed the content of toosendanin was about 15%. Crude extract from Melia toosendan Sieb. et Zucc inhibited cancer cells growth in a dose- and time-dependent manner. The 50% inhibitory concentration （IC50, 72 h） was 0.6 mg/L for SMMC-7721 cells and 0.8 mg/L for Hep3B cells. Both high-dose [0.69 mg/（kg·d）] and low-dose [0.138 mg/（kg·d）] crude extract could markedly suppress cancer growth, and the inhibition rate was greater than 50%. Hematoxylin and eosin staining showed necrotic area in cancers and transmission electron microscopy displayed necrotic and apoptotic cancer cells with apoptotic bodies. Immunohistochemistry showed that the expression of Bax and Fas increased and the expression of Bcl-2 reduced. Conclusions： Toosendanin extract has potent anti-cancer effects via suppressing proliferation and inducing apoptosis of cancer cells in vivo and in vitro. The mechanism of apoptosis involves in mitochondrial pathway and death receptor pathway.展开更多
In the present study, two new limonoids, 1α, 7α-dihydroxyl-3α-acetoxyl-12α-ethoxylnimbolinin(1) and 1α-tigloyloxy-3α-acetoxyl-7α-hydroxyl-12β-ethoxylnimbolinin(2), together with other four known limonoids(3-6)...In the present study, two new limonoids, 1α, 7α-dihydroxyl-3α-acetoxyl-12α-ethoxylnimbolinin(1) and 1α-tigloyloxy-3α-acetoxyl-7α-hydroxyl-12β-ethoxylnimbolinin(2), together with other four known limonoids(3-6), were isolated from the fruits of Melia toosendan. Their structures were elucidated by means of extensive spectroscopic analyses(NMR and ESI-MS) and comparisons with the data reported in the literature. The isolated compounds were evaluated for their antibacterial activities. Compound 4 exhibited significant antibacterial activity against an oral pathogen, Porphyromonas gingivalis ATCC 33277, with an MIC value of 15.2 μg·m L-1. Compound 2 was also active against P. gingivalis ATCC 33277, with an MIC value of 31.25 μg·m L-1. In conlcusion, our resutls indicate that these compounds may provide a basis for future development of novel antibiotics.展开更多
基金supported by Natural Key R&D Program of China(No.2018YFC1707000).
文摘Background:The traditional Chinese medicine Toosendan Fructus has certain hepatotoxicity,which is used after being processed by stir-frying to attenuate toxicity.However,there are few studies on its attenuating toxicity mechanism.The effects of Toosendan Fructus on the activities of CYP450P1A2,CYP2E1 and CYP3A4 were studied in vivo and in vitro and the dose-toxicity mechanism of hepatotoxicity before and after stir-frying was explored to provide the basis for safe,rational use of Toosendan Fructus.Methods:The rat liver microsomes in vitro incubation method and in vivo pharmacokinetics were used to detect the concentrations of phenacetin,chlorzoxazone and dapsone in the liver microsomes in vitro incubation system and the rat plasma to study the effect of stir-frying of Toosendan Fructus on the activity of CYP450P1A2,CYP2E1,CYP3A4.Results:The results of pharmacokinetics in vivo showed that the AUC of phenacetin and dapsone in different groups was lower,and CL value was higher than those of the normal group.At the same dose,the AUC of stir-fried Toosendan Fructus was higher than that of the raw,while CL value was lower.For the same processed product,AUC value was high-dose>low-dose>middle-dose group,CL value was high-dose<low-dose<middle-dose.AUC and CL values of chlorzoxazone showed no difference from those of the normal group.The results of pharmacokinetics in vivo showed that Toosendan Fructus can induce the activity of CYP3A4 in a dose-dependent manner and the induction effect will decrease after stir-frying in vitro.Conclusion:The toxicity attenuation of Toosendan Fructus may be related to the decrease of induction effect after stir-frying.These results would provide the basis for safe,rational use of Toosendan Fructus.
文摘Two new phenylpropanetriol glycosides, named as meliadanoside A (3 - methoxy- 5 - hydroxy-9- (1' - O-β-D-glucopyranosyl) - threo - phenylpropanetriol ) and meliadanoside B (4- hydroxy-7, 8- (2', 1' - O- β- D -glucopyranosyl) - phenylpropanetriol), were isolated from the water-soluble extract of the fruits of Meliatoosendan Sieb. et Zucc., along with threo-guaiacylglycerol. Their structures were elucidated by spectroscopic and chendcal analysis.
文摘Two new limonoid-type triterpenoids, named 12-o-ethyl-l-deacetylnimbolinin B and 1-o-tigloyl-1-o-debenzoylohchinal, have been isolated from the fruit of Melia toosendan Sieb. et Zucc. Their structures were elucidated by spectral methods, including 2D-NMR spectra.
文摘Two new limonoids,1α-tigloyloxy-3α-acetoxyl-7α-hydroxyl-12α-ethoxyl nimbolinin（1） and lα-benzoyloxy-3α-acetoxyl-7α- hydroxyl-12α-ethoxyl nimbolinin（2）,were isolated from the fruits of Melia toosendan.Their structures were established on the basis of various NMR spectroscopic analyses,including 2D-NMR techniques（HSQC,HMBC,NOESY） and HR-ESI-MS.
文摘Objective:Objective:To analyze and explore the key targets and molecular mechanisms of action of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity and the relationship between corresponding compounds based on network pharmacology.Methods:Using network pharmacology,a"traditional Chinese medicine-chemical composition-key target-pathway"analysis was conducted on Radix Paeoniae Alba for the treatment of Toosendan Fructus-induced hepatotoxicity.The possible mechanism of action was analyzed in terms of function.Results:The core targets,such as interleukin(IL)-6,tumor necrosis factor(TNF),heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator-activated receptor gamma(PPARG),prostaglandin-endoperoxide synthase 2(PTGS2),heme oxygenase 1(HMOX1),Jun proto-oncogene(JUN),caspase-3,estrogen receptor 1(ESR1),and aryl hydrocarbon receptor(AHR)were screened from the targets of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity.Biological process(BP)of toxic targets(BP terms)involved"response to drug;activation of cysteine-type endopeptidase activity involved in apoptotic process,”positive regulation of transcription.Cellular components(CC terms)mainly involved cytosol and membrane rafts.Molecular function(MF)terms included"protein homodimerization activity,"RNA polymerase II transcription factor activity and enzyme binding,etc."The Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway included the TNF signaling pathway,cancer pathways,and apoptosis.Conclusion:Radix Paeoniae Alba might alleviate Toosendan Fructus-induced hepatotoxicity through IL6,TNF,HSP90AA1,PPARG,PTGS2,HMOX1,and other targets,possibly via the activation of cysteine-type endopeptidase activity involved in these pathways.
基金Project supported by Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital,(No.202016)。
文摘Objective:To explore the potential mechanism of hepatotoxicity induced by Fructus Meliae Toosendan(FMT)through network pharmacology.Methods:The active components and targets of FMT were identified and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database,PubChem Database and Swiss Target Prediction database,etc.Genecards,pharmGKB,and OMIM databases were used to collect relevant targets of hepatotoxicity,and intersect them with the targets of active ingredients to obtain the potential targets of hepatotoxicity caused by FMT.A compound-target network was constructed with Cytoscape 3.8.0 software.The String 11.0 database was used to construct the protein-protein interaction(PPI)network of the targets and to screen out the core targets.In addition,Gene Ontology(GO)terms and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted by R software,and then the pathways directly related to hepatotoxicity were integrated.Results:In this study,9 active ingredients of FMT and 265 targets were obtained.There are 533 hepatotoxicity-related targets,and 76 potential targets for hepatotoxicity caused by FMT,among which quercetin,melianone,and nimbolin A are the key active components for hepatotoxicity caused by FMT,and MYC,STAT3,JUN,and RELA were the core target proteins of FMT’s hepatotoxicity.There were 2353 GO entries(P<0.05),including 2181 Biological Process(BP),41 Cellular Component(CC)and 131 Molecular Function(MF).KEGG enrichment analysis revealed 165 pathways(P<0.05),of which Th17 cell differentiation,HIF-1 signaling pathway,PI3K-Akt signaling pathway were strongly correlated with the hepatotoxicity of FMT.Conclusion:Through network pharmacology,it was found that many potential components in azadirachia chinaberry may be involved in the regulation of apoptosis,excessive inflammatory response and mitochondrial dynamics through multi-target and multi-pathway,resulting in the generation of hepatotoxicity.
基金supported by National Natural Science Foundation of China(No.31440027)Natural Science Foundation of Shanxi Province,China(No.201601D011123)+1 种基金Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(No.2014133)Science and Technology Innovation Found of Shanxi Medical University(No.C01201008)
文摘Two new limonoids, 12-ethoxynimbolinins G and H(compounds 1 and 2), and one known compound, toosendanin(Chuanliansu)(compound 3), were isolated from the bark of Melia toosendan. Their structures were elucidated by spectroscopic analysis and X-ray techniques. The absolute configuration of toosendanin(3) was established by single-crystal X-ray diffraction. Compounds 1-3 were evaluated for their cytotoxicity against five tumor cell lines.
基金Supported by the Natural Science Foundation Project of Science Committee of Chongqing,China(No.CQ CSTC2009BB5258)
文摘Objective： To investigate the anti-cancer effects of crude extract from Melia toosendan Sieb. et Zucc and its possible molecular mechanisms in vitro and in vivo. Methods： Transonic alcohol-chloroform extraction method was used to extract toosendanin from the bark of Melia toosendan Sieb. et Zucc, and the content of toosendanin in the crude extract was measured by high performance liquid chromatography （HPLC）. Anti-cancer effects of crude extract from Melia toosendan Sieb. et Zucc were investigated in in vivo and in vitro studies. In the in vitro experiment, human hepatocellular carcinoma cell lines SMMC-7721 and Hep3B were co-incubated with toosendanin crude extract of different concentrations, respectively. In the in vivo experiment, BALB/c mice were subcutaneously inoculated with mouse hepatocellular carcinoma H22 cells and treated with crude extract. Results： HPLC revealed the content of toosendanin was about 15%. Crude extract from Melia toosendan Sieb. et Zucc inhibited cancer cells growth in a dose- and time-dependent manner. The 50% inhibitory concentration （IC50, 72 h） was 0.6 mg/L for SMMC-7721 cells and 0.8 mg/L for Hep3B cells. Both high-dose [0.69 mg/（kg·d）] and low-dose [0.138 mg/（kg·d）] crude extract could markedly suppress cancer growth, and the inhibition rate was greater than 50%. Hematoxylin and eosin staining showed necrotic area in cancers and transmission electron microscopy displayed necrotic and apoptotic cancer cells with apoptotic bodies. Immunohistochemistry showed that the expression of Bax and Fas increased and the expression of Bcl-2 reduced. Conclusions： Toosendanin extract has potent anti-cancer effects via suppressing proliferation and inducing apoptosis of cancer cells in vivo and in vitro. The mechanism of apoptosis involves in mitochondrial pathway and death receptor pathway.
基金supported by National Natural Science Foundation of China(No.31440027)the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(No.2014133)+2 种基金Natural Science Foundation for Young Scientists of Shanxi Province,China(No.2011021007-3)the Science and Technology Innovation Found of Shanxi Medical University(No.C01201008)the Program for the Top Science and Technology Innovation Teams of Higher Learning Institutions of Shanxi Province,China
文摘In the present study, two new limonoids, 1α, 7α-dihydroxyl-3α-acetoxyl-12α-ethoxylnimbolinin(1) and 1α-tigloyloxy-3α-acetoxyl-7α-hydroxyl-12β-ethoxylnimbolinin(2), together with other four known limonoids(3-6), were isolated from the fruits of Melia toosendan. Their structures were elucidated by means of extensive spectroscopic analyses(NMR and ESI-MS) and comparisons with the data reported in the literature. The isolated compounds were evaluated for their antibacterial activities. Compound 4 exhibited significant antibacterial activity against an oral pathogen, Porphyromonas gingivalis ATCC 33277, with an MIC value of 15.2 μg·m L-1. Compound 2 was also active against P. gingivalis ATCC 33277, with an MIC value of 31.25 μg·m L-1. In conlcusion, our resutls indicate that these compounds may provide a basis for future development of novel antibiotics.
