目的:基于网络药理学探讨浙贝母-夏枯草治疗甲状腺结节(thyroid nodules)的作用机制。方法:在中药系统药理数据库和分析平台(traditional Chinese medicine systems pharmacology database and analysis platform, TCMSP)检索浙贝母、...目的:基于网络药理学探讨浙贝母-夏枯草治疗甲状腺结节(thyroid nodules)的作用机制。方法:在中药系统药理数据库和分析平台(traditional Chinese medicine systems pharmacology database and analysis platform, TCMSP)检索浙贝母、夏枯草的化学成分,利用PharmMapper数据库获取化学成分靶点,并采用Cytoscape 3.7.1软件构建“药物-活性成分-靶点”网络。基于Genecards数据库、在线人类孟德尔遗传数据库、治疗靶点数据库获得甲状腺结节相关靶点。将有效成分相关靶点与疾病靶点导入韦恩图网站进行在线分析,获得交集靶点,并利用STRING数据库构建蛋白互作网络(protein-protein interaction networks, PPI)模型,利用Cytoscape 3.7.1软件构建PPI网络并筛选核心靶点。将药物及其活性成分、交集靶点及疾病导入Cytoscape 3.7.1软件绘制成“药物-活性成分-交集靶点-疾病”网络图。利用Metascape数据库对交集靶点进行基因本体(gene ontology, GO)功能分析和京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)信号通路富集分析。采用AutoDock软件对关键靶点与活性成分进行分子对接。结果:浙贝母-夏枯草药对共15个活性成分,171个相关靶点。甲状腺结节疾病靶点1 563个。经韦恩图网站在线分析后得到浙贝母-夏枯草治疗甲状腺结节相关的靶点108个。交集靶点PPI网络分析得到AKT1、肿瘤蛋白P53(tumor protein P53,TP53)、丝裂原活化蛋白激酶1(mitogen-activated protein kinase 1,MAPK1)为核心靶点。GO富集分析得到生物过程1 705条、分子功能136条、细胞组分115条。KEGG富集分析获得202个信号通路。分子对接结果表明,浙贝母-夏枯草主要有效活性成分与靶点受体蛋白可以较好的结合。结论:浙贝母-夏枯草药对可通过多成分、多靶点、多通路治疗甲状腺结节。展开更多
This paper reports on a new microporous composite silica membrane prepared via acid-catalyzed polymeric route of sol-gel method with tetraethylorthosilicate(TEOS)and a bridged silsesquioxane[1,2-bis(triethoxysilyl)eth...This paper reports on a new microporous composite silica membrane prepared via acid-catalyzed polymeric route of sol-gel method with tetraethylorthosilicate(TEOS)and a bridged silsesquioxane[1,2-bis(triethoxysilyl)ethane, BTESE]as precursors.A stable nano-sized composite silica sol with a mean volume size of^5 nm was synthesized. A 150 nm-thick defect-free composite silica membrane was deposited on disk support consisting of macroporous α-Al2O3 and mesoporousγ-Al2O3 intermediate layer by using dip-coating approach,followed by calcination under pure nitrogen atmosphere.The composite silica membranes exhibit molecular sieve properties for small gases like H2,CO2,O2,N2,CH4 and SF6 with hydrogen permeances in the range of(1-4)×10 -7mol·m -2·s -1·Pa -1(measured at 200°C,3.0×105 Pa).With respect to the membrane calcined at 500°C,it is found that the permselectivities of H 2 (0.289 nm)with respect to N2(0.365 nm),CH4(0.384 nm)and SF6(0.55 nm)are 22.9,42 and>1000,respectively, which are all much higher than the corresponding Knudsen values(H2/N2=3.7,H2/CH4=2.8,and H2/SF6=8.5).展开更多
It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approve...It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.展开更多
Mn（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cu（Ⅱ）, Pd（Ⅱ） and Ru（Ⅲ） complexes of Schiff bases derived from the condensation of sulfaguanidine with 2,4-dihydroxy benzaldehyde （HL1）, 2-hydroxy-l-naphthaldehyde （HL2） and ...Mn（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cu（Ⅱ）, Pd（Ⅱ） and Ru（Ⅲ） complexes of Schiff bases derived from the condensation of sulfaguanidine with 2,4-dihydroxy benzaldehyde （HL1）, 2-hydroxy-l-naphthaldehyde （HL2） and salicylaldehyde （HL3） have been synthesized. The structures of the prepared metal complexes were proposed based on elemental analysis, molar conductance, thermal analysis （TGA, DSC and DTG）, magnetic susceptibility measurements and spectroscopic techniques （IR, UV-Vis, and ESR）. In all complexes, the ligand bonds to the metal ion through the azomethine nitrogen and a-hydroxy oxygen atoms. The structures of Pd（Ⅱ） complex 8 and Ru（Ⅲ） complex 9 were found to be polynuclear. Two kinds of stereochemical geometries; distorted tetrahedral and distorted square py- ramidal, have been realized for the Cu（Ⅱ） complexes based on the results of UV-Vis, magnetic susceptibility and ESR spectra whereas octahedral geometry was predicted for Co（Ⅱ）, Mn（Ⅱ） and Ru（Ⅲ） complexes. Ni（Ⅱ） com- plexes were predicted to be square planar and tetrahedral and Pd（Ⅱ） complexes were found to be square planar. The antimicrobial activity of the ligands and their metal complexes was also investigated against the gram-positive bac- teria Staphylococcus aures and Bacillus subtilis and gram-negative bacteria, Escherichia coli and Pesudomonas aeruginosa, by using the agar dilution method. Chloramphenicol was used as standard compound. The obtained data revealed that the metal complexes are more or less, active than the parent ligand and standard. The X-ray crys- tal structure of HL3 has been also reported.展开更多
基金supported by the Key Scientific"Twelfth Five-Year"National Technology Support Program(2011BAE06B01-17)the Innovation Project of Shanghai Education Commission(12YZ078)+2 种基金the National Natural Science Foundation of China(21102092)the Leading Academic Discipline Project of Shanghai Normal University(DXL123)Shanghai Key Laboratory of Rare Earth Functional Materials,and Shanghai NormalUniversity(07dz22303)
文摘目的:基于网络药理学探讨浙贝母-夏枯草治疗甲状腺结节(thyroid nodules)的作用机制。方法:在中药系统药理数据库和分析平台(traditional Chinese medicine systems pharmacology database and analysis platform, TCMSP)检索浙贝母、夏枯草的化学成分,利用PharmMapper数据库获取化学成分靶点,并采用Cytoscape 3.7.1软件构建“药物-活性成分-靶点”网络。基于Genecards数据库、在线人类孟德尔遗传数据库、治疗靶点数据库获得甲状腺结节相关靶点。将有效成分相关靶点与疾病靶点导入韦恩图网站进行在线分析,获得交集靶点,并利用STRING数据库构建蛋白互作网络(protein-protein interaction networks, PPI)模型,利用Cytoscape 3.7.1软件构建PPI网络并筛选核心靶点。将药物及其活性成分、交集靶点及疾病导入Cytoscape 3.7.1软件绘制成“药物-活性成分-交集靶点-疾病”网络图。利用Metascape数据库对交集靶点进行基因本体(gene ontology, GO)功能分析和京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)信号通路富集分析。采用AutoDock软件对关键靶点与活性成分进行分子对接。结果:浙贝母-夏枯草药对共15个活性成分,171个相关靶点。甲状腺结节疾病靶点1 563个。经韦恩图网站在线分析后得到浙贝母-夏枯草治疗甲状腺结节相关的靶点108个。交集靶点PPI网络分析得到AKT1、肿瘤蛋白P53(tumor protein P53,TP53)、丝裂原活化蛋白激酶1(mitogen-activated protein kinase 1,MAPK1)为核心靶点。GO富集分析得到生物过程1 705条、分子功能136条、细胞组分115条。KEGG富集分析获得202个信号通路。分子对接结果表明,浙贝母-夏枯草主要有效活性成分与靶点受体蛋白可以较好的结合。结论:浙贝母-夏枯草药对可通过多成分、多靶点、多通路治疗甲状腺结节。
基金Supported by the National Natural Science Foundation of China(20906047)the State Key Laboratory of Chemical Engineering(SKL-ChE-09A01)the State Key Laboratory of Materials-Oriented Chemical Engineering(ZK201002)
文摘This paper reports on a new microporous composite silica membrane prepared via acid-catalyzed polymeric route of sol-gel method with tetraethylorthosilicate(TEOS)and a bridged silsesquioxane[1,2-bis(triethoxysilyl)ethane, BTESE]as precursors.A stable nano-sized composite silica sol with a mean volume size of^5 nm was synthesized. A 150 nm-thick defect-free composite silica membrane was deposited on disk support consisting of macroporous α-Al2O3 and mesoporousγ-Al2O3 intermediate layer by using dip-coating approach,followed by calcination under pure nitrogen atmosphere.The composite silica membranes exhibit molecular sieve properties for small gases like H2,CO2,O2,N2,CH4 and SF6 with hydrogen permeances in the range of(1-4)×10 -7mol·m -2·s -1·Pa -1(measured at 200°C,3.0×105 Pa).With respect to the membrane calcined at 500°C,it is found that the permselectivities of H 2 (0.289 nm)with respect to N2(0.365 nm),CH4(0.384 nm)and SF6(0.55 nm)are 22.9,42 and>1000,respectively, which are all much higher than the corresponding Knudsen values(H2/N2=3.7,H2/CH4=2.8,and H2/SF6=8.5).
文摘It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.
文摘Mn（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cu（Ⅱ）, Pd（Ⅱ） and Ru（Ⅲ） complexes of Schiff bases derived from the condensation of sulfaguanidine with 2,4-dihydroxy benzaldehyde （HL1）, 2-hydroxy-l-naphthaldehyde （HL2） and salicylaldehyde （HL3） have been synthesized. The structures of the prepared metal complexes were proposed based on elemental analysis, molar conductance, thermal analysis （TGA, DSC and DTG）, magnetic susceptibility measurements and spectroscopic techniques （IR, UV-Vis, and ESR）. In all complexes, the ligand bonds to the metal ion through the azomethine nitrogen and a-hydroxy oxygen atoms. The structures of Pd（Ⅱ） complex 8 and Ru（Ⅲ） complex 9 were found to be polynuclear. Two kinds of stereochemical geometries; distorted tetrahedral and distorted square py- ramidal, have been realized for the Cu（Ⅱ） complexes based on the results of UV-Vis, magnetic susceptibility and ESR spectra whereas octahedral geometry was predicted for Co（Ⅱ）, Mn（Ⅱ） and Ru（Ⅲ） complexes. Ni（Ⅱ） com- plexes were predicted to be square planar and tetrahedral and Pd（Ⅱ） complexes were found to be square planar. The antimicrobial activity of the ligands and their metal complexes was also investigated against the gram-positive bac- teria Staphylococcus aures and Bacillus subtilis and gram-negative bacteria, Escherichia coli and Pesudomonas aeruginosa, by using the agar dilution method. Chloramphenicol was used as standard compound. The obtained data revealed that the metal complexes are more or less, active than the parent ligand and standard. The X-ray crys- tal structure of HL3 has been also reported.
