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Insulin-sensitizing effects of a novel α-methyl-α-phenoxylpropionate derivative in vitro

Acta Pharmacologica Sinica 2007年第3期28卷 417-422页

作者： Hao-shu WU~(2,4) Juan-hong YU~(3,4) Ying-yin LI~2 Yu-she YANG~3 Qiao-jun HE~2 Yi-jia LOU~(2,5) Ru-yun JI~3 ~2Department of Pharmacology and Toxicology,College of Pharmaceutical sciences,Zhejiang University,Hangzhou 310058,china ~3state key laboratory of drug research,shanghai institute of materia medica,shanghai institutes for biological sciences,graduate school of the chinese academy of sciences,shanghai 2.12.3,china Department of Pharmacology and Toxicology College of Pharmaceutical Sciences Zhejiang University Hangzhou 310058 China Department of state key laboratory of drug research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Graduate School of the Chinese Academy of Sciences Shanghai 201203 China

Aim:To examine the insulin sensitizing effects of a novel α-methyl-α-phenoxylpropionate derivative YY20 in insulin-sensitive cell ***:Theperoxisome proliferator-activated receptor γ（PPARγ）agonist bioactivities of YY20were detected by a preadipocyte differentiation ***-PCR and Westernblotting analysis were used to detect the expression of the target gene or *** effects of YY20 on insulin-mediated glucose consumption were determined inthe HepG2 human hepatocellular carcinoma ***:YY20 could enhancethe differentiation of preadipocytes to adipocytes and upregulate the gene ex-pression of PPARγ2,as well as the protein expression of insulin receptor sub-strate-1（IRS-1）,glucose transporter-4（GLUT4）,and adiponectin（ACRP30）.Theeffects on GLUT4 and ACRP30 could be reversed by the PPARγ inhibitor ***,YY20 efficiently reduced glucose consumptions in HepG2 cells after24 h culture,and the effects were related to insulin and YY20 ***:YY20,a potential insulin-sensitizing agent like rosiglitazone,couldenhance glucose consumption in HepG2 cells in a concentration-and insulin-dependent *** may improve the insulin resistance associated with type 2diabetes.

关键词： YY20 peroxisome proliferator-activated receptor y insulin sensitivity glucose consumption

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A New Flavan-3-ol Glucoside from Daphniphyllum oldhami

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chinese Chemical Letters 2003年第9期14卷 926-929页

作者： Zhi Yu SHAO, Da Yuan ZHU, Yue Wei GUOstate key laboratory of drug research, institute of materia medica, shanghai institutes for biological sciences, chinese academy of sciences, shanghai 200031 state key laboratory of drug research Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031

A new flavan-3-ol glucoside, (-)-afzelechin-7-O-β-D-glucopyranoside (1), has been isolated from the stem of Daphniphyllum oldhami. The structure of the new compound was elucidated on the basis of detailed spectroscop... 详细信息

关键词： Daphniphyllum oldhami flavan-3-ol (-)-afzelechin-7-O-β-D-glucopyranoside.

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Rational redesign of inhibitors of furin/kexin processing proteases by electrostatic mutations

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Acta Pharmacologica Sinica 2004年第12期25卷 146-152页

作者： Xiao-hui CAI, Qing ZHANG, Da-fu DING2 key laboratory of Proteomics, institute of Biochemistry and Cell Biology, shanghai institutes for biological sciences, chinese academy of sciences, graduate school of the chinese academy of sciences, shanghai 200031, china key laboratory of Proteomics Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Graduate School of the Chinese Academy of Sciences Shanghai 200031 China

AIM: To model the three-dimensional structure and investigatethe interaction mechanism ofthe proprotein convertase furin/kexin and their inhibitors (eglin c mutants). METHODS: The three-dimensional complex structures of furin/ kexin with its inhibitors, eglin c mutants, were generated by modeller program using the newly published X-ray crystallographical structures of mouse furin and yeast kexin as templates. The electrostatic interaction energy of each complex was calculated and the results were compared with the experimentally determined inhibition con- stants to find the correlation between them. RESULTS: High quality models of furin/kexin-eglin c mutants were obtained and used for calculation of the electrostatic interaction energies between the proteases and their inhibitors. The calculated electrostaticenergies of interaction showeda linear correlation to the experimental inhibition constants. CONCLUSION: The modeled structures give good explanations of the specificity of eglin c mutants to furin/ kexin. The electrostatic interactions play important roles in inhibitory activity of eglin c mutants to furin/kexin. The results presented here provided quantitative structural and functional information concerning the role of the charge- charge interactions in the binding of furin/kexin and their inhibitors.

关键词： furin kexin eglin c drug design electrostatic mutation

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Synthesis of N^(11)-anchoring biotinylated artemisinin derivatives and their preliminary biological assessment

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Science china Chemistry 2010年第1期53卷 119-124页

作者： PAN QiYu1,2,WANG ShaoZhong1,LU JinJian3,MENG LingHua3 & YAO ZhuJun1,2 1Nanjing National laboratory of Microstructures(NNLM),school of Chemistry and Chemical Engineering,Nanjing University,Nanjing 210093,china 2Joint laboratory of Green Chemistry,Department of Chemistry,University of Science and Technology of china,Hefei 230026,china 3state key laboratory of drug research,shanghai institute of materia medica,shanghai institutes for biological sciences,chinese academy of sciences,shanghai 2.12.3,china. 1. Nanjing National laboratory of Microstructures (NNLM) School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093 China2. Joint Laboratory of Green Chemistry Department of Chemistry University of Science and Technology of China Hefei 230026 China3. State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

Unique endoperoxide moiety of artemisinin and its derivatives has been considered the functionality exhibiting highly potent antimalarial and anticancer *** investigate the mechanisms of their biological actions,development of suitable molecular probes including biotinylated derivatives is of extreme *** synthesis and preliminary biological assessment of four new biotinylated artemisinin derivatives have been reported in this work.

关键词： artemisinin endoperoxide biotinylated derivative synthesis anticancer activity

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Catechol-Bisphosphonate Conjugates: New Potential Chelating Agents for Metal Intoxication Therapy

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chinese Chemical Letters 2004年第12期15卷 1403-1406页

作者： Guang Yu XU Chun Hao YANG Bo LIU Xi Han WU Yu Yuan XIE state key laboratory of drug research, shanghai institute of materia medica, shanghai institutes for biological sciences, shanghai 2.12.3 state key laboratory of drug research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences

In a quest for better chelating therapy drugs for the treatment of intoxication by Fe, Al, oractinides, two new series of mixed catechol-bisphosphonate through amide linkage were synthesized.Benzyl group was used as protecting group to avoid the breakage of amide by acid hydrolysis orimcomplete reaction in silylation-dealkylation using bromotrimethylsilane.

关键词： Bisphosphonates catechol chelating agents metal intoxication therapy.

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Conformational flexibility of β-secretase: molecular dynamics simulation and essential dynamics analysis

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Acta Pharmacologica Sinica 2004年第6期25卷 3-11页

作者： Bing XIONG, Xiao-qin HUANG, Ling-ling SHEN, Jian-hua SHEN 2,Xiao-min LUO, Xu SHEN, Hua-liang JIANG2, Kai-xian CHENdrug Discovery and Design Center, state key laboratory of drug research, shanghai institute of materia medica,shanghai institutes for biological sciences, chinese academy of sciences, shanghai 2.12.3, china drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

AIM: Based on the structural analysis to reveal the mechanism of ligand binding to b-secretase and the specificityof each binding sub-site. METHODS: Molecular dynamics was used to simulate on the ligand free b-secretase andligand bound b-secretase. The trajectories were analyzed using the essential dynamics, and the significant confor-mational change was illustrated employing the DynDom program. RESULTS: The essential dynamics and DynDomanalyses clearly showed that the b-secretase experienced a large conformational change upon the substrate orinhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate theligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysisrevealed that residues at P2, P1, and P1 positions of the inhibitor were very important for the binding, and residuesat P2 and P3 positions may be modified to improve the binding specificity. S3 subsite of the enzyme still hadspace to modify the inhibitors in increasing the binding affinity. CONCLUSION: The information presented hereis valuable and could be used to identify small molecular inhibitors of b-secretase.

关键词： molecular dynamics secretase essential dynamics computer simulation Alzheimer disease

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Tetrahydroacridine inhibits voltage-dependent Na~+ current in guinea-pig ventricular myocytes

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Acta Pharmacologica Sinica 2004年第9期 36-42页

作者： Wei WANG, Yi-ping WANG, Guo-yuan HUstate key laboratory of drug research, The First Department of Pharmacology, shanghai institute of materia medica, shanghai institutes for biological sciences, chinese academy of sciences, shanghai 2.12.3, china

AIM: To study the effects of tetrahydroacridine (tacrine) on voltage-gated Na+ channels in cardiac tissues. METHODS: Single ventricular myocytes were enzymatically dissociated from adult guinea-pig heart. Voltage-depe... 详细信息

关键词： Alzheimer disease cholinesterase inhibitors sodium channels tetrahydroacridine (tacrine) myocardium patch-clamp techniques

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Magnesium lithospermate B ameliorates renal cortical microperfusion in rats

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Acta Pharmacologica Sinica 2006年第2期27卷 217-222页

作者： Chun-guang CHEN~(2,3) Yi-ping WANG~(2,4) ~2state key laboratory of drug research.shanghai institute of materia medica,shanghai institutes for biological sciences graduate school of the chinese academy of sciences,chinese academy of sciences,shanghai 2.12.3,china statekeylaboratoryofdrugresearch ShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciences graduateschoolofthechineseacademyofsciences ChineseAcademyofSciencesShanghai201203China

Aim:To investigate the effects of magnesium lithospermate B（MLB）isolatedfrom Salviae miltiorrhizae on renal microcirculation,and renal and systemic he-modynamics in Sprague-Dawley ***:MLB（10,30,and 60 mg/kg）wasinjected intravenously and renal blood flow（RBF）,renal cortical microperfusion（RCM）,and systemic hemodynamic function parameters including heart rate（HR）,mean arterial pressure（MAP）,left ventricular systolic pressure（LVSP）,left ven-tricular end-diastolic pressure（LVEDP）,and maximal velocity of pressure increase(dp/dtmax)were measured for 45 min after ***:IntravenousMLB at doses of 10,30,and 60 mg/kg increased RCM significantly,but had noobvious effects on RBF or systemic *** effect of MLB on RCMreached its peak 15 rain after injection and returned to baseline after 45 *** to60 mg/kg MLB increased RCM by 62.4%±20.2%（changes from baseline,P3.7%±9.7% vs baseline）and renal vascular resistance（-1.4%±9.1%vs baseline）did not obviously ***:These results indicate thatMLB ameliorates renal microcirculation in a dose-dependent manner,which maybe related to the renoprotective effects of MLB.

关键词： magnesium lithospermate B hemodynamics renal blood flow renal cortical microperfusion

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Comparative studies of huperzine A,donepezil,and rivastigmine on brain acetylcholine,dopamine,norepinephrine,and 5-hydroxytryptamine lev-els in freely-moving rats

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Acta Pharmacologica Sinica 2006年第9期27卷 1127-1136页

作者： Yan-qi LIANG Xi-can TANG~2 state key laboratory of drug research,shanghai institute of materia medica,shanghai Instituties for biological sciences,graduate school of the chinese academy of sciences,chinese academy of sciences,shanghai 2.12.3.china state key laboratory of drug research Shanghai Institute of Materia Medica Shanghai Instituties for Biological Sciences Graduate School of the Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 201203 China. eds.ufl.edu

Aim:To assess the effects of cholinesterase inhibitors huperzine A,donepeziland rivastigmine on cerebral neurotransmitters in the cortex and hippocampus infreely-moving ***:Double-probe cerebral microdialysis and HPLC withelectrochemical detection were used to detect ***:Ourresults showed that huperzine A(0.***.0.5,and 0.75μmol/kg,po)dose-depen-dently elevated extracellular acetylcholine(ACh)levels in the medial prefrontalcortex(mPFC)and *** administration of donepezil(5.4μmol/kg)orrivastigmine(1μmol/kg)also elicited significant increases in ACh in the mPFC *** time course of cortical acetylcholinesterase(ACHE)inhibitionwith the 3 inhibitors minored the increases of ACh at the same *** markedelevation of ACh after oral administration of huperzine A(0.5μmol/kg)anddonepezil(5.4μmol/kg)was associated with a significantly increased release ofdopamine(DA)in the mPFC or *** of the 3 inhibitors affectednorepinephrine(NE)and 5-hydroxytryptamine(5-HT)levels in the mPFC *** effects of huperzine A and rivastigmine did not depend on theroute of administration,but donepezil was less efficacious by the oral route thanby ip *** ability of huperzine A to increase ACh levels was unchangedwhen tests were performed after multiple oral administration of the drug at 0.5μmol/kg,once per day for 30 ***:The present findings showed that,inmolar terms,huperzine A had similar potency on increasing mPFC ACh and DAlevels as compared to the 11-and 2-fold dosages of donepezil and rivastigmine,respectively,and had longer lasting effects after oral dosing.

关键词： huperzine A donepezil rivastigmine acetylcholine dopamine norepinephrine 5-hydroxy tryptamine Alzheimer’s disease rats

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Development of a complex scintillation proximity assay for highthroughput screening of PPAR7 modulators

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Acta Pharmacologica Sinica 2005年第3期26卷 339-344页

作者： Bin WU Jie GAO Ming-wei WANG~2 The National Center for drug Screening,shanghai institute of materia medica,shanghai institutes for biological sciences,chinese academy of sciences graduate school of chinese academy of sciences,shanghai 2.12.3,china The National Center for drug Screening Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences graduate school of chinese academy of sciences Shanghai 201203 China

Aim:To develop a complex high-throughput screening （HTS） assay based onscintillation proximity assay （SPA） technology for identification of novel peroxi-some proliferator-activated receptor gamma （PPARγ） ***:Full-length PPARγ and retinoid X receptor alpha （RXRα）,biotinylated PPAR responseelement （PPRE）,[3H]BRL49653 and streptavidin-coated FlashPlate or microbeadwere used to develop an HTS assay based on SPA ***‘ABCDE’method was validated against conventional hydroxyapatite （HA） assay and ap-plied to large-scale screening of 16 000 synthetic compounds and natural ***:（1） IC50values of positive control compounds （BRL49653 andtroglitazone） obtained from the‘ABCDE’method and HA assay were compa-rable and consistent with those reported elsewhere;（2） Approximately 178compounds,showing more than 70% competitive inhibition on BRL49653 bind-ing to PPARγ,were identified initially by the‘ABCDE’method （microbead）;（3）Secondary screening using FlashPlate and cross-reactivity studies with RARα,β,γ and RXRα,β,γ confirmed that 12 compounds possessed specific PPARγ bind-ing properties including 2 with IC50values less than 0.5 μmol/L and novel chemi-cal ***:The‘ABCDE’method using either FlashPlate ormicrobead,is a highly efficient,automatable,and robust tool to screen potentialPPARγ modulators in HTS *** application may be expanded to othernuclear receptors that form heterodimers upon activation.

关键词： peroxisome proliferator-activated receptor gamma retinoid X receptor alpha scintillation proximity assay high-throughput screening

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