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

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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 201203,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

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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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 201203 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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Centrophenoxine improves chronic cerebral ischemia induced cognitive deficit and neuronal degeneration in rats

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Acta Pharmacologica Sinica 2004年第12期25卷 24-30页

作者： Yun LIAO2, Rui WANG, Xi-can TANG3 state keylaboratory of drug research, shanghai institute of materia medica, shanghai institutes for biological sciences, chinese academyofsciences, shanghai 201203, china.2Tongjimedical College of Huazhong Universityof Science & Technology, Wuhan 430030, china Tongji medical College of Huazhong University of Science & Technology Wuhan 430030 China

AIM: To study the effects of centrophenoxine (CPH, meclofenoxate) on chronic cerebral hypoperfusion induced deficits in rats. METHODS: Chronic hypoperfusion in rats was performed by permanent bilateral ligation of the common carotid arteries. Morris water maze was used to measure spatial memory performance. Spectrophoto- metrical techniques were used to assay SOD, GPx activities, MDA content, TXB2, and 6-keto-PGF1α levels. Mor- phological change was examined by HE staining. The expression of Bax and p53 protein were assayed by immuno- histochemistry analysis. RESULTS: Chronic hypoperfusion in rats resulted in spatial memory impairments shown by longer escape latency and shorter time spent in the target quadrant. These behavioral dysfunction were accom- panied by increase in SOD and GPx activities, the content of MDA, the levels of pro-inflammatory mediators (TXB2, 6-keto-PGF1α), overexpression of Bax and P53 protein, and delayed degeneration of neurons in cortex and hippocampus. Oral administration of CPH (100 mg/kg, once per day for 37 d) markedly improved the memory impairment, reduced the increase in antioxidant enzyme activities, MDA content and the levels of pro-inflammatory mediators to their normal levels, and attenuated neuronal damage. CONCLUSION: The abilities of CPH to attenu- ate memory deficits and neuronal damage after ischemia may be beneficial in cerebrovascular type dementia.

关键词： meclofenoxate brain ischemia free radicals maze learning TXB2 6-keto-PGF1α Bax protein p53 protein

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 201203, 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

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 201203, 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

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

Progress in studies of huperzine A,a natural cholinesterase inhibitor from chinese herbal medicine

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Acta Pharmacologica Sinica 2006年第1期27卷 1-26页

作者： Rui WANG Hart YAN Xi-can TANG state key Lahoratory of drug research.shanghai institute of materia medica.shanghai institutes for biological sciences chinese academy of sciences.shanghai 201203,china statekeylaboratoryofdrugresearch ShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciencesChineseAcademyofSciencesShanghai201203China

Huperzine A (HupA),a novel alkaloid isolated flom the chinese herb Huperziaserrata,is a potent,highly specific and reversible inhibitor of acetylcholinesterase(ACHE).Compared with tacrine,donepezil,and rivastigmine,HupA has betterpenetration through the blood-brain barrier,higher oral bioavailability,and longerduration of AChE inhibitory *** has been found to improve cognitivedeficits in a broad range of animal *** possesses the ability to protectcells against hydrogen peroxide,β-amyloid protein (or peptide),glutamate,ischemia and staurosporine-induced cytotoxicity and *** protec-tive effects are related to its ability to attenuate oxidative stress,regulate theexpression of apoptotic proteins ***,P53,and caspase-3,protectmitochondria,upregulate nerve growth factor and its receptors,and interfere withamyloid precursor protein *** effects of HupA on N-me-thyl-D-aspartate receptors and potassium currents may also contribute to itsneuroprotection as *** studies in rodents,canines,and healthyhuman volunteers indicated that HupA was absorbed rapidly,distributed widelyin the body,and eliminated at a moderate rate with the property of slow andprolonged release after oral *** and clinical safety tests showedthat HupA had no unexpected toxicity,particularly the dose-limiting hepalotoxic-ity induced by *** phase Ⅳ clinical trials in china.have demonstratedthat HupA significantly improved memory deficits in elderly people with benignsenescent forgetfulness,and patients with Alzheimer disease and vasculardementia,with minimal peripheral cholinergic side effects and no *** can also be used as a protective agent against organophosphateintoxication.

关键词： huperzine A Alzheimer disease acetylcholinesterase cholinesterase inhibitors cognitive enhancer neuroprotect agents oxidative stress apoptosis

Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC12 cells

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Acta Pharmacologica Sinica 2005年第6期26卷 673-678页

作者： Li-li TANG, Rui WANG, Xi-can TANG~2 state key laboratory of drug research, shanghai institute of materia medica, shanghai institutes for biological sciences, chinese academy of sciences, shanghai 201203, china statekeylaboratoryofdrugresearch ShanghaiInstituteofMateriaMedicaShanghaiInstitutesforBiologicalSciencesChineseAcademyofScienc

Aim: To study the effects of huperzine A (HupA) on neuritogenic activity and the expression of nerve growth factor (NGF). Methods: After being treated with 10 μmol/L HupA, neurite outgrowth of PC 12 cells was observed and counted under phase-contrast microscopy. Mitogenic activity was assayed by [~3H]thymidine incorporation. Cell cytotoxicity was evaluated by lactate dehydrogenase (LDH) release. AChE activity, mRNA and protein expression were measured by the Ellman’s method, RT-PCR, and Western blot, respectively. NGF mRNA and protein levels were determined by RT-PCR and ELISA assays. Results: Treatment of PC 12 cells with 10 渭mol/L HupA for 48 h markedly increased the number of neurite-bearing cells, but caused no significant alteration in cell viability or other signs of cytotoxicity. In addition to inhibiting AChE activity, 10 渭mol/L HupA also increased the mRNA and protein levels of this enzyme. In addition, following 2 h exposure of the astrocytes to 10 渭mol/L HupA, there was a significant up-regula-tion of mRNA for NGF and P75 low-affinity NGF receptor. The protein level of NGF was also increased after 24 h treatment with HupA. Conclusion: Our findings demonstrate for the first time that HupA has a direct or indirect neurotrophic activity, which might be beneficial in treatment of neurodegenerative disorders such as Alzheimer disease.

关键词： huperzine A nerve growth factor neurite outgrowth: acetylcholinesterase inhibitors