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Synthesis and Characterization of A Small Molecule CFTR Chloride Channel Inhibitor

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Chemical Research in Chinese Universities 2004年第3期20卷 334-337页

作者： HECheng-yan ZHANGHeng-jun SUZhong-min ZHOUJin-song YANGHong MATong-hui MembraneChannelResearchLaboratory InstituteofFunctionalMaterialChemistry NortheastNormalUniversityChangchun130024P.R.China DepartmentofLaboratoryMedicine China-JapanUnionHospitalJilinUniversityChangchun130033P.R.China

A thiazolidinone CFTR inhibitor(CFTR_ inh-172 ) was synthesized by a three-step procedure with trifluromethylaniline as the starting material. The synthesized CFTR inhibitor was characterized structurally by means of 1H NMR and functionally in a CFTR-expressing cell line FRT/hCFTR/EYFP-H148Q by both fluorescent and electrophysiological methods. A large amount(100 g) of high-quality small molecule thiazolidinone CFTR chloride channel inhibitor,CFTR_ inh-172 ,can be produced with this simple three-step synthetic procedure. The structure of the final product 2-thioxo-3-(3-trifluromethylphenyl)-5-[4-carboxyphenyl- methylene]-4-thiazolidinone was confirmed by 1H NMR. The overall yield was 58% with a purity over 99% as analyzed by HPLC. The synthesized CFTR_ inh-172 specifically inhibited CFTR chloride channel function in a cell-based fluorescence assay( K _d≈1.5 μmol/L) and in a Ussing chamber-based short-circuit current assay( K _d≈0.2 μmol/L),indicating better quality than that of the commercial combinatorial compound. The synthesized inhibitor is nontoxic to cultured cells at a high concentration and to mouse at a high dose. The synthetic procedure developed here can be used to produce a large amount of the high-quality CFTR_ inh-172 suitable for antidiarrheal studies and for creation of cystic fibrosis models in large animals. The procedure can be used to synthesize radiolabled CFTR_ inh-172 for in vivo pharmacokinetics studies.

关键词： Cystic fibrosis transmembrane conductance regulator(CFTR) CFTR chloride channel Fisher rat thyroid(FRT) Yellow fluorescent protein(YFP) Diarrhea Cystic fibrosis

Involvement of VLA-5 and VLA-6 in facilitating endothelium-oriented transmigration of hematopoietic stem/progenitor cells

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吉林大学学报（医学版） 2003年第3期29卷 249-254页

作者： JINLing WANGWei-zhong LIChun-jiang Dept.ofClinicalLaboratory China-JapanUnionHospitalJilinUniversityChangchun130031China CentralLabaratory China-JapanUnionHospitalJilinUniversity InstituteofEnvironmentalStudies GraduateSchoolofFrontierSciencetheUniversityofTokyoHongo7-3-1Bunkyo-kuTokyoJapan

目的 :研究 VLA- 5及 VLA- 6是否参与内皮细胞促进的造血干 /祖细胞定向移行。方法 :对纯化人 CD34+ 细胞进行体外移行及阻断实验 ,观察其穿移覆盖人脐静脉内皮细胞 ( HUVECs)滤膜的能力。应用四色荧光活化流式细胞术 ( FACS)检测 CD34... 详细信息

目的 :研究 VLA- 5及 VLA- 6是否参与内皮细胞促进的造血干 /祖细胞定向移行。方法 :对纯化人 CD34+ 细胞进行体外移行及阻断实验 ,观察其穿移覆盖人脐静脉内皮细胞 ( HUVECs)滤膜的能力。应用四色荧光活化流式细胞术 ( FACS)检测 CD34+细胞其粘附分子及趋化因子受体CXCR- 4的表达谱。结果 :基质由来因子 ( SDF) - 1 α介导的动员外周血 ( m PB)及骨髓 ( BM)来源的CD34+ 细胞穿透覆盖 HUVECs滤膜百分率分别为 ( 5 6.6± 2 0 .1 ) %及 ( 1 5 .6± 1 .8) % ,显著高于其穿移未覆盖 HUVECs滤膜的比率。预先对 CD34+ 细胞进行抗 VLA- 5和 /或 VLA- 6中和抗体处理可消除这一促进效应。此外 ,BM来源的 CD34+细胞其穿移覆盖及未覆盖 HUVECs滤膜的能力均显著低于 m PB CD34+细胞 ,两者间穿移能力的差异与其 VLA- 5及 VLA- 6(而非 VLA- 4及趋化因子受体 CXCR- 4)抗原表达水平相关。结论 :VLA- 5和 VLA- 6参与 HUVECs促进 HS/PCs穿移能力。

关键词：落户穿内皮移行人脐静脉内皮细胞基质衍生因子-1α 造血干/祖细胞晚期激活抗原-5 晚期激活抗原-6

Pitfalls and sources of error of color duplex ultrasonography in detecting deep vein thrombosis of proximal lower extremities

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中国医学影像技术 2004年第3期20卷 472-476页

作者： GAO Jing YI Lian-hua Auh Yong Ho NewYorkPresbyterian UniversityHospitalofColumbiaandCornellNewYorkUSA china-japanunionhospital JilinUniversityChangchunChina

Purpose To analyze the sources of errors and discuss the techniques to eliminate pitfalls in detecting deep vein thrombosis (DVT) of the proximal lower extremities with color duplex ultrasonography (CDUS). Methods Sixty-eight cases with initial and repeat venous CDUS of the proximal lower extremities were retrospectively reviewed. The repeat was done within 24 hours after initial CDUS scanning. Comparing repeated images to initial ones, the pitfalls and sources of error in CDUS of the proximal lower extremities were discussed. Results In total 68 repeat studies, there were 62 results as same as initials and 4 cases of false negative DVT and 2 cases of false positive DVT. Conclusion Venous CDUS in detecting DVT is observer dependent. Some pitfalls and errors can be eliminated and corrected with proper scan techniques. CDUS is the most valuable imaging modality for assessing suspected DVT in the proximal lower extremities.

关键词：深静脉血栓静脉造影彩色多普勒伪影影像学诊断质量控制

Activation of G551D-CFTR by Bicyclooctane Compounds Is cAMP-dependent and Exhibits Low Sensitivity to Thiazolidinone CFTR Inhibitor CFTRinh-172

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Chemical Research in Chinese Universities 2005年第2期21卷 183-186页

作者： WANGYing ZHAOLu HECheng-yan XULi-na YANGHong MembraneChannelResearchLaboratory NortheastNormalUniversityChangchun130024P.R.China CollegeofTraditionalChineseMedicineMaterial JilinAgriculturalUniversityChangchun130118P.R.China china-japanunionhospital JilinUniversityChangchun130033P.R.China.

The G551D-CFTR mutation causing cystic fibrosis(CF) results from a missense mutation at codon 551(G551D) in the gene encoding of the cystic fibrosis transmembrane conductance regulator(CFTR). The G551D mutation in CFTR results in a reduced functional channel but G551D-CFTR is appropriately inserted in the apical membrane. In previous studies we discovered a class of high-affinity bicyclooctane(BCO) G551D-CFTR activators(G551D_ BCOs) with K_d down to 1 μmol/L. In this study, we analyzed the pharmacological activation of G551D-CFTR by the G551D_ BCOs by means of short circuit current analysis and cell-based fluorescence quenching assay. The G551D_ BCOs-induced G551D-CFTR activation is cAMP-dependent and is less sensitive to thiazolidinone CFTR inhibitor CFTRinh-172. These data suggest that (1) the phosphorylation of G551D-CFTR by protein kinase A is required for the activation by G551D_ BCOs; (2) G551D_ BCOs and CFTRinh-172 may act at the same site on the G551D-CFTR molecule.

关键词： Cystic fibrosis(CF) Cystic fibrosis transmembrane conductance regulator(CFTR) Short circuit current analysis Pharmacological activation

Cloned s-Lap Gene Coding Area, Expression and Localization of s-Lap/GFP Fusion Protein in Mammal Cells

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Chemical Research in Chinese Universities 2005年第3期21卷 298-300页

作者： SONGYi-shu SONGZhi-yu LIHong-jun WuYin BAOYong-li TANDa-peng LIYu-xin InstituteofGeneticsandCytology NortheastNormalUniversityChangchun130024P.R.China DepartmentofUrology theFirstHospitalJilinUniversityChangchun130021P.R.China china-japanunionhospital JilinUniversityChangchun130023P.R.China

s-Lap is a new gene sequence from pig retinal pigment epithelial(RPE) cells, which was found and cloned in the early period of apoptosis of RPE cells damaged with visible light. We cloned the coding area sequence of the novel gene of s-Lap and constructed its recombinant eukaryotic plasmid pcDNA3.1-GFP/s-lap with the recombinant DNA technique. The expression and localization of s-lap/GFP fusion protein in CHO and B_~16 cell lines were studied with the instantaneously transfected pcDNA3.1-GFP/s-lap recombinant plasmid. ~s-Lap/GFP fusion protein can be expressed in CHO and B_~16 cells with a high rate expression in the nuclei.

关键词： s-Lap gene Fusion protein Mammal cell Expression Localization

A High-affinity Activator of G551D-CFTR Chloride Channel Identified By High Throughput Screening

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Chemical Research in Chinese Universities 2004年第6期20卷 738-742页

作者： ZHAOLu HECheng-yan LIUYan-li ZHOUHong-lan ZHOUJin-song SHANGDe-jing YANGHong MembraneChannelResearchLaboratory NortheastNormalUniversityChangchun130024P.R.China china-japanunionhospital JilinUniversityChangchun130033P.R.China FacultyofLifeSciences LiaoningNormalUniversityDalian116029P.R.China

A stably transfected CHO cell line coexpressing G551D-CFTR and iodide-sensitive yellow fluorescent protein mutant EYFP-H148Q-I152L was successfully established and used as assay model to identify small-molecule activators of G551D-CFTR chloride channel from 100000 diverse combinatorial compounds by high throughput screening on a customized Beckman robotic system. A bicyclooctane compound was identified to activate G551D-CFTR chloride channel with high-affinity(K d=1.8 μmol/L). The activity of the bicyclooctane compound is G551D-CFTR-specific, reversible and non-toxic. The G551D-CFTR activator may be useful as a tool to study the mutant G551D-CFTR chloride channel structure and transport properties and as a candidate drug to cure cystic fibrosis caused by G551D-CFTR mutation.

关键词： Cystic fibrosis Yellow fluorescent protein(YFP) High throughput screening(HTS) Small molecule

Synthesis, Structure Characterization and Biological Activity of a Novel Polyoxovanadate Cluster: [NH_3(CH_2)_2NH_2(CH_2)_2NH_3]_4·[V_6~Ⅴ V_(12)~Ⅳ O_(42)(PO_4)](PO_4)·2H_2O

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Chemical Research in Chinese Universities 2005年第4期21卷 381-385页

作者： FUPing-ping WANGXin-long WANGEn-bo QINChao XULin InstituteofPolyoxometalateChemistry FacultyofChemistryNortheastNormalUniversityChangchun130024P.R.China／／China-JapanUnionHospitalJilinUniversityChangchun130024P.R.China InstituteofPolyoxometalateChemistry FacultyofChemistryNortheastNormalUniversityChangchun130024P.R.China

A new polyoxovanadate cluster, [NH_3(CH_2)_2NH_2(CH_2)_2NH_3]_4[VⅤ_6VⅣ_ 12O_ 42(PO_4)](PO_4)·2H_2O, has been synthesized and characterized by means of elemental analysis, IR spectrometry, EPR spectrometry, TG analysis and single crystal X-ray diffraction. This compound crystallizes in a monoclinic space group C2/c with a= 2.3912(5) nm, b=1.3002(3) nm, c=2.0172(4) nm, β=105.75(3)°, V=6.036(2) nm3, Z=2, R_1=0.0572, wR_2=0.1476. It has a superKeggin structure with a Keggin unit capped by six [VO_5] moieties on the pits on every side of the Keggin unit. The anti-tumor activity of the compound was estimated in three human tumor cell lines in vitro.

关键词： Polyoxovanadate Keggin structare Crystal structure Anti-tumor activity

Reversal of MDR1 gene-dependent multidrug resistance using short hairpin RNA expression vectors

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Chinese Medical Journal 2005年第11期118卷 893-902页

作者： GANHui-zhu ZHANGGui-zhen ZHAOJi-sheng ZHANGFeng-chun BULi-sha YANGShao-juan PIAOSong-lan DUZhen-wu GAOShen ZHENGDe-ming CentralResearchDepartment China-JapanUnionHospitalJilinUniversityChangchun130031China DepartmentofSurgery China-JapanUnionHospitalJilinUniversityChangchun130031China DepartmentofOncology RenjiHospitalSecondMedicalUniversityShanghai200001China

Background RNA interference using short hairpin RNA (shRNA) can mediate sequence-specific inhibition of gene expression in mammalian cells. A vector-based approach for synthesizing shRNA has been developed recently. Overexpression of P-glycoprotein (P-gp), the MDR1 gene product, confers multidrug resistance (MDR) to cancer cells. In this study, we reversed MDR using shRNA expression vectors in a multidrug-resistant human breast cancer cell line (MCF-7/AdrR). Methods The two shRNA expression vectors were constructed and introduced into MCF-7/AdrR cells. Expression of MDR1 mRNA was assessed by RT-PCR, and P-gp expression was determined by Western Blot and immunocytochemistry. Apoptosis and sensitization of the breast cancer cells to doxorubicin were quantified by flow cytometry and methyl thiazolyl tetrazolium (MTT) assays, respectively. Cellular daunorubicin accumulation was assayed by laser confocal scanning microscopy (LCSM). Statistical significance of differences in mean values was evaluated by Student’s t tests. P<0.05 was considered statistically *** In MCF-7/AdrA cells transfected with MDR1-A and MDR1-B shRNA expression vectors, RT-PCR showed that MDR1 mRNA expression was reduced by 40.9% (P<0.05), 30.1% (P<0.01) (transient transfection) and 37.6 % (P<0.05), 28.0% (P<0.01) (stable transfection), respectively. Western Blot and immunocytochemistry showed that P-gp expression was significantly and specifically inhibited. Resistance against doxorubicin was decreased from 162-fold to 109-fold (P<0.05), 54-fold (P<0.01) (transient transfection) and to 108-fold (P<0.05), 50-fold (P<0.01) (stable transfection). Furthermore, shRNA vectors significantly enhanced the cellular daunorubicin accumulation. The combination of shRNA vectors and doxorubicin significantly induced apoptosis in MCF-7/AdrR cells. Conclusions shRNA expression vectors effectively reduce MDR expression in a sustained fashion and can restore the sensitivity of drug-resistant cancer cell

关键词： multi-drug resistance · MDR · gene therapy · breast neoplasm · shRNA

A Class of High-affinity Bicyclooctane G551D-CFTR Activators Identified by High Throughput Screening

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Chemical Research in Chinese Universities 2004年第6期20卷 743-746页

作者： HECheng-yan ZHAOLu LIUYan-li XULi-na SHANGDe-jing YANGHong china-japanunionhospital JilinUniversityChangchun130033P.R.China CollegeofTraditionalChineseMedicineMaterial JilinAgriculturalUniversityChangchun130118P.R.China MembraneChannelResearchLaboratory NortheastNormalUniversityChangchun130024P.R.China FacultyofLifeSciences LiaoningNormalUniversityDalian116029P.R.China

The glycine-to-aspartic acid missense mutation at the codon 551(G551D) of the cystic fibrosis transmembrane conductance regulator(CFTR) is one of the five most frequent cystic fibrosis(CF) mutations associated with a severe CF phenotype. To explore the feasibility of pharmacological correction of disrupted activation of CFTR chloride channel caused by G551D mutation, we developed a halide-sensitive fluorescence miniassay for G551D-CFTR in Fisher rat thyroid(FRT) epithelial cells for the discovery of novel activators of G551D-CFTR. A class of bicyclooctane small molecule compounds that efficiently stimulate G551D-CFTR chloride channel activity was identified by high throughput screening via the FRT cell-based assay. This class of compounds selectively activates G551D-CFTR with a high affinity, whereas little effect of the compounds on wildtype CFTR can be seen. The discovery of a class of bicyclooctane G551D-CFTR activators will permit the analysis of structure-activity relationship of the compounds to identify ideal leads for in vivo therapeutic studies.

关键词： Cystic fibrosis G551D-CFTR Activators Cell-based assay Small molecule High throughput screening