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Chinese Medical Journal 2012年第4期125卷 719-719页

作者： Cheng Yan Ning Gang Song Bin Guo Ying-kun Li Xue-sheng Sichuan Univ W China Univ Hosp 2 Dept Radiol Chengdu 610041 Sichuan Peoples R China Sichuan Univ W China Hosp Dept Radiol Chengdu 610041 Sichuan Peoples R China

To the Editor： cystic fibrosis （CF） is quite rare in the Asian population that an epidemiological study in the Japanese population revealed the incidence of CF being about I in 350000.

关键词： cystic fibrosis sweat chloride genetic test chronic cough hemoptysis

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

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

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

Potential of Helper-Dependent Adenoviral Vectors in Modulating Airway Innate Immunity

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Cellular & Molecular Immunology 2007年第2期4卷 81-89页

作者： Rahul Kushwah Huibi Cao Jim Hu Physiology and Experimental Medicine Programme the Hospital for Sick Children 555 University Avenue Toronto Ontario Canada M5G1X8 Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada M5S IA1

Innate immune responses form the first line of defense against foreign insults and recently significant advances have been made in our understanding of the initiation of innate immune response along with its ability to modulate inflammation. In airway diseases such as asthma, COPD and cystic fibrosis, over reacting of the airway innate immune responses leads to cytokine imbalance and airway remodeling or damage. Helper-dependent adenoviral vectors have the potential to deliver genes to modulate airway innate immune responses and have many advantages over its predecessors. However, there still are a few limitations that need to be addressed prior to their use in clinical applications.

关键词： adenovirus gene therapy innate immune response cystic fibrosis

The Ca^(2+)-activated chloride channel ANO1/TMEM16A:An emerging therapeutic target for epithelium-originated diseases?

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1412-1433页

作者： Yani Liu Zongtao Liu KeWei Wang Department of Pharmacology School of PharmacyQingdao University Medical CollegeQingdao 266073China Institute of Innovative Drugs Qingdao UniversityQingdao 266021China Department of Clinical Laboratory Qingdao Third People's HospitalQingdao 266041China

Anoctamin 1(ANO1) or TMEM16 A gene encodes a member of Ca^(2+) activated Cl^(-) channels(CaCCs) that are critical for physiological functions,such as epithelial secretion,smooth muscle contraction and sensory signal *** attraction and interest in ANO1/TMEM16 A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases,including asthma,neuropathic pain,hypertension and ***,the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic *** review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools,hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation.

关键词： Ca^(2+)-activated Cl^(-)channels(CaCCs) ANO1 TMEM16A CaCCinh-A01 T16Ainh-A01 Drug target Cancer cystic fibrosis

Establishment and characterization of a rat pancreatic stellate cell line by spontaneous immortalization

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World Journal of Gastroenterology 2003年第12期9卷 2751-2758页

作者： Atsushi Masamune Masahiro Satoh Kazuhiro Kikuta Noriaki Suzuki Tooru Shimosegawa Division of Gastroenterology Tohoku University Graduate School of MedicineSendaiJapan A.M.and M.S.equally contributed to this work

AIM: Activated pancreatic stellate cells (PSCs) have been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Primary PSCs can be subcultured only several times because of their limited growth potential. A continuous cell line may therefore be valuable in studying molecular mechanisms of these pancreatic disorders. The aim of this study was to establish a cell line of rat PSCs by spontaneous ***: PSCs were isolated from the pancreas of male Wistar rats, and conventional subcultivation was performed repeatedly. Telomerase activity was measured using the telomere repeat amplification protocol. Activation of transcription factors was assessed by electrophoretic mobility shift *** of mitogen-activated protein (MAP) kinases was examined by Western blotting using anti-phosphospecific antibodies. Expression of cytokine-induced neutrophil chemoattractant-1 was determined by enzyme ***: Conventional subcultivation yielded actively growing cells. One clone was obtained after limiting dilution,and designated as SIPS. This cell line has been passaged repeatedly more than 2 years, and is thus likely *** cells retained morphological characteristics of primary,culture-activated PSCs. SIPS expressed α-smooth muscle actin, glial acidic fibrillary protein, vimentin, desmin, type Ⅰ collagen, fibronectin, and prolyl hydroxylases. Telomerase activity and p53 expression were negative. Proliferation of SIPS cells was serum-dependent, and stimulated with platelet-derived growth factor-BB through the activation of extracellular signal-regulated kinase. Interleukin-1β activated nuclear factor-κB, activator protein-1, and MAP ***-1β induced cytokine-induced neutrophil chemoattractant-1 expression through the activation of nuclear factor-κB and MAP ***: SIPS cells can be useful for in vitro studies of cell biology and signal transduction of PSCs.

关键词： Animals Base Sequence Cell Culture Techniques Cell Line, Transformed Cells, Cultured cystic fibrosis Cytoskeletal Proteins Extracellular Matrix Proteins Immunohistochemistry NF-kappa B Oligonucleotide Probes Pancreas Rats Research Support, Non-U.S. Gov't Transcription Factor AP-1

Activation of CFTR-mediated Cl^- Transport by Magnolin

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Chemical Research in Chinese Universities 2008年第2期24卷 187-191页

作者： JIN Ling-ling LIU Xin SUN Yan LIN Sen ZHOU Na XU Li-na YU Bo HOU Shu-guang YANG Hong Liaoning Province Key Laboratory of Biotechnology and Drug Discovery Liaoning Normal UniversityDalian 116029 P. R. China China-Japan Union Hospital Jilin University Changchun 130033P R. China Qianwei Affiliate Hospital Jilin University Changchun 130021 P. R. China

Magnolin is a herbal compound from Magnolia biondii Pamp. It possesses numerous biological activities. cystic fibrosis transmembrane conductance regulator（CFTR） is an epithelial chloride channel that plays a key role in the fluid secretion of various exocrine organs. In the present study, the activation of CFTR-mediated chloride transport by magnolin is indentified and characterized. In CFTR stably transfected FRT cells, magnolin increases CFTR CI- currents in a concentration-dependent manner. The activation of magnolin on CFTR is rapid, reversible, and cAMP-dependent. Magnolin does not elevate cellular cAMP level, indicating that it activates CFTR by direct binding and interaction with CFTR protein. Magnolin selectively activates wildtype CFTR rather than mutant CFTR. Magnolin may present a novel class of therapeutic lead compound tbr the treatment of diseases associated with reduced CFTR function such as keratoconjunctivitis sicca, idiopathic chronic pancreatiti, and chronic constipation.

关键词： cystic fibrosis CFTR Mutation Magnolin Activator

Increased Sensitivity of Porcine ΔF508-CFTR Chloride Channel to Specific Small Molecule CFTR Inhibitors

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Chemical Research in Chinese Universities 2009年第4期25卷 497-499页

作者： ZHAO Hai-feng YU Ting LIU Xin LIU Rui ZHENG Lan SONG Li-na JIA Li YANG Hong HE Cheng-yan Pepartment of Clinical Laboratory China-Japan Union Hospital Jilin University Changchun 130033 P. R. China The Second Hospital Jilin University Changchun 130021 P. R. China Liaoning Provicial Key Laboratory of Biotechnolgy and Drug Discovery School of Life Sciences Liaoning Normal University Dalian 116029 P. R. China

Deletion of the codon encoding the phenylalanine residue at position 508（ΔF508） in the cystic fibrosis transmembrane conductance regulator（CFTR） is the most common mutation causing cystic fibrosis（CF）.The human ΔF508 mutation results in a CFTR protein with impaired folding,trafficking,and gating in human and *** studies suggest that pig ΔF508-CFTR can be efficiently processed to the plasma membrane as maturely glycosylated protein,indicating species difference of the molecular mechanisms of CFTR cellular *** this study,the functional characterization in stably transfected FRT cells cultured at 37 ℃ demonstrates that pig ΔF508-CFTR is remarkably more sensitive to specific CFTR inhibitors CFTRinh-172 and GlyH101 than wildtype pig *** wildtype pig CFTR is more sensitive to GlyH101 than to *** present study indicates that the gating property of ΔF508-CFTR chloride channel is altered and GlyH101 may be a more suitable small molecule probe for generating CF phenotypes in pig tissues.

关键词： ΔF508-CFTR Pig CFTR Inhibitor cystic fibrosis