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Pharmacophore modeling for the identification of small-molecule inhibitors of TACE

中国药理学与毒理学杂志 2015年第S1期29卷 95-96页

作者： Li-juanLIU Ka-HoLEUNG ShengLIN DanielShiu-HinCHAN DewiSUSANTI Wei-dongRAO PhilipWaiHongCHAN Dik-LungMA Chung-hangLEUNG State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Chemistry Hong Kong Baptist University Hongkong China Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University Singapore 637371 Singapore School of Chemistry Monash University Ciayton 3800 Victoria Australiate

OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophore model from a set of TACE-selective inhibitor using the Common Feature Pharmacophore Model protocol implemented in Discovery Studio 3.1.1.A fluorimetric assay was used to investigate the potential ability of compounds to inhibit TACE enzymatic activity.The ability of compound 1 to inhibit TACE activity in a human monocyte THP-1 cell line was evaluated by ELISA.RESULTS In this study,apharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds,from which compound 1 emerged as a top candidate.In a cell-free assay,compound 1inhibited TACE enzymatic activity in a dose-dependent manner.Moreover,compound 1 inhibited the production of soluble TNF-αin human acute monocytic leukemia THP-1 cells without impacting nitric oxide production,and exhibited anti-proliferative activity against THP-1cells.CONCLUSION Compound 1 was found to inhibit TACE enzymatic activity in a cell-free system and LPS-induced TNF-αsecretion in cellulo.We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors.

关键词： pharmacophore TACE tumor necrosis factor virtual s

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Virtual screening and optimization of typeⅡ inhibitors of JAK2 from a natural product library

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中国药理学与毒理学杂志 2015年第S1期29卷 98-99页

作者： Dik-LungMA DanielShiu-HinCHAN GuoWEI Hai-jingZHONG HuiYANG LaiToLEUNG ElizabethA.GULLEN PaulineChIU Yung-ChiCHENG Chung-hangLEUNG Department of Chemistry Hong Kong Baptist University Hong Kong China Department of Chemistry and the State Key Laboratory of Synthetic Chemistry University of Hong Kong Hong Kong China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA

OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of JAK2 using the DOLPHIN protocol.METHODS Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of JAK2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in silico.The novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for JAK2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral activity.RESULTS The top eleven highest-scoring compounds were generated from the initial high-throughput virtual screening.Amentoflavone 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological evaluation.In dose-response experiments,amentoflavone 1ainhibited JAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·L-1.As a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of 1a.The octyl(C8)analogue 1bdisplayed superior potency against JAK2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this study.Moreover,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of JAK2.CONCLUSION Amentoflavone 1ahas been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library.In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo.Molecular modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of JAK2.

关键词： JAK2 natural products virtual screening structure-

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Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening

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中国药理学与毒理学杂志 2015年第S1期29卷 95-95页

作者： Li-juanLIU Ka-HoLEUNG DanielShiu-HinCHAN Dik-LungMA Chung-hangLEUNG State Key Laboratory of Quality Research in Chinese Medicine University of Macao Macao SAR China Department of Chemistry Hong Kong Baptist University Kowloon Tong Hong Kong China

OBJECTIVE To apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90 000 natural product and natural product-like compounds.METHODS Molecular docking was used for the virtual screening campaign and hit validation of STAT3 inhibitor.To further evaluate the potency of candidates at inhibiting STAT3-DNA binding activity,a STAT3 and STAT1transcription factor ELISA was performed.A dual-luciferase reporter assay,co-immunoprecipitation assay and Western blotting were carried out for the investigation of effect of compound 1 on STAT3-driven transcription,STAT3 dimerization and STAT3 phosphorylation.Finally,the cell toxicity of compound 1 was assessed by using MTT assay on different cell lines.RESULTS The virtual screening campaign furnished fourteen hit compounds,from which compound 1 emerged as a top candidate.Compound 1inhibited STAT3DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and comparable potency to the wellknown STAT3 inhibitor S3I-201.Furthermore,compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation.Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro.CONCLUSION The benzofuran derivative 1 was identified as a potential inhibitor of STAT3 dimerization using in silico screening.Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain.To the best of our knowledge,compound 1 has not been reported as a STAT3 inhibitor and no biological activity of compound 1 has been presented in the literature.

关键词： STAT3 natural products virtual screening dimerizat

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Glycyrrhetinic acid-triggered cytoprotective autophagy via inositolrequiring enzyme 1α-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells

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中国药理学与毒理学杂志 2015年第S1期29卷 81-81页

作者： Zheng-haiTANG Le-leZHANG TingLI Jia-hongLU Chung-hangLEUNG Xiu-pingCHEN Yi-taoWANG Jin-jianLU State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China

OBJECTIVE Glycyrrhetinic acid(GA),one of the main bioactive constituents of the famous Chinese medicinal herb Glycyrrhizauralensis Fisch,presents potent cytotoxicity to various cancer cells both in vitro and in vivo.Herein,we′d like to determine whether GA triggers autophagy in non-small cell lung cancer cells and the mechanisms involved.METHODS Cell proliferation was determined by MTT assay and colony formation.AnnexinⅤ/PI staining,Hoechst33342 staining,and Western blotting were used to detect GA-induced apoptosis.GA-induced autophagy was measured by expression of the lipid modification of light chain-3(LC3)and transfected with GFP-LC3 or GFP-RFP-LC3 plasmid.Pharmacological regulators,siRNA,and plasmid transfection were used to study the mechanisms of GA-triggered autophagy.RESULTS GA inhibited cell proliferation and induced apoptosis in a concentrationdependent manner in non-small cell lung cancer A549 cells.GA induced autophagyas evidenced by up-regulation of LC3-Ⅱexpression when combined treatment with chloroquine and induction of the red punta after GFP-RFP-LC3 plasmid transfection.Knockdown of autophagy related proteins(ATG)7,ATG 5,or beclin 1by siRNA,the expression of LC3-Ⅱand GFP-LC3 punt atriggered by GA were decreased.Furthermore,the c-Jun N-terminal kinase(JNK)pathways were activated after treatment with GA,and pretreatment with JNK inhibitor SP600125 or silence of JNK pathway by siRNA of JNK or c-jun obviously reduced GA-induced LC3-Ⅱexpression and GFP-LC3 punta formation.GA also stimulate dendoplasmic reticulum stress response by triggering inositol-requiring enzyme 1α(IRE1α)pathway,and knockdown of IRE1αinhibited the activation of JNK pathway and autophagy induced by GA.In addition,GA-induced cell proliferative inhibition and apoptosis were both enhanced when silence of autophagy as well as JNK pathway.CONCLUSION Our study demonstrated,for the first time,that GA induced a cytoprotective autophagy in non-small cell lung cancer cells by activating the IRE1α-JNK pathway,which might decreased the anti-c

关键词： glycyrrhetinic acid autophagy A549 IRE JNK

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A review of regenerative therapies as penile rehabilitation in men following primary prostate cancer treatment:Evidence for erectile restoration and cavernous nerve regeneration

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Asian Journal of Urology 2022年第3期9卷 287-293页

作者： Eric chung AndroUrology Centre BrisbaneQLDAustralia University of Queensland Princess Alexandra HospitalBrisbaneQLDAustralia Macquarie University Hospital SydneyNSWAustralia

Objective:The following article explores our evolving understandings of the role of regenerative technology as an effective penile rehabilitation tool in men with erectile dysfunction(ED)in the setting of prostate cancer(PCa)treatment and PCa survivorship.Methods:This narrative clinical review paper summarizes what is currently known about various modalities of regenerative therapy in restoring spontaneous erectile function(EF)in men following PCa treatment with an emphasis on penile rehabilitation strategies.Results:Conventional medical therapy often does not reverse underlying endothelial dysfunction or promote neuro-vasculogenesis to preserve penile health in men with ED.Over the past decade,there has been considerable interest in the role of regenerative therapy to restore endothelial dysfunction and ED without future dependency on medical therapy.Regenerative therapy can be classified into cellular-based(immunomodulators,stem cells,and platelet-rich plasma),biomaterials(nerve graft transfer),and device-related technology(low-intensity shockwave).Although published literature shows early promise in the role of regenerative technology for ED,there is a paucity of high-quality clinical trials in the setting of penile rehabilitation and PCa survivorship to support their use as standard care and be adopted in clinical guidelines.

关键词： Regenerative therapy Low-intensity shockwave therapy Stem cell therapy Platelet-rich plasma Immunomodulator Nerve transfer Erectile dysfunction Penile rehabilitation

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The genetics of race differentiation——should it be studied?

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National Science Review 2023年第4期10卷 6-7页

作者： chung-I Wu NSR School of Life Sciences Sun Yat-sen University

In this issue, NSR publishes an article entitled ‘Expression profiles of east-west highly differentiated genes in Uyghur genomes’ by Ning et al.(2023) [1]. Briefly, it is about the regulation of gene expression in Uyghur genomes, which are admixed between Asian and European genomes. In evolutionary terms, this is a case of post-isolation secondary contact over a time span of thousands of years. In most other cases, such as African Americans, the admixture has a time span of <300 years. Furthermore,

关键词： DROSOPHILA-MELANOGASTER INCIPIENT SPECIATION SEXUAL ISOLATION

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Overview of harmful algal blooms(red tides)in Hong Kong during 1975–2021

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Journal of Oceanology and Limnology 2022年第6期40卷 2094-2106页

作者： Kin chung HO Department of Geography University of Hong KongHong Kong Special Administrative RegionHong Kong 999077China College of Marine Ecology and Environment Shanghai Ocean UniversityShanghai 201306China

Hong Kong has a long historical record of harmful algal blooms(HABs).In the 1980s-1990s,HABs were mainly pollution-related and most of the events happened in estuaries and enclosed embayment such as Tolo Harbour and Port Shelter.The major cause of HABs in 1980s-1990s was closely related to nutrients enrichment;included but not limited to changes in the concentration and ratio of soluble N and P in seawater.The major causative organisms of HABs in Hong Kong by then were meso-plankton such as selected species of diatoms and dinofl agellates.Sometimes,zooplankton was also a cause of red tides(the common name of HABs).There has been gradual change after the 2000s.It is attributed to higher and higher influences from the region,namely the Zhujiang(Pearl)River delta.There are increasing influences from Chinese mainland due to extraordinary social and economic growths during the past 20 years.In the past10 years,HABs in Hong Kong was mainly subject to regional impacts in the Zhujiang River delta.Both the duration period and covered areas have been enlarged which overwhelmed the localized influences of stream pollution and self-contamination of aquaculture zones.More flagellates of uncommon happening become dominant species in HAB now.Nevertheless,the seasonal impact of Noctiluca scintillans in late winter to mid spring remained.

关键词： harmful algal blooms(HABs) Tolo Harbour long-term trend regional eutrophication and environmental impacts

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Artificial urinary sphincter surgery in the special populations:neurological,revision,concurrent penile prosthesis and female stress urinary incontinence groups

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Asian Journal of Andrology 2020年第1期22卷 45-50页

作者： Eric chung AndroUrology Centre BrisbaneQLD 4000Australia University of Queensland Princess Alexandra HospitalBrisbaneQLD 4000Australia Macquarie University Hospital SydneyNSW 2109Australia

The artificial urinary sphincter(AUS)remains the standard of care in men with severe stress urinary incontinence(SUI)following prostate surgery and radiation.While the current AUS provides an effective,safe,and durable treatment option,it is not without its limitations and complications,especially with regard to its utility in some“high-risk”populations.This article provides a critical review of relevant publications pertaining to AUS surgery in specific high-risk groups such as men with spinal cord injury,revision cases,concurrent penile prosthesis implant,and female SUI.The discussion of each category includes a brief review of surgical challenge and a practical action-based set of recommendations.Our increased understandings of the pathophysiology of various SUI cases coupled with effective therapeutic strategies to enhance AUS surgery continue to improve clinical outcomes of many patients with SUI.

关键词： artificial urinary sphincter female stress incontinence penile prosthesis implant revision surgery spinal cord injury urinary incontinence

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Penile prosthesis implant in the special populations:diabetics,neurogenic conditions,fibrotic cases,concurrent urinary continence surgery,and salvage implants

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Asian Journal of Andrology 2020年第1期22卷 39-44页

作者： Eric chung AndroUrology Centre BrisbaneQLD 4000Australia University of Queensland Princess Alexandra HospitalBrisbaneQLD 4000Australia Macquarie University Hospital SydneyNSW 2109Australia

Penile prosthesis implant(PPI)remains an effective and safe treatment option for men with erectile dysfunction(ED).However,PPI surgery can be associated with a higher risk of complications in certain populations.This article provides a critical review of relevant publications pertaining to PPI in men with diabetes,significant corporal fibrosis,spinal cord injury,concurrent continence surgery,and complex salvage cases.The discussion of each category of special populations includes a brief review of the surgical challenges and a practical action-based set of recommendations.While specific patient populations posed considerable challenges in PPI surgery,strict pre-and postoperative management coupled with safe surgical practice is a prerequisite to achieving excellent clinical outcomes and high patient satisfaction rate.

关键词： continence surgery diabetes erectile dysfunction penile prosthesis implant Peyronie’s disease priapism salvage surgery spinal cord injury

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Comparison between multiple logistic regression and machine learning methods in prediction of abnormal thallium scans in type 2 diabetes

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World Journal of Clinical Cases 2023年第33期11卷 7951-7964页

作者： chung-Chi Yang chung-Hsin Peng Li-Ying Huang Fang Yu Chen Chun-Heng Kuo chung-Ze Wu Te-Lin Hsia chung-Yu Lin Division of Cardiovascular Medicine Taoyuan Armed Forces General HospitalTaoyuan City 32551Taiwan Division of Cardiovascular Tri-service General HospitalTaipei City 114202TaiwanChina Department of Urology Cardinal Tien HospitalNew Taipei City 23148TaiwanChina School of Medicine Fu-Jen Catholic UniversityNew Taipei City 242062TaiwanChina Department of Internal Medicine Department of Medical EducationSchool of MedicineFu Jen Catholic University HospitalNew Taipei City 243TaiwanChina School of Medicine College of MedicineFu Jen Catholic UniversityNew Taipei City 243TaiwanChina Department of Endocrinology Fu Jen Catholic University HospitalNew Taipei City 243TaiwanChina Division of Endocrinology and Metabolism Department of Internal MedicineFu Jen Catholic University HospitalNew Taipei City 243TaiwanChina Division of Endocrinology Shuang Ho HospitalNew Taipei City 23561TaiwanChina School of Medicine Taipei Medical UniversityTaipei City 11031TaiwanChina Department of Internal Medicine Cardinal Tien HospitalNew Taipei City 23148TaiwanChina Department of Cardiology Fu Jen Catholic University HospitalNew Taipei City 24352TaiwanChina Graduate Institute of Business Administration Fu Jen Catholic UniversityNew Taipei City 242062TaiwanChina

BACKGROUND The prevalence of type 2 diabetes(T2D)has been increasing dramatically in recent decades,and 47.5%of T2D patients will die of cardiovascular disease.Thallium-201 myocardial perfusion scan(MPS)is a precise and noninvasive method to detect coronary artery disease(CAD).Most previous studies used traditional logistic regression(LGR)to evaluate the risks for abnormal CAD.Rapidly developing machine learning(Mach-L)techniques could potentially outperform LGR in capturing non-linear relationships.AIM To aims were:(1)Compare the accuracy of Mach-L methods and LGR;and(2)Found the most important factors for abnormal TMPS.METHODS 556 T2D were enrolled in the study(287 men and 269 women).Demographic and biochemistry data were used as independent variables and the sum of stressed score derived from MPS scan was the dependent variable.Subjects with a MPS score≥9 were defined as abnormal.In addition to traditional LGR,classification and regression tree(CART),random forest,Naïve Bayes,and eXtreme gradient boosting were also applied.Sensitivity,specificity,accuracy and area under the receiver operation curve were used to evaluate the respective accuracy of LGR and Mach-L methods.RESULTS Except for CART,the other Mach-L methods outperformed LGR,with gender,body mass index,age,low-density lipoprotein cholesterol,glycated hemoglobin and smoking emerging as the most important factors to predict abnormal MPS.CONCLUSION Four Mach-L methods are found to outperform LGR in predicting abnormal TMPS in Chinese T2D,with the most important risk factors being gender,body mass index,age,low-density lipoprotein cholesterol,glycated hemoglobin and smoking.

关键词： Myocardial perfusion scintigraphy Machine learning Type 2 diabetes Thallium-201

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