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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： chris Chun-Yiu Chan Qian Guo Jasper Fuk-Woo Chan Kaiming Tang Jian-Piao Cai Kenn Ka-Heng Chik Yixin Huang Mei Dai Bo Qin Chon Phin Ong Allen Wing-ho Chu Wan-Mui Chan Jonathan Daniel Ip Lei Wen Jessica Oi-Ling Tsang Tong-Yun Wang Yubin Xie Zhenzhi Qin Jianli Cao Zi-Wei Ye Hin Chu Kelvin Kai-Wang To Xing-Yi Ge Tao Ni Dong-Yan Jin Sheng Cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of Infectious Diseases and Microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

Regulation of gene expression in chickens by heat stress

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Journal of Animal Science and Biotechnology 2021年第2期12卷 438-450页

作者： Akshat Goel chris Major Ncho Yang-ho Choi Department of Animal Science Gyeongsang National UniversityJinju 52828Republic of Korea Division of Applied Life Sciences(BK21 Plus Program) Gyeongsang National UniversityJinju 52828Republic of Korea Full list of author information is available at the end of the article

High ambient temperatures are a critical challenge in the poultry industry which is a key producer of the animal-based *** evaluate heat stress levels,various parameters have been used,including growth rates,blood metabolites,and *** most recent advances have explored expression profiling of genes that may play vital roles under stress.A high ambient temperature adversely affects nutrient uptake and is known to modulate the expression of genes encoding for sodium-dependent glucose transporters,glucose transporters,excitatory amino acid transporters,and fatty acidbinding proteins which are responsible for the absorption of macronutrients in the *** defensive activities are stimulated to protect the cell of different tissues from the heat-generated stress,including expression of early stress response genes coding for heat shock protein(HSP),c-FOS like protein,brain-derived neurotrophic factor(BDNF),and neuronal nitric oxide synthase(nNOS);antioxidant enzyme genes such as superoxide dismutase(SOD),catalase(CAT),and nicotinamide adenine dinucleotide phosphate oxidase(NOX4);and immune-related genes such as cytokines and toll-like receptors(TLRs).The potential role of HSPs in protecting the cell from stress and their presence in several tissues make them suitable markers to be evaluated under heat *** and c-FOS genes expressed in the hypothalamus help cells to adapt to an adverse *** causes damage to the cell by generating reactive oxygen species(ROS).The NOX4 gene is the inducer of ROS under heat stress,which is in turns controlled by antioxidant enzymes such as SOD and *** are responsible for protecting against pathogenic attacks arising from enhanced membrane permeability,and cytokines help in controlling the pathogen and maintaining ***,the evaluation of nutrient transporters and defense mechanisms using the latest molecular biology tools has made it possible to shed light on the complex cellular mechan

关键词： Antioxidant Gene expression Heat stress Immunity Metabolism Nutrient transporter Poultry

Embryonic modulation through thermal manipulation and in ovo feeding to develop heat tolerance in chickens

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Animal Nutrition 2023年第2期13卷 150-159页

作者： Akshat Goel chris Major Ncho Vaishali Gupta Yang-ho Choi Department of Animal Science Gyeongsang National UniversityJinju 52828Republic of Korea Institute of Agriculture and Life Sciences Gyeongsang National UniversityJinju 52828Republic of Korea Division of Applied Life Sciences(BK21 Plus Program) Gyeongsang National UniversityJinju 52828Republic of Korea

Healthy chickens are necessary to meet the ever-increasing demand for poultry *** are subjected to numerous stressful conditions under commercial rearing systems,including variations in the envi-ronmental ***,it is difficult to counter the effects of global warming on the livestock *** environmental temperature is a stressful condition that has detrimental effects on growth and production performance,resulting in decreased feed intake,retarded growth,compromised gut health,enhanced oxidative stress,and altered immune *** approaches include nutritional modification and housing management to mitigate the harmful effects of hot ***,broiler chickens are more susceptible to heat stress(HS)than layer chickens because of their high muscle mass and metabolic *** this review,we explored the possibility of in ovo manipulation to combat HS in broiler *** their short lifespan from hatching to market age,embryonic life is thought to be one of the critical periods for achieving these *** embryos can be modulated through either temperature treatment or nourishment to improve thermal tolerance during the rearing *** first provided a brief overview of the harmful effects of HS on *** in-depth evaluation was then presented for in ovo feeding and thermal manipulation as emerging strategies to combat the negative effects of ***,we evaluated a combination of the two methods using the available *** together,these investigations suggest that embryonic manipulation has the po-tential to confer heat resistance in chickens.

关键词： Embryo Thermal manipulation In ovo feeding Heat stress Poultry

Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver

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World Journal of Gastroenterology 2005年第2期11卷 176-181页

作者： Joanna W.ho Ronnie T.Poon chris K.Sun Sheung-Tat Fan Centre tor the Study of Liver Disease and Departments of Surgery and PathologyThe University of Hong KongPokfulam Hong Kong China

AIM: The expression pattern of endoglin (CD105) in hepatocellular carcinoma (HCC) has not been reported so far. We hypothesized that CD105 could differentially highlight a subset of microvessels in HCC, and intratumoral microvessel density (IMVD) by CD105 immunostaining (IMVD-CD105) could provide better prognostic information than IMVD by CD34 immunostaining (IMVD-CD34).METhoDS: Paraffin blocks of tumor and adjacent nontumorous liver tissues from 86 patients who underwent curative resection of HCC were used for this study. Serial sections were stained for CD105 and CD34, respectively,to highlight the microvessels. IMVD was counted according to a standard ***: In the HCC tissues, CD105 was either negatively or positively stained only in a subset of microvessels. In contrast, CD34 showed positive and more extensive microvessel staining in all cases examined. however, in the adjacent non-tumorous liver sections, CD105 showed a diffuse pattern of microvessel staining in 20 of 86 cases,while CD34 showed negative or only focal staining of the sinusoids around portal area. Correlation with clinicopathological data demonstrated that lower scores of IMVD-CD105 were found in larger sized tumors [mean 41.4/0.74 mm2 (＞5 cm tumor) vs 65.9/0.74 mm2(≤ 5 cm tumor), P = 0.043] and more aggressive tumors,as indicated by venous infiltration [36.8/0.74 mm2 (present)vs 64.2/0.74 mm2 (absent), P = 0.020], microsatellite nodules [35.1/0.74 mm2 (present) vs 65.9/0.74 mm2(absent), P = 0.012], and advanced TNM tumor stage [38.8/0.74 mm2 (stage 3 or 4) vs 68.3/0.74 mm2 (stage 1or 2), P = 0.014]. No prognostic significance was observed when median values were used as cut-off points using either IMVD-CD105 or IMVD-CD34. however, the presence of the diffuse pattern of CD105 expression in the adjacent non-tumorous liver tissues predicted a poorer disease-free survival (median 8.6 vs 21.5 mo, P = 0.026).CONCLUSION: Our data demonstrate that a lower IMVDCD105 is associated with larger

关键词： Hepatocellular carcinoma Endoglin Intratumoral microvessel density

Comparison of modified injection molding and conventional machining in biodegradable behavior of perforated cannulated magnesium hip stents

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Journal of Materials Science & Technology 2021年第4期63卷 145-160页

作者： Haiyue Zu Kelvin Chau Temitope Olumide Olugbade Lulu Pan chris Halling Dreyer Dick ho-Kiu Chow Le Huang Lizhen Zheng Wenxue Tong Xu Li Ziyi Chen Xuan He Ri Zhang Jie Mi Ye Li Bingyang Dai Jiali Wang Jiankun Xu Kevin Liu Jian Lu Ling Qin Musculoskeletal Research Laboratory Department of Orthopaedics&TraumatologyThe Chinese University of Hong KongShatin999077Hong Kong Special Administrative RegionChina Zoltrix Material International Limited Wan ChaiHong Kong Island999077Hong Kong Special Administrative RegionChina Department of Mechanical and Biomedical Engineering City University of Hong KongKowloon999077Hong Kong Special Administrative RegionChina Orthopaedic Research Laboratory Department of Orthopaedics&TraumatologyOdense University HospitalInstitute of Clinical ResearchUniversity of Southern DenmarkOdense C5000Denmark Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongShatin999077Hong Kong Special Administrative RegionChina

In this study,perforated cannulated magnesium(Mg)hip stents were fabricated via modified Mg injection molding and conventional machining,***,the stent canal was filled with paraffin to simulate injection of *** microstructure,mechanical performance,corrosion behavior,and biocompatibility were comparably *** electron microscopy(SEM)and energy dispersive spectroscopy(EDS)showed higher affinity of interstitial element such as oxygen and carbon as consequences of routine molding *** immersion in SBF,machining stents showed reduced degradation rate and increased deposition of calcium phosphate compared to molding *** resistance was improved via ***,the hemolysis and in vitro osteoblast cell culture models showed favourable biocompatibility in machining stents compared to molding ones,which was improved by paraffin-filling treatment as *** results implied that the feasibility of the prepared machining stents as the potential in vivo orthopaedic application where slower degradation is required,which could be enhanced by designing canal-filling injection of biomaterials as well.

关键词： corrosion microstructure injection

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Clearing the air

Photodynamic therapy-mediated modulation of inflammatory cytokine production by Epstein–Barr virus-infected nasopharyngeal carcinoma cells

2007年

作者： edited by Mun S. ho and chris P. Nielsen

来源：畅想之星图书光盘版（南... 评论

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畅想之星图书光盘版（南通市图书馆镜像）

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Cellular & Molecular Immunology 2010年第4期7卷 323-326页

作者： ho-Kee Koon Kwok-Wai Lo Kwok-Nam Leung Maria Li Lung chris Chi-Kwong Chang Ricky Ngok-Shun Wong Wing-Nang Leung Nai-Ki Mak Department of Biology Hong Kong Baptist UniversityKowloonHong Kong Department of Anatomical and Cellular Biology and State Key Laboratory in Oncology in South China Prince of Wales HospitalShatinHong Kong Department of Biochemistry and Food and nutritional Sciences Programme The Chinese University of Hong KongShatinHong Kong Department of Biology Hong Kong University of Science and TechnologyHong Kong Department of Chemistry Hong Kong University of Science and TechnologyKowloonHong Kong School of Chinese Medicine The Chinese University of Hong KongShatinHong Kong

Nasopharyngeal carcinoma(NPC)is a malignant disease associated with Epstein–Barr virus(EBV)*** study aims to examine the effects of EBV infection on the production of proinflammatory cytokines in NPC cells after the Zn-BC-AM photodynamic therapy(PDT)*** were treated with the photosensitiser Zn-BC-AM for 24 h before light *** ELISA was used to evaluate the production of *** the same experimental condition,HK-1-EBV cells produced a higher basal level of IL-1a(1561 pg/ml),IL-1b(16.6 pg/ml)and IL-8(422.9 pg/ml)than the HK-1 *** the light dose of 0.25–0.5 J/cm2,Zn-BC-AM PDT-treated HK-1-EBV cells were found to produce a higher level of IL-1a and IL-1b than the HK-1 *** production of IL-1b appeared to be mediated via the IL-1b-converting enzyme(ICE)-independent *** contrast,the production of angiogenic IL-8 was downregulated in both HK-1 and HK-1-EBV cells after Zn-BC-AM *** results suggest that Zn-BC-AM PDT might indirectly reduce tumour growth through the modulation of cytokine production.

关键词： Photodynamic therapy nasopharyngeal carcinoma cytokines Epstein-Barr virus

Chemistry and P-V-T equation of state of FeOH at the base of Earth’s lower mantle and their geophysical implications

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Science Bulletin 2021年第19期66卷 1954-1958,M0003页

作者： Ruilian Tang Jin Liu Duck Young Kim ho-Kwang Mao Qingyang Hu Bin Yang Yan Li chris J.Pickard Richard J.Needs Yu He Haozhe Liu Vitali B.Prakapenka Yue Meng Jinyuan Yan Center for High Pressure Science and Technology Advanced Research Changchun 130012China School of Materials Science and Engineering Changchun University of Science and TechnologyChangchun 130022China State Key Laboratory of Superhard Materials College of PhysicsJilin UniversityChangchun 130012China Department of Materials Science and Metallurgy University of CambridgeCambridge CB30FSUK Advanced Institute for Materials Research Tohoku UniversitySendai 980-8577Japan Theory of Condensed Matter Group Cavendish LaboratoryCambridge CB30HEUK Key Laboratory of High-Temperature and High-Pressure Study of the Earth’s Interior Institute of GeochemistryChinese Academy of SciencesGuiyang 550081China Center for Advanced Radiation Sources University of ChicagoChicago IL 60439USA X-ray Science Division Argonne National LaboratoryArgonne IL 60439USA Material Science Division Lawrence Berkeley National LaboratoryBerkeley CA 94720USA CAS Center for Excellence in Deep Earth Science Guangzhou 510640China

The hydrogen-absorbing ability of a mantle mineral in its structure determines the capacity of the water reservoirs hosted by the mineral. Water reservoirs at the base of Earth’s mantle directly influence the fate of water brought down by slab subduction and the seismic heterogeneity such as ultralow-velocity zones(ULVZs)at the core-mantle boundary. Pyrite-Fe O2 Hx(0≤x ≤1) presents a possibility of such reservoirs in the deep mantle [1–3].

关键词：地球科学研究地球深部地球物理核幔边界同步辐射X射线衍射弹性性质下地幔化学组分

占有者是被剥夺者———《下女》(1960年)与金绮泳的价值重估

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贵州大学学报（艺术版） 2023年第3期37卷 26-33页

作者：裴开瑞(chris Berry) 柳迪善(译) 伦敦国王学院电影学系英国伦敦中南民族大学文学与新闻传播学院湖北武汉430074

在韩国著名导演金绮泳执导的32部电影中,《下女》是最著名的一部,被公认为“韩国三大电影之一”。《汉江怪物》的导演奉俊昊宣称该片为韩国电影史上的《公民凯恩》。《下女》的意义体现在五个方面:第一,抓住了韩国的时代精神;第二,确立... 详细信息

在韩国著名导演金绮泳执导的32部电影中,《下女》是最著名的一部,被公认为“韩国三大电影之一”。《汉江怪物》的导演奉俊昊宣称该片为韩国电影史上的《公民凯恩》。《下女》的意义体现在五个方面:第一,抓住了韩国的时代精神;第二,确立了金绮泳作为作者导演及其品牌的地位;第三,开创了韩国电影的恐怖片类型;影片的许多元素不仅出现在金绮泳对该片的四次翻拍中,也出现在1998年金绮泳去世后上映的翻拍片中,在韩国的许多恐怖电影中,某些元素也被多次借用。这种持久的生命力表明该片不仅建立了金绮泳的导演品牌,也建构了韩国恐怖片的许多关键模式;第四,引发了对韩国电影史的重估;第五,这部电影的长期吸引力和受其启发的许多电影表明,该片不仅在1960年成为社会批评和票房轰动的重要文化事件,而且与当今时代也产生了积极的共鸣。

关键词：《下女》金绮泳作者品牌价值重估