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Targeting papain-like protease for broad-spectrum coronavirus inhibition

Protein & Cell 2022年第12期13卷 940-953页

作者： Shuofeng Yuan Xiaopan Gao Kaiming Tang Jian-Piao Cai menglong hu Peng Luo Lei Wen Zi-Wei Ye Cuiting Luo Jessica Oi-Ling Tsang Chris Chun-Yiu Chan Yaoqiang huang Jianli Cao Ronghui Liang Zhenzhi Qin Bo Qin Feifei Yin Hin Chu Dong-Yan Jin Ren Sun Jasper Fuk-Woo Chan Sheng Cui Kwok-Yung Yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Microbiology Li Ka ShingFaculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCAUSA Key Laboratory of Tropical Translational Medicine of Ministry of Education Hainan Medical UniversityHaikou 571199China Academician Workstation of Hainan Province Hainan Medical UniversityHaikou 571199China Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory Guangzhou 510320China Department of Clinical Microbiology and Infection Control The University of Hong Kong-Shenzhen HospitalShenzhen 518053China

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics.Drugging the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds promise.However,none of the known coronavirus PLpro inhibitors has been shown to be in vivo active.Herein,we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity,including against the Sarbecoviruses(SARSCoV-1 and SARS-CoV-2),Merbecovirus(MERS-CoV),as well as the Alphacoronavirus(hCoV-229E and hCoVOC43).Importantly,F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice.F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage,as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity.Despite the significant difference of substrate recognition,mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue,whereas an allosteric inhibitor of MERSPLpro interacting with its 271E position.Our proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus agents.The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.

关键词： protease inhibitor coronavirus Nsp3 antiviral

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C1GALT1基因在胃癌组织中的表达及其对胃癌BGC-823细胞生物学行为的影响

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临床与实验病理学杂志 2024年第6期40卷 603-608页

作者：乔沐川李俊儒罗玲夏童陈艳华胡梦龙谢海龙南华大学衡阳医学院肿瘤研究所/湖南省肿瘤细胞分子病理学重点实验室衡阳421009 南华大学附属第二医院肿瘤内科衡阳421009

目的探讨C1GALT1在胃癌组织中的表达及其对胃癌细胞BGC-823生物学行为的影响。方法采用生物信息学、qRT-PCR和Western blot法分析C1GALT1 mRNA和蛋白在胃癌组织和正常胃黏膜组织、胃癌细胞和正常胃黏膜细胞中的表达,以C1GALT1 cDNA序列... 详细信息

目的探讨C1GALT1在胃癌组织中的表达及其对胃癌细胞BGC-823生物学行为的影响。方法采用生物信息学、qRT-PCR和Western blot法分析C1GALT1 mRNA和蛋白在胃癌组织和正常胃黏膜组织、胃癌细胞和正常胃黏膜细胞中的表达,以C1GALT1 cDNA序列为靶点设计siRNA瞬时转染BGC-823细胞,采用Transwell实验检测C1GALT1-siRNA对胃癌BGC-823细胞迁移和侵袭能力的影响。运用Western blot法检测BGC-823细胞在转染C1GALT1-siRNA后上皮-间充质转化(epithelial-mesenchymal transition,EMT)相关蛋白的表达。结果C1GALT1在胃癌组织和细胞(BGC-823、SGC-7901、MGC-803)中呈高表达(P<0.05);干扰BGC-823细胞中C1GALT1表达后,BGC-823细胞迁移和侵袭能力均下降(P<0.05),上皮细胞标志物E-cadherin和Claudin-1蛋白表达水平均升高,间充质细胞标志物vimentin和Slug蛋白表达水平均下降(P<0.05)。结论C1GALT1在胃癌组织和细胞中高表达,C1GALT1基因沉默后能抑制胃癌细胞BGC-823的迁移和侵袭能力,其机制可能与EMT相关。

关键词：胃肿瘤 C1GALT1 侵袭迁移上皮-间充质转化

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Immunoglobulin-like domains of PECAM-1 contribute to trans-homophilic interaction

Immunoglobulin-like domains of PECAM-1 contribute to trans-h...

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第五届中国结构生物学学术讨论会

作者： menglong hu Quan Hao School of Biomedical Sciences University of Hong Kong

Platelet–endothelial-cell adhesion molecule-1（PECAM-1） plays important roles in cell adhesion and communication. It acts as a significant intermediary of tight cellular junction between adjacent surfaces of endothelia and most embryonic cells through its homophilic binding pattern. Heterophilic interaction with those candidates（CD177, glycosaminoglycans, CD38 and integrin αVβ3） happens in processes like leukocyte migration and tumor cell invasion. However, the conformational change of PECAM-1 mediated endogenous and exogenous signal transmission remains to be elaborated, and the mechanisms of homophilic and heterophilic binding pattern are still unclear. Here, we resolved the crystal structure of PECAM-1 Ig-like domain 1-2 trans-dimer without glycosylation. Both Ig-like domain 1 and 2 share the classical Ig domain structure which is composed of two layers β-sheets with seven antiparallel β-strands, and are anchored by a pair of cysteines that consist of a disulfide bond. And the trans-dimer of Ig domain 1-2 is resulted from hydrophobic interfaces on Ig-like domain 1 and 2 separately. The status of dimer in solution also indicate the homophilic binding pattern of PECAM-1. In addition, cell adhesion assay shows few differences on PECAM-1 derived cellular junction between proteins with and without glycosylation on first three putative glyco-sites of PECAM-1, which announces mutations on glyco-sites for crystallographic study does not affect original status of dimmer. Our finding shows the details of how PECAM-1 assemble with each other among adjacent endothelia cells and form a barrier between hematologic system and tissues.

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The Effect of Blending Ratio on the Structure and Properties of the PPR/PS In situ Fiber Reinforced System Prepared by Multi-Flow Vibration Injection Molding

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Chinese Journal of Polymer Science 2024年第6期42卷 851-863页

作者： Yan-Jiang Li Meng-Long hu Jun-Wen Zhang Qiang Fu Jie Zhang College of Polymer Science and Engineering State Key Laboratory of Polymer Materials EngineeringSichuan UniversityChengdu610065China

To enhance the mechanical properties of polypropylene random copolymer(PPR),polystyrene(PS)with four different contents were added to the PPR matrix through melt blending.Subsequently,using the Multi-Flow Vibration Injection Molding(MFVIM)technology,PPR/PS in situ microfiber composites(MFC)with different blending ratios were prepared.The results indicated that blending ratio had a great impact on the phase morphology and crystal structure of MFVIM samples,which was different from those of conventional injection molding(CIM)samples.PS ultrafine fibers could be formed under the shear field and could absorb the PPR molecular chains to form hybrid shish-kebab structures.Meanwhile,the PPR matrix could also form shish-kebab structures under the effect of strong shear.When the PS content reached 20%,under the combined action of PS in situ microfibers and highly oriented crystal structure,the tensile strength and Young’s modulus of the sample were obviously improved and the impact strength remained at a relatively high level.So a strong and tough balanced PPR based material was obtained.These results provide valuable insights for expanding the industrial and daily-life applications of PPR and show promising development prospects.

关键词： PPR MFVIM In situ microfibers Shearfield Hybrid shish-kebab structures

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围手术期加速康复理念在漏斗胸中的应用进展

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临床小儿外科杂志 2022年第6期21卷 582-585页

作者：胡梦珑戚继荣南京医科大学附属儿童医院心胸外科南京210008

加速康复外科(enhanced recovery after surgery,ERAS)理念在成人外科领域已得到推广并取得良好效果。近年来ERAS理念被引入小儿外科,但由于儿童疾病谱的特殊性以及对麻醉、手术的耐受性与成人不同,ERAS在儿童外科的应用面临挑战。就漏... 详细信息

加速康复外科(enhanced recovery after surgery,ERAS)理念在成人外科领域已得到推广并取得良好效果。近年来ERAS理念被引入小儿外科,但由于儿童疾病谱的特殊性以及对麻醉、手术的耐受性与成人不同,ERAS在儿童外科的应用面临挑战。就漏斗胸而言,患儿围手术期的疼痛、腹胀、心理或进食障碍等,严重影响手术后的加速康复;同时漏斗胸患儿往往年龄偏大,在临床处理上更接近成人,因此,能否借鉴成人外科在ERAS方面的经验用于漏斗胸患儿的围手术期加速康复,是近年来国内外关注的热点。本文就儿童漏斗胸围手术期镇痛、心理疏导以及术后加速康复策略进行综述。

关键词：漏斗胸/外科学漏斗胸/康复围手术期医护/方法加速康复外科

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Novel protein-RNA interaction motifs involving hydrolase-related and WD40-like domains

Novel protein-RNA interaction motifs involving hydrolase-rel...

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中国生物化学与分子生物学会2016年全国学术会议

作者： Na Yang Zhenyu Yu Yi Wang menglong hu Chaopei Liu Mingzhu Wang Rui-Ming Xu National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences University of Chinese Academy of Sciences

Spatial and temporal control of m RNA localization and translation plays critical roles in many events during germ cell development and asymmetric body pattern formation.Aberrant m RNA localization and untimely protein synthesis during oogenesis can lead to defect and mis-patterning of germ cell formation,causing embryonic lethality and sterility.We focus

关键词： RNA binding motif hydrolase fold WD40 fold crystal structure

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Cinobufotalin prevents bone loss induced by ovariectomy in mice through the BMPs/SMAD and Wnt/β-catenin signaling pathways

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Animal Models and Experimental Medicine 2024年第3期7卷 208-221页

作者： Da-zhuang Lu Li-jun Zeng Yang Li Ran-li Gu Meng-long hu Ping Zhang Peng Yu Xiao Zhang Zheng-wei Xie Hao Liu Yong-sheng Zhou Department of Prosthodontics Peking University School and Hospital of StomatologyBeijingChina National Center of Stomatology BeijingChina National Clinical Research Center for Oral Diseases BeijingChina Beijing Key Laboratory of Digital Stomatology BeijingChina Department of Cariology and Endodontology Peking University School and Hospital of StomatologyBeijingChina Peking University International Cancer Institute Peking University Health Science CenterPeking UniversityBeijingChina Central Laboratory Peking University School and Hospital of StomatologyBeijingChina National Engineering Research Center of Oral Biomaterials and Digital Medical Devices BeijingChina

Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.

关键词： BMPs/SMAD bone loss cinobufotalin hBMMSCs osteogenesis osteoporosis Wnt/β-catenin signaling pathways

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近红外光谱监测在先天性心脏病围术期的应用进展

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中华实用儿科临床杂志 2022年第1期37卷 77-80页

作者：曹怡佳戚继荣胡梦珑南京医科大学附属儿童医院心胸外科南京210008

近红外光谱(NIRS)通过监测局部组织血氧饱和度(rSO_(2)),实时、无创地反映测量部位氧代谢情况和局部有效血流灌注,已广泛应用于不同疾病状态下脑、肾脏以及胃肠道血流灌注监测和脏器功能评估。先天性心脏病(CHD)围术期血流动力学波动易... 详细信息

近红外光谱(NIRS)通过监测局部组织血氧饱和度(rSO_(2)),实时、无创地反映测量部位氧代谢情况和局部有效血流灌注,已广泛应用于不同疾病状态下脑、肾脏以及胃肠道血流灌注监测和脏器功能评估。先天性心脏病(CHD)围术期血流动力学波动易引起脏器灌注不足,导致缺氧缺血的发生和内环境紊乱,组织氧合状态发生有害变化,但此时机体的动脉血氧饱和度(SaO_(2))甚至混合静脉饱和度(SvO_(2))尚未改变,而NIRS可以灵敏监测组织的rSO_(2)改变,从而预警组织缺氧缺血并及早干预,防止进一步损伤的发生。现简述NIRS的基本原理、局限性及在CHD围术期应用新进展,旨在为其在CHD围术期的临床应用提供新的思路及方向,早期评估患者病情,并指导临床工作。

关键词：儿童先天性心脏病近红外光谱围术期

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Paracrine function amplifies pro-tumor electrochemical signal within neuron-glioma synapses

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Science China(Life Sciences) 2024年第6期67卷 1318-1320页

作者： Yan hu Peishan hu Xiaozhong Peng Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengdu 610041China Guangdong Institute of Gastroenterology Department of General SurgeryGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China Department of Molecular Biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100730China State Key Laboratory of Respiratory Health and Multimorbidity Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100730China Institute of Laboratory Animal Science Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

Neuronal activity plays a pivotal role in various physiological processes,including tissue development,homeostasis,and adaptability.Advances in recent years have improved our understanding of neuronal activity in brain cancers,such as glioblastoma(GBM)and diffuse midline gliomas(DMG),which are among the most prevalent and lethal cancers affecting children and adults.Generally,the neurons regulate brain cancers via two routes.

关键词： glioma homeostasis function

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Influencing Factors on Cardiovascular Health in China

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Journal of Geriatric Cardiology 2024年第1期21卷 4-33页

作者： Sheng-Shou hu 无 Fuwai Hospital Chinese Academy of Medical Sciences BeijingChina the Writing Committee of the Report on Cardiovascular Health and Diseases in China

The Annual Report on Cardiovascular Health and Diseases in China(2022)intricate landscape of cardiovascular health in China.This is the first section of the report,which dissects influential factors across diverse domains.The investigation identifies tobacco use as a paramount concern,portraying China as the global epicenter of tobacco consumption.Cigarette smoking,exacerbated by second-hand smoke exposure,emerges as a critical and preventable risk factor,contributing to a surge in attributable deaths over the past three decades.In the realm of dietary nutrition,the study discerns an overall improvement,yet discerns worrisome deviations,notably an escalating fat intake surpassing recommended guidelines.The shifting dietary structure reveals diminished consumption of cereals and vegetables juxtaposed with an uptick in animal foods,while excessive intake of cooking oil and salt persists,straying substantially from endorsed levels.The exploration of physical activity patterns unfolds a nuanced narrative.Varied trends are observed among students,with concerns arising from sedentary behaviors and inadequate adherence to recommended guidelines.The analysis spans a trajectory of declining physical activity in Chinese adults,coupled with an alarming surge in sedentary leisure time,ultimately linking these factors to heightened risks of cardiovascular diseases and increased adiposity.An examination of overweight and obesity trends uncovers a relentless upward trajectory,projecting substantial prevalence by 2030.Noteworthy prevalence rates underscore the imperative for targeted interventions to curtail this burgeoning health crisis,with the anticipated prevalence extending to nearly two-thirds of the adult population.Psychological factors,notably depression,constitute an integral facet of cardiovascular health.Prevalence rates among patients with coronary artery disease and acute myocardial infarction underscore the intricate interplay between mental health and cardiovascular outcomes.Additionally,persistent depressive sym

关键词： Influencing smoke linking

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