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Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152):a novel triple angiokinase inhibitor for cancer therapy

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1453-1475页

作者： Yuqin Yao Zhuowei Liu manyu zhao Zhengxia Chen Peng Li Yang Zhang Yuxi Wang Chengjian zhao Chaofeng Long Xiaoxin Chen Jinliang Yang State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China School of Public Health and West China Fourth HospitalSichuan UniversityChengdu 610041China Guangdong Zhongsheng Pharmaceutical Co. Ltd.Dongguan 523325China West China School of Public Health and West China Fourth Hospital Healthy Food Evaluation Research CenterSichuan UniversityChengdu 610041China Guangdong Raynovent Biotech Co. Ltd.Dongguan 523325China WuXi AppTec Ltd.Shanghai 200131 China

Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and *** conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.

关键词： inhibited clinical synthesis

Decreased soil pH weakens the positive rhizosphere effect on denitrification capacity

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Pedosphere 2024年第5期34卷 905-915页

作者： Jun WANG Zongxiang ZHANG Fei LIANG zhao CHE Yongkang WEN manyu ZHANG Wenjun JIN zhaorong DONG He SONG College of Agronomy Anhui Agricultural University Key Laboratory of Arable Land Quality Monitoring and Evaluation Ministry of Agriculture and Rural Affairs Institute of Agricultural Resources and Regional Planning Chinese Academy of Agricultural Sciences (CAAS) College of Resources and Environmental Sciences China Agricultural University

The stimulating effect of rhizosphere on denitrification is considered to be an unavoidable loss of soil nitrogen（N） and detrimental to crop N use efficiency,which is regulated by crop growth and soil properties. Soil acidification, occurring rapidly in many intensive farming lands, affects both crop growth and soil properties, thereby altering rhizosphere effect on denitrification. However, the mechanism by which soil acidification regulates rhizosphere denitrification still remains unclear. Here, we determined the denitrification capacity（DC） and associated community compositions of nirK-and nirS-type denitrifiers in maize rhizosphere and bulk soils at four acidity gradients（pH = 6.8, 6.1, 5.2, and 4.2）. Results showed that the stimulating effect of rhizosphere on DC strongly depended on soil pH. Compared to bulk soil, rhizosphere soil had significantly higher DC at pH 5.2, but not at pH of 4.2. With increasing soil acidity, the stimulation of rhizosphere on DC（calculated as the difference in DC between rhizosphere and bulk soils） decreased from 8.01 to 0.01 mg N ***, soil acidification significantly reduced the differences in dissolved organic carbon（DOC） and abundance of key nirK-type denitrifier taxa between rhizosphere and bulk soils, both of which were positively related to the stimulation of rhizosphere on DC. These findings demonstrated that soil acidification could weaken the positive rhizosphere effect on denitrification via regulated C availability and associated nirK-type denitrifier community, potentially reducing N loss risk in rhizosphere soil. The independent role of soil p H should be fully considered when modelling N behaviour in plant-soil systems.

关键词： bacterial abundance denitrifier community dissolved organic carbon operational taxonomic unit soil acidification

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基于叙事图景的瑶族节庆可视化设计策略

装饰 2023年第9期 128-131页

作者：徐皎赵曼煜中南大学

民族节庆作为一种文化符号,是记录民族发展和传播民族文化的重要渠道。本文以瑶族为例,试图将叙事性设计引入信息可视化中,挖掘瑶族节庆的文化内涵及相关知识,用图像、图表等易于理解的语言形式对瑶族节庆内容进行解释、阐述与表现,重... 详细信息

民族节庆作为一种文化符号,是记录民族发展和传播民族文化的重要渠道。本文以瑶族为例,试图将叙事性设计引入信息可视化中,挖掘瑶族节庆的文化内涵及相关知识,用图像、图表等易于理解的语言形式对瑶族节庆内容进行解释、阐述与表现,重构节庆活动的叙事情境,以互动叙事的方式引导受众参与节庆活动体验,深层次理解瑶族节庆的文化特质,以承载和延续瑶族的文化记忆。

关键词：瑶族节庆叙事图景可视化设计

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一类时滞异质网络的拟同步控制

计算机工程与应用 2021年第12期57卷 86-92页

作者：赵曼宇叶军南京邮电大学理学院南京210023

针对含时变时滞的非线性异质复杂网络,研究其在含输入时滞的采样控制下实现拟同步的问题。建立包含更多时滞信息以及采样间隔信息的Lyapunov-Krasovskii泛函,基于Lyapunov-Krasovskii稳定性理论、积分不等式方法和线性矩阵不等式方法,... 详细信息

针对含时变时滞的非线性异质复杂网络,研究其在含输入时滞的采样控制下实现拟同步的问题。建立包含更多时滞信息以及采样间隔信息的Lyapunov-Krasovskii泛函,基于Lyapunov-Krasovskii稳定性理论、积分不等式方法和线性矩阵不等式方法,通过引入一个领导者获得了保证非线性异质复杂网络实现拟同步的充分条件。所有的异质跟随者都能在一个有界范围内追踪到领导者。并估计出实现拟同步的误差上界。通过数值仿真证明了理论结果的有效性。

关键词： Lyapunov-Krasovskii泛函异质动态网络拟同步采样控制

Targeting fibrosis: mechanisms and clinical trials

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2469-2489页

作者： manyu zhao Liqun Wang Mengzhu Wang Shijie Zhou Ying Lu Huijie Cui Alexandra C.Racanelli Ling Zhang Tinghong Ye Bisen Ding Ben Zhang Jinliang Yang Yuqin Yao West China School of Public Health and West China Fourth Hospital Sichuan UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengdu 610041China Division of Pulmonary and Critical Care Medicine Joan and Sanford I.Weill Department of MedicineWeill Cornell MedicineNew YorkNY 10021USA NewYork-Presbyterian Hospital Weill Cornell MedicineNew YorkNY 10021USA College of Polymer Science and Engineering Sichuan universityChengdu 610000China Key Laboratory of Birth Defects of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengdu 610041China

Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair *** organs can develop fibrosis,including the liver,kidney,heart,and *** such as liver cirrhosis,idiopathic pulmonary fibrosis,and cystic fibrosis caused substantial disease *** abnormal activation of myofibroblasts mediated by various signals,such as transforming growth factor,platelet-derived growth factor,and fibroblast growh factor,has been recongized as a major event in the occurrence and progression of *** the mechanisms driving organ-specific fibrosis have not been fully elucidated,drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical *** this review,we briefly introduce the aetiology and epidemiology of several fibrosis diseases,including liver fibrosis,kidney fibrosis,cardiac fibrosis,and pulmonary ***,we summarise the abnormal cells(epithelial cells,endothelial cells,immune cells,and fibroblasts)and their interactions in *** addition,we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation,extracellular matrix cross-linking,metabolism,and inflammation in ***,we discuss the anti-fibrotic drugs based on their targets and clinical *** review provides reference for further research on fibrosis mechanism,drug development,and clinical trials.

关键词： drugs epidemiology organs

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铁死亡调控机理及其在肿瘤治疗中的应用

科技导报 2021年第7期39卷 63-74页

作者：黄珊赵漫玉张佩景华中科技大学生命科学与技术学院武汉430074

铁死亡(ferroptosis)为最近鉴定出的一种新的细胞程序性死亡模式,越来越多证据表明铁死亡在肿瘤的发生发展中扮演了重要角色。综述了近年来铁死亡的调控机制研究进展,包括经典和非经典的铁死亡诱导过程、活性氧自由基(reactive oxygen s... 详细信息

铁死亡(ferroptosis)为最近鉴定出的一种新的细胞程序性死亡模式,越来越多证据表明铁死亡在肿瘤的发生发展中扮演了重要角色。综述了近年来铁死亡的调控机制研究进展,包括经典和非经典的铁死亡诱导过程、活性氧自由基(reactive oxygen species,ROS)及非编码RNA在铁死亡调控中的作用。论述了铁死亡与肿瘤的关系,包括肿瘤抑制因子、缺氧诱导因子、NRF2和细胞间质化状态参与铁死亡敏感性的调控,以及利用铁死亡来靶向治疗肿瘤,介绍了研发出的4类铁死亡诱导剂:Ⅰ、Ⅱ、Ⅲ和Ⅳ型。总结了可能的肿瘤细胞抵抗铁死亡的机制,为靶向这一新的细胞死亡模式提供分子依据,从而提高肿瘤治疗效果。

关键词：铁死亡铁死亡诱导剂肿瘤细胞

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数字经济下中华老字号品牌国际化探究

时代经贸 2023年第2期20卷 118-120页

作者：赵曼玉首都经济贸易大学北京100070

在疫情防控常态化和数字经济发展的背景下,实体经济的发展前景受到了冲击,诸多传统企业选择通过网络宣传将品牌推向国际社会,以寻求更多的市场与机遇。中华老字号在品牌国际化过程中面临着诸多挑战,文化差异、营销不足、知识产权意识薄... 详细信息

在疫情防控常态化和数字经济发展的背景下,实体经济的发展前景受到了冲击,诸多传统企业选择通过网络宣传将品牌推向国际社会,以寻求更多的市场与机遇。中华老字号在品牌国际化过程中面临着诸多挑战,文化差异、营销不足、知识产权意识薄弱等问题限制了品牌走向国际,同时“一带一路”倡议的实施、数字经济的发展等为中华老字号品牌实现国际化创造了机遇。本文提出五条中华老字号品牌国际化的发展建议:借助“一带一路”促进传播;融合内外消费者需求差异实现创新;拓宽销售渠道持续数字化转型;加强企业知识产权意识积极维护品牌资产;建立人才培养体系实现持久传承。最后通过同仁堂、瑞蚨祥等品牌国际化案例,总结实现品牌国际化老字号企业的共同特点,为其他老字号开拓国际市场提供启示。

关键词：数字经济中华老字号品牌国际化

Maresin 1 alleviates neuroinflammation and cognitive decline in a mouse model of cecal ligation and puncture

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中南大学学报（医学版） 2024年第6期49卷 890-902页

作者： LI Longyan XING manyu WANG Lu zhao Yixia Department of Anesthesiology Xiangya HospitalCentral South UniversityChangsha 410008 Department of Cardiology Xiangya HospitalCentral South UniversityChangsha 410008 National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China

Objective:Inflammation in the central nervous system plays a crucial role in the occurrence and development of sepsis-associated *** study aims to explore the effects of maresin 1(MaR1),an anti-inflammatory and pro-resolving lipid mediator,on sepsis-induced neuroinflammation and cognitive ***:Mice were randomly assigned to 4 groups:A sham group(sham operation+vehicle),a cecal ligation and puncture(CLP)group(CLP operation+vehicle),a MaR1-LD group(CLP operation+1 ng MaR1),and a MaR1-HD group(CLP operation+10 ng MaR1).MaR1 or vehicle was intraperitoneally administered starting 1 h before CLP operation,then every other day for 7 *** rates were monitored,and serum inflammatory cytokines[tumor necrosis factor alpha(TNF-α),interleukin(IL)-1β,and IL-6]were measured 24 h after operation using enzyme-linked immunosorbent assay(ELISA).Cognitive function was assessed 7 days after operation using the Morris water maze(MWM)test and novel object recognition(NOR)*** mRNA expression of TNF-α,IL-1β,IL-6,inducible nitric oxide synthase(iNOS),IL-4,IL-10,and arginase 1(Arg1)in cortical and hippocampal tissues was determined by real-time reverse transcription PCR(RT-PCR).Western blotting was used to determine the protein expression of iNOS,Arg1,signal transducer and activator of transcription 6(STAT6),peroxisome proliferator-activated receptor gamma(PPARγ),and phosphorylated STAT6(p-STAT6)in hippocampal *** activation was visualized via *** were also treated with the PPARγantagonist GW9662 to confirm the involvement of this pathway in MaR1’s ***:CLP increased serum levels of TNF-α,IL-1β,and IL-6,and reduced body weight and survival rates(all P0.05).MWM test and NOR t

关键词： sepsis cognitive decline maresin 1 microglia neuroinflammation

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WBS在宁波某油库设计项目中的应用研究

项目管理技术 2010年第10期8卷 73-77页

作者：赵曼宇中国寰球工程公司辽宁分公司

以宁波某油库项目的基础设计阶段为例，从WBS分解入手，对WBS在设计项目中的分解原则和分解方法进行了阐述，并对结构和代码的设计进行了系统的研究，详细介绍了该设计项目的WBS，具有较强的借鉴价值。

关键词： WBS 油库设计项目应用研究