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Engineering prodrug nanomicelles as pyroptosis inducer for codelivery of PI3K/mTOR and CDK inhibitors to enhance antitumor immunity

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3139-3155页

作者： Qichao Yang Xianbin Ma Yao Xiao Tian Zhang Leilei Yang Shaochen Yang mengyun liang Shuo Wang Zhizhong Wu Zhigang Xu Zhijun Sun The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory of Oral Biomedicine Ministry of Education School&Hospital of StomatologyWuhan UniversityWuhan 430079China Key Laboratory of Luminescence Analysis and Molecular Sensing(Southwest University) Ministry of EducationSchool of Materials and Energy&Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and DevicesSouthwest UniversityChongqing 400715China

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response.However,single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways.The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications.To circumvent this issue,we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle(PNM)for cancer therapy.PNM was engineered by integrating the PI3K/m TOR inhibitor PF-04691502(PF)and the broad spectrum CDK inhibitor flavopiridol(Flav)into a single nanoplatform,which showed tumor-specific accumulation,activation and deep penetration in response to the high glutathione(GSH)tumoral microenvironment.The codelivery of PF and Flav could trigger gasdermin E(GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response.Furthermore,the combination of PNM-induced immunogenic pyroptosis with antiprogrammed cell death-1(a PD-1)immunotherapy further boosted the antitumor effect and prolonged the survival time of mice.Collectively,these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/m TOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.

关键词： Pyroptosis Prodrug Stimuli-responsive Immunotherapy Targeted therapy Tumor microenvironment

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Microenvironment-responsive chemotherapeutic nanogels for enhancing tumor therapy via DNA damage and glutathione consumption

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Chinese Chemical Letters 2022年第9期33卷 4197-4202页

作者： Mengjie Ye Yuan Gao mengyun liang Wei Qiu Xian bin Ma Jiming Xu Junfeng Hu Peng Xue Yuejun Kang Zhigang Xu Key Laboratory of Luminescence Analysis and Molecular Sensing(Southwest University) Ministry of EducationSchool of Materials and Energy and Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and DevicesSouthwest UniversityChongqing 400715China Key Laboratory of Laser Technology and Optoelectronic Functional Materials of Hainan Province College of Chemistry and Chemical EngineeringHainan Normal UniversityHaikou 571158China

Although targeted therapy and immunotherapy are now shining in the treatment of some cancers,chemotherapy is still the cornerstone of drug treatment for many cancer patients.The emergence of chemotherapy prodrugs can improve the drug activity and reduce the side effects of chemotherapy.When used,the tumor microenvironment has characteristics different from normal tissues,and the existence of the microenvironment provided a more convenient way to design responsive nanodrugs.Herein,we designed a glutathione(GSH)-responsive prodrug nanogels for enhancing tumor chemotherapy.In the nanogels of HHNP,10-hydroxycamptothecin(HCPT)played an essential role in killing cancer cells.HCPT was jointed with a cross-linker agent with disulfide bond and was further coated with polyethylene glycol,which not only prolonged the half-life of the drug,but also made HCPT accurate transport to the tumor fractions and achieved precise and controllable release.The proposal of HHNP effectively retained the biological activity of the drug,and introduced functions such as targeting,selective release and biodegradation,which greatly improved the medical efficiency of the drug and effectively reduced the toxic and side effects.This chemotherapeutic prodrug nanogel offers a new window for constructing efficient drug delivery platform.

关键词： Nanogel Prodrug GSH-responsive DNA damage Chemotherapy

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Cylindrical polymer brushes-anisotropic unimolecular micelle drug delivery system for enhancing the effectiveness of chemotherapy

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Bioactive Materials 2021年第9期6卷 2894-2904页

作者： Shuang Bai Die Jia Xianbin Ma mengyun liang Peng Xue Yuejun Kang Zhigang Xu Key Laboratory of Luminescence Analysis and Molecular Sensing(Southwest University) Ministry of EducationSchool of Materials and EnergySouthwest UniversityChongqing400715PR China State Key Laboratory of Molecular Engineering of Polymers Fudan UniversityShanghai200438China Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices Southwest UniversityChongqing400715PR China

Polymer systems can be designed into different structures and morphologies according to their physical and chemical performance requirements,and are considered as one of the most promising controlled delivery systems that can effectively improve the cancer therapeutic index.However,the majority of the polymer delivery systems are designed to be simple spherical nanostructures.To explore morphology/size-oriented delivery performance optimization,here,we synthesized three novel cylindrical polymer brushes(CPBs)by atom transfer radical polymerization(ATRP),which were cellulose-g-(CPT-b-OEGMA)(CCO)with different lengths(~86,~40,and~21 nm).The CPBs are composed of bio-degradable cellulose as the carrier,poly(ethylene glycol)methyl ether methacrylate(OEGMA)as hydrophily block,and glutathione(GSH)-responsive hydrophobic camptothecin(CPT)monomer as loaded anticancer drug.By controlling the chain length of the initiator,three kinds of polymeric prodrugs with different lengths(CCO-1,CCO-2,and CCO-3)could be self-organized into unimolecular micelles in water.We carried out comparative studies of three polymers,whose results verified that the shorter CPBs exhibited higher drug release efficiency,more cellular uptake,and enhanced tumor permeability,accompanied by shortened blood circulation time and lower tumor accumulation.As evidenced by in vivo experiments,the shorter CPBs exhibited higher anti-tumor efficiency,revealing that the size advantage has a higher priority than the anisotropic structure advantage.This provided vital information as to design an anisotropic polymer-based drug delivery system for cancer therapy.

关键词： Cylindrical polymer brushes Unimolecular micelles Prodrug Reduction-responsive Cancer therapy

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ACBP4-WRKY70-RAP2.12 module positively regulates submergence-induced hypoxia response in Arabidopsis thaliana

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Journal of Integrative Plant Biology 2024年第6期66卷 1052-1067页

作者： mengyun Guo Yingjun Yao Kangqun Yin† Luna Tan Meng Liu Jing Hou Han Zhang Ruyun liang Xinran Zhang Heng Yang Xiaoxiao Chen Jinrui Tan Yan Song Shangling Lou Liyang Chen Xuejing Liu Si Tang Yongqi Hu Jin Yan Wensen Fu Kai Yang Ruijia Zhang Xuerui Li Yao Liu Zhen Yan Wei Liu Yu Han Jianquan Liu Kangshan Mao Huanhuan Liu Key Laboratory for Bio‐resources and Eco‐environment&State Key Lab of Hydraulics&Mountain River Engineering Sichuan Zoige Alpine Wetland Ecosystem National Observation and Research StationKey Laboratory for Bio‐resource and Eco‐environment of Ministry of EducationCollege of Life SciencesSichuan UniversityChengdu 610065China

ACYL-CoA-BINDING PROTEINs(ACBPs)play crucial regulatory roles during plant response to hypoxia,but their molecular mechanisms remain poorly understood.Our study reveals that ACBP4 serves as a positive regulator of the plant hypoxia response by interacting with WRKY70,influencing its nucleocytoplasmic shuttling in Arabidopsis thaliana.Furthermore,we demonstrate the direct binding of WRKY70 to the ACBP4 promoter,resulting in its upregulation and suggesting a positive feedback loop.Additionally,we pinpointed a phosphorylation site at Ser638 of ACBP4,which enhances submergence tolerance,potentially by facilitating WRKY70's nuclear shuttling.Surprisingly,a natural variation in this phosphorylation site of ACBP4 allowed A.thaliana to adapt to humid conditions during its historical demographic expansion.We further observed that both phosphorylated ACBP4 and oleoyl-Co A can impede the interaction between ACBP4 and WRKY70,thus promoting WRKY70's nuclear translocation.Finally,we found that the overexpression of orthologous Bna C5.ACBP4and Bna A7.WRKY70 in Brassica napus increases submergence tolerance,indicating their functional similarity across genera.In summary,our research not only sheds light on the functional significance of the ACBP4 gene in hypoxia response,but also underscores its potential utility in breeding flooding-tolerant oilseed rape varieties.

关键词： ACBP4 Arabidopsis thaliana humid adaptation natural variation RAP2.12 WRKY70

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调节阀低温空化流动特性的数值仿真

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火箭推进 2024年第2期50卷 98-106页

作者：梁文栋赵梦芸刘博郭文君北京航天动力研究所北京100076

采用数值计算的方法针对某型液体火箭发动机中液氧调节阀的流场分布和空化流动特性进行了研究。数值计算获得的阀门流通面积与液流实验数据基本吻合,验证了数值模型的准确性。分析了球阀内部流道压力、温度、涡和空穴结构的分布特性及... 详细信息

采用数值计算的方法针对某型液体火箭发动机中液氧调节阀的流场分布和空化流动特性进行了研究。数值计算获得的阀门流通面积与液流实验数据基本吻合,验证了数值模型的准确性。分析了球阀内部流道压力、温度、涡和空穴结构的分布特性及不同工况下的演化规律。研究结果表明:液氧流经球阀,压力变化分为缓慢下降、急剧下降、急剧回升、缓慢下降和缓慢回升这5个阶段。在阀芯流道内部观察到了显著的Q等值面结构。相同压差时,水的空化数大于液氧。空穴结构主要分布在阀芯入口,随着空化数的降低,逐渐向流道内部发展。对于常温水,发生空化的临界空化数为1.38左右。空穴结构的发展受空化数和热力学效应的耦合影响。液氧温度从95 K上升到100 K时,空化数减小,名义温降增加,此时热力学效应影响起主导作用,空穴的发展受到抑制。

关键词：调节阀液氧空化模型热力学效应

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多利益主体协同视角下非物质文化遗产在乡村空间建设中的应用研究——以河南乡建项目为例

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装饰 2024年第1期 34-41页

作者：郑昌辉谢梦云胡晓青肖亮奚雪松中国农业大学人文与发展学院武汉大学城市设计学院四川大学建筑与环境学院中国农业大学水利与土木工程学院

乡村的优质文旅空间建设是多利益主体博弈的结果,是不同群体的需求与审美在空间中的耦合。不同群体偏好的空间格局与形态差异较大,协同差异的媒介与机制成为项目成败的关键。本研究从多利益主体协同的视角梳理广义非遗的当代应用,发现... 详细信息

乡村的优质文旅空间建设是多利益主体博弈的结果,是不同群体的需求与审美在空间中的耦合。不同群体偏好的空间格局与形态差异较大,协同差异的媒介与机制成为项目成败的关键。本研究从多利益主体协同的视角梳理广义非遗的当代应用,发现非遗可以成为不同群体共同认同的媒介与空间协调的重要驱动力;非遗除了能实现文创产品的衍生化之外,也能在空间建设中进行应用与转译,能留存传统的乡土生活、乡土工艺与乡土记忆,还能拟合不同利益群体偏好并形成新乡土文化节点的共建。广义非遗意味着对时间、范围与方法的全面拓展,用未来50年的眼光往回看,日常的乡土遗产的价值就能被发现;用泛化的概念来定义,非遗的空间应用范围就能被扩展;用新乡土工艺的方法来操作,历史风貌与当代生活就能被协同。多利益主体协同的广义非遗振兴乡村的空间策略要义就是将乡村视为更多群体的共同故乡,将单向度的工程设计推向多维度的社会设计。

关键词：广义非物质文化遗产多利益主体乡村振兴文旅融合社会设计

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聚合物表面空间环境防护涂层热应力分析方法研究进展

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中国表面工程 2024年第2期37卷 115-136页

作者：徐梦芸张锦麟马佳玉唐登航许文彬王亮谷红宇章俞之宋力昕中国科学院上海硅酸盐研究所特种无机涂层重点实验室上海200050 中国科学院大学材料与光电研究中心北京100049 上海宇航系统工程研究所上海201109 中国科学院上海硅酸盐研究所集成计算材料研究中心上海200050

柔性聚合物材料作为航天器表面用关键材料,易受到空间环境的协同损伤,在其表面制备防护涂层是实现长期服役的重要技术。但由于常用防护涂层与基体间的性能差异,涂层易因应力出现开裂和剥落,因此应力分析对于材料的设计和优化非常重要。... 详细信息

柔性聚合物材料作为航天器表面用关键材料,易受到空间环境的协同损伤,在其表面制备防护涂层是实现长期服役的重要技术。但由于常用防护涂层与基体间的性能差异,涂层易因应力出现开裂和剥落,因此应力分析对于材料的设计和优化非常重要。对于涂层应力的分析方法,主要可以分为基于试验测量以及基于数值仿真的有限元分析方法两类。梳理目前常见的试验测量方法,分析有损法和无损法试验测量的应用,整理归纳基于数值仿真的有限元分析方法的原理以及相关应用,比较不同方法的优缺点,总结其局限性以及应用前景。不同应力测试分析方法在材料的服役寿命和失效形式预测中发挥了重要作用,但传统的机械有损测量方法难对应力情况进行实时监测,近年来发展起来的无损法也存在一定的应用局限性,有限元模拟具有实时、全面的应力测量优点,但是与实际涂层模型具有一定的差距。基于目前试验方法与有限元仿真各自的局限性,提出将有限元仿真与试验表征结合成为进一步指导涂层设计的有效方法,有望有效预测涂层失效机制,优化涂层材料制备工艺,开发具有低应力结构的涂层材料,为聚合物表面用关键涂层材料的轻量化发展和长期可靠服役提供技术支撑。

关键词：聚合物材料空间环境防护涂层热应力应力分析方法有限元模拟

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A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome

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Frontiers of Medicine 2023年第2期17卷 330-338页

作者： Hequn Huang mengyun Chen Xia Liu Xixi Xiong Lanbo Zhou Zhonglan Su Yan Lu Bo liang Institute of Dermatology and Department of Dermatology the First Affiliated HospitalAnhui Medical UniversityHefei 230000China Key Laboratory of Dermatology(Anhui Medical University) Ministry of EducationHefei 230000China Inflammation and Immune Mediated Diseases Laboratory of Anhui Province Hefei 230000China Huai’an District Skin Disease Prevention and Treatment Hospital Huai’an 223000China Department of Dermatology The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210000China Department of Clinical Laboratory The First Affiliated HospitalAnhui Medical UniversityHefei 230000China

Clouston syndrome(OMIM#129500),also known as hidrotic ectodermal dysplasia type 2,is a rare autosomal dominant skin disorder.To date,four mutations in the GJB6 gene,G11R,V37E,A88V,and D50N,have been confirmed to cause this condition.In previous studies,the focus has been mainly on gene sequencing,and there has been a lack of research on clinical manifestations and pathogenesis.To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease,we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree.Detailed clinical examination included histopathology,hair microscopy,and scanning electron microscopy.We found a novel heterozygous missense variant(c.134G>C:p.G45A)for Clouston syndrome.We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients’hair under scanning electron microscopy.Our data reveal that a novel variant(c.134G>C:p.G45A)plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.

关键词： Clouston syndrome whole exome sequencing GJB6 gene novel variant unique phenotype

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基于马赫-曾德光纤传感的儿童肺炎诊断系统

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国际生物医学工程杂志 2022年第3期45卷 207-212页

作者：梁涵倪倩宋明昝香怡曹鹏飞徐大丽李玉霞曹婕文豪梁梦云邓毓博兰州大学第二医院心内二科兰州730030 兰州大学第二医院儿科兰州730030 兰州大学信息科学与工程学院兰州730000 兰州大学第二医院呼内科兰州730030 甘肃省药品监督管理局审核查验中心兰州730070 甘肃中医药大学附属医院儿科兰州730000

目的:探索一种根据呼吸信号对儿童肺炎进行快速准确判别的方法,避免传统诊断时X射线产生的儿童癌症诱导性。方法:采用马赫-曾德光纤传感器搭建儿童肺炎呼吸信号(RSP)检测系统,依据儿童肺部啰音产生的振动信号,提取被监测者的RSP。通过... 详细信息

目的:探索一种根据呼吸信号对儿童肺炎进行快速准确判别的方法,避免传统诊断时X射线产生的儿童癌症诱导性。方法:采用马赫-曾德光纤传感器搭建儿童肺炎呼吸信号(RSP)检测系统,依据儿童肺部啰音产生的振动信号,提取被监测者的RSP。通过离散余弦变换等预处理方法,进行信号压缩和去噪;通过Hilbert变换、自回归(AR)模型谱估计等信号处理方法,实现RSP的多特征提取;构建支持向量机(SVM)分类模型对采集的RSP进行分类。结果:所提出的方法对患肺炎与未患肺炎儿童RSP的分类准确率为94.41%,较以往方法提升较大。结论:基于光纤传感器的儿童肺炎诊断系统具有较高的检测准确率,有希望在临床中推广使用。

关键词：呼吸信号儿童肺炎支持向量机分类准确率 F_(1)分数

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基于壳-弹簧模型的预制地下管廊横向抗震分析

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自然灾害学报 2022年第2期31卷 102-110页

作者：甘梦云梁建文李东桥赵华天津大学建筑工程学院天津300350 天津市建筑设计院天津300074

利用ABAQUS有限元软件,采用壳单元模拟预制装配式地下管廊,非线性弹簧模拟管段承插口接头的力学行为,非线性地基弹簧模拟土-结构间相互作用,文中提出一种适用于预制管廊横向抗震分析的壳-弹簧计算模型。以天津市某拟建地下管廊为例,对4... 详细信息

利用ABAQUS有限元软件,采用壳单元模拟预制装配式地下管廊,非线性弹簧模拟管段承插口接头的力学行为,非线性地基弹簧模拟土-结构间相互作用,文中提出一种适用于预制管廊横向抗震分析的壳-弹簧计算模型。以天津市某拟建地下管廊为例,对4个计算工况进行了横向抗震分析。结果表明,壳-弹簧模型内力较梁-弹簧模型均有所增大,轴力、剪力、弯矩分别增大17.4%、22.7%和27.9%;考虑管段间钢绞线预应力时,内力在幅宽上有明显变化且在承插口接头处明显增高;引入管廊结构材料塑性后,管廊层间变形显著增大,且较之线弹性模型增大了68.7%。文中的壳-弹簧模型可反映预制综合管廊结构的弹塑性行为及接头钢绞线预应力影响,对预制综合管廊抗震设计有一定指导作用。

关键词：预制地下管廊横向抗震分析反应位移法钢绞线预应力承插口接头壳-弹簧模型梁-弹簧模型

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