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Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Acta Pharmaceutica Sinica B 2024年第1期14卷 350-364页

作者： Yongshun Zhang Lan Yang Yangsen Ou Rui Hu Guangsheng Du Shuang Luo Fuhua Wu Hairui Wang Zhiqiang Xie Yu Zhang Chunting He Cheng Ma Tao Gong Ling Zhang Zhirong Zhang Xun Sun Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China Med-X Center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and cpg,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

关键词： Triple therapy Adeno-associated virus PTEN PPSG@anti-PD-1 cpg Immunogenic cell death Antitumor immune response Immune memory

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cpg和poly I:C增强口蹄疫病毒样颗粒疫苗免疫效果的研究

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中国兽医科学 2024年第7期 859-865页

作者：任丽华罗新董虎谭书桢郭慧琛孙世琪魏彦明滕志东甘肃农业大学动物医学院中国农业科学院兰州兽医研究所兰州大学动物医学与生物安全学院动物疫病防控全国重点实验室

本研究旨在评估cpg和poly I:C对口蹄疫（FMD）病毒样颗粒（VLPs）疫苗的免疫增强效果。以纯化的O型FMDVLPs抗原为基础，使用VLPs-cpg和VLPs-poly I:C刺激小鼠骨髓源性树突状细胞（BMDC），通过流式细胞术分析CD40和CD86在BMDC中的表达... 详细信息

本研究旨在评估cpg和poly I:C对口蹄疫（FMD）病毒样颗粒（VLPs）疫苗的免疫增强效果。以纯化的O型FMDVLPs抗原为基础，使用VLPs-cpg和VLPs-poly I:C刺激小鼠骨髓源性树突状细胞（BMDC），通过流式细胞术分析CD40和CD86在BMDC中的表达水平。进一步将VLPs、VLPs-cpg和VLPs-poly I:C分别与ISA206乳化制备疫苗，并免疫豚鼠，通过检测特异性抗体、中和抗体、脾淋巴细胞增殖以及攻毒试验评估cpg和poly I:C对VLPs疫苗免疫效果的影响。结果显示，VLPs-cpg组和VLPs-poly I:C组的CD86表达水平高于VLPs组，ISA206佐剂联合poly I:C、cpg均能提高攻毒保护率，而且ISA206联合cpg可以加速特异性抗体及中和抗体反应，提高脾淋巴细胞增殖水平。本研究结果表明，cpg和poly I:C均能增强FMDVLPs疫苗的免疫效果，具有潜在的开发应用价值。

关键词：口蹄疫病毒样颗粒 cpg poly I:C 免疫效果

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配子及早期胚胎发育过程中的DNA甲基化动态改变

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实用妇产科杂志 2024年第1期40卷 6-9页

作者：李明皓潘洁雪黄荷凤复旦大学附属妇产科医院生殖与发育研究院上海200001 中国医学科学院胚胎源性疾病创新单元上海200001 浙江大学附属妇产科医院教育部生殖遗传重点实验室浙江杭州310000

近年来,随着对染色质DNA、组蛋白、RNA化学修饰了解的深入,表观遗传学在胚胎发育、疾病发生发展中的生物学作用被逐步揭示。其中,DNA甲基化作为一种重要的表观遗传学修饰,在基因表达调控与染色质结构调节中具有重要作用。在哺乳动物细胞... 详细信息

近年来,随着对染色质DNA、组蛋白、RNA化学修饰了解的深入,表观遗传学在胚胎发育、疾病发生发展中的生物学作用被逐步揭示。其中,DNA甲基化作为一种重要的表观遗传学修饰,在基因表达调控与染色质结构调节中具有重要作用。在哺乳动物细胞中,胞嘧啶-鸟嘌呤二核苷酸(cpg)中胞嘧啶第5位碳原子甲基化(5mC)占99%,是最主要的甲基化类型。因此,本文关于配子和胚胎发育过程中的甲基化变化讨论也以5mC为主。

关键词： DNA甲基化表观遗传学早期胚胎发育染色质结构基因表达调控碳原子化学修饰 cpg

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尾鳍驱动仿生机器鱼的cpg控制

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机械设计与制造 2024年第1期395卷 231-235,241页

作者：王洋陈坤袁亮新疆大学机械工程学院新疆乌鲁木齐830047

随着人们对海洋资源关注度的增加,对仿生机器鱼的游动性能提出更高要求,为了使机器鱼游动更贴近真实鱼的游动效果,根据Light Hill的大摆幅细长体理论的鱼体波曲线对水下仿生机器鱼的游动模式进行了研究,并采用HOPF神经元振荡器模型建立... 详细信息

随着人们对海洋资源关注度的增加,对仿生机器鱼的游动性能提出更高要求,为了使机器鱼游动更贴近真实鱼的游动效果,根据Light Hill的大摆幅细长体理论的鱼体波曲线对水下仿生机器鱼的游动模式进行了研究,并采用HOPF神经元振荡器模型建立非线性振荡器模型,运用最近相邻耦合关系构建了cpg控制网络拓扑图,建立了cpg控制模型,通过调节cpg控制参数实现了机器鱼多运动模态的控制与切换。针对鲹科仿生机器鱼的游动方式进行SolidWorks三维建模,在ADAMS中进行运动仿真,并搭建实体样机。实验结果表明,采用基于HOPF的链式耦合中枢模式发生器对舵机的驱动进行控制,机器鱼尾鳍的摆动具有很好的运动柔顺性,易于实现运动模态平滑切换,游动更加灵活。这为机器鱼在海洋执行更复杂任务的研究打下了坚实基础。

关键词：多关节机器鱼 cpg HOPF振荡器游动方式多模态游动虚拟样机

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Methyl cpg binding domain protein 2(MBD2)in inflammation

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Chinese Medical Journal 2022年第23期135卷 2880-2882页

作者： Qian Lei Wei Zhang Department of Critical Care Medicine Affiliated Hospital of Zunyi Medical UniversityZunyiGuizhou 563000China Department of Critical Care Medicine Kweichou Moutai HospitalRenhuaiGuizhou 563000China

To the Editor:Methyl cpg binding domain protein 2(MBD2)belongs to the histone deacetylase family,which promotes multi-gene expression by inhibiting methylation and participates in the pathological process of various diseases.Apoptosis and inflammatory response are the main mechanisms leading to a variety of immune diseases.MBD2,as an important methylation protein reader,has in recent years been shown to be indispensable in the inflammatory response.This paper summarizes the current understanding of inflammatory MBD2 biology and provides additional direction for the study of inflammatory mechanisms by summarizing the current understanding of the regulatory mechanisms of MBD2 in inflammatory diseases and the inflammatory pathways that may regulate dysfunction.PubMed,Embase,and Wanfang Data were searched up to May 2022 with no language restriction for reports on MBD2 in inflammatory pathways,immune cell differentiation,and macrophage polarization,among others.

关键词： MBD2 inflammation cpg

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Crosstalk between cpg Methylation and Polymorphisms (cpg-SNPs) in the Promotor Region of DIO2 in Kashin-Beck Disease

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Chinese Medical Sciences Journal 2022年第1期37卷 52-59页

作者： Rongqiang Zhang Dandan Zhang Di Zhang Xiaoli Yang Qiang Li Chen Wang Xuena Yang Yongmin Xiong School of Public Health Shaanxi University of Chinese MedicineXianyangShaanxi712046China Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases National Health Commission of the People’s Republic of ChinaSchool of Public HealthXi′an Jiaotong University Health Science CenterXi′an 710061China

Objective This study was designed to determine the methylation profile of four cpgs and the genotypes of two cpg-SNPs located in promoter region of DIO2 in patients with Kashin-Beck disease(KBD).We also analyzed the interaction between the cpgs methylations and cpg-SNPs.Methods Whole blood specimens were collected from 16 KBD patients and 16 healthy subjects.Four cpgs and two cpg-SNPs in the promoter regions of DIO2 were detected using matrix-assisted laser desorption ionization time of flight mass spectrometry(MALDI-TOF-MS).The cpgs methylation levels were compared between samples from KBD patients and healthy subjects.The methylation levels were also analyzed in KBD patients with different cpg-SNP genotypes.Results The mRNA expression of DIO2 in whole blood of KBD patients was significnatly lower than in healthy controls(Pcpg_3 in KBD patients were significantly higher than those in healthy controls(Pcpgs were not significantly different between KBD patients and healthy controls.The methylation level of DIO2-1_cpg_3 in the promoter region of DIO2 in KBD patients with GA/AA genotype was significantly higher than that of KBD patients with GG genotype(Pcpg-SNPs DIO2 rs955849187.

关键词： Kashin-Beck disease DNA methylation cpg cpg-SNP

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Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy

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Asian Journal of Pharmaceutical Sciences 2022年第4期17卷 557-570页

作者： Shengmei Wang Xuanjun Liu Minghua Yang Linqi Ouyang Jinsong Ding Shengfeng Wang Wenhu Zhou Department of Pharmacy The Third Xiangya HospitalCentral South UniversityChangshaHunan410013China Xiangya School of Pharmaceutical Sciences Central South UniversityChangshaHunan410013China Postdoctoral Research Station of Clinical Medicine and Department of Pediatrics The Third Xiangya HospitalCentral South UniversityChangshaHunan410013China The First Hospital of Hunan University of Chinese Medicine ChangshaHunan410007China

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity,while they are programmed toM2 phenotype in established tumors and instead promote cancer development and metastasis.Here,we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities.The nanomedicine has a core-shell structure to co-load IPI549,a PI3Kγinhibitor,and cpg,a Toll-like receptor 9 agonist.Specifically,the hydrophobic IPI549 is self-assembled into a pure drug nano-core,while MOF shell layer is coated for cpg encapsulation,achieving extra-high total drugs loading of 44%.Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity,displaying excellent biocompatibility.After entering macrophages,the released IPI549 and cpg exert a synergistic effect to switch macrophages from M2 to M1 phenotype,which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines.Moreover,tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators,resulting in infiltration and activation of cytotoxic T lymphocytes.As a result,the nanosystem triggers a robust antitumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis.This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

关键词： Core-shell nanoparticles Metal-organic-framework cpg IPI549 Tumor immunotherapy

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cpg Control for Biped Hopping Robot in Unpredictable Environment

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Journal of Bionic Engineering 2012年第1期9卷 29-38页

作者： Tingting Wang Wei Guo Mantian Li Fusheng Zha Lining Sun State Key Laboratory of Robotics and System Harbin Institute of TechnologyHarbin 150080P.R.China

A cpg control mechanism is proposed for hopping motion control of biped robot in unpredictable environment. Based on analysis of robot motion and biological observation of animal＇s control mechanism, the motion control task is divided into two simple parts： motion sequence control and output force control. Inspired by a two-level cpg model, a two-level cpg control mechanism is constructed to coordinate the drivers of robot joint, while various feedback information are introduced into the control mechanism. Interneurons within the control mechanism are modeled to generate motion rhythm and pattern promptly for motion sequence control; motoneurons are modeled to control output forces of joint drivers in real time according to feedbacks. The control system can perceive changes caused by unknown perturbations and environment changes according to feedback information, and adapt to unpredictable environment by adjusting outputs of neurons. The control mechanism is applied to a biped hopping robot in unpredictable environment on simulation platform, and stable adaptive motions are obtained.

关键词： biped robot unpredictable environment hopping motion control bionic control cpg

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用于降低网格穿越误差的对流粒子高斯积分插值法

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Acta Mechanica Sinica 2023年第6期39卷 108-124页

作者：彭雪峰傅中志吉恩跃陈生水钟启明 Department of Geotechnical Engineering Nanjing Hydraulic Research InstituteNanjing 210024China Key Laboratory of Failure Mechanism and Safety Control Techniques of Earth-rock Dam of the Ministry of Water Resources Nanjing 210029China

对流粒子域插值法(CPDI)是物质点法(MPM)的一种改进算法,能够抑制粒子跨越网格引起的数值噪声.然而,在大变形情况下,CPDI仍无法保证预期的收敛率.因此,本文提出了一种新方法,称为对流粒子高斯积分插值法(cpgI).通过高斯积分极大地提高... 详细信息

对流粒子域插值法(CPDI)是物质点法(MPM)的一种改进算法,能够抑制粒子跨越网格引起的数值噪声.然而,在大变形情况下,CPDI仍无法保证预期的收敛率.因此,本文提出了一种新方法,称为对流粒子高斯积分插值法(cpgI).通过高斯积分极大地提高了计算精度,并为扩展到三维计算提供了便捷路径.cpgI将粒子域视为多个独立的角点组成,利用高斯积分推导出粒子到网格节点的插值方程.通过三个数值基准算例:轴向振动、广义涡流和三维碰撞,证明了cpgI算法在粒子穿越网格的过程中有效地减少了数值噪声.此外,通过比较不同初始构型和派生物质点法,对cpgI的综合运算能力进行了评估.从结果来看,本算法在精度方面具有明显的优势,并能有效地降低计算成本.

关键词：计算成本物质点法高斯积分网格节点 cpg 三维计算轴向振动收敛率

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CD205-TLR9-IL-12 axis contributes to cpg-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells

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Cellular & Molecular Immunology 2017年第8期14卷 675-684页

作者： Xin Hou Xiaolei Hao Meijuan Zheng Congfei Xu Jun Wang Rongbin Zhou Zhigang Tian Anhui Provincial Laboratory of Microbiology and Parasitology Department of Microbiology and ParasitologyAnhui Medical UniversityHefei 230032China Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease School of Life Sciences and Medical CenterUniversity of Science and Technology of ChinaHefei 230027China Department of Clinical Laboratory First Affiliated Hospital of Anhui Medical UniversityHefei 230022China Innovation Center for Cell Biology Hefei National Laboratory for Physical Sciences at MicroscaleHefei 230027China

Gut-derived bacterial products contribute to liver inflammation and injury during chronic hepatitis B virus infection;however,the underlying mechanisms remain obscure.In this study,hepatitis B surface antigen transgenic(HBs-Tg)mice and their wild-type(WT)control C57BL/6 mice were injected with cpg-oligodeoxynucleotides(ODNs)to mimic the translocation of gut microbial products into the systemic circulation.We found that,compared with the WT mice,the HBs-Tg mice were oversensitive to cpg-ODN-induced liver injury,which was dependent on natural killer T(NKT)cells.cpg-ODN injection enhanced the expression of Fas ligand(FasL)on NKT cells.In addition,hepatocytes from the HBs-Tg mice expressed higher levels of Fas than did those from the WT mice,which was further augmented by cpg-ODN.Interaction of Fas and FasL was involved in the cytotoxicity of NKT cells against hepatocytes in the HBs-Tg mice.Moreover,Kupffer cells in the HBs-Tg mice expressed higher levels of CD205 and produced greater amounts of interleukin(IL)-12 than did those in the WT mice.Finally,the depletion of Kupffer cells,neutralization of IL-12 or specific silencing of CD205 on Kupffer cells significantly inhibited cpg-ODN-induced liver injury and NKT activation in the HBs-Tg mice.Our data suggest that CD205-expressing Kupffer cells respond to cpg-ODNs and subsequently release IL-12 to promote NKT cell activation.Activated NKT cells induce liver damage through the Fas signaling pathway in HBs-Tg mice.

关键词： cpg hepatitis B virus Kupffer cell liver injury NKT cell

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