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Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model

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Science China Life Sciences 2024年

作者： Weiwei Zhang Linghuan Wang yujia Wang Yan Fang Ruihua Cao Zhiyi Fang Dong Han Xu Huang Zhenghui gu Yingjie Zhang Yan Zhu Yan Ma Feng Cao Department of Cardiology The Second Medical Centre Chinese PLA General Hospital National Clinical Research Center for Geriatric Diseases School of Medicine Nankai University Department of Cardiology Beijing Friendship Hospital Capital Medical University

Atherosclerosis is the pathological cause of atherosclerotic cardiovascular disease （ASCVD）, which rapidly progresses during the cellular senescence. Sodium-glucose cotransporter 2 inhibitors （SGLT2is） reduce major cardiovascular events in patients with ASCVD and have potential antisenescence effects. Here, we investigate the effects of the SGLT2 inhibitor dapagliflozin on cellular senescence in atherosclerotic mice. Compared with ApoE-/-control mice treated with normal saline, those in the ApoE-/-dapagliflozin group, receiving intragastric dapagliflozin （0.1 mg kg-1d-1） for 14 weeks, exhibited the reduction in the total aortic plaque area （48.8%±6.6%vs. 74.6%±8.0%,P<0.05）, the decrease in the lipid core area (（0.019±0.0037） mm2vs.（0.032±0.0062） mm2, P<0.05) and in the percentage of senescent cells within the plaques （16.4%±3.7%vs. 30.7%±2.0%, P<0.01）, while the increase in the thickness of the fibrous cap (（21.6±2.1）μm vs.（14.6±1.5）μm, P<0.01). Transcriptome sequencing of the aortic arch in the mice revealed the involvement of the PPARα and the fatty acid metabolic signaling pathways in dapagliflozin’s mechanism of ameliorating cellular aging and plaque progression. In vitro, dapagliflozin inhibited the expression of PPARα and its downstream signal FABP4, by which the accumulation of senescent cells in human aortic smooth muscle cells （HASMCs） was reduced under high-fat conditions. This effect was accompanied by a reduction in the intracellular lipid content and alleviation of oxidative stress. However, these beneficial effects of dapagliflozin could be reversed by the PPARα *** analysis and molecular docking simulations revealed that dapagliflozin might exert its effects by directly interacting with the RXRA protein, thereby influencing the expression of the PPARα signaling pathway. In conclusion, the cellular senescence of aortic smooth muscle cells is potentially altered by dapagliflozin through the suppression of the RXRA-PPARα-FABP4 s

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Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

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Cellular & Molecular Immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong Lamao Meichao gu Xuanxuan Jin Ying Liu Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao Thomas S.Fulford Adam P.Uldrich catherine C.L Wong Wensheng Wei Biomedical Pioneering Innovation Center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina Center for Precision Medicine Multi-Omics Research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity The University of MelbourneParkvilleVIC3010Australia Cancer Immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key Laboratory for Complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate *** our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer *** found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T *** coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX ***,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer *** our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T ***,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell Cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite Immunotherapy

Multi-omics joint analysis revealed the metabolic profile of retroperitoneal liposarcoma

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Frontiers of Medicine 2024年第2期18卷 375-393页

作者： Fu’an Xie yujia Niu Lanlan Lian Yue Wang Aobo Zhuang guangting Yan Yantao Ren Xiaobing Chen Mengmeng Xiao Xi Li Zhe Xi Gen Zhang Dongmei Qin Kunrong Yang Zhigang Zheng Quan Zhang Xiaogang Xia Peng Li Lingwei gu Ting Wu Chenghua Luo Shu-Hai Lin Wengang Li Cancer Research Center Xiang’an Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen361102China State Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life SciencesXiamen UniversityXiamen361102China Xiamen University Research Center of Retroperitoneal Tumor Committee of Oncology Society of Chinese Medical Association Xiamen UniversityXiamen361102China Department of Laboratory Medicine Xiang’an Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen361102China Department of Retroperitoneal Tumor Surgery Peking University International HospitalBeijing102206China School of Public Health Harvard UniversityBostonMA02115USA Laboratory of Biochemistry and Molecular Biology Research Department of Clinical LaboratoryFujian Medical University Cancer HospitalFuzhou350014China Surgery Department Affiliated Fuzhou First Hospital of Fujian Medical UniversityFuzhou350009China National Institute for Data Science in Health and Medicine Xiamen UniversityXiamen361102China Department of Hepatobiliary Surgery Xiang’an Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen361102China

Retroperitoneal liposarcoma(RLPS)is the main subtype of retroperitoneal soft sarcoma(RSTS)and has a poor prognosis and few treatment options,except for *** proteomic and metabolic profiles of RLPS have remained *** aim of our study was to reveal the metabolic profile of ***,we performed proteomic analysis(n=10),metabolomic analysis(n=51),and lipidomic analysis(n=50)of retroperitoneal dedifferentiated liposarcoma(RDDLPS)and retroperitoneal well-differentiated liposarcoma(RWDLPS)tissue and paired adjacent adipose tissue obtained during *** analysis mainly revealed that glycolysis,purine metabolism,pyrimidine metabolism and phospholipid formation were upregulated in both RDDLPS and RWDLPS tissue compared with the adjacent adipose tissue,whereas the tricarboxylic acid(TCA)cycle,lipid absorption and synthesis,fatty acid degradation and biosynthesis,as well as glycine,serine,and threonine metabolism were *** particular importance,the glycolytic inhibitor 2-deoxy-D-glucose and pentose phosphate pathway(PPP)inhibitor RRX-001 significantly promoted the antitumor effects of the MDM2 inhibitor RG7112 and CDK4 inhibitor *** study not only describes the metabolic profiles of RDDLPS and RWDLPS,but also offers potential therapeutic targets and strategies for RLPS.

关键词： RLPS proteomics metabolomics lipidomics metabolism

无压烧结工艺对浆料直写式定向多孔铜组织及致密度的影响

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材料导报 2024年第3期38卷 131-136页

作者：万胤辰王匀李瑞涛徐磊于超顾宇佳江苏大学机械工程学院江苏镇江212013

管式炉无压烧结工艺对浆料直写(Direct ink writing,DIW)式定向多孔铜的组织和致密性起决定性作用。本工作通过浆料直写和烧结制备定向多孔铜,通过X射线衍射仪(XRD)和扫描电子显微镜(SEM)对比高纯氩气和Ar-H_(2)混合气下烧结后的定向多... 详细信息

管式炉无压烧结工艺对浆料直写(Direct ink writing,DIW)式定向多孔铜的组织和致密性起决定性作用。本工作通过浆料直写和烧结制备定向多孔铜,通过X射线衍射仪(XRD)和扫描电子显微镜(SEM)对比高纯氩气和Ar-H_(2)混合气下烧结后的定向多孔铜的微观组织,分析烧结时定向多孔铜的氧化行为。在不同烧结参数下对定向多孔铜进行烧结处理,研究烧结温度以及保温时间对定向多孔铜致密度的影响规律。结果表明:在高纯氩气下烧结时,定向多孔铜发生严重氧化并生成Cu_(2)O,而Ar-H_(2)混合气通过还原作用有效避免定向多孔铜的氧化;烧结温度1100℃、保温时间6 h为最佳烧结工艺参数,在此条件下,定向多孔铜的致密度达到了87.2%,收缩率为33.3%。本研究可为管式炉无压烧结DIW打印多孔铜提供理论指导。

关键词：管式炉无压烧结浆料直写(DIW) 定向多孔铜烧结工艺

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公共图书馆场景营销实现路径研究

图书馆理论与实践 2024年第3期 35-42页

作者：王毅顾雨佳上海大学文化遗产与信息管理学院

场景营销是一种综合运用来自场景和用户的信息,以与用户之间建立深层次连接为核心目标的新营销理论,将其引入公共图书馆有利于提升图书馆文化服务水平,加强图书馆品牌建设发展。文章阐述了场景及场景营销的内涵意义,梳理当前图书馆场景... 详细信息

场景营销是一种综合运用来自场景和用户的信息,以与用户之间建立深层次连接为核心目标的新营销理论,将其引入公共图书馆有利于提升图书馆文化服务水平,加强图书馆品牌建设发展。文章阐述了场景及场景营销的内涵意义,梳理当前图书馆场景营销的研究现状,总结国内外公共文化机构场景营销的两类主体内容和三种模式,借鉴其经验并提出叙事型、体验型和共创型的公共图书馆场景营销实现路径。

关键词：公共图书馆场景营销文化数字化品牌建设图书馆营销

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冰片修饰的胡椒碱醇质体的制备、表征及透皮吸收研究

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中国医院药学杂志 2024年第6期44卷 663-670页

作者：霍雨佳谷娟呼胜楠陈栋黄河科技学院医学院河南郑州450005 河南大学药学院河南开封475001

目的:制备冰片修饰胡椒碱醇质体(borneol-modified piperine ethosomes,Bor-Pip-ES),并对其经皮渗透性能进行比较。方法:选择脂药比、磷脂与胆固醇用量比、乙醇体积分数和冰片占载体百分比为主要影响因素,Box-Behnken设计-效应面法优化B... 详细信息

目的:制备冰片修饰胡椒碱醇质体(borneol-modified piperine ethosomes,Bor-Pip-ES),并对其经皮渗透性能进行比较。方法:选择脂药比、磷脂与胆固醇用量比、乙醇体积分数和冰片占载体百分比为主要影响因素,Box-Behnken设计-效应面法优化Bor-Pip-ES处方工艺。制备成Bor-Pip-ES凝胶,并进行理化性质、流变学特性等研究。采用Franz扩散池法考察BorPip-ES凝胶体外透皮性能。结果:Bor-Pip-ES最佳处方为脂药比13.5:1,磷脂与胆固醇用量比14.4:1,乙醇体积分数12.7%,冰片占载体百分比1.9%。Bor-Pip-ES平均包封率为(81.52±1.36)%,载药量为(5.24±0.15)%,粒径为(170.98±9.18)nm,Zeta电位为–(8.16±0.73)mV。Bor-Pip-ES形态为球形或椭圆形。流变学显示Bor-Pip-ES凝胶具有固体弹性性质。透皮试验结果表明,Bor-Pip-ES凝胶显著提高了胡椒碱的透皮速率、累积渗透量和皮肤滞留量。结论:Bor-Pip-ES凝胶黏度适宜,易于涂展,为后续研究奠定实验基础。

关键词：胡椒碱醇质体经皮渗透

Power System Flow Adjustment and Sample Generation Based on Deep Reinforcement Learning

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Journal of Modern Power Systems and Clean Energy 2020年第6期8卷 1115-1127页

作者： Shuang Wu Wei Hu Zongxiang Lu yujia gu Bei Tian Hongqiang Li the Department of Electrical Engineering Tsinghua UniversityBeijingChina State Grid Ningxia Electric Power Co.Ltd. YinchuanChina

With the increasing complexity of power system structures and the increasing penetration of renewable energy,the number of possible power system operation modes increases *** is difficult to make manual power flow adjustments to establish an initial convergent power flow that is suitable for operation mode *** present,problems of low efficiency and long time consumption are encountered in the formulation of operation modes,resulting in a very limited number of generated operation *** this paper,we propose an intelligent power flow adjustment and generation model based on a deep network and reinforcement ***,a discriminator is trained to judge the power flow convergence,and the output of this discriminator is used to construct a value ***,the reinforcement learning method is adopted to learn a strategy for power flow convergence ***,a large number of convergent power flow samples are generated using the learned adjustment *** with the traditional flow adjustment method,the proposed method has significant advantages that the learning of the power flow adjustment strategy does not depend on the parameters of the power system ***,this strategy can be automatically learned without manual intervention,which allows a large number of different operation modes to be efficiently *** verification results of a case study show that the proposed method can independently learn a power flow adjustment strategy and generate various convergent power flows.

关键词： Deep reinforcement learning power flow adjustment system operation mode sample generation

乌梁素海鱼类群落结构特征及其与环境因子的关系

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湖泊科学 2024年第5期36卷 1459-1469,I0014页

作者：姚禹佳毛志刚谷孝鸿王奕杨曾庆飞陈辉辉兰海今中国科学院南京地理与湖泊研究所湖泊与环境国家重点实验室南京210008 中国科学院南京地理与湖泊研究所湖泊与流域水安全重点实验室南京210008 中国科学院大学北京100049 内蒙古自治区乌梁素海生态保护中心巴彦淖尔051500

根据2021年周年野外调查数据与渔业捕捞历史资料,本文分析了乌梁素海湖区的鱼类群落结构变化特征及其与主要环境因子的关系。与历史资料相比,乌梁素海鱼类群落结构已经发生较大变化,表现为土著鱼类减少,优势种组成改变,鱼类群落结构呈... 详细信息

根据2021年周年野外调查数据与渔业捕捞历史资料,本文分析了乌梁素海湖区的鱼类群落结构变化特征及其与主要环境因子的关系。与历史资料相比,乌梁素海鱼类群落结构已经发生较大变化,表现为土著鱼类减少,优势种组成改变,鱼类群落结构呈现小型化。根据鱼类群落在湖中的分布特征,本研究将乌梁素海分为西部、东部和南部3个湖区。单因子相似性分析和相似性百分比分析结果显示,不同湖区间鱼类群落组成存在显著差异,两两湖区之间的平均差异性均在70%以上,且这种差异性主要由鲫、麦穗鱼和鲤造成。多样性的分析结果表明,全湖及各湖区鱼类群落的多样性指数较低(H′东部湖区>南部湖区。此外,Mantel test分析和典型相关分析表明,浊度和叶绿素a是目前影响乌梁素海鱼类群落结构的主要环境因子。各湖区间鱼类种群和多样性的差别在一定程度上反映出鱼类群落结构与湖泊环境特征相适应的特点。通过讨论鱼类群落结构变化及其空间分布特征,本文从不同角度对乌梁素海未来渔业管理规划提出可参考方向:1)重视禁渔休渔政策和人工增殖放流在乌梁素海的重要意义;2)充分利用鱼类群落与环境特征间的关系,尽可能通过改善鱼类群落结构促进水体营养物质循环。

关键词：渔业资源小型化优势种生物多样性环境因子多元统计分析乌梁素海

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安宁疗护中的镇痛管理

中华老年医学杂志 2024年第7期43卷 797-801页

作者：冯通慧陈新宇顾梦婷项巧珍李雨珈夏燕飞浙江医院麻醉手术部杭州310012 浙江医院消化科杭州310012 浙江医院医疗照护病房杭州310012

疼痛是恶性肿瘤和非恶性肿瘤疾病终末期最常见的症状之一,也是患者最恐惧的症状,严重影响生命末期的生存质量。安宁疗护为疾病终末期的患者及家属提供身体、心理、精神等方面的照护,减轻患者的痛苦和不适症状,疼痛管理作为重要的症状管... 详细信息

疼痛是恶性肿瘤和非恶性肿瘤疾病终末期最常见的症状之一,也是患者最恐惧的症状,严重影响生命末期的生存质量。安宁疗护为疾病终末期的患者及家属提供身体、心理、精神等方面的照护,减轻患者的痛苦和不适症状,疼痛管理作为重要的症状管理内容之一,是安宁疗护的基石。随着我国肿瘤和慢性疾病发病率的升高以及人口老龄化的加速,患严重疾病的老年人数量快速增加,疼痛控制需求迅速增长。对安宁疗护患者开展镇痛管理,需要对疼痛进行全面的评估以明确其类型及特点,运用病因治疗、药物治疗、介入治疗、物理治疗、心理治疗及舒适照护等方法开展多模式管理,科学使用阿片类药物,减少药物不良反应,达到最佳的疼痛控制,提高患者生命末期的生活质量。

关键词：临终医护疼痛镇痛药,阿片类安宁疗护