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新型降脂药物的研究进展

中国循证心血管医学杂志 2022年第9期14卷 1148-1150页

作者：王昱渊黎子微崔鹏辉武军铎吉林大学第二医院心血管内科长春130041

冠状动脉疾病(CAD)是目前世界第三大死亡原因,每年与1780万人的死亡有关,给全球带来了巨大的经济负担。据估计,美国仅用于治疗CAD的总费用每年就高达2000亿美元[1]。而血脂异常尤其是低密度脂蛋白胆固醇(LDL-C)和甘油三酯(TG)升高被认... 详细信息

冠状动脉疾病(CAD)是目前世界第三大死亡原因,每年与1780万人的死亡有关,给全球带来了巨大的经济负担。据估计,美国仅用于治疗CAD的总费用每年就高达2000亿美元[1]。而血脂异常尤其是低密度脂蛋白胆固醇(LDL-C)和甘油三酯(TG)升高被认为是冠状动脉(冠脉)疾病发病率增加的主要危险因素。

关键词：冠状动脉疾病降脂药物低密度脂蛋白胆固醇人的死亡死亡原因血脂异常主要危险因素疾病发病率

TyG指数与胰岛素抵抗、糖尿病肾脏病研究进展

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齐齐哈尔医学院学报 2024年第19期45卷 1877-1881页

作者：王淑婷马晓丹崔鹏辉赵文化长治医学院山西长治046000 长治医学院附属长治市人民医院内分泌科山西长治046000 长治医学院附属长治市人民医院心血管内科山西长治046000

糖尿病肾脏病(Diabetic kidney disease,DKD)作为糖尿病最严重的并发症之一,其发病率逐年升高,严重威胁着糖尿病患者的预后和生存质量。早期诊断DKD并进行有效干预对于改善患者预后及生活质量具有重要意义。DKD发病机制十分复杂,很多学... 详细信息

糖尿病肾脏病(Diabetic kidney disease,DKD)作为糖尿病最严重的并发症之一,其发病率逐年升高,严重威胁着糖尿病患者的预后和生存质量。早期诊断DKD并进行有效干预对于改善患者预后及生活质量具有重要意义。DKD发病机制十分复杂,很多学者认为胰岛素抵抗(Insulin resistance,IR)参与多种途径诱导DKD发生,而国内外研究结果都表明,甘油三酯-葡萄糖指数(Triglyceride Gucose index,TyG指数)是评估IR较为理想、简便的有效工具。故本文将对TyG指数、IR、DKD进行阐述,旨在为建立DKD预测模型以及药物治疗新靶点提供理论依据。

关键词：甘油三酯-葡萄糖指数糖尿病肾脏病胰岛素抵抗

新型降糖药在糖尿病合并心力衰竭患者中的应用现状及进展

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中国循证心血管医学杂志 2021年第2期13卷 250-251,256页

作者：崔鹏辉王宙曲云鹏芦中林武雪冰张静吉林大学第二医院心血管内科长春130041

我国糖尿病(DM)与充血性心力衰竭(CHF)的发病率居高不下。DM和心力衰竭(HF)之间关系密切,互为因果,DM患者罹患HF的风险显著高于非DM患者,而HF合并DM患者也大多存在胰岛β细胞生理功能缺陷、胰岛素抵抗等问题。因此,HF是DM患者所不能忽... 详细信息

我国糖尿病(DM)与充血性心力衰竭(CHF)的发病率居高不下。DM和心力衰竭(HF)之间关系密切,互为因果,DM患者罹患HF的风险显著高于非DM患者,而HF合并DM患者也大多存在胰岛β细胞生理功能缺陷、胰岛素抵抗等问题。因此,HF是DM患者所不能忽视的一项重大问题。近年来,降糖药物的心血管获益性及风险性备受各学界关注。目前,传统降糖药物二甲双胍已被证实具有抗动脉粥样硬化以及减少HF发作风险的心血管益处。与此同时,新近涌现的一些新型降糖药物,钠-葡萄糖协同转运蛋白-2抑制剂(SGLT-2i)、胰高血糖素样肽-1受体激动剂(GLP-1 RAs)以及二肽基肽酶-4抑制剂(DPP-4i)也先后被多项临床研究证实同样兼具一定的心血管益处。本文现就SGLT-2i、GLP-1 RAs以及DPP-4i在DM合并HF患者中的研究现状与进展作一综述。

关键词：降糖药物新型降糖药二肽基肽酶胰岛素抵抗糖尿病合并心力衰竭胰岛β细胞抗动脉粥样硬化二甲双胍

Whole‑genome transcriptome and DNA methylation dynamics of pre‑implantation embryos reveal progression of embryonic genome activation in buffaloes

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Journal of Animal Science and Biotechnology 2023年第6期14卷 2411-2427页

作者： penghui Fu Du Zhang Chunyan Yang Xiang Yuan Xier Luo Haiying Zheng Yanfei Deng Qingyou Liu Kuiqing cui Fei Gao Deshun Shi State Key Laboratory for Conservation and Utilization of Subtropical Agro‑Bioresources&Guangxi Key Laboratory of Animal Breeding and Disease Control Guangxi UniversityNanning 530004China. College of Animal Science and Technology Southwest UniversityChongqing 402460China. Genome Analysis Laboratory of the Ministry of Agriculture Agricultural Genomics Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhen 518120China. Guangxi Key Laboratory of Buffalo Genetics Reproduction and BreedingGuangxi Buffalo Research InstituteChinese Academy of Agricultural ScienceNanning 530001China Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region Nanning 530016China. Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding School of Life Science and Engineering Foshan UniversityFoshan 528225China. Comparative Pediatrics and Nutrition Department of Veterinary and Animal SciencesFaculty of Health and Medical SciencesUniversity of CopenhagenDK 1870 C FrederiksbergDenmark.

Background During mammalian pre-implantation embryonic development(PED),the process of maternal-to-zygote transition(MZT)is well orchestrated by epigenetic modification and gene sequential expression,and it is related to the embryonic genome activation(EGA).During MZT,the embryos are sensitive to the environment and easy to arrest at this stage in ***,the timing and regulation mechanism of EGA in buffaloes remain *** Buffalo pre-implantation embryos were subjected to trace cell based RNA-seq and whole-genome bisulfite sequencing(WGBS)to draw landscapes of transcription and *** typical developmental steps were classified during buffalo *** major EGA was identified at the 16-cell stage by the comprehensive analy-sis of gene expression and DNA methylation *** weighted gene co-expression network analysis,stage-spe-cific modules were identified during buffalo maternal-to-zygotic transition,and key signaling pathways and biological process events were further *** and continuous activation of these pathways was necessary for success of buffalo *** addition,the hub gene,CDK1,was identified to play a critical role in buffalo *** Our study provides a landscape of transcription and DNA methylation in buffalo PED and reveals deeply the molecular mechanism of the buffalo EGA and genetic programming during buffalo *** will lay a foundation for improving the in vitro development of buffalo embryos.

关键词： Buffalo DNA methylome Embryonic genome activation Maternal-to-zygote transition Transcriptome

Highly ordered crystallization of α-FAPbl_(3) films via homogeneous seeds for efficient perovskite solar cells

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Journal of Energy Chemistry 2024年第7期94卷 625-634页

作者： Guohui Luo Linfeng Zhang Liyun Guo Xiuhong Geng penghui Ren Yi Zhang Haihua Hu Xiaoping Wu Lingbo Xu Ping Lin Haiyan He Xuegong Yu Peng Wang Can cui Key Laboratory of Optical Field Manipulation of Zhejiang Province Department of PhysicsZhejiang Sci-Tech UniversityHangzhou 310018ZhejiangChina Zhejiang Provincial Key Laboratory of Fiber Materials and Manufacturing Technology Zhejiang Sci-Tech UniversityHangzhou 310018ZhejiangChina Hangzhou City University Hangzhou 310015ZhejiangChina Key Laboratory of Solar Energy Utilization and Energy Saving Technology of Zhejiang Province Zhejiang Baima Lake Laboratory Co.Ltd.Hangzhou 310012ZhejiangChina State Key Laboratory of Silicon Materials and School of Materials Science and Engineering Zhejiang UniversityHangzhou 310027ZhejiangChina

Formamidine lead triiodide(FAPbI_(3))perovskites have become the most promising photovoltaic materials for perovskite solar cells with record power conversion efficiency(PCE).However,random nucleation,phase transition,and lattice defects are still the key challenges limiting the quality of FAPbI_(3) *** studies show that the introduction or adding of seeds in the precursor is effective to promote the nucleation and crystallization of perovskite ***,the seed-assisted approach focuses on heterogeneous seeds or hetero-composites,which inevitably induce a lattice-mismatch,the genera-tion of strain or defects,and the phase segregation in the perovskite ***,we first demonstrate that high-quality perovskite films are controllably prepared using α-and δ-phases mixed FAPbI_(3) micro-crystal as the homogeneous seeds with the one-step antisolvent *** partially dissolved seeds with suitable sizes improve the crystallinity of the perovskite flm with preferable orientation,improved carrier lifetime,and increased carrier *** importantly,the α-phase-containing seeds promote the formation of α-phase FAPbI_(3) films,leading to the reduction of residual lattice strain and the suppres-sion of I-ion ***,the adding of dimethyl 2,6-pyridine dicarboxylate(DPD)into the pre-cursor further suppresses the generation of defects,contributing to the PCE of devices prepared in air ambient being significantly improved to 23.75%,among the highest PCEs for fully air-processed FAPbI_(3) solar *** unpackaged target devices possess a high stability,maintaining 80%of the initial PCE under simulated solar illumination exceeding 800 h.

关键词： Perovskite solar cells FAPbI_(3) Homogeneous seeds Strain Phase stability

Serine metabolism orchestrates macrophage polarization by regulating the IGF1–p38 axis

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Cellular & Molecular Immunology 2022年第11期19卷 1263-1278页

作者： Xiao Shan penghui Hu Lina Ni Long Shen Yanan Zhang Zemin Ji Yan cui Meihua Guo Haoan Wang Liyuan Ran Kun Yang Ting Wang Lei Wang Bin Chen Zhi Yao Vingjie Wu Qiujing Yu Tianjin Institute of Immunology Key Laboratory of Immune Microenvironment and Disease of the Ministry of EducationThe Province and Ministry Co-sponsored Collaborative Innovation Center for Medical EpigeneticsTianjin Key Laboratory of Inflammation BiologyDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical University Division of Infectious Disease Second Hospital of Tianjin Medical UniversityTianjin300070China Institute for Genome Engineered Animal Models of Human Diseases National Center of Genetically Engineered Animal Models for International ResearchDalian Medical UniversityDalian116044LiaoningChina Shandong Provincial Hospital School of Laboratory Animal and Shandong Laboratory Animal CenterScience and Technology Innovation CenterShandong First Medical University and Shandong Academy of Medical SciencesJinan250021ShandongChina The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Department of Pharmacology and Tianjin Key Laboratory of Inflammation BiologySchool of Basic Medical SciencesTianjin Medical UniversityTianjin300070China Tianjin Institute of Immunology Key Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina Department of Molecular Pathobiology New York University College of DentistryNew YorkNY10010USA

Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.

关键词： Serine metabolism PHGDH Macrophage polarization SAM IGF1 p38

受损神经来源的mtDNA通过GRP75增加线粒体内Ca2+水平诱导U87细胞凋亡和小鼠痛觉敏化

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陆军军医大学学报 2024年第18期46卷 2081-2091页

作者：黄鹏辉李丽崔剑陆军军医大学(第三军医大学)第一附属医院疼痛科重庆400038

目的探讨受损神经来源的线粒体DNA(mitochondrial DNA,mtDNA)对人脑星形胶质母细胞瘤细胞(human glioblastoma cell line U-87MG,U87)内GRP75蛋白表达、线粒体Ca^(2+)水平、细胞凋亡的影响,及其诱导小鼠痛觉敏化的机制。方法采用坐骨神... 详细信息

目的探讨受损神经来源的线粒体DNA(mitochondrial DNA,mtDNA)对人脑星形胶质母细胞瘤细胞(human glioblastoma cell line U-87MG,U87)内GRP75蛋白表达、线粒体Ca^(2+)水平、细胞凋亡的影响,及其诱导小鼠痛觉敏化的机制。方法采用坐骨神经慢性缩窄(chronic constriction injury,CCI)建立小鼠神经病理性疼痛(neuropathic pain,NeP)模型,采用随机数字表法将20只C57BL/6雄性小鼠(6~8周龄,体质量20~30 g)分为4组:假手术组、CCI-7天组、CCI-14天组、CCI-21天组,行为学检测痛觉敏化情况,实时荧光定量PCR法(quantitative Real-time PCR,qPCR)检测小鼠脊髓中mtDNA含量变化。从H_(2)O_(2)处理的人神经母细胞瘤细胞(human neuroblastoma cell line SH-SY5Y,SH-SY5Y)提取mtDNA。采用浓度为0~1 ng/μL的mtDNA处理U87细胞。CCK-8检测细胞活力变化,根据结果选择适宜的实验浓度。将U87细胞分为5组:对照组、mtDNA组、mtDNA+GRP75抑制剂(MKT-0771μg/mL)组、mtDNA+钙螯合剂(BAPTA-AM 10μmol/L)组和mtDNA+MKT-077+BAPTA-AM组,mtDNA处理前2 h分别予以MKT-077、BAPTA-AM预处理。Western blot检测GRP75蛋白(glucose-regulated protein 75,GRP75)的表达,内质网-线粒体共定位染色观察内质网-线粒体连接;钙离子荧光探针检测线粒体Ca^(2+)水平;活性氧(reactive oxygen species,ROS)及线粒体膜电位检测评估线粒体氧化应激功能;PI荧光标记检测U87细胞凋亡率。结果与假手术组相比,CCI-21天组小鼠脊髓中用于检测mtDNA含量的细胞色素c氧化酶I(cytochrome c oxidase I,CO1)和NADH脱氢酶亚基1(nicotinamide adenine dinucleotide dehydrogenase 1,ND1)均升高,CO1:1.01±0.20 vs 2.22±0.26(P<0.05),ND1:1.00±0.12 vs 1.79±0.07(P<0.05)。CCK-8结果显示:mtDNA(1 ng/μL)可抑制U87细胞活力(P<0.01);0.2 ng/μL mtDNA可上调GRP75蛋白的表达(P<0.05),促进内质网-线粒体偶联,增加线粒体Ca^(2+)水平(109.4±62.6 vs 540.3±150.3,P<0.05),并诱使线粒体释放ROS增多(P<0.05)。MKT-077或/和BAPTA-AM处理后,线粒体Ca^(2+)量减少,线粒体膜电位改善,PI检测显示U87细胞凋亡率降低[mtDNA组vs mtDNA+MKT-077组:(18.39±2.09)vs(13.22±1.42),P<0.05;mtDNA组vs mtDNA+BAPTA-AM组:(18.39±2.09)vs(12.09±1.53),P<0.05;mtDNA组vs mtDNA+MKT-077+BAPTA-AM组:(18.39±2.09)vs(11.65±2.09),P<0.05]。结论受损神经来源的mtDNA可上调GRP75蛋白的表达、干扰线粒体Ca^(2+)水平、加剧线粒体氧化应激,以诱导U87细胞凋亡,这可能是一种参与NeP形成的新机制。

关键词：神经病理性疼痛 mtDNA GRP75 钙凋亡

氧化应激通过TDP-43激活mtDNA-cGAS/STING通路诱发神经元损伤和小鼠痛觉敏化

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陆军军医大学学报 2024年第18期46卷 2036-2045页

作者：李丽黄鹏辉崔剑陆军军医大学(第三军医大学)第一附属医院疼痛科重庆400038

目的探索TAR DNA结合蛋白43(transactive response DNA binding protein 43,TDP-43)在氧化应激诱导的小鼠神经元(neuro-2a,N2a)细胞损伤及小鼠痛觉敏化中的作用及机制。方法①为评估最佳诱导浓度,不同浓度的H_(2)O_(2)处理N2a细胞分为4... 详细信息

目的探索TAR DNA结合蛋白43(transactive response DNA binding protein 43,TDP-43)在氧化应激诱导的小鼠神经元(neuro-2a,N2a)细胞损伤及小鼠痛觉敏化中的作用及机制。方法①为评估最佳诱导浓度,不同浓度的H_(2)O_(2)处理N2a细胞分为4组:对照组、200μmol/L H_(2)O_(2)组、400μmol/L H_(2)O_(2)组和800μmol/L H_(2)O_(2)组。②为评估最佳诱导时间,400μmol/L H_(2)O_(2)处理N2a细胞分为4组:对照组、6 h H_(2)O_(2)组、12 h H_(2)O_(2)组和24 h H_(2)O_(2)组。③为验证线粒体DNA(mitochondria DNA,mtDNA)释放途径,使用环孢素(cyclosporin,CsA)抑制线粒体通透性转换孔(mitochondrial permeability transition pore,mPTP)分为3组:对照组、24 h H_(2)O_(2)组和24 h H_(2)O_(2)+CsA组。④为验证TDP-43介导的细胞损伤机制,siRNA抑制TDP-43后分为3组:对照组、24 h H_(2)O_(2)组、24 h H_(2)O_(2)+siTDP-43组。⑤采用CCK-8检测细胞活性,EdU检测细胞增殖,Western blot检测TDP-43、神经元标志物(neuronal nuclei,NeuN)、环状GMP-AMP合酶(cylic GMP-AMP synthase,cGAS)和干扰素基因刺激因子(stimulator of interferon,STING)表达,qPCR检测mtDNA,免疫染色观察细胞内TDP-43表达变化,Calcein AM染色评估mPTP开放。⑥为验证TDP-43在神经病理性疼痛(neuropathic pain,NP)中的作用,将24只6~8周健康SPF级雄性C57BL/6J小鼠(体质量25~30 g)使用随机数字表法分为3组:对照组、慢性压迫性损伤(chronic constriction injury,CCI)组、CCI+siTDP-43组,术前1 d和术后7、14、21 d进行鞘内注射siTDP-43;术前1 d和术后1、3、5、7、14、21 d通过von Frey纤维丝和热辐射法测定小鼠机械痛阈值和热痛阈值,免疫荧光检测术后21 d腰段(L5-L6)脊髓背角中TDP-43与NeuN的变化。结果氧化应激刺激诱导N2a中TDP-43蛋白表达增加,刺激mtDNA通过mPTP释放,上调cGAS、STING的表达,影响N2a的细胞活性(P<0.05);CsA抑制mPTP通道的开放并减少mtDNA释放(P<0.05);下调TDP-43的表达后可显著降低mtDNA的释放,抑制cGAS和STING的表达,并恢复N2a细胞的增殖能力(P<0.05)。CCI术后5 d,小鼠机械痛阈值和热痛阈值出现明显下降并持续至21 d(P<0.05);CCI小鼠术后21 d脊髓背角神经元中TDP-43表达增加(P<0.05);鞘内注射siRNA抑制TDP-43后,可提高CCI小鼠的机械痛阈值和热痛阈值(P<0.05)。结论氧化应激诱导神经元细胞TDP-43蛋白增加,刺激mtDNA通过mPTP释放到细胞质,激活cGAS/STING通路,导致神经元损伤并加重CCI小鼠痛觉敏化。

关键词：神经病理性疼痛 TDP-43 cGAS/STING通路 mtDNA 氧化应激

Accumulation of mtDNA activates microglia via cGAS/STING in vitro and spinal dorsal cord of neuropathic pain mice

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Accumulation of mtDNA activates microglia via cGAS/STING in ...