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GTF2H4 regulates partial EndMT via NF-κB activation through NCOA3 phosphorylation in ischemic diseases

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The Innovation 2024年第2期5卷 27-41页

作者： Zheyan Fang Gang Zhao Shuang Zhao Xueting Yu Runyang Feng You-en Zhang Haomin Li Lei Huang Zhenyang Guo Zhentao Zhang Mukaddas Abdurahman Hangnan Hong Peng Li Bing Wu jinhang Zhu Xin Zhong Dong Huang Hao Lu Xin Zhao Zhaoyang chen Wenbin Zhang Junjie Guo Hongchao Zheng Yue He Shengying Qin Haojie Lu Yun Zhao Xiangdong Wang Junbo Ge Hua Li Department of Cardiology Zhongshan HospitalFudan UniversityShanghai Institute of Cardiovascular DiseasesShanghai 200032China Department of Cardiology Zhongshan HospitalFudan UniversityShanghai 200032China Department of Medical Examination Shanghai Xuhui District Central HospitalShanghai 200031China Department of Cardiology and Institute of Clinical Medicine Renmin HospitalHubei University of MedicineShiyan 442000China Clinical Data Center Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Molecular Celland Cancer BiologyUniversity of Massachusetts Chan Medical SchoolWorcesterMA 01605USA Bio-X Institute Key Laboratory for The Genetics of Developmental and Neuropsychiatric DisordersShanghai Jiao Tong UniversityShanghai 200030China Department of Cardiology Heart Center of Fujian ProvinceFujian Medical University Union HospitalFuzhou 350001China Department of Cardiology Sir Run Run Shaw Hospitalaffiliated with Zhejiang University School of MedicineHangzhou 310020China Department of Cardiology The Affiliated Hospital of Qingdao UniversityQingdao 266003China Department of Cardiology Shanghai Xuhui District Central HospitalShanghai 200031China Department of Cardiology Shanghai Eighth People’s HospitalShanghai 200235China Department of Chemistry and Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China State Key Laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China School of Life Science and Technology Shanghai Tech University100 Haike RoadShanghai 201210China Key Laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Department of Pulmonary and Critical Care Medicine Zhongshan Hospital

Partial endothelial-to-mesenchymal transition(EndMT)is an intermediate phenotype observed in endothelial cells(ECs)undergoing a transition toward a mesenchymal state to support neovascularization during(patho)physiological angiogenesis.Here,we investigated the occurrence of partial EndMT in ECs under hypoxic/ischemic conditions and identified general transcription factor IIH subunit 4(GTF2H4)as a positive regulator of this process.In addition,we discovered that GTF2H4 collaborates with its target protein excision repair cross-complementation group 3(ERCC3)to co-regulate partial EndMT.Furthermore,by using phosphorylation proteomics and site-directed mutagenesis,we demonstrated that GTF2H4 was involved in the phosphorylation of receptor coactivator 3(NCOA3)at serine 1330,which promoted the interaction between NCOA3 and p65,resulting in the transcriptional activation of NF-κB and the NF-kB/Snail signaling axis during partial EndMT.In vivo experiments confirmed that GTF2H4 significantly promoted partial EndMT and angiogenesis after ischemic injury.Collectively,our findings reveal that targeting GTF2H4 is promising for tissue repair and offers potential opportunities for treating hypoxic/ischemic diseases.

关键词： ischemic activation GTF

含多类型储能的综合能源系统低碳经济运行双层优化方法研究

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动力工程学报 2024年第3期44卷 498-508页

作者：李金航佟曦陈衡潘佩媛徐钢刘文毅华北电力大学能源动力与机械工程学院北京102206

针对含多类型储能的综合能源系统(IES)协同低碳优化调度问题,提出构建一种多类型储能-综合能源系统(MTES-IES)低碳经济的双层模型,并通过构建氢能枢纽,充分利用氢气转化过程中损失的热能,实现能源梯级利用,提高了整个系统的能源利用。... 详细信息

针对含多类型储能的综合能源系统(IES)协同低碳优化调度问题,提出构建一种多类型储能-综合能源系统(MTES-IES)低碳经济的双层模型,并通过构建氢能枢纽,充分利用氢气转化过程中损失的热能,实现能源梯级利用,提高了整个系统的能源利用。在双层优化模型中,上层以MTES经济性最优化为目标,下层实现IES的最优低碳经济运行,采用Karush-Kuhn-Tucher(KKT)条件将下层模型转化为上层模型的约束条件,采用大M法将问题进行线性化处理。通过3个不同场景仿真结果分析表明,提出的MTES-IES双层模型,通过协调优化不同子系统的运行调度策略,能够降低系统运行成本并实现系统整体低碳运行。

关键词：多类型储能综合能源系统低碳运行双层优化 KKT条件

基于NF-κB/NLRP3通路和代谢组学的复方枳葛饮对慢性酒精性肝损伤的保护作用及机制研究

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中华中医药杂志 2024年第5期39卷 2297-2307页

作者：王浩史雯馨邵仕娟周锦航陈运中湖北中医药大学药学院武汉430065 湖北省中药保健食品工程技术研究中心武汉430065 湖北时珍实验室武汉430065

目的:探讨复方枳葛饮对慢性酒精性肝损伤的治疗作用,并通过核因子κB(NF-κB)/NOD样受体热蛋白结构域相关蛋白3(NLRP3)通路和代谢组学的方法探究其发挥作用的机制。方法:将小鼠分为空白组,模型组,联苯双酯组,复方枳葛饮水提物高、低剂量... 详细信息

目的:探讨复方枳葛饮对慢性酒精性肝损伤的治疗作用,并通过核因子κB(NF-κB)/NOD样受体热蛋白结构域相关蛋白3(NLRP3)通路和代谢组学的方法探究其发挥作用的机制。方法:将小鼠分为空白组,模型组,联苯双酯组,复方枳葛饮水提物高、低剂量组,醇提物高、低剂量组。除空白组外,其余各组予以酒精灌胃制备慢性酒精性肝损伤模型,并同时给予相应的药物治疗,8周后,检测小鼠肝脏谷草转氨酶(AST)、谷丙转氨酶(ALT)、超氧化物歧化酶(SOD)、丙二醛(MDA)、甘油三酯(TG)、总胆固醇(TC)指标,HE染色来观察小鼠肝脏病理改变,ELISA法检测小鼠血清炎症因子白介素-18(IL-18)、肿瘤坏死因子α(TNF-α)、白介素-1β(IL-1β)水平,qRT-PCR检测小鼠肝脏TNF-α、IL-6、IL-1β mRNA表达,Western Blot检测肝脏NF-κB和NLRP3蛋白表达,采用液相色谱-质谱联用仪(LC-MS)非靶向代谢组学技术分析血清及肝脏内源性代谢产物变化及复方枳葛饮的作用途径。结果:与模型组比较,复方枳葛饮水提物和醇提物均能显著降低小鼠肝脏ALT、AST、TC、TG,血清TNF-α水平、肝脏炎症基因IL-1β mRNA水平表达、肝脏NF-κB蛋白及NLRP3蛋白的表达(P<0.05,P<0.01);水提物还能显著升高小鼠SOD活力,显著降低小鼠肝脏MDA、TNF-α mRNA表达(P<0.05,P<0.01);醇提物还能显著降低血清IL-18水平(P<0.05);血清代谢组学筛选出10种与醇提物治疗酒精性肝损伤相关的血清代谢物,其中可上调6个、下调4个,12种与水提物治疗酒精性肝损伤相关的血清代谢物,其中可上调6个、下调6个;肝脏代谢组学筛选出21种与水提物治疗酒精性肝损伤相关的肝脏代谢物,其中可上调13个、下调8个,涉及的代谢途径主要为抗坏血酸和醛酸代谢、嘌呤代谢、精氨酸生物合成等途径;筛选出21种与醇提物治疗酒精性肝损伤相关的肝脏代谢物,其中可上调2个、下调19个,涉及的代谢通路主要为淀粉和蔗糖代谢、牛磺酸和低牛磺酸代谢、抗坏血酸盐和醛酸盐代谢等途径,水提物和醇提物均可调节的肝脏代谢物有8个;水提物和醇提物均可作用的代谢途径有抗坏血酸和醛酸代谢、鞘脂代谢、淀粉和蔗糖代谢。结论:复方枳葛饮水提物及醇提物均具有治疗酒精性肝损伤的作用,其作用机制可能通过调节NF-κB/NLRP3信号通路减轻炎症因子水平,以及调节血清及肝脏代谢紊乱发挥作用。

关键词：复方枳葛饮酒精性肝损伤 NF-κB/NLRP3 血清代谢组学肝脏代谢组学机制

口腔鳞状细胞癌E2F转录因子1的表达与临床的意义

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口腔颌面外科杂志 2024年第2期34卷 100-107页

作者：王锦航崔子峰杨凯成陈彦平彭士雄石家庄市第二医院口腔科石家庄050000 河北医科大学第四医院口腔颌面外科石家庄050000

目的:探讨E2F转录因子1(E2F transcription factor 1,E2F1)在口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)中的表达和临床意义,并阐明其在细胞凋亡和周期中的作用。方法:基于R语言和癌症基因组图谱(the cancer genome atlas,TCGA)数据库分析OSCC中E2F1的表达和临床病理的相关性,通过基因集富集分析(gene set enrichment analysis,GSEA)发现E2F1参与的主要生物学过程。蛋白质印迹法(Western blotting)和实时定量聚合酶链反应(real-time quantitative polymerase chain reaction,RT-qPCR)检测E2F1在OSCC患者组织中的表达。通过细胞转染升高和敲低SCC15细胞系中E2F1的表达后,利用流式细胞术检测E2F1表达的改变对SCC15细胞凋亡和周期的影响。结果:E2F1在OSCC相关TCGA数据集中呈高表达,与T分期(T2或T4 vs T1)、组织学分级(G2或G3 vs G1)、临床分期(Ⅲ期vsⅠ期)、年龄(中年人vs青年人)和性别(男vs女)相关(P<0.05),多富集于细胞周期或核苷酸切除修复等基因组[P<0.05,错误发现率(false discovery rate,FDR)<0.25]。在37例OSCC患者组织中,E2F1的mRNA和蛋白均表达上调(P<0.001),表达上调的E2F1可降低SCC15细胞的凋亡率(P<0.05),以及在细胞周期中降低G1期的比率(P<0.01),并升高S期的比率(P<0.001)。结论:E2F1在OSCC中呈高表达,且可抑制细胞凋亡并促进细胞周期中G1/S期的转换。

关键词：口腔鳞状细胞癌 E2F转录因子1 生物信息学分析细胞凋亡细胞周期

Glutaredoxin-1 alleviates acetaminophen-induced liver injury by decreasing its toxic metabolites

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Journal of Pharmaceutical Analysis 2023年第12期13卷 1548-1561页

作者： Ying Xu Yan Xia Qinhui Liu Xiandan Jing Qin Tang jinhang Zhang Qingyi Jia Zijing Zhang Jiahui Li Jiahao chen Yimin Xiong Yanping Li Jinhan He Department of Pharmacy Institute of Metabolic Diseases and PharmacotherapyWest China HospitalSichuan UniversityChengdu610041China

Excessive N-acetyl-p-benzoquinone imine(NAPQI)formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen(APAP)overdose caused acute liver failure(ALF).S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity.Glutaredoxin-1(Glrx1),a glutathione-specific thioltransferase,is a primary enzyme to catalyze deglutathionylation.The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP.The Glrx1 knockout mice(Glrx1^(-/-))and liver-specific overexpression of Glrx1(AAV8-Glrx1)mice were produced and underwent APAPinduced ALF.Pirfenidone(PFD),a potential inducer of Glrx1,was administrated preceding APAP to assess its protective effects.Our results revealed that the hepatic total protein S-glutathionylation(PSSG)increased and the Glrx1 level reduced in mice after APAP toxicity.Glrx1^(-/-)mice were more sensitive to APAP overdose,with higher oxidative stress and more toxic metabolites of APAP.This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p4503a11(Cyp3a11),which likely increased the activity of Cyp3a11.Conversely,AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11,which reduced the toxic metabolites of APAP and oxidative stress.PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress.We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose.Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.

关键词： Glutaredoxin-1 S-glutathionylation Acetaminophen Toxic metabolites Cyp3a11

基于生物信息学构建口腔鳞状细胞癌免疫基因的预后模型

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疑难病杂志 2024年第1期23卷 78-85页

作者：王锦航彭士雄杨凯成陈彦平崔子峰石家庄市第二医院口腔科 050000 河北医科大学第四医院口腔科

目的旨在构建免疫相关基因(IRGs)的风险预测模型,以预测口腔鳞状细胞癌(OSCC)患者的预后。方法应用生物信息学技术分析OSCC的转录组测序数据,鉴定出差异表达的IRGs(DEIRGs)。通过Cox回归分析构建DEIRGs的风险预测模型,并对其预测能力进... 详细信息

目的旨在构建免疫相关基因(IRGs)的风险预测模型,以预测口腔鳞状细胞癌(OSCC)患者的预后。方法应用生物信息学技术分析OSCC的转录组测序数据,鉴定出差异表达的IRGs(DEIRGs)。通过Cox回归分析构建DEIRGs的风险预测模型,并对其预测能力进行评估。分析该模型与临床病理和免疫细胞浸润的相关性。结果通过比较OSCC和正常样本共鉴定出3634个差异表达基因,其中包括330个DEIRGs(FDR1)。单因素Cox回归分析筛选出与预后相关的20个DEIRGs(P<0.05),多因素Cox回归分析筛选出其中15个DEIRGs用于构建风险预测模型。该模型可作为OSCC患者的独立预后因素(P<0.001),预测患者预后的能力具有较高的准确性(AUC=0.732),并与临床分期(t=-3.484,P<0.001)、B细胞(Cor=-0.180,P=0.002)和CD4^(+)T细胞(Cor=-0.127,P=0.026)密切相关。结论基于15个预后相关DEIRGs构建的风险预测模型能够有效地预测OSCC患者的预后,可帮助临床医生为不同风险的OSCC患者选择个性化的治疗策略。

关键词：口腔鳞状细胞癌免疫相关基因预后风险预测模型癌症基因组图谱数据库

社区老年2型糖尿病患者糖尿病痛苦和抑郁症状对自我管理行为的影响

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中国健康心理学杂志 2024年第5期32卷 724-730页

作者：袁磊陆丽君赵锦航杨颖朱怡萱陈伟李殿江刘思浚南京医科大学公共卫生学院 211166 南京医科大学第一临床医学院南京市鼓楼区疾病预防控制中心

目的:了解社区老年2型糖尿病(Type 2 Diabetes Mellitus,T2DM)患者糖尿病痛苦(Diabetes Distress,DD)、抑郁症状(Depression Symptom,DS)和自我管理行为现状,探讨DD和DS对老年2型糖尿病患者自我管理行为的影响,为制定有效的干预策略提... 详细信息

目的:了解社区老年2型糖尿病(Type 2 Diabetes Mellitus,T2DM)患者糖尿病痛苦(Diabetes Distress,DD)、抑郁症状(Depression Symptom,DS)和自我管理行为现状,探讨DD和DS对老年2型糖尿病患者自我管理行为的影响,为制定有效的干预策略提供参考依据。方法:采用方便抽样的方法对南京市8家社区卫生服务中心注册的588名老年T2DM患者进行问卷调查,问卷内容包括一般资料问卷,糖尿病痛苦量表、九条目患者健康问卷和自我管理行为量表。结果:①社区老年T2DM患者DD和DS的患病率分别为28.4%和39.1%,糖尿病自我管理行为处于中等水平。②DD(r=-0.43,P<0.01)和DS(r=-0.28,P<0.01)均与糖尿病自我管理行为呈显著负相关。③在校正可能的混杂因素后,多元线性回归结果显示较高的DD得分(B=-0.594,P<0.01)和DS得分(B=-0.799,P<0.01)均能单独预测患者的自我管理行为。当DD和DS同时纳入回归模型时,DS(B=-0.224,P=0.071)对自我管理行为的影响不再显著,而DD(B=-0.529,P<0.01)依旧显著,可以解释自我管理行为总变异的20.8%。结论:社区医疗保健专业人员需对老年T2DM患者的DD和DS进行常规评估,实施侧重于降低DD水平的干预策略可能对于改善患者的自我管理行为具有重要意义。

关键词：糖尿病痛苦抑郁症状老年人自我管理行为 2型糖尿病

CUMS and dexamethasone induce depression- like phenotypes in mice by differentially altering gut microbiota and triggering macroglia activation

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General Psychiatry 2021年第6期34卷 5-15,I0002-I0005页

作者： Jing Wu jinhang Li Chhetri Gaurav Usman Muhammad Yantian chen Xueyi Li Jinghong chen Zejian Wang School of Pharmacy Shanghai Jiao Tong UniversityShanghaiChina Shanghai Mental Health Center ShangHai Jiao Tong University School of MedicineShanghaiChina Shanghai Key Laboratory of Psychotic Disorders ShangHai Jiao Tong University School of MedicineShanghaiChina

Background Although the link between gut microbiota and depression has been suggested,changes of gut microbiota vary largely among individuals with depression.Aims Explore the heterogeneity of microbiota-gut-brain axis and new pathogenic characteristics in murine models of depression.Methods Adolescent female mice were randomly divided into control(CON)group(n=10),chronic unexpected mild stress(CUMS)group(n=15)and dexamethasone(DEX)group(n=15).Mice in the DEX group were gavaged twice a day with 0.2 mg/kg of DEX for 5 weeks,whereas CON mice were given the same amount of solvent.Mice in the CUMS group were exposed to stressors.After behavioural evaluations,all mice were sacrificed for harvesting tissues and blood samples.Enzyme-linked immunosorbent assay(ELISA)was conducted for measuring levels of corticosterone(CORT)and interleukin-1β(IL-1β)in sera,whereas levels of protein expression in colon and hippocampal tissues were examined by western blot.Faecal microbial communities were analysed by sequencing 16S rDNAs.Results Mice in CUMS and DEX groups exhibited severe depression-like behaviours.Compared with CON mice,CUMS-exposed mice showed a significant increase in bothαandβdiversity.Prevotellaceae and Desulfovibrio were enriched,whereas Bacilli were decreased in the faeces of mice in the CUMS group.DEX-treated mice had a decrease in the abundance of Clostridium XVIII.Levels of occludin in colon tissue of DEX-treated mice were reduced.Relative to mice in the CON and CUMS groups,DEX-treated mice contained higher serum levels of CORT and IL-1β.Compared with CON mice,mice in the DEX and CUMS groups had higher levels of IL-1βin sera and lower levels of glial fibrillary acidic protein(GFAP),Nestin,Synapsin-1 and P2Y12 receptor in the hippocampus.Conclusions Changes of gut microbiota diversity,intestinal integrity and neuroinflammation in the brain contribute to CUMS-induced depression,whereas pathobionts and excessive immunosuppression with damaged neuronal synapses is a basis of the DEX-induced depression.

关键词： CUMS colon activation

Drug response biomarkers of Pien Tze Huang(片仔癀) treatment for hepatic fibrosis induced by carbon tetrachloride

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Journal of Traditional Chinese Medicine 2022年第4期42卷 530-538页

作者： ZHANG Di WEI Muyun chen Luan WU Hao WANG Ting ZHANG Zhiruo ZHANG Ying YU Juan HUANG Jinming ZHU jinhang QIN Shengying School of Life Sciences Anhui Medical UniversityHefei 230032China Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China Fujian Provincial Key Laboratory of Pien Tze Huang Natural Medicine Research and Development Zhangzhou Pien Tze Huang Pharmaceutical Co.Ltd.Zhangzhou 350000China

OBJECTIVE:To explore biomarkers of Pien Tze Huang(片仔癀)that ameliorated the symptoms of hepatic fibrosis.METHODS:Two groups of carbon tetrachloride-induced hepatic fibrosis(HF)mice model were constructed in our study:one group received PZH treatment and another group received no treatment.We performed this study to investigate the role of PZH in the regulation process of hepatic fibrosis.RESULTS:We identified 31 down-regulated and 39 upregulated mi RNAs using small RNA-seq analysis.Combining RNA-Seq data analysis,our study revealed 7 significant target genes(Sp4,Slc2 a6,Tln2,Hmga2,Ank3,Pax9,Fgf9).The results of real-time quantitative polymerase chain reaction analysis suggested that the expression level of 6 genes(Sp4,Tln2,Hmga2,Ank3,Pax9,Fgf9)were down-regulated compared to control group.On the other hand,the expression level of Slc2 a6 appeared to be up-regulated.The protein mass spectrometry showed that PZH group had lower protein expression of Tln2 compared to control group.CONCLUSION:We identified 7 genes that were significantly related to PZH response in HF mice using multiple conjoint analysis methods.These genes could participate in underlying regulation mechanism of hepatic fibrosis during PZH treatment.

关键词： liver cirrhosis biomarkers RNA-Seq carbon tetrachloride fibroblast growth factor 9 Pien Tze Huang