关键词： aortic aneurysm and dissection   cGAS-STING pathway   DNA stability   micronuclei formation   P21  

摘要： BackgroundSporadic aortic aneurysm and dissection (AAD) is a critical condition characterised by the progressive loss of vascular smooth muscle cells (VSMCs) and the breakdown of the extracellular matrix. However, the molecular mechanisms responsible for the phenotypic switch and loss of VSMCs in AAD are not fully *** and resultsIn this study, we employed a discovery-driven, unbiased approach. This approach encourages us to explore the unknown functions of activating transcription factor 3 (ATF3) rather than merely confirming existing hypotheses, while no assumptions were made about ATF3 prior to the experiments. We ensured the unbiased nature of our assessment by conducting morphological evaluations with two independent observers in a blinded manner. We identified elevated expression of ATF3 in both human sporadic AAD tissues and mouse AAD models. VSMC-specific ATF3 conditional knockout (Atf3 cKO) mice showed notable enlargement, dissection and rupture in both thoracic and abdominal aortic regions after exposure to Ang II. Interestingly, older Atf3 cKO mice exhibited spontaneous aortic dissections and senescence of the aortic wall. Mechanistically, ATF3 deficiency led to the degradation of P21 through ubiquitination. Impaired DNA repair in VSMCs resulted in micronuclei formation in the cytoplasm, activating the cyclicGMP-AMP synthase- stimulator of interferon genes (cGAS-STING) pathway and inducing VSMC phenotypic switching and apoptosis. Finally, both pharmacological complementation of P21 function and knockdown of STING expression alleviated ATF3 deficiency-induced *** study indicates that ATF3 is essential for genomic DNA stability in VSMCs through the P21-cGAS-STING pathway, suggesting that enhancing ATF3 expression in VSMCs could help prevent sporadic *** points ATF3 deficiency led to degradation of P21 through ubiquitination, which abolished the G1 phase arrest. VSMCs had no time window to repair the damaged DNA, leading to g

关键词： Adipose mesenchymal stem cells   Exosome   ATF3   Ferroptosis   Myocardial infarction  

摘要： Objective. During acute myocardial infarction (AMI), ferroptosis occurs in cardiomyocytes, leading to ventricular remodeling. To investigate the influence of exosomes (Exo) derived from adipose mesenchymal stem cells (AD-MSCs) on cardiomyocytes, a therapeutic approach to resolve AMI may be discovered. Methods. The Exo of AD-MSCs was isolated and identified, and internalized into cardiomyocytes. In vitro, oxygen-sugar deprivation (OGD) was performed to cultivate H9C2 cells to simulate the AMI model, and H9C2 cells incubated with Exo. In addition, an AMI rat model was constructed, and Exo was injected into the edge of myocardial infarction. The levels of MDA, Fe2+, GSH, and GPX4 were detected using corresponding kit, the expression levels of ATF3, SLC7A11, PTGS2, and GPX4 were detected using western blot. The oe-ATF3 plasmid was transfected into H9C2 cells to explore the mechanism of ferroptosis regulation by Exo. Results. Exo was isolated and identified successfully, and further confirmed that it could be internalized into H9C2 cells. Compared with the control group, the level of apoptosis and ferroptosis in OGD group was significantly increased, while the level of cell vitality was significantly decreased. After Exo treatment, the level of ferroptosis and apoptosis was significantly decreased, while the level of cell vitality was significantly increased. However, after overexpression of ATF3 in cells, it was found that the ferroptosis level down-regulated by Exo was reversed. Further examination of the SLC7A11/Xct system showed that ATF3 could inhibit the expression of SLC7A11. In addition, compared with the AMI+PBS group, the infarct size of the AMI+Exo group was significantly reduced, and the level of cardiomyocyte apoptosis and ferroptosis was also significantly improved. Conclusion. Exo derived from AD-MSCs can inhibit the expression of ATF3, promote the transport of Fe2+ by SLC7A11/Xct system, thus inhibiting the ferroptosis of myocardial cells in AMI, increasi

关键词： Tumors  

摘要： Immunotherapy has transformed cancer treatment, but its effectiveness in breast cancer remains suboptimal. Tumor-associated macrophages (TAMs), a key component of the tumor microenvironment (TME), contribute significantly to immune evasion. In this study, we identified gamma-interferon-inducible lysosomal thiol reductase (IFI30) as a critical regulator of TAM function in breast cancer. IFI30 expression is upregulated in breast cancer via enhanced Histone 3 lysine 27 acetylation (H3K27ac) modification and promotes tumor progression and metastasis in an immune-dependent manner. Mechanistically, IFI30 in breast cancer cells recruits TAMs by activating the ATF3-CCL5 axis. Within macrophages, it promotes M2-like polarization and PD-L1 upregulation, fostering an immunosuppressive TME. Our findings established IFI30 as a promising therapeutic target for disrupting TAM-mediated immune suppression and enhancing breast cancer immunotherapy. © 2025 The Author(s)

关键词： 冠状动脉性心脏病   急性冠脉综合征   胆固醇-25-羟化酶   激活转录因子3   危险因素  

摘要： 目的: 本论文主要探讨血清中激活转录因子3（Activating transcription factor3,ATF3）和胆固醇-25-羟化酶（Cholesterol-25-hydroxylase,CH25H）水平与急性冠脉综合征（Acute coronary syndrome,ACS）的关系及其对ACS的影响,为今后ACS的治疗和预防提供一种新的方向。 方法: 连续入选在2023年2月至2024年4月期间就诊于承德医学院附属医院并接受冠状动脉造影（Coronary angiography,CAG）的患者共263例。基于ACS的诊断标准及CAG的结果,入选患者被分为两组:Non-ACS组（66例）、ACS组（197例）。收集入选患者的基线资料,并用酶联免疫吸附实验（Enzyme linked immunosorbent assay,ELISA）对血清样本中的ATF3和CH25H水平进行检测。数据处理:用Kolmogorov-Smirnov检验判断是否符合正态性。若符合正态分布,定量资料的两组间比较用独立样本t检验;若呈偏态分布,定量资料两组间的比较用Mann-Whitney U检验;比较两组间定性资料采用χ2检验。通过建立多因素二元Logistic回归模型评价血清中ATF3和CH25H对ACS的患病风险。利用受试者工作特征（Receiver Operating Characteristic,ROC）曲线分析评价两者的预测诊断价值及计算最佳截断值。本研究均为双侧检验,P<0.05为差异有统计学意义。 结果: 1.两组基线特征的比较 ACS组的男性[142（72.1%）vs.19（28.8%）]、吸烟史[126（64.0%）vs.11（16.7%）]、高血压病[135（68.5%）vs.20（30.3%）]、糖尿病[51（25.8%）vs.5（7.6%）]患者中的比例均高于Non-ACS组。ACS组患者在BMI（25kg/m2vs.23.69kg/m2）、白细胞计数（7.74×10～9/L vs.5.80×10～9/L）、中性粒细胞绝对值（5.52×10～9/L vs.3.35×10～9/L）、单核细胞绝对值（0.47×10～9/L vs.0.385×10～9/L）、总胆红素（13.2μmol/L vs.11.95μmol/L）、肌酐（64μmol/L vs.57.05μmol/L）、尿酸（315.35μmol/L vs.270.23μmol/L）、甘油三酯（1.33mmol/L vs.1.23mmol/L）、同型半胱氨酸（13.04μmol/L vs.11.05μmol/L）均高于Non-ACS组。ACS组白蛋白（40.43g/L vs.42.025g/L）、高密度脂蛋白胆固醇（1.14mmol/L vs.1.29mmol/L）低于Non-ACS组。差异均有统计学意义（P<0.05）。 2.两组血清中ATF3、CH25H水平的比较 ACS组血清中ATF3（1116.50pg/mL vs.738.75pg/mL）、CH25H（124.11ng/L vs.91.55 ng/L）的水平均高于Non-ACS组,均P<0.05。 3.二元Logistic回归分析ACS的患病风险 设置哑变量:将基线资料中差异有统计学意义的定量资料转换为二分类定性资料,如下:高BMI组（n=154,BMI>23.9kg/m2）、低BMI组（n=109,BMI≤23.9kg/m2）,白细胞升高组（n=130,WBC>7.23×10～9/L）、非白细胞升高组（n=133,WBC≤7.23×10～9/L）,中性粒细胞绝对值升高组（n=131,NEUT>4.63×10～9/L）、非中性粒细胞绝对值升高组（n=132,NEUT≤4.63×10～9/L）,单核细胞绝对值升高组（n=50,MONO>0.6×10～9/L）、非单核细胞绝对值升高组（n=213,MONO≤0.6×10～9/L）,白蛋白升高组（n=130,ALB>40.8 g/L）、非白蛋白升高组（n=133,ALB≤40.8 g/L）,总胆红素升高组（n=15,TBIL>22μmol/L）、非总胆红素升高组（n=248,TBIL≤22μmol/L）,肌酐升高组（n=9,Cr>92μmol/L）、非肌酐升高组（n=254,Cr≤92μmol/L）;尿酸升高组（n=53,UA>369μmol/L）、非尿酸升高组（n=210,UA≤369μmol/L）,甘油三酯升高组（n=83,TG>1.7mmol/L）、非甘油三酯升高组（n=180,TG≤1.7mmol/L）,高密度脂蛋白胆固醇升高组（n=22,HDL-C>1.55mmol/L）、非高密度脂蛋白胆固醇升高组（n=241,HDL-C≤1.55m

关键词： Atf3   inflammation   NF-kappaB/p65   oxidative stress   spinal cord injury  

摘要： Background: Spinal cord injury (SCI) is a central nervous system disorder characterized by oxidative stress and inflammatory responses. Activating transcription factor 3 (Atf3) is an early-response stress-regulating gene whose abnormal upregulation exacerbates oxidative stress and inflammation. However, despite its known association with oxidative stress, the mechanism of Atf3 in SCI remains incompletely understood. This study aimed to investigate the role and mechanisms of Atf3 in ***: Bioinformatics analysis was performed using multiple GEO datasets to identify hub genes and key signaling pathways associated with post-SCI oxidative stress. The rat SCI model and a lipopolysaccharide (LPS)-induced PC12 cell injury model were established in vivo and in vitro to investigate whether Atf3 could ameliorate SCI progression, neuronal damage, oxidative stress, and inflammation. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) and luciferase reporter assays were used to analyze the interaction between Atf3 and NF-kappa B/p65, as well as the promoter activity of the p65 gene. Finally, the NF-kappa B signaling pathway was activated to observe the role of Atf3 in neuronal injury and ***: Bioinformatics analysis revealed significant enrichment of Atf3 and the NF-kappa B signaling pathway in SCI datasets. Atf3 primarily colocalized with NeuN but minimally with GFAP or Iba-1. Knockdown of Atf3 significantly alleviated SCI damage, reduced oxidative stress (decreased MDA/MPO and increased SOD/GSH levels), and suppressed inflammation (reduced TNF-alpha, IL-1 beta and IL-6 levels) in both SCI rats and LPS-treated PC12 cells. However, activation of NF-kappa B counteracted these protective effects. ChIP-qPCR and luciferase reporter assays demonstrated that Atf3 overexpression enhanced its binding to the p65 promoter and promoted NF-kappa B/p65 activation, whereas Atf3 knockdown reversed these ***: Downregulation of Atf3 mitigates oxidative stress

关键词： 激活转录因子3   呼吸系统疾病   哮喘   慢性阻塞性肺疾病   肺癌  

摘要： 激活转录因子3(activating transcription factor 3, ATF3)是一种应激诱导转录因子，属于cAMP响应元件结合蛋白(ATF/CREB)家族，其参与机体内多种信号通路和复杂的病理生理过程，如炎症、免疫、氧化应激、细胞增殖及死亡等，在调节细胞功能、维持机体正常生命活动和疾病演变中起着至关重要的作用。最近多项研究表明，ATF3在包括哮喘、慢阻肺和肺癌等在内的呼吸系统相关疾病的炎症反应、黏液分泌、药物敏感性及预后评估等诸多发生发展过程中发挥关键作用。本文综述ATF3在呼吸系统相关疾病中的作用机制及研究进展，旨在发掘ATF3在治疗呼吸系统相关疾病的价值，为相关防治提供新思路。

关键词： 高血压肾病   细胞衰老   差异表达基因   生物信息学   作用机制  

摘要： 目的 借助生物信息学技术研究细胞衰老在高血压肾病中可能发生的机制及相关信号通路。方法 查找基因表达数据库下载微阵列数据GSE37455,用R软件合并数据并去除批次效应，获取差异表达基因。从细胞衰老基因CellAge数据库获取细胞衰老基因，通过R包“ggVennDiagram”获取与细胞衰老相关差异基因。导入基因相互作用网络String数据库获取蛋白质互作(PPI)网络图，用Cytoscape 3.8.0软件挖掘核心差异基因。用基因本体(GO)、京都基因与基因组百科全书(KEGG)、基因集富集分析(GSEA)对核心差异基因进行功能和通路分析。结果 共获得41个差异基因，包括32个上调基因和9个下调基因。取交集后获得4个与细胞衰老相关差异基因。通过PPI分析和Cytoscape处理获得核心差异基因激活转录因子3(ATF3)。GSEA分析显示，细胞衰老可能通过线粒体解偶联蛋白1产热、Ⅰ型干扰素反应(TYPE-Ⅰ-IFN)的信号传导等途径在高血压肾病中发挥作用。结论 细胞衰老在高血压肾病中可能通过线粒体解偶联蛋白1产热、TYPE-Ⅰ-IFN等途径发生作用，为高血压肾病的研究提供治疗靶点。

关键词： Brain damage   Gene expression   Hemorrhage   Platelet activation   Heme   Apoptosis   Genetic networks   Protein interaction networks  

摘要： Background Secondary brain injury following intracerebral hemorrhage (ICH) is a critical clinical challenge, yet the molecular mechanisms driving neuronal damage remain poorly understood. This study investigates the role of the transcription factor ATF3 and its downstream effector, VASP, in mediating neuronal injury via the platelet activation *** Differential gene expression analysis of the GSE24265 dataset was conducted using the limma package in R to identify key regulators in hemorrhagic conditions. Protein-protein interaction network analysis and bioinformatic predictions were employed to pinpoint central regulatory nodes and downstream targets. Validation experiments utilized the HT22 mouse hippocampal neuronal cell line, combining ATF3 overexpression/knockdown, dual luciferase reporter assays, and functional assessments (propidium iodide/Calcein-AM staining, flow cytometry). Enrichment analysis linked identified targets to biological *** ATF3 was significantly upregulated in hemorrhagic conditions and identified as a central regulatory node. Bioinformatic and experimental validation confirmed VASP as a direct downstream target of ATF3. Enrichment analysis revealed VASP's predominant association with platelet activation pathways. Functional assays demonstrated that ATF3 overexpression exacerbated heme-induced cytotoxicity in HT22 cells, implicating hyperactive platelet activation in secondary neuronal *** This study identifies a novel ATF3-VASP signaling axis as a key driver of secondary neuronal injury post-ICH. Our findings advance the mechanistic understanding of post-hemorrhagic brain damage and suggest that therapeutic targeting of the ATF3-VASP pathway may mitigate secondary injury, offering a potential strategy to improve clinical outcomes.