关键词： Crassostrea gigas   Granulocytes   Phagocytic capacity   Transcription signature ATF3   Transcriptional activator  

摘要： Phagocytosis is a major cellular mechanism for mollusk granulocytes to eliminate nonself substances and dead cells, and thus to preserve the immune homeostasis. The knowledge of the regulatory mechanisms controlling phagocytic capacity is vital to understanding the immune system. In the present study, an ATF3 homolog (CgATF3) with a typical bZIP domain was identified in the Pacific oyster Crassostrea gigas. Its highly conserved bZIP domain consisted of two structural features, a basic region for DNA binding and a leucine zipper region for dimerization. Its transcript was found to be abundantly expressed in haemocytes, which was induced by Vibrio splendidus stimulation and recombinant CgTNF-2 treatment, along with an increase of its protein content in the nucleus. Moreover, CgATF3 showed a consistent and specific high expression in granulocytes, and CgATF3+ granulocytes were characterized morphologically by the largest diameter, smaller nucleus to cytoplasmic ratio, and abundant cytoplasmic granules, and functionally by a higher capacity for phagocytosis. When CgATF3 expression was inhibited by RNAi, the expression levels of CgRab1, CgRab33 and CgCathepsin L1, as well as the phagocytic rate and index of granulocytes all decreased after V. splendidus stimulation. These results together demonstrated the involvement of CgATF3 in regulating the expressions of Rabs and Cathepsin L1, as well as the phagocytosis of granulocytes in oyster C. gigas. © 2024

关键词： ATF3   IL-17   IgAN   JUN   bioinformatics   ferroptosis  

摘要： Exploring key genes and potential molecular pathways of ferroptosis in immunoglobulin A nephropathy (IgAN). The IgAN datasets and ferroptosis-related genes (FRGs) were obtained in the Gene Expression Omnibus (GEO) and FerrDb database. Differentially expressed genes (DEGs) were identified using R software and intersected with FRGs to obtain differentially expressed FRGs (DE-FRGs). After that, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis (PEA) and Gene Ontology (GO) functional annotation were performed on DE-FRGs. In the Search Tool for the Retrieval of Interacting Genes (STRING) website, we construct a protein-protein interaction (PPI) network. The PPI network was further investigated with screening hub genes with Cytoscape software. The core genes were then subjected to gene set enrichment analysis (GSEA). Finally, the samples were analyzed for immune infiltration in R, and the correlation between hub genes and immune cells was analyzed. A total of 347 DEGs were identified. CD44, CDO1, CYBB, IL1B, RRM2, AKR1C1, activated transcription factor-3 (ATF3), CDKN1A, GDF15, JUN, MGST1, MIOX, MT1G, NR4A1, PDK4, TNFAIP3, and ZFP36 were determined as DE-FRGs. JUN, IL1B, and ATF3 were then screened as hub genes. GSEA and immune infiltration analysis revealed that the hub genes were closely associated with immune inflammatory responses such as NOD-like receptor signaling, IL-17 signaling, and TNF signaling. Our results show that JUN and ATF3 are possibly critical genes in the process of IgAN ferroptosis and may be related with immune cell infiltration.

关键词： AR   ATF3   Ethyl acetate extracts of semen impatientis   Network pharmacology   Prostate cancer   Transcriptomics  

摘要： Ethnopharmacological relevance: Prostate cancer (PCa) is the most common malignancy of the male genitourinary system and currently lacks effective treatment. Semen Impatientis, the dried ripe seed of Impatiens balsamina L., is described by the Chinese Pharmacopoeia as a traditional Chinese medicine (TCM) and is used in clinical practice to treat tumors, abdominal masses, etc. In our previous study, the ethyl acetate extracts of Semen Impatientis (EAESI) was demonstrated to be the most effective extract against PCa among various extracts. However, the biological effects of EAESI against PCa in vivo and the specific antitumor mechanisms involved remain unknown. Aim of the study: In this study, we aimed to investigate the antitumor effect of EAESI on PCa in vitro and in vivo by performing network pharmacology analysis, transcriptomic analysis, and experiments to explore and verify the underlying mechanisms involved. Materials and methods: The antitumor effect of EAESI on PCa in vitro and in vivo was investigated via CCK-8, EdU, flow cytometry, and wound healing assays and xenograft tumor models. Network pharmacology analysis and transcriptomic analysis were employed to explore the underlying mechanism of EAESI against PCa. Activating transcription factor 3 (ATF3) and androgen receptor (AR) were confirmed to be the targets of EAESI against PCa by RT‒qPCR, western blotting, and rescue assays. In addition, the interaction between ATF3 and AR was assessed by coimmunoprecipitation, immunofluorescence, and nuclear–cytoplasmic separation assays. Results: EAESI decreased cell viability, inhibited cell proliferation and migration, and induced apoptosis in AR+ and AR− PCa cells. Moreover, EAESI suppressed the growth of xenograft tumors in vivo. Network pharmacology analysis revealed that the hub targets of EAESI against PCa included AR, AKT1, TP53, and CCND1. Transcriptomic analysis indicated that activating transcription factor 3 (ATF3) was the most likely critical target of EA

关键词： SARS-CoV-2   MVA-S vaccine   K18-hACE2 mice   RNA-Seq   Transcriptomic   NEGATIVE REGULATOR   T-CELLS   VIRUS   ATF3   GRANZYME   MALARIA   BIOLOGY  

摘要： Unravelling the molecular mechanism of COVID-19 vaccines through transcriptomic pathways involved in the host response to SARS-CoV-2 infection is key to understand how vaccines work, and for the development of optimized COVID-19 vaccines that can prevent the emergence of SARS-CoV-2 variants of concern (VoCs) and future outbreaks. In this study, we investigated the effects of vaccination with a modified vaccinia virus Ankara (MVA)-based vector expressing the full-length SARS-CoV-2 spike protein (MVA-S) on the lung transcriptome from susceptible K18-hACE2 mice after SARS-CoV-2 infection. One dose of MVA-S regulated genes related to viral infection control, inflammation processes, T-cell response, cytokine production and IFN-gamma signalling. Down-regulation of Rhcg and Tnfsf18 genes post-vaccination with one and two doses of MVA-S may represent a mechanism for controlling infection immunity and vaccine-induced protection. One dose of MVA-S provided partial protection with a distinct lung transcriptomic profile to healthy animals, while two doses of MVA-S fully protected against infection with a transcriptomic profile comparable to that of non-vaccinated healthy animals. This suggests that the MVA-S booster generates a robust and rapid antigen-specific immune response preventing virus infection. Notably, down-regulation of Atf3 and Zbtb16 genes in mice vaccinated with two doses of MVA-S may contribute to vaccine control of innate immune system and inflammation processes in the lungs during SARS-CoV-2 infection. This study shows host transcriptomic mechanisms likely involved in the MVA-S vaccine-mediated immune response against SARS-CoV-2 infection, which could help in improving vaccine dose assessment and developing novel, well-optimized SARS-CoV-2 vaccine candidates against prevalent or emerging VoCs.

关键词： ATF3/CFS1 axis   M2 macrophages   miR-27a-3p   NSCLC   TAM  

摘要： Non-small cell lung cancer (NSCLC) imposes a significant economic burden on patients and society due to its low overall cure and survival rates. Tumour-associated macrophages (TAM) affect tumour development and may be a novel therapeutic target for cancer. We collected NSCLC and tumour-adjacent tissue samples. Compared with the tumour-adjacent tissues, the Activation Transcription Factor 3 (ATF3) and Colony Stimulating Factor 1 (CSF-1) were increased in NSCLC tissues. Levels of ATF3 and CSF-1 were identified in different cell lines (HBE, A549, SPC-A-1, NCI-H1299 and NCI-H1795). Overexpression of ATF3 in A549 cells increased the expression of CD68, CD206 and CSF-1. Moreover, levels of CD206, CD163, IL-10 and TGF-beta increased when A549 cells were co-cultured with M0 macrophages under the stimulation of CSF-1. Using the starbase online software prediction and dual-luciferase assays, we identified the targeting between miR-27a-3p and ATF3. Levels of ATF3, CSF-1, CD206, CD163, IL-10 and TGF-beta decreased in the miR-27a mimics, and the tumour growth was slowed in the miR-27a mimics compared with the mimics NC group. Overall, the study suggested that miR-27a-3p might inhibit the ATF3/CFS1 axis, regulate the M2 polarization of macrophages and ultimately hinder the progress of NSCLC. This research might provide a new therapeutic strategy for NSCLC.

关键词： Myocardial infarction   Myocardial fibrosis   Cardiac remodeling   Autophagy   ATF3   CARDIAC FIBROSIS   HEART-FAILURE   REPAIR   FIBROBLASTS   PROTECTS  

摘要： Background & objective: Myocardial fibrosis remodeling is a key event in the development of heart anomalousness and dysfunction after myocardial infarction (MI). The purpose of this study was to explore the effect of activating transcription factor 3 (ATF3) on myocardial fibrosis remodeling after MI and its underlying mechanism, so as to provide a theoretical basis for the clinical development of new strategies for MI ***: MI mouse formers were structured by hypodesmus of the left anterior descending (LAD) arteria coronaria of mice, and primary cardiac fibroblasts (CFs) were separated and cultivated to investigate the effect of ATF3 on myocardial fibrosis after MI and its mechanism. Results: Increased collagen content and autophagic flux were found in the left ventricle (LV) tissues of MI mice as shown by Sirius red staining and Western blotting (WB) analysis. Meanwhile, immunofluorescence staining and WB analysis showed that ATF3 was raised in response to MI damage. After remedy with angiotensin II (AngII), the activity and differentiation of CFs were significantly raised, the expression of collagens was increased, and the level of autophagy was notably increased. Furthermore, AngII stimulation remarkably raised the expression of ATF3. Interestingly, knockdown of ATF3 in AngII-CFs reversed the above changes. In addition, after intervention with 3-methyladenine (3-MA), an autophagy restrainer, the activity and differentiation of AngII-CFs, as well as the relative collagen levels and autophagic flux were reduced. However, up-regulation of ATF3 protein expression partially reversed the effect of 3-MA on AngII-CFs. Conclusion: ATF3 can regulate the proliferation of CFs and collagen production by affecting autophagy, thus affecting myocardial fibrosis remodeling after MI.

关键词： 糖尿病肾病   血胰岛素样生长因子-1   转录激活因子3   蛋白尿   相关性  

摘要： 目的探讨糖尿病肾病患者血清血胰岛素样生长因子-1(IGF-1)、转录激活因子3(ATF3)水平与蛋白尿的相关性。方法纳入收治的100例糖尿病肾病患者,根据Mogensen分期和蛋白尿排泄率(UAER)将患者分为微量蛋白尿组(45例)和大量蛋白尿组(55例)。观察2组患者血清IGF-1、ATF3、尿素氮(BUN)、尿酸(UA)水平,通过ROC分析血清IGF-1、ATF3、UA、BUN预测糖尿病肾病患者发生大量蛋白尿的价值,然后通过多因素分析采取非条件logistic逐步回归分析明确糖尿病肾病患者发生大量蛋白尿的危险因素;相关性用Person系数分析。结果微量蛋白尿组患者IGF-1、ATF3、UA、BUN水平显著低于大量蛋白尿组(P<0.05);经ROC分析证实IGF-1、ATF3、UA、BUN可用于糖尿病肾病患者发生大量蛋白尿的预测,曲线下面积分别为0.911、0.893、0.861、0.887;多因素分析显示IGF-1≥226.618μg/L、ATF3≥1250.689 pg/mL、UA≥315.655μmol/L、BUN≥97.210 mmol/L是糖尿病肾病患者发生大量蛋白尿的危险因素;相关性分析显示IGF-1、ATF3、UA、BUN与蛋白尿均呈正相关(P<0.05)。结论糖尿病肾病患者蛋白尿与血清IGF-1、ATF3、UA、BUN水平呈正相关,且IGF-1≥226.618μg/L、ATF3≥1250.689 pg/mL、UA≥315.655μmol/L、BUN≥97.210 mmol/L可用于糖尿病肾病患者发生大量蛋白尿的预测。

关键词： acute stress   ATF3   HPA axis   immediate early gene   traumatic brain injury   ACTIVATING TRANSCRIPTION FACTOR-3   HEAD-INJURY   HPA AXIS   C-JUN   MILD   ATF3   MODEL   NEUROINFLAMMATION   INFLAMMATION   RECEPTORS  

摘要： Psychological stress and traumatic brain injury (TBI) result in long-lasting emotional and behavioral impairments in patients. So far, the interaction of psychological stress with TBI not only in the brain but also in peripheral organs is poorly understood. Herein, the impact of acute stress (AS) occurring immediately before TBI is investigated. For this, a mouse model of restraint stress and TBI was employed, and their influence on behavior and gene expression in brain regions, the hypothalamic-pituitary-adrenal (HPA) axis, and peripheral organs was analyzed. Results demonstrate that, compared to single AS or TBI exposure, mice treated with AS prior to TBI showed sex-specific alterations in body weight, memory function, and locomotion. The induction of immediate early genes (IEGs, e.g., c-Fos) by TBI was modulated by previous AS in several brain regions. Furthermore, IEG upregulation along the HPA axis (e.g., pituitary, adrenal glands) and other peripheral organs (e.g., heart) was modulated by AS-TBI interaction. Proteomics of plasma samples revealed proteins potentially mediating this interaction. Finally, the deletion of Atf3 diminished the TBI-induced induction of IEGs in peripheral organs but left them largely unaltered in the brain. In summary, AS immediately before brain injury affects the brain and, to a strong degree, also responses in peripheral organs. Exposure to traumatic brain injury (TBI) results in hematoma formation and immediate early gene (IEG) expression in the brain and peripheral organs. IEG induction and hematoma formation are significantly reduced by pre-exposure to acute restraint stress (AS). This AS-induced reduction of hematoma formation and TBI-induced IEG expression in the periphery are in part dependent on the transcription factor Atf3 (activating transcription factor 3). Additionally, mice demonstrated behavioral alterations following TBI, which were modulated by AS pre-exposure and the Atf3 ***

关键词： Diabetes   Beta -cells   Hexachlorocyclohexane   Insulin   ATP citrate lyase   Perilipin-2   PERSISTENT ORGANIC POLLUTANTS   ATP-CITRATE LYASE   GLUCOSE-TRANSPORTER   INSULIN-SECRETION   ALPHA-HEXACHLOROCYCLOHEXANE   ORGANOCHLORINE PESTICIDES   BILIVERDIN REDUCTASE   TYPE-1   GENE   ATF3  

摘要： Decades after most countries banned hexachlorocyclohexane, HCH isomers still pollute the environment. Many studies described HCH as a pro-diabetic factor; nevertheless, the effect of HCH isomers on pancreatic beta-cells remains unexplored. This study investigated the effects of a one-month exposure to alpha-HCH, beta-HCH, and gamma-HCH on protein expression in human (NES2Y) and rat (INS1E) pancreatic beta-cell lines. alpha-HCH and gamma-HCH increased proinsulin and insulin levels in INS1E cells, while beta-HCH showed the opposite trend. alpha-HCH altered the expression of PKA, ATF3, and PLIN2. beta-HCH affected the expression of GLUT1, GLUT2, PKA, ATF3, p-eIF2 alpha, ATPCL, and PLIN2. gamma-HCH altered the expression of PKA, ATF3, PLIN2, PLIN5, and IDH1. From the tested proteins, PKA, ATF3, and PLIN-2 were the most sensitive to HCH exposure and have the potential to be used as biomarkers.

关键词： Osteosarcoma   Butyrate   Ferroptosis   ATF3   HISTONE DEACETYLASE INHIBITORS   SUPPRESS   SLC7A11  

摘要： Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the efficacy and survival rate of patients with OS. Butyrate (NaBu) has been reported as a new antitumor drug for inhibiting proliferation and inducing apoptosis in various cancer cells. However, the effect of NaBu on the ferroptosis of OS is still unknown. This study aimed to investigate whether NaBu promotes erastin-induced ferroptosis in OS cells and to uncover the underlying mechanism. Here, we found that NaBu significantly enhanced erastin-induced ferroptosis in vitro and in vivo. Compared with the group that erastin used alonely, pre-treating with NaBu exacerbated erastin-meditated GSH depletion, lipid peroxidation, and mitochondrial morphologic changes in OS cells. In a subcutaneous OS model, NaBu combined with erastin significantly reduced tumor growth and increased the levels of 4-HNE. Mechanistically, NaBu downregulated SLC7A11 transcription via regulating ATF3 expression. Overexpression of ATF3 facilitated erastin to induce ferroptosis, while ATF3 knockdown attenuated NaBu-induced ferroptosis sensitivity. In conclusion, our findings revealed a previously unidentified role of NaBu in erastin-induced ferroptosis by regulating SLC7A11, suggesting that NaBu may be a potential therapeutic agent for OS treatment.