关键词： Bing Liu a   Pulsatilla saponin D   Osteosarcoma   JNK/ATF3 signaling pathway   Apoptosis   Cell cycle  

摘要： Osteosarcoma (OS) is a highly malignant and aggressive bone tumor associated with early lung metastasis and high mortality. Traditional chemotherapy does not effectively improve the efficacy and survival rate of patients with OS. Thus, it is vital to search for alternative therapies. Pulsatilla saponin D (PSD) is a potent bioactive compound that has been widely employed in cancer therapy due to its diverse bioactivities and minimal adverse effects. However, any effect on OS remains unclear. We found that PSD induced apoptosis of OS cells and investigated the mechanisms thereof. In vitro, PSD dose-dependently induced apoptosis and inhibited the viability of HOS and K7M2 cells. Furthermore, PSD significantly suppressed cell migration and invasion, and caused cell cycle arrest at the G0/G1 phase. Mechanistically, PSD upregulated ATF3 and JUN transcription by controlling JNK expression. Compared to cells treated with PSD alone, cells pre-treated with SP600125 (a JNK inhibitor), or in which ATF3 had been knocked down ATF3 with siRNA, did not exhibit PSD-mediated cell apoptosis. In a murine OS model, PSD exhibited a powerful anti-cancer effect and an excellent safety profile. Our data imply that PSD could effectively prevent OS occurrence and progression.

关键词： ATF3   Bladder   GDF15   In silico   Tumorigenesis   EMT  

摘要： Background: The functions of activating transcription factor 3 (ATF3) within the human bladder remain unexplored. This study delves into the expressions, functions, and regulatory mechanisms of ATF3 in human bladder cancer. Material and methods: Gene expressions were determined by immunoblot, RT-qPCR, and reporter assays. Assays of Ki67, colony formation, Matrigel invasion, and the xenograft animal study were used to assess the cell proliferation, invasion, and tumorigenesis in vitro and in vivo. Silico analysis from TCGA database examined the correlations between GDF15 and ATF3 expressions, clinicopathologic features, and progression-free survival rates. Results: Silico analysis confirmed that ATF3 is an antitumor gene, and the expression positively correlates with GDF15 in bladder cancer tissues. Multivariate analysis revealed that low ATF3/GDF15 but not a single low expression of ATF3 is an independent prognostic factor for progression-free survival of bladder cancer patients. Ectopic overexpression of ATF3 downregulated cell proliferation and invasion in bladder cancer cells in vitro, while ATF3-knockdown reversed these results. Knockdown of ATF3 upregulated EMT markers to enhance cell invasion in vitro and downregulated GDF15, NDRG1, and KAI-1 to elevate tumor growth in vivo. The activation of metformin on ATF3 and GDF15 in bladder cancer cells was blocked by SB431542, a TGF beta receptor inhibitor. ATF3 positively regulated GDF15 expression in bladder cancer cells through a feedback loop. Conclusions: Our results identify that ATF3 is a metformin-upregulated antitumor gene. Results of Silico analysis align with cell-based studies suggesting that low ATF3/GDF15 could be a negative prognostic marker for bladder cancer.

关键词： ATF3   biomarkers   chemoimmunotherapy   IFN signaling pathway   NSCLC   pathological response  

摘要： BackgroundNeoadjuvant chemoimmunotherapy has achieved high downstaging and pathologic response rates in nonsmall-cell lung cancer (NSCLC), but outcomes vary significantly. Early identification of beneficiaries remains a *** study analyzed baseline transcriptomic data from 24 NSCLC patients (9 major pathological response [MPR], 15 nonmajor pathological response [NMPR]) treated with neoadjuvant chemoimmunotherapy, sourced from the GEO database. Molecular analyses and immune infiltration analyses were performed using pathologic response as an endpoint. After identifying the interferon signaling subset NeoIGS, we analyzed the relationship between NeoIGS and immune scores, immune cell infiltration, and immunotherapy efficacy. A key gene in NeoIGS was screened by reveiver operating characteristic curve (ROC) analysis. Subsequently, the expression of the key gene was assessed by immunohistochemistry in 53 NSCLC patients receiving neoadjuvant *** signaling pathway expression and CD8+ T-cell infiltration were higher in the MPR group. NeoIGS predicted pathological response to neoadjuvant chemoimmunotherapy (AUC = 0.926) and also demonstrated predictive value in the ICIs monotherapy cohort. IPS and TIDE scores also confirmed NeoIGS's association with immunotherapy in the TCGA NSCLC dataset. Furthermore, patients with higher NeoIGS scores had more immune cell infiltration and increased expression of ICI targets. ROC analysis identified ATF3 as NeoIGS's key gene. In the clinical cohort, ATF3 outperformed PD-L1 in predicting pathologic response, with a 90.0% MPR rate in the high-expression *** established that a subset of interferon signaling pathways, NeoIGS, is closely associated with immunotherapy. Among them, ATF3 is the most critical gene that accurately predicts pathological remission in neoadjuvant chemoimmunotherapy.

关键词： ATF3   Metabolism   Histone modification   Post-translational modification (PTM)   Oncotherapy  

摘要： Cellular stress response is a pivotal process in tumor development and therapy. Activating transcription factor 3 (ATF3), a representative stress-responsive protein, plays pleiotropic roles in various biological processes. Over the past decade, studies have described not only the general role of ATF3 in tumor metabolism but also the complexity of ATF3 expression regulation and its associated modifications, including phosphorylation, ubiquitination, SUMOylation, and NEDDylation. Interestingly, beyond being a transcription factor, ATF3 can act as a modifier to control the ubiquitination of target molecules, such as p53, to exert its function in tumors. These advances in uncovering ATF3 biological function have yielded new insights into the cellular stress response during tumor development and will be instrumental in developing novel interventions. In this review, we update the role of ATF3 as a nexus in amino acid metabolism, lipid metabolism, glycometabolism, and other metabolic pathways in tumors;delineate the underlying mechanisms involving DNA level regulation, epigenetic regulation, and post-translational modifications of ATF3;and summarize the progression of tumor mono/combination therapies related to ATF3. In particular, we discuss the challenges that need to be addressed to provide a new conceptual framework for further understanding the potential therapeutic value of ATF3 in ongoing clinical trials.

关键词： Berberine   AMPK   ATF3   Rheumatoid arthritis   MAPK  

摘要： This study aimed to explore the protective effects of berberine against rheumatoid arthritis (RA) and clarify the role of activating transcription factor 3 (ATF3) in the mechanism of action of berberine, using a lipopolysaccharide (LPS)-stimulated SW982 human synovial cell line. Berberine treatment resulted in a concentrationdependent reduction in LPS-induced proinflammatory cytokines and matrix metalloproteinases (MMPs) in SW982 cells. These inhibitory effects were associated with increased ATF3 expression, reduced nuclear translocation of nuclear factor-kappa B (NF-kappa B), and diminished phosphorylation of mitogen-activated protein kinase (MAPK). In contrast, ATF3 knockdown reversed the suppressive effects of berberine on proinflammatory cytokines and MMP production, leading to enhanced MAPK phosphorylation;however, it had minimal impact on adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Furthermore, AMPK knockdown negated the protective effects of berberine and reduced ATF3 levels, whereas treatment with 5-aminoimidazole4-carboxamide ribonucleotide, an AMPK activator, replicated the beneficial effects of berberine. In an in vivo collagen-induced arthritis (CIA) mouse model, intraperitoneal administration of berberine significantly reduced paw edema and arthritis severity, accompanied by ATF3 induction and increased AMPK phosphorylation in the synovial tissue. These findings highlighted the pivotal role of ATF3 in mediating the protective effects of berberine in RA- and LPS-activated synoviocytes, suggesting its potential as a therapeutic agent for RA management.

关键词： Adrenocortical carcinoma   ATF3   ATF4   ER stress   Mitotane   RNAseq  

摘要： Adrenocortical Carcinoma is a rare and aggressive endocrine malignancy, that arises from cells of one of the three cortical layers of the adrenal gland. Radical surgery is the only curative treatment, even if recurrence rates are high. Therapeutic options are limited, with mitotane as the cornerstone of medical therapy. Despite 50 years of clinical use, the mechanism of action of mitotane has not yet been fully established, possibly due to the drug's susceptibility to interaction with confounding factors that reduce its biological activity. In the present study, we evaluated by RNAseq the effect of mitotane on gene expression in the H295R cell line, in an environment free of known confounding factors. Our approach allowed us to identify transcriptional deregulation of the ATF4/ATF3 axis, often involved in ER stress. These results were also validated by ddPCR in independent experiments. Mitotane-mediated ATF4 overexpression was also confirmed at the protein level. We observed how an incremental concentration of mitotane could deregulate main biological pathways. Further, we confirmed, both at RNAseq and ddPCR level, the mitotane-mediated downmodulation of genes such as STAR, CYP11A1, CYP21A2, and HSD3B2, highlighting its effect on steroid hormones biosynthesis. Through our approach, we identified biological pathways altered by mitotane in early response stages and with low drug concentrations. Some of these pathways could potentially be investigated in the future as functional biomarkers to monitor adrenocortical carcinoma treatment or as new pharmacological targets for this rare disease. © 2025 The Authors

关键词： circSLC8A1通路   ATF3通路   癫痫进程   氧化应激   铁活性   细胞活性  

摘要： 目的分析circSLC8A1介导转录激活因子3(activating transcription factor 3,ATF3)通路影响癫痫细胞氧化应激及铁活性的机制。方法采用无Mg2+方法构建人神经元-海马细胞癫痫模型,检测健康对照组和模型组细胞的circSLC8A1、ATF3表达水平,采用质粒转染方式建立敲除circSLC8A1组、敲除ATF3组、敲除circSLC8A1+过表达ATF3组、敲除ATF3+过表达circSLC8A1组,转染6h后更换正常培养基培养48h。检测并比较不同干预组的细胞活力、铁活性、活性氧(reactive oxygen species,ROS)、乳酸脱氢酶(lactate dehydrogenase,LDH)和谷胱甘肽(glutathione,GSH)差异。结果模型组细胞的circSLC8A1、ATF3、ROS、LDH表达水平及铁活性均显著高于健康对照组,细胞活力和GSH表达水平均显著低于健康对照组(P<0.05);敲除circSLC8A1可显著降低癫痫模型细胞circSLC8A1表达量,敲除ATF3可显著降低癫痫模型细胞ATF3表达量(P<0.05);敲除circSLC8A1或ATF3,可使癫痫模型细胞的细胞活力升高,铁活性降低,氧化应激反应缓解,敲除circSLC8A1并过表达ATF3可逆转上述趋势,但敲除ATF3过表达circSLC8A1并不会导致上述现象。结论circSLC8A1能够通过介导ATF3通路,对癫痫模型对细胞活性、氧化应激反应及铁活性进程产生一定影响,可为癫痫产生机制及靶向治疗提供借鉴。

关键词： ACTH   Adrenocorticotropic hormone   AD   Alzheimer's disease   AKT   Protein Kinase B/PKB   ATF3   Activating transcription factor 3   ATF6   Activating transcription factor 6   Axin2   Axin-related protein 2   AVP   Arginine vasopressin   Aβ   Amyloid β   Bax   Bcl-2-associated X protein   BBB   Blood-brain barrier   Bcl-2   B-cell lymphoma 2   BD   Bipolar disorder   BDNF   Brain-derived neurotrophic factor   BMSCs   Bone marrow mesenchymal stem cells   BrdU   Bromodeoxyuridine   Btk   Bruton's tyrosine kinase   CD86   Cluster of differentiation 86   CDKL5   Cyclin-dependent kinase-like 5   CNS   Central nervous system   Con-Exos   Exosomes from control mice   CREB   cAMP response element-binding protein   CRH   Corticotropin-releasing hormone   CRS   Chronic restraint stress   CRS-Exos   Exosomes from chronic restraint stress-induced depressed mice   CSF   Cerebrospinal fluid   CTNND1   Catenin Delta-1   CUMS   Chronic unpredictable mild stress   CUS   Chronic unpredictable stress   CVSD   Cerebral small vessel disease   CXCL8   C-X-C motif chemokine ligand 8   DA   Dopamine   DCX   Doublecortin   DG   Dentate gyrus   DIANA-miRPath   Digital Identification And Network Analysis - microRNA Pathway Analysis   DNA   Deoxyribonucleic acid   ER   Endoplasmic reticulum   ERK1/2   Extracellular signal-regulated protein kinases1/2   EVs   Extracellular vesicles   E2   Estrogen   FZD2   Frizzled class receptor 2   GCs   Glucocorticoids   GDNF   Glial cell line-derived neurotrophic factor   GFAP   Glial fibrillary acidic protein   GR   Glucocorticoid receptor   GSH   Glutathione   GSK3β   Glycogen synthase kinase 3 β   HPA   Hypothalamic-pituitary-adrenal   HSP70   Heat shock protein 70   IFN   Interferon   IFN-α   Interferon-α   IFN-γ   Interferon-γ   IGF-1   Insulin-like growth factor-1   IκB   Inhibitor of κB   IκBα   Inhibitor of κBα   IKK   IκB Kinase   IKKα   IκB kinase α   IKKβ   IκB Kinase β   IL-1β   Interleukin-1β   IL-2   Interleukin-2   IL-4   Interleukin-4   IL-6   Interleukin-6   IL-10   Interleukin-10   IL-13   Interleukin-13   IL-1Rα   Interleukin-1 receptor alpha   INOS   Inducible nitric oxide synthase   INS   Insulin   INSR   Insulin receptor   IR   Insulin resistance   IRAK4   Interleukin-1 receptor-associated kinase 4   IRS-1   Insulin receptor substrate 1   ISEV   Internatio  

摘要： Major depressive disorder, a debilitating neurological disorder, remains enigmatic in its etiology, and current treatments are still inadequate. Therefore, unraveling its pathogenesis and discovering novel therapeutics is imperative. Exosomes are small extracellular nanoscale vesicles containing biomolecules, such as lipids, proteins, and nucleic acids, and have the ability to facilitate intercellular communication. Their potential as diagnostic indicators and therapeutic agents in conditions like autoimmune diseases, cardiovascular diseases, and cancer has been increasingly recognized. This review briefly introduces the relationship between exosomes and major depressive disorder, providing a systematic overview of how exosomal constituents contribute to the pathogenesis and progression. Furthermore, it underscores the significance of exosome research for advancing diagnostic and therapeutic approaches in major depressive disorder, offering a promising avenue for developing more effective clinical strategies.

摘要： Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra and/or intracellular changes. In this study, we observed that one of the ATFs, Activating transcription factor 3 (ATF3), is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1 alpha) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. In addition, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion-conducive extracellular matrix (ECM) under hypoxic conditions. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. Interestingly, involvement of ATF3 in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Furthermore, we also show that the demethylated DNA region of intron 9a then becomes accessible to CCCTC-binding factor (CTCF). Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA Pol II pause at intron 9a via CTCF, leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results reveal a novel hypoxia-induced HIF1 alpha-ATF3-P4HA1 axis which can potentially be exploited as a therapeutic target to impede EMT and ultimately breast cancer *** induced ATF3 regulates P4HA1 e