关键词： Myocardial infarction   Myocardial fibrosis   Cardiac remodeling   Autophagy   ATF3  

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： Activating transcription factor 3   inflammatory response   neuroinflammation   acute brain injuries  

摘要： Activating transcription factor 3 (ATF3) is one of the most important transcription factors that respond to and exert dual effects on inflammatory responses. Recently, the involvement of ATF3 in the neuroinflammatory response to acute brain injury (ABI) has been highlighted. It functions by regulating neuroimmune activation and the production of neuroinflammatory mediators. Notably, recent clinical evidence suggests that ATF3 may serve as a potential ideal biomarker of the long-term prognosis of ABI patients. This mini-review describes the essential inflammation modulatory roles of ATF3 in different disease contexts and summarizes the regulatory mechanisms of ATF3 in the ABI-induced neuroinflammation.

关键词： acute stress   ATF3   HPA axis   immediate early gene   traumatic brain injury  

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： Osteosarcoma   Butyrate   Ferroptosis   ATF3  

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.

摘要： Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.

摘要： Endometriosis is a gynecological inflammatory disease that is linked with immune cells, specifically macrophages. IL-33 secreted from macrophages is known to accelerate the progression of endometriosis. The periodic and repeated bleeding that occurs in women with endometriosis leads to excess iron in the microenvironment that is conducive to ferroptosis, a process related to intracellular ROS production, lipid peroxidation and mitochondrial damage. It is suggested that eESCs may specifically be able to inhibit ferroptosis. However, it is currently unclear whether IL-33 directly regulates ferroptosis to influence the disease course in endometriosis. In this study, eESCs co-cultured with macrophages or stimulated with IL-33/ST2 were observed to have increased cell viability and migration. Additionally, IL-33/ST2 decreased intracellular iron levels and lipid peroxidation in eESCs exposed to erastin treatment. Furthermore, IL-33/ST2 treatment resulted in a notable upregulation in SLC7A11 expression in eESCs due to the downregulation of negative transcription factor ATF3, thereby suppressing ferroptosis. The P38/JNK pathway activated by IL-33/ST2 was also found to inhibit the transcription factor ATF3. Therefore, we concluded that IL-33/ST2 inhibits the ATF3-mediated reduction in SLC7A11 transcript levels via the P38/JNK pathway. The findings reveal that macrophage-derived IL-33 upregulates SLC7A11 in eESCs through the p38/JNK/ATF3 pathway, ultimately resulting in protection against ferroptosis in eESCs. Moreover, we conducted an experiment using endometriosis model mice that showed that a combination of IL-33-Ab and erastin treatment alleviated the disease, showing the promise of combining immunotherapy and ferroptosis therapy.

关键词： RNF146   ACSL4   ATF3   ischemic stroke   GPX4  

摘要： Ischemic stroke (IS) is one of the leading causes of disability and death worldwide. Long-chain fattyacid-coenzyme A ligase 4 (ACSL4) is a critical isozyme for ferroptosis that participates in the progression of IS. RING finger protein 146 (RNF146) is an E3 ligase predicted to interact with ACSL4 and regulated by activating transcription factor 3 (ATF3). The molecular mechanism of the RNF146/ACSL4 axis in IS is still unclear. Oxygenglucose deprivation/reperfusion (OGD/R) treatment was used as the in vitro model, and middle cerebral artery occlusion (MCAO) mice were established for the in vivo model for IS. The protein level of ACSL4 was monitored by Western blot during ischemic injury. RNF146 was overexpressed in vitro and in vivo. The interaction of RNF146 and ACSL4 was determined by co-immunoprecipitation (Co-IP) assay. Chromatin immunoprecipitation (ChIP) assay and luciferase assay were utilized to determine the regulation of ATF3 on RNF146. Ferroptosis was evaluated by the levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), Fe2+, and protein levels of related genes including ACSL4, SLC7A11, and GPX4. ACSL4 was downregulated upon OGD treatment and then increased by re-oxygenation. RNF146 was responsible for the ubiquitination and degradation of ACSL4 protein. RNF146 overexpression could prevent the stimulation of OGD/R-induced LDH, MDA, and Fe2+ levels and ferroptosis-related gene expression. ATF3 could activate the transcription and expression of RNF146, leading to the inhibition of OGD/R-induced neuron ferroptosis. The ATF3-mediated RNF146 could alleviate neuronal damage in IS by regulating ACSL4 ubiquitination and ferroptosis, providing a novel theoretical basis for exploring therapeutic targets and strategies. (c) 2023 Published by Elsevier Ltd on behalf of IBRO.