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.

关键词： Cancer microenvironment   Chromatin structure   Targeted therapies  

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.

关键词： Apoptosis   Cell death and immune response   DNA metabolism   Immunoproliferative disorders   Interleukins  

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.

关键词： Tianhuang formula   Non-alcoholic fatty liver diseases   Type 2 diabetes mellitus   CRLS1-ATF3/ChREBP pathway  

摘要： Objective Tianhuang Formula (THF) is a hospital formula summarized by Professor Jiao Guo's 30 years of clinical experience. Some studies have shown that it can alleviate dyslipidemia in the body. The purpose of this study is to confirm whether THF can improve non-alcoholic fatty liver diseases (NAFLD) in type 2 diabetic mice induced by high-fat diet (HFD)/streptomycin (STZ) and to clarify its potential mechanism. Methods After induction of diabetes, mice were administrated with THF (60 ​mg/kg or 120 ​mg/kg) once daily for 10 weeks. Blood glucose (FBG), glucose tolerance, and insulin resistance (IR) were assayed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Blood lipids, alanine transaminase (ALT), and aspartate transaminases (AST) were detected. Serum fasting insulin (INS) and adiponectin (APN) levels were measured using ELISA. Histological changes in liver and pancreatic islets were observed by H&E staining, followed by Oil Red O staining for liver lipid quantification and periodic acid-Schiff (PAS) staining to detect glycogen accumulation. Western blotting detected the levels of fatty cardiolipin synthase 1 (CRLS1), transcription factor activator 3 (ATF3), and carbohydrate-responsive element binding protein (ChREBP) in the liver. The mRNA transcripts of hepatic inflammatory factors, lipogenesis and lipolysis-related genes, and gluconeogenic enzyme-phosphoenolpyruvate carboxykinase (PEPCK), CRLS1, ATF3, and ChREBP mRNA levels were evaluated by RT-qPCR. Results THF restored impaired glucose tolerance and insulin resistance, respectively. There was an improvement in HFD/STZ-induced liver and islet damage, high serum HDL-C and ANP levels, and a significant decrease in FBG, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), FFA, INS, ALT, and AST, and lipid droplet counts in the T2DM mice treated with THF. CREBBP binding protein ATF3 mediated the insulin resistance signaling pathway, which regulated glucos

关键词： circRNA   hepatocellular carcinoma   N-6-methyladenosine modification   mRNA decay   protein encoding   RNA-binding protein  

摘要： Background: Circular RNAs (circRNAs) play a significant role in the initiation and progression of various cancers, including hepatocellular carcinoma (HCC). Circular syntaxin 6 (circSTX6, also known as hsa_circ_0007905) has been identified as a microRNA (miRNA) sponge in pancreatic adenocarcinoma. However, its full range of functions in terms of protein scaffold and translation remain largely unexplored in the context of ***: The expression of circSTX6 and its encoded protein was examined in HCC tumour tissues. N-6 -methyladenosine (m(6) A) on circSTX6 was verified and quantified by methylated RNA immunoprecipitation (Me-RIP), RIP and dual luciferase reporter assays. The biological functions of circSTX6 and its encoded protein in HCC were clarified by in vitro and in vivo experiments. Mechanistically, the interaction between circSTX6 and heterogeneous nuclear ribonucleoprotein D (HNRNPD) was investigated by RNA pull-down, RIP and fluorescence in situ hybridization (FISH)/IF. The regulatory effects of circSTX6 and HNRNPD on activating transcription factor 3 (ATF3) mRNA were determined by mRNA stability and RIP assays. Furthermore, the presence of circSTX6-encoded protein was verified by mass ***: CircSTX6 and its encoded 144 amino acid polypeptide, circSTX6-144aa, were highly expressed in HCC tumour tissues and served as independent risk factors for overall survival in HCC patients. The expression of circSTX6 was regulated by METTL14 in an m(6) A-dependent manner. Functionally, circSTX6 accelerated HCC proliferation and tumourigenicity and reinforced tumour metastasis in vitro and in vivo. Mechanistically, circSTX6 acted as a sponge for HNRNPD protein, facilitating its binding to ATF3 mRNA, consequently promoting ATF3 mRNA decay. Meanwhile, circSTX6-144aa promoted HCC proliferation, migration and invasion independent of circSTX6 ***: Collectively, our study reveals that m(6) A-modified circSTX6 drives malignancy in HCC through t

关键词： Non-alcoholic fatty liver disease   E6446   ATF3   Liver-adipose axis  

摘要： Due to the complexity and incomplete understanding of the crosstalk between liver and adipose tissue, especially the processes of hepatic lipogenesis and adipogenic differentiation, there are currently no effective drugs for the treatment of nonalcoholic fatty liver disease (NAFLD). Stearoyl-coenzyme A desaturase 1 (SCD1), which is abundantly expressed in liver and adipose tissue, may mediate the cross-talk between liver and adipose tissue. Thus, it is essential to develop specific SCD1 inhibitors that target the liver-adipose axis. Herein, we identified a novel SCD1 inhibitor, E6446, through a high-throughput virtual screen. E6646 significantly inhibited adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. The SPR results showed that E6446 had a strong interaction ability with SCD1 (KD:4.61 mu M). Additionally, E6646 significantly decreased hepatic steatosis, hepatic lipid droplet accumulation and insulin resistance in high-fat diet (HFD)-fed mice. Taken together, our findings not only suggest that E6446 can serve as a new, safe and highly effective anti-NAFLD agent for future clinical use but also provide a molecular basis for the future development of SCD1 inhibitors that inhibit both adipogenic differentiation and hepatic lipogenesis.-_fLbJcbqbtKciFUEE_QdNVideo Abstract