关键词： Nonalcoholic fatty liver disease   Ginsenoside-Rg1   RNA-seq   Atf3   Acox2  

摘要： Aims: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease and lacks for safe and effective drug to therapy completely. Ginsenoside-Rg1 is one of the main components of ginseng and has been proved to counteract a variety of diseases. However, there is currently a lack of sufficient evidence to support the efficacy of ginsenoside-Rg1 in the treatment of NAFLD. Our aim was to investigate whether Ginsenoside-Rg1 is a potential drug for NAFLD. Main methods: NAFLD model in rats was established by giving a high-fat diet (HFD), ginsenoside-Rg1 was intragastrically administered 100 mg/kg/d for 8 weeks in NAFLD rat. Serum biochemical indices were measured. Liver tissues were stained with hematoxylin and eosin (HE) and oil red O. Total RNA was extracted from liver and was used for high throughput sequencing to identify the changes of transcriptome. The relevant hub genes were verified by quantitative real-time PCR and western blot. Key findings: Serum biochemical analysis indicated that ginsenoside-Rg1 improved liver function. Additionally, the staining of HE and oil red O indicated ginsenoside-Rg1 could remit pathology process of NAFLD. The transcriptome changes also support this result and reveals Atf3 and Acox2 were key genes. Significance: Taken together, these results suggest that the efficiency of ginsenoside-Rg1 against NAFLD and confirmed that ginsenoside-Rg1 is a potential effective drug in treatment of NAFLD.

关键词： 转录激活因子3   急性肾损伤   慢性肾脏病   作用机制  

摘要： 肾功能不全依据肾功恶化的速度及病因可分为急性肾损伤(AKI)及慢性肾脏病(CKD)。在我国,每年约有140~290万AKI患者入院,院内死亡率高达12.4%[1];经流行病学调查,2017年全球CKD平均患病率为9.1%,较1990年增加了29%,其中近六分之一CKD患者在中国,我国患病总人数高达1.32亿[2],可见AKI及CKD发病率逐渐升高,威胁人群健康,增加社会医疗负担,是亟待解决的健康问题。

关键词： apoptosis   ATF   fluorizoline   ISR   NOXA   prohibitins  

摘要： Fluorizoline is a new synthetic molecule that induces p53-independent apoptosis, in several tumor cell lines and in primary leukemia cells, by selectively targeting prohibitins (PHBs). In this study, we describe how fluorizoline induces BCL-2 homology 3-only protein NOXA, without modulating the protein levels of anti-apoptotic B-cell lymphoma-2 (BCL-2) family members prior to caspase activation, as well as how it synergizes with the BCL-2 and BCL-X(L)inhibitor ABT-737 to induce apoptosis. Interestingly, fluorizolinetreatment triggers the activation of the integrated stress response (ISR) in HeLa and HAP1 cells, with increased eukaryotic translation initiation factor 2 alpha phosphorylation, and induction of ATF3, ATF4, and CHOP. Moreover, PHB downregulation induces similar ISR activation and apoptosis as with fluorizoline treatment. In addition, we studied the essential role of the pro-apoptotic protein NOXA in fluorizoline-induced apoptosis and we describe its mechanism of induction in HeLa and HAP1 cells. Moreover, we identified ATF3 and ATF4 as the transcription factors that bind to NOXA promoter upon fluorizoline treatment. Furthermore, usingATF3andATF4CRISPR HeLa and HAP1 cells, we confirmed that both factors mediate the induction of NOXA and apoptosis by fluorizoline. In conclusion, fluorizoline treatment triggers the activation of the ISR that results in the induction of ATF3 and ATF4, important regulators of NOXA transcription in fluorizoline-induced apoptosis.

关键词： Cancers and neoplasms   Cell migration   Prostate cancer   Hyperexpression techniques   Nuclear staining   Small interfering RNA   Cell staining   Wound healing  

摘要： Activating transcription factor 3 (ATF3) is a key transcription factor involved in regulating cellular stress responses, with different expression levels and functions in different tissues. ATF3 has also been shown to play crucial roles in regulating tumor development and progression, however its potential role in oral squamous cell carcinomas has not been fully explored. In this study, we examined biopsies of tongue squamous cell carcinomas (TSCCs) and found that the nuclear expression level of ATF3 correlated negatively with the differentiation status of TSCCs, which was validated by analysis of the ATGC database. By using gain- or loss- of function analyses of ATF3 in four different TSCC cell lines, we demonstrated that ATF3 negatively regulates the growth and migration of human TSCC cells in vitro. RNA-seq analysis identified two new downstream targets of ATF3, interferon alpha inducible proteins 6 (IFI6) and 27 (IFI27), which were upregulated in ATF3-deleted cells and were downregulated in ATF3-overexpressing cells. Chromatin immunoprecipitation assays showed that ATF3 binds the promoter regions of the IFI6 and IFI27 genes. Both IFI6 and IFI27 were highly expressed in TSCC biopsies and knockdown of either IFI6 or IFI27 in TSCC cells blocked the cell growth and migration induced by the deletion of ATF3. Conversely, overexpression of either IFI6 or IFI27 counteracted the inhibition of TSCC cell growth and migration induced by the overexpression of ATF3. Finally, an in vivo study in mice confirmed those in vitro findings. Our study suggests that ATF3 plays an anti-tumor function in TSCCs through the negative regulation of its downstream targets, IFI6 and IFI27. Author summary Activating transcription factor 3 (ATF3), a stress response gene, has been shown to play either tumor promoting or tumor suppressing functions depending on the type of tumor cell and the stromal context. Here we discovered that ATF3 plays an anti-tumor role in tongue squamous cell carcinoma (

关键词： Cardiac remodeling   Hypertrophy   Heart failure   Pressure overload   Cardiomyocytes fibroblasts   Conditional knockout  

摘要： Background: Activating transcription 3 (ATF3) is a member of the basic leucine zipper family of transcription factors. ATF3 is an immediate early gene expressed following various cellular stresses. ATF3 acts through binding to cyclic AMP response elements found in the promoters of key regulatory proteins that determine cell fate. In the heart, multiple cardiac stresses result in chronic ATF3 expression. Transgenic mice with ATF3 expression in cardiomyocytes clearly demonstrate that ATF3 serves a leading role in heart hypertrophy, cardiac fibrosis, cardiac dysfunction and death. In contrast, the use of ATF3 whole body knockout mice resulted non-conclusive results. The heart is composed of various cell types such as cardiomyocytes, fibroblasts, endothelial and immune cells. The question that we addressed in this study is whether ablation of ATF3 in unique cell types in the heart results in diverse cardiac phenotypes. Methods: ATF3-flox mice were crossed with alpha MHC and Postn specific promoters directing CRE expression and thus ATF3 ablation in cardiomyocytes and myofibroblast cells. Mice were challenged with transverse aortic constriction (TAC) for eight weeks and heart function, ventricle weight, hypertrophic markers, fibrosis markers and ATF3 expression were assessed by qRT-PCR. Results: The results of the study show that ATF3 deletion in cardiomyocytes followed by TAC resulted in reduced heart growth and dampened fibrosis response while ATF3 ablation in myofibroblasts displayed a reduced hypertrophic gene program. Conclusions: TAC-operation results in increased ATF3 expression in both myofibroblasts and cardiomyocytes that promotes a hypertrophic program and fibrotic cardiac growth, respectively. (C) 2020 The Authors. Published by Elsevier B.V.

关键词： ATF3   Hepatocellular carcinoma   Database mining   Prognostic value   Functional network analysis  

摘要： BackgroundThe abnormal expression of activating transcription factor 3 (ATF3), a member of the basic leucine zipper (bZIP) family of transcription factors, is associated with carcinogenesis. However, the expression pattern and exact role of ATF3 in the development and progression of hepatocellular carcinoma (HCC) remain *** used UALCAN, ONCOMINE, Kaplan-Meier plotter, and cBioPortal databases to investigate the prognostic value of ATF3 expression in ***3 was found to be expressed at low levels in multiple HCC tumor tissues. Moreover, low ATF3 expression was significantly associated with clinical cancer stage and pathological tumor grade in patients with HCC. Therefore, low expression of ATF3 was significantly associated with poor overall survival in patients with HCC. Functional network analysis showed that ATF3 regulates cytokine receptors and signaling pathways via various cancer-related kinases, miRNAs, and transcription factors. ATF3 expression was found to be correlated with macrophage infiltration levels and with macrophage immune marker sets in HCC *** data mining methods, we clarified the role of ATF3 expression and related regulatory networks in HCC, laying a foundation for further functional research. Future research will validate our findings and establish clinical applications of ATF3 in the diagnosis and treatment of HCC.

关键词： ASC-J9 (R)   ATF3   Prostate cancer   ATF3 response element   PTK2  

摘要： BackgroundEarly studies indicated that ASC-J9 (R), an androgen receptor (AR) degradation enhancer, could suppress the prostate cancer (PCa) progression. Here we found ASC-J9 (R) could also suppress the PCa progression via an AR-independent mechanism, which might involve modulating the tumor suppressor ATF3 *** lentiviral system was used to modify gene expression in C4-2, CWR22Rv1 and PC-3 cells. Western blot and Immunohistochemistry were used to detect protein expression. MTT and Transwell assays were used to test the proliferation and invasion ***-J9 (R) can suppress PCa cell proliferation and invasion in both PCa C4-2 and CWR22Rv1 cells via altering the ATF3 expression. Further mechanistic studies reveal that ASC-J9 (R) can increase the ATF3 expression via decreasing Glutamate-cysteine ligase catalytic (GCLC) subunit expression, which can then lead to decrease the PTK2 expression. Human clinical studies further linked the ATF3 expression to the PCa progression. Preclinical studies using in vivo mouse model also proved ASC-J9 (R) could suppress AR-independent PCa cell invasion, which could be reversed after suppressing ***-J9 (R) can function via altering ATF3/PTK2 signaling to suppress the PCa progression in an AR-independent manner.

关键词： glioma   brucine   ferroptosis   ATF3   hydrogen peroxide   ER stress   NOX4  

摘要： Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H2O2 via Fenton reaction,in which the role of activating transcription factor 3 (ATF3) remains *** is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica,which has shown potent antitumor activity against various tumors,including *** this study,we showed that brucine inhibited glioma cell growth in vitro and in vivo,which was paralleled by nuclear translocation of ATF3,lipid peroxidation,and increases of iron and ***,brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate(500 μM).Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell ***,knockdown of ATF3 prevented brucine-induced accumulation of iron and H2O2 and glioma cell *** revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER ***3 promoted brucine-induced H2O2 accumulation via upregulating NOX4 and SOD1 to generate H2O2 on one hand,and downregulating catalase and xCT to prevent H2O2 degradation on the other hand.H2O2 then contributed to brucine-triggered iron increase and transferrin receptor upregulation,as well as lipid *** was further verified by treating glioma cells with exogenous H2O2 ***,H2O2 reversely exacerbated brucine-induced ER *** together,ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H2O2 and iron.

关键词： Atherosclerosis   ATF3   Macrophage   Bioinformatics analysis   PI3K-AKT pathway  

摘要： ATF3 (activating transcription factor 3) is a member of the mammalian activation transcription factor/cAMP-responsive element-binding (CREB) family. It plays a role in inflammation and innate immunity, and suggests that ATF3 is associated with atherosclerosis. In our study, we analyzed datasets of atherosclerosis from the NCBI-GEO (Gene Expression Omnibus) database and found that expression levels of ATF3 were lower in macrophages from ruptured atherosclerotic plaques than from stable atherosclerotic plaques. Expression levels of ATF3 correlated with the stability of atherosclerotic plaques. KEGG analysis of different expression genes (DEGs) between ruptured and stable atherosclerotic plaques was performed by Metascape database. The PI3K-AKT pathway may be a potential pathway of the formation of ruptured atherosclerotic plaques. High-fat diet-induced atherosclerosis apoE(-/-)mice were divided into two groups: a model group and an ATF3 overexpression (OE)-group. Tests on atherosclerotic plaques in the aortic root suggested that absence of ATF3 and increase of macrophages may be risk factors for the formation of ruptured atherosclerotic plaques. We found decreased areas of lesions in aortic roots and branches of aortic arch, as well as increased lesional content of macrophages as well as TUNEL-positive areas. Consistent with these results, we found reduced degradation and incidence of elastic plate cracks accompanied by suppressed MMPs expression and transduction pathway protein PI3K/AKT activation. These data suggest that ATF3 is a signaling molecule that mediates the progression and stability of atherosclerotic plaques. ATF3 could be a potential new biomarker for the prognosis of atherosclerosis and may be a therapeutic target to reduce atherosclerosis.

摘要： Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr(-/-) or Apoe(-/-) mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone. Mechanistically, hepatocyte ATF3 enhances high-density lipoprotein (HDL) uptake, inhibits intestinal fat and cholesterol absorption and promotes macrophage reverse cholesterol transport by inducing scavenger receptor group B type 1 (SR-BI) and repressing cholesterol 12 alpha-hydroxylase (CYP8B1) in the liver through its interaction with p53 and hepatocyte nuclear factor 4 alpha, respectively. Our data demonstrate that hepatocyte ATF3 is a key regulator of HDL and bile acid metabolism and atherosclerosis. Xu et al. show that liver ATF3 expression is inhibited by hydrocortisone, thus promoting the development of atherosclerosis through effects on HDL cholesterol and bile acid metabolism.