关键词： Osthole   Pancreatic cancer   Autophagy   ATF3   mTOR  

摘要： Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide, and few effective therapeutics are available. Osthole (OST), a natural coumarin, has been proven to be a potential anticancer compound. In this study, we found that OST significantly inhibited PC growth both in vitro and in vivo. Notably, the anti-PC effect of OST is mediated by excessive autophagosome accumulation and consequent apoptosis in PC cells. Mechanistically, OST increased the number of autophagosomes via two pathways. First, OST induced autophagy initiation by suppressing the Akt/mTOR signaling pathway. Second, OST induced autophagic arrest by blocking autophagosome-lysosome fusion. Consistently, inhibition of autophagy initiation restored PC cell growth, whereas autophagic flux inhibitors exacerbated the antitumor effect of OST in PC cells, suggesting a cytotoxic role of OST-induced autophagosome accumulation. In addition, we found that OST upregulates the expression of activating transcription factor 3 (ATF3), resulting in inactivation of the Akt/mTOR signaling pathway and autophagy initiation in PC cells. ATF3 overexpression increased the activation of autophagy, and inhibition of ATF3 expression decreased autophagy. Taken together, our study provides new insights into the OST-induced growth inhibitory effect on PC cells, suggesting a promising potential therapeutic role of OST for PC treatment.

关键词： 激活转录因子3   ATF3   脂肪组织   脂质代谢  

摘要： 激活转录因子3(activating transcription factor3,ATF3)属于转录因子ATF/CREB(cAMP response element-binding)家族成员,参与葡萄糖代谢,免疫反应和肿瘤发生等生理过程,同时还参与动物脂肪组织的调节过程。本文主要总结近年来国内外关于ATF3基因在脂肪组织中的调控作用,为该基因在畜牧业肉用品种选育和基因功能研究提供理论基础。

关键词： Apoptosis   Necroptosis   Intestinal homeostasis   Mettl3   m6A modification   RIPK1  

摘要： Intestinal epithelial cells(IECs)are pivotal for maintaining intestinal homeostasis through self-renewal,proliferation,differentiation,and regulated cell *** apoptosis and necroptosis are recognized as distinct pathways,their intricate interplay remains *** this study,we report that Mettl3-mediated­m6A modification maintains intesti-nal homeostasis by impeding epithelial cell ***3 knockout induces both apoptosis and necroptosis in *** different modes of cell death with specific inhibitors unveils that RIPK1 kinase activity is critical for the cell death triggered by Mettl3 ***,this occurs via the­m6A-mediated transcriptional regulation of Atf3,a transcription factor that directly binds to Cflar,the gene encoding the anti-cell death protein *** inhibits RIPK1 activity,thereby suppressing downstream apoptotic and necroptotic ***,these find-ings delineate the essential role of the METTL3-ATF3-cFLIP axis in homeostatic regulation of the intestinal epithelium by blocking RIPK1 activity.

摘要： Reactivation of endogenous retroviruses (ERVs) has been proposed to be involved in aging. However, the mechanism of reactivation and contribution to aging and age-associated diseases is largely unexplored. In this study, we identified a subclass of ERVs reactivated in senescent cells (termed senescence-associated ERVs (SA-ERVs)). These SA-ERVs can be bidirectional transcriptionally activated by activating transcription factor 3 (ATF3) to generate double-stranded RNAs (dsRNAs), which activate the RIG-I/MDA5-MAVS signaling pathway and trigger a type I interferon (IFN-I) response in senescent fibroblasts. Consistently, we found a concerted increased expression of ATF3 and SA-ERVs and enhanced IFN-I response in several tissues of healthy aged individuals and patients with Hutchinson-Gilford progeria syndrome. Moreover, we observed an accumulation of dsRNAs derived from SA-ERVs and higher levels of IFN beta in blood of aged individuals. Together, these results reveal a previously unknown mechanism for reactivation of SA-ERVs by ATF3 and illustrate SA-ERVs as an important component and hallmark of aging.

关键词： Breast cancer   TGF-beta 1   ATF3   Non-coding RNAs   MicroRNAs   Circular RNAs  

摘要： A potent growth inhibitor for normal mammary epithelial cells is transforming growth factor beta 1 (TGF-beta 1). When breast tissues lose the anti-proliferative activity of this factor, invasion and bone metastases increase. Human breast cancer (hBC) cells express more activating transcription factor 3 (ATF3) when exposed to TGF-beta 1, and this transcription factor is essential for BC development and bone metastases. Non-coding RNAs (ncRNAs), including circular RNAs (circRNAs) and microRNAs (miRNAs), have emerged as key regulators controlling several cellular processes. In hBC cells, TGF-beta 1 stimulated the expression of hsa-miR-4653-5p that putatively targets ATF3. Bioinformatics analysis predicted that hsa-miR-4653-5p targets several key signaling components and transcription factors, including NFKB1, STAT1, STAT3, NOTCH1, JUN, TCF3, p300, NRF2, SUMO2, and NANOG, suggesting the diversified role of hsa-miR-4653-5p under physiological and pathological conditions. Despite the high abundance of hsa-miR-4653-5p in hBC cells, the ATF3 level remained elevated, indicating other ncRNAs could inhibit hsa-miR-4653-5p's activity. In silico analysis identified several circRNAs having the binding sites for hsa-miR-4653-5p, indicating the sponging activity of circRNAs towards hsa-miR-4653-5p. The study's findings suggest that TGF-beta 1 regulates circRNAs and hsa-miR-4653-5p, which in turn affects ATF3 expression, thus influencing BC progression and bone metastasis. Therefore, focusing on the TGF-beta 1/circRNAs/hsa-miR-4653-5p/ATF3 network could lead to new ways of diagnosing and treating BC.

关键词： ATF3   Ferritin   RNA expression   Osteoarthritis   Immune infiltration   RNA analysis method  

摘要： Osteoarthritis (OA) is a widespread joint disorder that is primarily noted for the progressive degeneration of joint cartilage, accompanied by a significant inflammatory response. Recently, there has been a growing interest in understanding the roles of ATF3 and ferritin-related RNAs in the context of immune responses and inflammatory processes. However, their specific functions and mechanisms in the progression of osteoarthritis have remained largely ambiguous and underexplored. The primary objective of this study was to thoroughly investigate the changes in expression levels of ATF3 and ferritin-related RNAs within osteoarthritic tissues, as well as to examine their potential effects on immune cell infiltration. To achieve this, advanced RNA sequencing technology was employed to meticulously analyze the expression levels of ATF3 and the ferritin-related RNAs. Furthermore, bioinformatics methods were utilized to assess the infiltration patterns of various immune cells and to explore the correlation between these infiltration patterns and the expression levels of RNA. The findings from this study revealed that both ATF3 and ferritin-related RNAs exhibited significantly elevated expression levels in tissues affected by osteoarthritis. Additionally, the immunoinfiltration analysis highlighted a positive correlation between the degree of infiltration of T cells and macrophages and the levels of ferritin-related RNAs. Such findings suggest that the presence of these immune cells is intricately linked to the expression of ferritin-associated RNAs. Further investigations indicated that ferritin-associated RNAs play a critical role in the progression of osteoarthritis by modulating inflammatory responses and influencing the activity of various immune cells. Consequently, both ATF3 and ferritin-related RNAs demonstrate abnormal expression patterns in osteoarthritis, which are closely associated with the infiltration of immune cells.

关键词： 1 alpha   25-hydroxyvitamin D 3   Rotavirus   Ferroptosis   IPEC-J2 cell  

摘要： Rotavirus (RV) mainly infects mature intestinal epithelial cells and impairs intestinal absorption function, which leads to the death of infected cells and eventually fatal diarrhea. Ferroptosis is a novel regulatory cell death pattern, which can be caused by virus infection. 1 alpha,25-hydroxyvitamin D3 (1,25D3) has an anti-RV infection effect and can regulate ferroptosis. However, whether RV infection can induce ferroptosis, and whether 1,25D3 can inhibit RV infection by regulating ferroptosis has not yet been studied. Present study shows that RV infection or erastin treatment induces IPEC-J2 cell death, which results in mitochondrial shrinkage, decreased mitochondrial membrane potential (MMP) and glutathione (GSH) content, increased MMP, intracellular Fe2+, reactive oxygen species (ROS), and malondialdehyde (MDA) contents. Meanwhile, ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), and deferoxamine (DFO) treatment can effectively reverse the increase of intracellular Fe2+, ROS and MDA levels induced by RV infection. Moreover, RV infection increases activating transcription factor 3 (ATF3) mRNA and protein expressions, and inhibited SLC7A11 and glutathione peroxidase 4 (GPX4) expressions, which was partially alleviated by siATF3. 1,25D3 treatment significantly eliminates RV induced ferroptosis via ATF3-SLC7A11-GPX4 axis. Therefore, these results reveals that RV infection induces ferroptosis in IPEC-J2 cell and 1,25D3 alleviates RV induced ferroptosis by regulating the ATF3-SLC7A11-GPX4 axis.

关键词： Acute lung injury   Alveolar macrophages   Activating transcription factor 3   NLRP3   Inflammation   Pyroptosis  

摘要： Background: Acute lung injury (ALI) ranks among the leading reasons for death in septic patients. As an essential transcription factor associated with stress, activating transcription factor 3 (ATF3) participates in a variety of pathophysiological processes, including immunology and inflammation. However, the specific mechanism of ATF3 in pyroptosis of sepsis-induced ALI remains elusive. Methods: A mouse model of ALI was established by administering lipopolysaccharide (LPS) in vivo and LPS combined with adenosine triphosphate (ATP) in vitro to compare differences in ATF3 expression level. The role of ATF3 in pyroptosis was then assessed by knocking down ATF3 using small interfering RNA. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha, IL-1 beta, and IL-18 in mouse serum and cell culture supernatants were measured using enzyme-linked immunosorbent assay. Moreover, immunohistochemistry, immunofluorescence, Western blotting, co-immunoprecipitation, and quantitative reverse transcription polymerase chain reaction were employed for examining pyroptosis and pyroptotic pathways. Results: Both in vitro and in vivo ALI models were successfully established. LPS could activate the pyroptotic signaling pathway, and the expression level of ATF3 peaked 6 h after LPS and ATP stimulation in vitro. ATF3 could interact with NLRP3 and potentially influence the assembly of the inflammasome. This mechanism could involve the inhibition of the classical pyroptotic pathway, including Caspase-1 and Gasdermin D transcription and cleavage, as well as the inhibition of the non-classical pyroptotic pathway, including transcription and cleavage of Caspase-11. Conclusion: The results indicated that inhibition of ATF3 could exacerbate sepsis-induced ALI by regulating pyroptotic pathways. The potential of targeting ATF3 as a future treatment strategy for ALI is noteworthy.

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

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.