关键词： ATF3   elevated hydrostatic pressure   apoptosis   glaucoma  

摘要： AIM：To investigate the effect of activating transcription factor-3（ATF3）-deletion on apoptosis of cultured retinal ganglion cells（RGCs）.METHODS：Three ATF3 siR NA（ATF3-rat-651, ATF3-rat-319, ATF3-rat-520） were constructed, and were transiently transfected into RGC-5 cells. Quantitative real-time polymerase chain reaction（PCR） was used to examine ATF3 expression and the most effective ATF3 siR NA was selected for further studies. Flow cytometry was applied to investigate the effects of ATF3 deletion on RGC-5 apoptosis under elevated hydrostatic pressure. Quantitative realtime PCR and Western blot were performed to validate differentially expressed genes and proteins in ATF3-knockdown RGC-5 ***：ATF3 specific siR NA effectively down-regulated ATF3 expression and significantly inhibited cell apoptosis in RGC-5 cells. Quantitative real-time PCR and Western blot confirmed that ATF3 knockdown remarkably decreased Jun-B and increased c-Jun at both m RNA and protein levels in RGC-5 ***：ATF/cA MP-response element-binding family of transcription factors may be involved in the development of glaucoma and could be novel treatment targets for glaucoma.

关键词： ACTIVATION  

关键词： ATF3   lung cancer   tumor progression   COLON-CANCER   TUMOR-SUPPRESSOR   ATF3 FUNCTIONS   RESPONSE GENE   METASTASIS   INHIBITION   STATISTICS   RECEPTOR   CHINA   P53  

摘要： BackgroundLung cancer remains the most common cause of cancer-related death, with high rates of recurrence and poor outcomes. An abnormally high expression of activating transcription factor 3 (ATF3) in various cancers suggests an oncogenic role; however, its function in lung cancer is largely unknown. MethodsSixty-four pairs of lung cancer tissues were collected for ATF3 expression analysis by quantitative real-time PCR, immunoblotting, and immunohistochemistry staining. Correlations between ATF3 expression with clinicopathological features and overall survival were analyzed. ATF3 expression in a panel of lung cancer cell lines together with normal bronchial epithelial Beas-2B cells was also determined. Human H1299 and A549 cells were used for ATF3 knockdown and/or overexpression assays. Alterations in cell proliferation, cell cycle attribution, migration, and invasion were all assessed in vitro. ResultsIncreased ATF3 messenger RNA and protein expression were observed in lung cancer tissues/cells compared with normal tissues/cells. High tumorous ATF3 expression was significantly correlated with positive advanced tumor grade, lymph node metastasis, and shorter overall survival. Experimentally, we found that RNA interference mediated knockdown of ATF3 significantly inhibited the cell proliferation, cell cycle progression, migration, and invasion capacities of lung cancer cells in vitro, whereas forced expression of ATF3 did the opposite. ConclusionUpregulation of ATF3 in lung cancer promotes cell proliferation, migration, and invasion, and may represent a novel therapeutic target for lung cancer.

关键词： Apoptosis   Cell death   Alpha-lactalbumin   Histone deacetylase inhibition   Involution NF-kappa B   NF-KAPPA-B   KILLS TUMOR-CELLS   POLYACRYLAMIDE-GEL ELECTROPHORESIS   MAMMARY EPITHELIAL-CELLS   CANCER-CELLS   INDUCE APOPTOSIS   GLAND INVOLUTION   HAMLET INTERACTS   LEUKEMIA-CELLS   MILK PROTEIN  

摘要： alpha-lactalbumin is a protein of dual function found in milk of most mammals. alpha-lactalbumin binds beta-1,4galactosyltransferase to form the regulatory subunit for lactose synthesis and has also been shown to cause cell death. This study shows, for the first time, that alpha-lactalbumin isolated in a rare 28 kDa dimeric form induces cell death, while 14 kDa monomeric alpha-lactalbumin is inactive. In contrast to the casein derived and chemically induced alpha-lactalbumin variants, MAL and HAMLET/BAMLET, the effects of 28 kDa alpha-lactalbumin are calcium independent and, unlike MAL and HAMLET, 28 kDa alpha-lactalbumin dimer causes cell death of primary mammary cells and a variety of immortalised cell lines, which are committed to cell death pathways within 1-4 h of exposure. Microarray analysis confirmed that cell death was the result of an apoptotic response. Functional assays determined that the mechanism by which 28 kDa alpha-lactalbumin kills cells involved inhibition of histone deacetylase activity mediated by NF-kB. We also show that 28 kDa alpha-lactalbumin occurs naturally in the milk of cows, goats and sheep, is low in concentration during mid-lactation, but accumulates during milk stasis, consistent with a role in involution. (C) 2017 Elsevier Inc. All rights reserved.

关键词： Insulin-like growth factor-1   Tumor necrosis factor-alpha   Activating transcription factor 3   Growth-associated protein 43   Neurite outgrowth   Neuron   Dorsal root ganglion   ACTIVATING TRANSCRIPTION FACTOR-3   GROWTH-ASSOCIATED PROTEIN-43   ROOT GANGLION NEURONS   FUNCTIONAL RECOVERY   NEURITE OUTGROWTH   NEUROPATHIC PAIN   FACTOR RECEPTOR   NERVOUS-SYSTEM   UP-REGULATION   FACTOR-I  

摘要： Upregulation of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-alpha exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration. The association of IGF-1 with TNF-alpha and the biological effects, produced by interaction of IGF-1 and TNF-alpha, on neuronal outgrowth status of primary sensory neurons are still to be clarified. In the present study, using an in vitro model of primary cultured rat dorsal root ganglion (DRG) neurons, we demonstrated that TNF-alpha challenge at different concentrations elicited diverse biological effects. Higher concentration of TNF-alpha (10 ng/mL) dampened neurite outgrowth, induced activating transcription factor 3 (ATF3) expression, reduced growth-associated protein 43 (GAP-43) expression, and promoted GAP-43 and ATF3 coexpression, which could be reversed by IGF-1 treatment; while lower concentration of TNF-alpha (1 ng/mL) promoted neurite sprouting, decreased ATF3 expression, increased GAP-43 expression, and inhibited GAP-43 and ATF3 coexpression, which could be potentiated by IGF-1 supplement. Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-alpha (10 ng/mL) challenge. In contrast, lower concentration of TNF-alpha (1 ng/mL) had no significant effect on Akt or S6K activation, and IGF-1 administration activated these two kinases. The effects of IGF-1 were abrogated by phosphatidylinositol 3-kinase (PI3K) inhibito

关键词： OXIDATION-SPECIFIC EPITOPES   ATHEROSCLEROSIS   MICE   DIFFERENTIATION   ATF3   MIGRATION   IMMUNITY   IDENTIFICATION   ACCUMULATION   REGULATORS  

摘要： Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (T-FH) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-T-FH cells, leading to PDL1-mediated suppression of TFH cell motility, alteration of T-FH cell differentiation, reduced T-FH abundance and suppression of the proatherogenic T-FH response. Our findings reveal a previously unsuspected role for MZB cells in controlling the T-FH-germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response.

关键词： Saturated fatty acid   HDL   Inflammation   Cell signaling   MAP kinase   ATF3   TOLL-LIKE RECEPTORS   HIGH-DENSITY-LIPOPROTEIN   INDUCED INFLAMMATION   ATF3   EXPRESSION   ACTIVATION   TRANSCRIPTION   GENE   CHOLESTEROL   MODULATION  

摘要： Background and aims: Peripheral insulin resistance is associated with several metabolic abnormalities, including elevated serum fatty acids that contribute to vascular injury and atherogenesis. Our goals were to examine whether saturated fatty acids can modify innate immune responses to subclinical concentrations of lipopolysaccharide (LPS) in endothelial cells, and to explore the underlying pathway and determine whether it is modified by high density lipoprotein (HDL) and other factors commonly altered in insulin resistance. Methods: Physiologic concentrations of palmitic acid were added to human aortic endothelial cells with and without a variety of inhibitors or HDL and measures of cell inflammation and function assessed. Results: Palmitic acid significantly amplified human aortic endothelial cell inflammatory responses to LPS. Similar results were obtained from lipolysis products of triglyceride rich lipoproteins. Metabolism of palmitic acid to ceramide and subsequent activation of PKC-zeta, MAPK and ATF3 appeared critical in amplifying LPS induced inflammation. The amplified response to palmitic acid/LPS was decreased by HDL, dose dependently, and this inhibition was dependent on activation of PI3K/AKT and reduction in ATF3. Conclusions: These results indicate that endothelial cell innate immune responses are modified by metabolic abnormalities commonly present in insulin resistance and provide evidence for a novel mechanism by which HDL may reduce vascular inflammation. (C) 2016 Published by Elsevier Ireland Ltd.

关键词： 2-OhβCD 2-hydroxy-beta-cyclodextrin   ATF3   ATF3 activating transcription factor 3   CEBP CCAAT/ enhancer binding protein   Cell signaling   DAMPs damage-associated molecular pattern molecules   ERK extracellular-signal-regulated kinase   HAECs human aortic endothelial cells   HDL   IL-1β interleukin 1 beta   IL-6 interleukin 6   IL-8 interleukin 8   Inflammation   JNK N-terminal kinase   LPS lipopolysaccharide   MβCD methyl-beta-cyclodextrin   MAP kinase   MAPKs mitogen-activated protein kinases   MIP-1α macrophage inflammatory protein 1 alpha   NF-κB nuclear factor kappa B   PA palmitic acid   PI3K Phosphoinositide 3-kinase   PKC protein kinase C   pPCR quantitative real-time PCR   Saturated fatty acid   TLRs Toll-like receptors  

摘要： Background and aims Peripheral insulin resistance is associated with several metabolic abnormalities, including elevated serum fatty acids that contribute to vascular injury and atherogenesis. Our goals were to examine whether saturated fatty acids can modify innate immune responses to subclinical concentrations of lipopolysaccharide (LPS) in endothelial cells, and to explore the underlying pathway and determine whether it is modified by high density lipoprotein (HDL) and other factors commonly altered in insulin resistance. Methods Physiologic concentrations of palmitic acid were added to human aortic endothelial cells with and without a variety of inhibitors or HDL and measures of cell inflammation and function assessed. Results Palmitic acid significantly amplified human aortic endothelial cell inflammatory responses to LPS. Similar results were obtained from lipolysis products of triglyceride rich lipoproteins. Metabolism of palmitic acid to ceramide and subsequent activation of PKC-ζ, MAPK and ATF3 appeared critical in amplifying LPS induced inflammation. The amplified response to palmitic acid/LPS was decreased by HDL, dose dependently, and this inhibition was dependent on activation of PI3K/AKT and reduction in ATF3. Conclusions These results indicate that endothelial cell innate immune responses are modified by metabolic abnormalities commonly present in insulin resistance and provide evidence for a novel mechanism by which HDL may reduce vascular inflammation. [ABSTRACT FROM AUTHOR]

关键词： Cigarette smoke   Activating transcription factor 3   Interleukin 6   Interleukin 8   Nuclear factor-kappa B   OBSTRUCTIVE PULMONARY-DISEASE   NEGATIVE REGULATOR   INFLAMMATION   CYTOKINE   ATF3   AIRWAY   INTERLEUKIN-8   PATHOGENESIS   INHIBITION   BIOLOGY  

摘要： Airway and lung inflammation is a fundamental hallmark of chronic obstructive pulmonary disease (COPD). Activating transcription factor 3 (ATF3) has been reported to negatively regulate many pro inflammatory cytokines and chemokines. However, little is known about the impact of ATF3 on the inflammatory response of COPD. Since cigarette smoke (CS) is considered to be the most important risk factor in the etiology of COPD, we attempted to investigate the effects and molecular mechanisms of ATF3 in CS-induced inflammation. We observed an increase in the expression of ATF3 in the lung tissues of CS exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. In vitro results indicated that ATF3 inhibition significantly increased the expression of proinflammatory cytokines interleukin 6 (IL6) and interleukin 8 (IL8) in CSE-stimulated HBE cells. Furthermore, in vivo data verified that CS induced inflammatory cell recruitment around the bronchus. In addition, neutrophil infiltration in bronchoalveolar lavage fluid (BALF) of CS-exposed Atf(3-/-) mice was markedly higher than in stimulated WT mice. Finally, ATF3 deficiency increased the in vitro and in vivo expression and phosphorylation of nuclear factor-kappa B (NF-kappa B), a positive mediator of inflammation. Thus, this study shows that ATF3 plays an important role in the negative regulation of CS-induced pro-inflammatory gene expression through downregulating NF-kappa B phosphorylation. (C) 2017 Elsevier B.V. All rights reserved.

关键词： STEM-CELL PROLIFERATION   INNATE IMMUNE-RESPONSES   DROSOPHILA-MELANOGASTER   TISSUE HOMEOSTASIS   SELF-RENEWAL   INFECTION   PATHWAYS   INFLAMMATION   ACTIVATION   EXPRESSION  

摘要： Epithelial barrier function is maintained by coordination of cell proliferation and cell loss, whereas barrier dysfunction can lead to disease and organismal death. JNK signalling is a conserved stress signalling pathway activated by bacterial infection and tissue damage, often leading to apoptotic cell death and compensatory cell proliferation. Here we show that the stress inducible transcription factor ATF3 restricts JNK activity in the Drosophila midgut. ATF3 regulates JNK-dependent apoptosis and regeneration through the transcriptional regulation of the JNK antagonist, Raw. Enterocyte-specific ATF3 inactivation increases JNK activity and sensitivity to infection, a phenotype that can be rescued by Raw overexpression or JNK suppression. ATF3 depletion enhances intestinal regeneration triggered by infection, but does not compensate for the loss of enterocytes and ATF3-depleted flies succumb to infection due to intestinal barrier dysfunction. In sum, we provide a mechanism to explain how an ATF3-Raw module controls JNK signalling to maintain normal intestinal barrier function during acute infection.