关键词： Editorials   activating transcription factor 3   cardiac remodeling   fibrosis   hypertrophy   p38 mitogen-activated protein kinases  

摘要： An introduction is presented in which the editor discusses various reports within the issue on topics including hypertensive heart disease, myofibroblasts, and myocyte hypertrophy.

关键词： Genetic effects   ATF3   CDKN1A   Milk production traits   Chinese Holstein  

摘要： Background: Our previous RNA-sequencing study revealed that the ATF3 and CDKN1A genes were remarkably differentially expressed between the mammary glands of lactating Holstein cows with extremely high and low milk protein and fat percentage so that both of them were considered as candidates for milk composition. Herein, we further verified whether these genes have genetic effects on milk production traits in a Chinese Holstein cow population. Results: By re-sequencing the entire coding and regulatory regions, we identified four SNPs in 5'promoter region, two in exons, seven in 3' un-translated region (UTR), and six in 3' flanking region of ATF3 gene, and one SNP in exon 5, two in 3' UTR, and two in 3' flanking region of CDKN1A gene. Of these, only the SNP, c.271C > T (rs442346530), in exon 5 of CDKN1A gene was predicted to result in an amino acid replacement from arginine to tryptophan. Subsequent genotype-phenotype association analysis revealed that 19 SNPs in ATF3 and 5 SNPs in CDKN1A were evidently associated with 305-days milk yield, fat yield, protein yield, or protein percentage (P = < 0.0001 similar to 0.0494). Whilst, no significant SNPs in ATF3 gene were associated with fat percentage in both first and second lactations (P > 0.05), and only two SNPs of CDKN1A gene, c.271C > T (P = 0.0377) and c.*654C > T (P = 0.0144), were markedly associated with fat percentage in the first lactation. Further, linkage disequilibrium (LD) analyses were conducted among the identified SNPs in ATF3 and/or CDKN1A genes to further confirm the association results. We also observed that the four SNPs, g.72834301C > A, g.72834229C > A, g. 72833969A > G, and g.72833562G > T altered the specific transcription factor (TF) binding sites in ATF3 promoter, and one SNP, c.271C > T, changed the CDKN1A protein secondary structure, suggesting they might be the promising potential functional mutations. Conclusion: Our findings first profiled the genetic effects of ATF3 and CDKN1A genes for mi

关键词： neuron   hippocampus   aging   proteasome   mahogunin   survival   ATF3   ubiquitin   stress response  

摘要： A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination.

关键词： CORONARY heart disease treatment   VENTRICULAR remodeling   HEART cells  

关键词： HEART cells   MACROPHAGES   TRANSCRIPTION factors  

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： Apoptosis   Cell death   Alpha-lactalbumin   Histone deacetylase inhibition   Involution NF-kappa B  

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  

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) inhibitor

关键词： ATF3   lung cancer   tumor progression  

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： 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]