关键词： ATF3   Axon regeneration   Bioenergetics   DRG neurons   Estrogen receptor   Mitochondria   PGC-1 alpha  

摘要： Adult rat dorsal root ganglion (DRG) sensory neurons express estrogen receptors (ERs) alpha and beta. Estrogen regulates multiple aspects of the nervous system including development, survival, and axonal outgrowth of DRG neurons. While previous studies have established estrogen's neuroprotective role in these neurons, the specific ER subtypes and downstream signaling pathways mediating these effects remain poorly defined. The objective of our study was to investigate the effects of 17 beta-estradiol (E2) on mitochondrial function and axonal regeneration of cultured DRG neurons and explore the pathways by which E2 acts. We observed that E2 treatment upregulated the levels of phosphorylated AMP-activated protein kinase (AMPK). E2 also increased the levels of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) and activating transcription factor 3 (ATF3), which are proteins involved in mitochondrial biogenesis and axonal regeneration. The Seahorse assay showed that E2 elevated basal respiration in cultured DRG neurons. Additionally, E2 treatment for 24 h significantly increased total neurite outgrowth of DRG neurons. Pharmacological inhibition of AMPK using Compound C inhibited E2-mediated increases in ATF3 expression and neurite outgrowth. The Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKK beta) inhibitor STO-609 blocked E2-mediated AMPK activation. Furthermore, we assessed whether these effects were mediated by ER alpha or ER beta by using the ER alpha selective agonist propyl pyrazole triol (PPT) and ER beta selective agonist diarylpropionitrile (DPN). PPT upregulated phosphorylated AMPK levels and increased total neurite outgrowth, whereas DPN was ineffective. The results demonstrate that E2 acts through ER alpha to promote neurite outgrowth via a pathway involving activation of CaMKK beta/AMPK in adult DRG neurons. Our findings identify ER alpha-mediated AMPK activation as a therapeutic target for enhancing neuronal rege

关键词： Wound healing   ATF3   Retin-A   Antimicrobial peptides  

摘要： Background: Wound healing is a complex and regulated process that involves the coordinated action of key signaling pathways. Activating transcription factor 3 (ATF3) is a stress-inducible protein that has recently emerged as a critical modulator of cellular responses to injury, including those involved in wound healing. Aim: The aim of this study was to explore the repurposing of existing pharmacological agents to activate ATF3 and evaluate their potential to enhance wound healing factors. Methods: We selected three compounds: retin-A, furosemide, and acrivastine based on their ability to modulate ATF3 expression and assessed their effects on wound healing processes in primary cell cultures. We evaluated wound healing-related genes such as LL-37, HBD-2, HBD-3, and VEGFA by qPCR, and a wound healing scratch assay using keratinocytes was conducted to evaluate cell migration. Results: Interestingly, retin-A induced the expression of key wound healing-related genes, including HBD-2, HBD-3, LL-37, and VEGF. Also, retin-A was the only compound showing wound healing effects, while furosemide and acrivastine did not exhibit any noticeable activity. Conclusion: Our research highlights the potential of retin-A as therapeutic agents to improve wound healing, particularly in chronic wound models.

关键词： activating transcription factor 3   Alzheimer's disease   cell division cycle 42/p38 mitogen-activated protein kinase signaling   dedicator of cytokinesis 8   microglia  

摘要： Background The involvement of microglia is likely to be pivotal in the pathogenesis of Alzheimer's disease (AD) by modulating the deposition of amyloid-beta (A beta) plaques. The deletion of Dedicator of cytokinesis 8 (DOCK8) has a protective effect in mouse with neurodegenerative diseases. Objective To explore the underlying mechanism of DOCK8 in AD. Methods In present study, we first the detected the expression of DOCK8 in the hippocampal tissue of APP/PS1 mice. Then, the expression of DOCK8 was knocked down in the hippocampal tissue of APP/PS1 mice, and the effects of DOCK8 down-regulation on cognitive function, the microglia migration around A beta plaques, and the cell division cycle 42 (Cdc42)/p38 mitogen-activated protein kinase (MAPK) signaling pathway were detected. Next, the effects of DOCK8 knockdown on A beta-induced migration and activation of BV-2 cells as well as the MAPK signaling pathway were detected. Finally, the transcriptional regulation of DOCK by transcription factor 3 (ATF3) was detected by a dual luciferase reporter assay. Results DOCK8 expression exerts a significant upregulation in the hippocampus of APP/PS1 mice. However, following the DOCK8 knockdown, there was a significant recovery in the results of the behavioral tests and a notable reduction in microglial expression. Moreover, the high expression of DOCK8 mediated by ATF3 successfully triggered the Cdc42/p38 MAPK signaling pathway, thereby enhancing the migration and recruitment of microglia towards senile plaques, accelerating the production of A beta plaques. Conclusions ATF3-mediated high expression of DOCK8 accelerates the production of A beta plaques, and participates in the pathogenesis of AD.

关键词： Metformin   ferroptosis   skin cutaneous melanoma   ATF3   RNA-seq  

摘要： Background: To explore the effects of metformin on the proliferation and ferroptosis of skin cutaneous melanoma (SKCM) and its potential molecular mechanisms, providing a new theoretical basis and strategy for the treatment of cutaneous melanoma. Methods: The CCK-8 experiment was used to detect the effect of metformin on the proliferation of skin cutaneous melanoma cells. Kits were used to detect glutathione (GSH) content, reactive oxygen species (ROS), lipid peroxide (LPO), and malondialdehyde (MDA) levels to evaluate ferroptosis-related indicators. RNA-seq sequencing and related analyses were used to screen differentially expressed genes and explore their involved biological functions and signaling pathways. Western blot was used to detect the expression levels of ATF3 and NRF2 proteins and analyze the regulatory effect of metformin on the ATF3/NRF2 axis. Results: Metformin significantly reduced the proliferation ability of skin cutaneous melanoma cells. The treated cells showed a decrease in GSH content and an accumulation of ROS, LPO, and MDA, suggesting that ferroptosis was regulated. RNA-seq analysis found 2068 differentially expressed genes, of which 897 were up-regulated and 1171 were down-regulated. The related pathways such as iron metabolism disorders and ferroptosis were activated. After metformin treatment, the expression of ATF3 mRNA in cells increased and was positively correlated with the concentration, while the expression in SKCM tissues decreased. At the same time, the expression of ATF3 protein increased and the expression of NRF2 protein decreased, suggesting that metformin may induce ferroptosis through the ATF3/NRF2 axis. Conclusion: Metformin can induce ferroptosis by regulating ATF3/NRF2 axis, which may be a novel strategy for improving the treatment of skin cutaneous melanoma.

关键词： ATF3   axon regeneration   facial nerve   neuropeptide   RAG  

摘要： Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce 'effector' RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide (Vip), Ngf, Grp, Gal, Pacap) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types.

关键词： Intervertebral disc degeneration   BATF2   ATF3   Mitochondrial dysfunction   Mitochondrial redox homeostasis  

摘要： Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, spinal instability, disc herniation and spinal stenosis, which is a serious risk to human health, yet its molecular mechanisms remain unknown. The basic leucine zipper ATF-like transcription factor 2 (BATF2) has been reported to play important roles in regulating cell proliferation, apoptosis, and inflammatory responses;however, its specific role in IVDD remains unknown. We firstly demonstrated BATF2 expression was significantly upregulated in degenerated nucleus pulposus (NP) tissues. Functional assays demonstrated that BATF2 overexpression promoted nucleus pulposus cell (NPC) apoptosis and extracellular matrix (ECM) catabolism in vitro and vivo. It is further demonstrated that BATF2 impairs mitochondrial function by disturbing mitochondrial redox homeostasis. Mechanistically, BATF2 stabilizes the activating transcription factor 3 (ATF3) by inhibiting the ubiquitination modification of ATF3. Notably, ATF3 overexpression accelerated NPC apoptosis and ECM degradation. More importantly, ATF3 knockdown reversed the effects of BATF2-induced mitochondrial dysfunction and IVDD progression. These results suggest that BATF2-ATF3 axis disrupts mitochondrial redox homeostasis to impair mitochondrial function, thereby exacerbating the progression of IVDD. Targeting BATF2-ATF3 axis could provide a potential strategy for IVDD treatment.

关键词： ATF3   Ischemic stroke   Genetic susceptibility   Single-nucleotide polymorphisms  

摘要： BackgroundGenetic factors play an important role in ischemic stroke (IS) onset. Activating transcription factor 3 (ATF3) is a known IS biomarker;however, the association between ATF3 polymorphisms and susceptibility to IS remains unclear. Therefore, we aimed to explore the association between ATF3 single-nucleotide polymorphisms (SNPs) and genetic susceptibility to IS in a population in Dali, Yunnan, *** included 145 patients with IS and 127 healthy controls in this case-control study. ATF3 SNP sites (rs1105899, rs1008737, rs1195474, and rs1195472) were genotyped using SNaPshot *** serum glucose (VSG), white blood cell count, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and systolic blood pressure (SBP) were IS risk factors;VSG had the highest impact on IS susceptibility, whereas SBP had the lowest. Genotype distributions of rs1105899, rs1008737, and rs1195472 polymorphisms in the control group conformed to the Hardy-Weinberg equilibrium. Association analysis between ATF3 polymorphisms and IS risk showed that rs1105899, rs1008737, and rs1195474 ATF3 polymorphisms were not significantly associated with IS risk. In the codominant and superdominant model of the rs1195472 [C/T] loci, CT genotype can reduce the risk of stroke, compared with TT and CC genotypes. Haplotype AGAC was an inhibitory factor for IS. The GTEx database showed that the rs1195472 CT genotype increased ATF3 expression and was associated with its expression in individual *** rs1195472 polymorphism was associated with IS risk in our study population;no significant correlation was noted between rs1105899, rs1008737, and rs1195474 polymorphisms and IS.

关键词： ATF3   cellular senescence   human periodontal ligament cell   osteoclast differentiation   periodontal diseases  

摘要： Oral cellular aging plays a critical role in the pathogenesis of chronic periodontitis and alveolar bone resorption. Although activating transcription factor 3 (ATF3) has been implicated as a senescence-associated factor, its specific role in periodontal ligament cell (PDLC) senescence remains unclear. Human PDLCs were exposed to lipopolysaccharide (LPS, 1 mu g/mL) and nicotine (5 mM) for 3 days to induce senescence. ATF3 expression was silenced using siRNA. The expression of senescence-associated secretory phenotype (SASP) factors (IFN gamma, IL6, IL8, TNF alpha, and IL1 beta) and the secretion of nitric oxide (NO) and prostaglandin E2 (PGE2) were assessed by RT-PCR and immunoassay. Conditioned media (CM) from these cells were applied to mouse bone marrow macrophages (BMMs) to evaluate osteoclast differentiation and bone resorption. In addition, key signaling pathways, including STAT3, ERK, NF-kappa B (p65), and AP-1, were investigated by Western blotting and immunofluorescence. ATF3 knockdown markedly reduced the LPS/nicotine-induced expression of SASP factors and decreased NO and PGE2 levels. CM from ATF3-silenced PDLCs markedly inhibited osteoclast differentiation, as evidenced by reduced tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and diminished bone resorption. Moreover, ATF3 inhibition led to a decreased RANKL/OPG ratio and attenuated the phosphorylation of STAT3 and ERK, along with the reduced nuclear translocation of p65 and AP-1 components. These findings suggest that ATF3 plays a critical role in mediating cellular senescence and osteoclastogenesis in PDLCs. Targeting ATF3 may represent a novel therapeutic strategy for managing age-related oral diseases, such as chronic periodontitis.

关键词： Arthritis   Senescence   Meniscus   Chondrocyte   scRNA-seq  

摘要： BackgroundMeniscus degeneration contributes to knee arthritis progression, but the cellular and molecular mechanisms of meniscus aging remain poorly understood. We aimed to characterize age-related changes in the rat meniscus using single-cell RNA sequencing (scRNA-seq) and identify key pathogenic cell populations and *** tissues from young (12 weeks) and aged (24 months) rats were processed for histology, flow cytometry, and scRNA-seq. Bioinformatics tools, including Seurat, Monocle 2, and CellChat, were used to analyze cellular composition, pseudotime trajectories, and intercellular communication. Senescence-related features and signaling pathways were *** joint of aged rats exhibited higher Osteoarthritis Research Society International (OARSI) scores and synovial inflammation. scRNA-seq revealed three major chondrocyte subpopulations: Sox9 + stable chondrocytes, Fndc1 + fibrochondrocytes, and Atf3 + senescent chondrocytes. Aging caused a significant increase in Atf3 + senescent chondrocytes, characterized by the expression of senescence markers (Cdkn1a/Cdkn2a) and activation of inflammatory pathways such as tumor necrosis factor (TNF) and nuclear factor-kappa B (NF-kappa B). These cells were predominantly located at the endpoint of differentiation trajectories. CellChat analysis identified the ANGPTL4-SDC4 axis as a key signaling pathway mediated by Atf3 + cells. Immunostaining confirmed elevated Angiopoietin-Like Protein 4 (ANGPTL4) expression in aged *** identified Atf3 + senescent chondrocytes as a key pathogenic population in the aging meniscus, driving degeneration via the ANGPTL4 pathway. Targeting Atf3 + cells or ANGPTL4 signaling may offer new therapeutic strategies for age-related meniscus degeneration and arthritis.

关键词： Leucine-rich alpha-2-glycoprotein 1   Structural features   Ligand-receptor interactions   Biomarkers   Therapeutic potential   ADCs   Antibody-drug conjugates   Apaf-1   Apoptotic protease activating factor-1   ATF3   Activating transcription factor 3   AUC   Area under the curve   ceRNA   Competing endogenous RNA   Cytc   Cytochrome   c   EMT   Epithelial-mesenchymal transition   ENG   Endoglin   GPCR   G protein-coupled receptor   HDR   Homologous recombination repair   HER   Human epidermal growth factor receptor   HIF-1α   Hypoxia-inducible factor-1α   HUVECs   Human umbilical vein endothelial cells   lncRNAs   Long non-coding RNAs   LPHN2   Latrophilin-2   LRG1   Leucine-rich alpha-2-glycoprotein 1   LRR   Leucine-rich repeat   MMAE   Mitotic payload monomethyl auristatin E   NEAT1   Nuclear paraspeckle assembly transcript 1   NETs   Neutrophil extracellular traps   NF-κB   Nuclear factor kappa-B   NHEJ   Non-homologous end joining   PAA   Pediatric acute appendicitis   PART1   Prostate androgen regulatory transcript 1   PDCs   Peptide-drug conjugates   PPARβ/δ   Peroxisome proliferators-activated receptor β/δ   PROTACs   Proteolysis-targeting chimeras   sgRNA   Stranded guide RNA   STAT3   Signal transducer and activator of transcription 3   TGFβ   Transforming growth factor-β   TGFβRs   TGFβ receptors   TβRI   TGFβ type I   VEGFR   VEGF receptor  

摘要： Background As the structural characterization of the Leucine-rich alpha-2-glycoprotein 1 (LRG1) protein progresses, its functional diversity has been increasingly unveiled, highlighting its clinical relevance in elucidating disease pathogenesis and identifying potential therapeutic targets. Aim of review Grounded in structural biology principles, this review systematically examines the regulatory mechanisms, pathological functions, and intervention strategies associated with LRG1, providing a theoretical foundation for translating these insights into clinical drug therapies. Key scientific concepts of review LRG1, distinguished by its leucine-rich repeat motifs, plays a pivotal role in various physiological and pathological processes. This review presents a comprehensive analysis of LRG1′s multifaceted characteristics and its implications in disease. Initially, the regulatory mechanisms modulating LRG1 gene expression are detailed, encompassing both transcriptional and post-transcriptional controls. The structural attributes and distributions of LRG1 are subsequently outlined, with an emphasis on the functional relevance of its leucine-rich repeat motifs. Furthermore, the review elaborates on the molecular interactions through which LRG1 engages with distinct receptors, triggering downstream signaling pathways involved in pathological processes. Finally, current therapeutic approaches targeting LRG1 and its receptors are summarized, alongside prospective research avenues for innovative therapeutic development.