关键词： Albiflorin   Acetaminophen-induced liver injury   ATF3   Blood-biliary barrier  

摘要： Background: Acetaminophen-induced hepatotoxicity remains a clinical challenge with limited targeted therapeutic options. While recent advances have identified blood-biliary barrier disruption as a critical pathogenic mechanism, effective interventions preserving this barrier are notably lacking. Albiflorin, a key bioactive constituent of Paeonia lactiflora Pall., exhibits unique bile acid modulation along with antioxidant and antiinflammatory activities, suggesting its potential efficacy in preventing acetaminophen-induced liver injury. However, its specific role and underlying mechanisms in alleviating acetaminophen-induced hepatotoxicity remain unclear. Objective: This study's objective was to examine the pharmacological effects and primary molecular mechanisms of albiflorin in alleviating acetaminophen-induced liver injury. Methods: An acetaminophen-induced liver injury mouse model was created using a 300 mg/kg dose of acetaminophen. The hepatoprotective effects of albiflorin were assessed through histological and biochemical analyses. Blood-biliary barrier integrity was evaluated via Evans blue dye tests, immunofluorescence, and bile acid assays. Transcriptomic analysis, gene overexpression and interference techniques, and ChIP-qPCR were employed to explore the molecular mechanisms underlying the protective effects of albiflorin. Results: Albiflorin significantly reduced acetaminophen-induced liver injury, as evidenced by improved biochemical profiles and hepatocyte morphology. It also prevented increases in blood-biliary barrier permeability and bile acid levels. RNA sequencing identified 3,184 differentially expressed genes, revealing critical pathways involved in maintaining blood-biliary barrier integrity. AF reversed the acetaminophen-induced changes in the expression of genes related to the blood-biliary barrier, particularly occludin, claudin 5, ABCG5, and ABCG8. Albiflorin protected the blood-biliary barrier and mitigated acetaminophen-induced liver inju

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： 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： 翼状胬肉   ATF3   Smad4   相互作用   初步探究  

摘要： 目的 初步探究转录激活因子3(ATF3)与Smad家族成员4(Smad4)在翼状胬肉中的表达及其相互作用。方法 通过生物信息学方法来分析NCBI数据库中的两套数据集GSE51995和GSE2513,筛选出以正常结膜作为对照时，翼状胬肉的关键差异表达基因ATF3。并通过实时荧光定量反转录聚合酶链反应(RT-qPCR)进一步检测生物信息学分析找出的差异基因。最后结合文献查找并通过基因转录调控数据库(GTRD)预测是否存在可能与目标基因结合的靶基因Smad4,RT-qPCR验证Smad4在正常结膜与翼状胬肉组织中的表达情况，并通过免疫共沉淀(Co-IP)探究ATF3与Smad4蛋白在翼状胬肉中是否存在相互作用。结果 生物信息学分析结果显示，以正常结膜组织为对照，翼状胬肉组织中存在有显著性差异的低表达基因ATF3(P<0.05)。RT-qPCR实验显示，与正常结膜组织相比，ATF3在翼状胬肉组织中低表达(P<0.001)。数据库(GTRD)中检索出Smad4基因与ATF3有两个结合位点，提示可能与ATF3存在相互作用。与正常结膜相比，RT-qPCR显示翼状胬肉组织中Smad4表达下调(P<0.01),Co-IP结果显示，在使用ATF3抗体进行免疫沉淀时，翼状胬肉组织中Smad4结合量增加(P<0.05)。结论 ATF3与Smad4在翼状胬肉中存在相互作用，二者在翼状胬肉组织中的低表达及其相互作用可能与翼状胬肉的发病相关。

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.