Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Methods: Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. Results: CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Conclusions: Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers.

Steroid-sensitive cancers (e.g., breast, ovarian, uterine, and prostate cancers) are difficult to control and frequently metastasize to lymph nodes, bone, or lung. Although endocrine research has greatly advanced our identification of the direct roles of steroid sex hormones such as androgens and estrogens on tumor cells in promoting metastasis or recurrence (e.g., treatment with gonadotropin releasing hormone agonists/antagonists, aromatase inhibitors, and estrogen and androgen receptor antagonists), mechanistic insight regarding indirect effects of steroid hormones, including how the innate immune system responds to cancer and is influenced by steroid hormones, is lacking. Despite technological advances in engineering more robust adaptive immunity to combat tumor growth (e.g., CART or checkpoint inhibitors), there remains a relative lack of investigation into the role of innate immunity as a key defense system. Here we discuss recent studies that highlight the significance of neutrophils and their response to tumorigenic conditions with or without steroid hormones in animal models of cancer. We will describe relationships between steroid hormones and neutrophils, with a specific focus on neutrophil extracellular traps (NETs), and how these interactions modulate tumor growth and invasion. Together, these data indicate that combinatorial regulation of both innate and adaptive immunity in the context of tumorigenesis may improve outcomes in cancer therapies.

Na+,K+-ATPase possesses a highly conserved glycine (G358 in the α3 isoform) that-together with a nearby isoleucine (I363 in α3)-is targeted by mutations causing some of the most severe neurological phenotypes of the clinical spectrum of α3-Na+,K+-ATPase mutations. The disease mutations α3-G358V and α3-I363N affect Na+ and K+ transport to an extent incompatible with cell growth. However, alanine replacement of the corresponding glycine G363 in the α1 isoform is compatible with cell growth, allowing the effects on Na+,K+-ATPase function to be addressed using enzymatic assays on plasma membranes isolated from transfected cells. Occlusion of Na+ appears to be defective in mutant G363A, resulting in a reduced rate of phosphorylation from ATP. Furthermore, the mutation displaces the major conformational equilibrium of Na+,K+-ATPase such that the K+-occluded state is destabilized and occluded K+ is released faster, thereby leading to accumulation of a non-productive state without bound Na+ or K+. The critical function of the glycine can be ascribed to a strategic location at the bending point between an α helix and a β strand, where it connects the catalytic ATP hydrolysis site in the cytoplasmic P domain with the ion-binding region in the membrane and coordinates important intramolecular domain movements during the Na+,K+-ATPase transport cycle.

Mastitis is a common inflammatory disease that harms mammary gland health. Its development is closely linked to dysregulated inflammatory signaling. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, has potential anti-inflammatory effects. However, its molecular mechanism in mastitis prevention remains unclear. In this study, we used both in vivo and in vitro models to evaluate how EPA pretreatment regulates mastitis-related inflammatory signaling. Transcriptome analysis showed that differentially expressed genes after EPA treatment were mainly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In an LPS-induced mastitis model, EPA restored the LPS-reduced PPARγ protein level and suppressed NF-κB p65 activation, consistent with reduced nuclear translocation of p65. Similar effects were observed in mammary epithelial cells, where EPA inhibited NF-κB activation at 50 and 100 μM. Functional experiments further showed that a PPARγ agonist mimicked the inhibitory effect of EPA on p65, whereas PPARγ antagonist partially abrogated EPA-mediated inhibition of p65. Collectively, these data indicate that EPA attenuates mastitis-associated inflammation at least in part through the PPARγ-NF-κB axis.

Oxidative stress is characterised by the production of free radicals in higher amounts than the antioxidant scavenging capacity. This may cause damage to several organs especially the main site of detoxification, the liver. In this study, the antioxidant activity of five novel lipophilic fluoroquinolones (FQs) derivatives was evaluated against oxidative stress induced by acetaminophen (APAP) and carbon tetrachloride (CCl4). Sixty-four male Wistar rats were divided into two oxidative-stress models. FQ compounds (25 mg/kg) were administered six hours after CCl4 or APAP administration. Serum liver enzymes including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Changes in antioxidant parameters were determined in the serum including measurement of total antioxidant status and reduced-glutathione levels as well as catalase, glutathione peroxidase and superoxide dismutase activities. Additionally, molecular docking analyses were performed against catalase, CYP3A4, and Keap-1 to elucidate the potential molecular interactions underlying the observed biological activities. A significant decrease in ALT and AST levels was seen following FQ compound administration in both models. In addition, FQ compounds exhibited excellent antioxidant activity, leading to increased antioxidant enzyme activity, high total antioxidant status, and elevated reduced-glutathione levels. The docking results revealed that compound 4A exhibited the highest binding affinities toward catalase, CYP3A4, and Keap-1. These interactions suggest a possible enhancement of catalase activity, modulation of CYP3A4, and activation of the Keap-1/Nrf2 signalling pathway. Overall, these findings demonstrate the promising therapeutic potential on hepatic injury and oxidative stress of the novel FQ derivatives.

Insulin-like growth factor 2 (IGF2) plays a pivotal role in regulating growth and development; however, its functional involvement in skeletal muscle satellite cells (SMSCs) remains incompletely understood. To elucidate the regulatory role of IGF2, goose SMSCs were engineered to overexpress IGF2 via lentiviral transduction, followed by comprehensive transcriptomic profiling. Comparative analysis revealed 2802 differentially expressed genes (DEGs) in IGF2-overexpressing cells relative to controls, comprising 1202 upregulated and 1600 downregulated genes. IGF2 overexpression markedly activated fibrogenic programs, as evidenced by the upregulation of AP-1 complex components (FOS, JUN), extracellular matrix-related genes (COL1A1, COL5A3), and Wnt signaling receptors (FZD1, FZD7). In contrast, genes involved in myogenic differentiation and contractile function were broadly suppressed, including key myogenic transcription factors (MEF2C, MEF2D), sarcomeric structural proteins (MYBPC1, ACTN2, MYOM3), and metabolic enzymes. Through the construction of protein-protein interaction networks coupled with functional enrichment analysis, we observed a concerted suppression of myogenic regulatory networks critical for myofiber formation. Quantitative real-time PCR validation further confirmed the reliability of the transcriptomic data. Collectively, these findings suggest that overexpression of IGF2 induces a phenotypic shift from myoblasts toward a fibroblast-like state, uncoupling proliferation from differentiation while enhancing fibrogenic identity. This study provides novel insights into IGF2-mediated regulatory mechanisms underlying skeletal muscle development and fibrotic processes.

Ocular infections and inflammation represent a clear risk to eye health, but standard eye masks often lack the necessary therapeutic features. Moreover, most existing studies employ a blended electrospinning approach, which leads to an inhomogeneous spatial distribution of the therapeutic agents. However, using the coaxial technique can address these limitations. This study develops a coaxial electrospun nanofibrous eye mask with dual antibacterial and antioxidant functions, aiming to provide an innovative ocular treatment tool for eye care. Generally, a core-shell structured bilayer polycaprolactone-polylysine/polyvinyl alcohol-resveratrol (PCL-PLs/PVA-RSV) membrane is successfully prepared by coaxial electrospinning, where the core is resveratrol-loaded PVA and the shell is PLs-loaded PCL. Results show uniform fiber morphology, favorable hydrophilicity, and potential for sustained release due to core-shell design. The membrane significantly inhibits the growth of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli); at the same time, it exhibits excellent free radical scavenging ability and good component biocompatibility, achieving slow release of the two drugs and long-term antioxidant effect. This multifunctional platform offers a synergistic approach to combating microbial infection and oxidative stress, showing great potential for eye care.

Understanding how viruses engage host cell surfaces is fundamental to infection biology and therapeutic development. While vaccines remain central to prevention, recent global crises have emphasized the need for complementary antiviral strategies that can be mobilized rapidly against both known and emerging pathogens. In this context, artificial intelligence (AI) systems for biomolecular structure prediction, culminating in AlphaFold 3, are reshaping what is experimentally and conceptually achievable. Here, we present "Interactys-AI", a framework designed to exploit AI-based structural modeling to systematically map virus-host protein-protein interactions (PPIs) and connect them to actionable drug repurposing opportunities. Beyond a technical workflow, Interactys-AI reflects a broader transformation toward predictive and anticipatory antiviral discovery. We describe the conceptual foundations of the platform, its implementation, and its application to influenza A H5N1 hemagglutinin. We further discuss how structural AI may redefine preparedness strategies, highlight current limitations, and outline future directions toward real-time therapeutic hypothesis generation.

Introduction: Ethanol consumption is a major global health concern associated with many disorders. Melatonin, a circadian neurohormone, also modulates dopamine signaling and drug-seeking behaviors central to addiction. Objective: To investigate the role of melatonergic receptors in reducing ethanol consumption and explore melatonin's therapeutic potential to overcome ethanol dependence in rats. Method: Male Wistar rats were acclimatized for 5 days, then divided into two groups: ethanol-naive (n = 6) and ethanol-exposed (n = 36). The ethanol group was given 10% ethanol (7 days), followed by limited access (27 days). On day 40, the ethanol group was divided into 6 sub-groups, receiving various treatments, including melatonin and receptor blockers (10 days). Ethanol and water consumption were measured daily. On day 49, the rats were sacrificed, and dopamine levels in the nucleus accumbens were quantified using an ELISA. Results: Both melatonin doses and naltrexone significantly reduced ethanol consumption (p < 0.05) compared to their pretreatment levels. Ethanol reduction was greater in the melatonin-treated groups than the control group (p = 0.004, p = 0.007). However, the melatonin's efficacy was blocked when coadministered with receptor antagonists, showing no significant ethanol reduction vs. control (p = 0.075 and p = 0.08). Conclusions: These findings suggest that melatonin reduces ethanol intake via specific receptor pathways, supporting its potential use in treating alcohol dependence.

Chronic kidney disease (CKD) leads to metabolic and cardiovascular complications, and the dysregulation of key biomolecules, namely fibroblast growth factor 23 (FGF23) and Klotho, plays a central role. This study investigated the effects of high-intensity interval training (HIIT) and moderate aerobic training (AT) on FGF23, Klotho, mineral metabolism, apoptosis markers (BAX, Bcl2), and atrial fibrillation (AF) in a rat CKD model. The study used 35 Wistar rats randomly assigned to control (CTL), sham (SH), CKD, CKD + HIIT, and CKD + AT groups. CKD was induced by 5/6 nephrectomy surgery. Exercise interventions consisted of eight weeks of HIIT (80-100% of maximum speed, 24-54 min/week) or AT (45-55% of maximum speed, 40-60 min/week), conducted three times weekly on a treadmill. We measured heart weight, blood levels of FGF23, Klotho, and mineral metabolism markers, as well as the heart expression of apoptosis proteins (i.e., BAX, Bcl2) and atrial fibrillation (AF). Both exercise types reduced the heart weight and heart/body weight ratio; attenuated CKD-induced elevations in FGF23 and reductions in Klotho; improved blood levels of phosphate, PTH, and vitamin D; and modulated apoptotic markers by decreasing BAX and increasing Bcl2 levels. Exercise improved cardiac function and reduced the AF duration. These findings emphasize that exercise could be a helpful non-pharmacological intervention to ameliorate CKD-induced cardiovascular and metabolic disturbances through the modulation of the FGF23 and Klotho pathways.