Oxidative stress, mitochondrial dysfunction, inflammation-associated cellular responses, and apoptosis are closely associated with the pathogenesis of neurodegenerative disorders. Therefore, identifying small molecules capable of modulating these interconnected cellular processes is important for the development of potential neuroprotective strategies. The present study investigated the protective effects of the imidazole derivative (IMD)-1 against hydrogen peroxide (H2O2)-induced oxidative injury in SH-SY5Y human neuroblastoma cells using integrated in vitro and in silico approaches. IMD-1 exhibited strong radical scavenging activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, reaching 96.8% inhibition at 1000 & micro;g/mL, which was comparable to the butylated hydroxyl toluene (BHT). IMD-1 pre-treatment significantly restored cell viability, reduced reactive oxygen species (ROS) production, and preserved mitochondrial membrane potential. IMD-1 also attenuated adenosine triphosphate (ATP) depletion. Moreover, IMD-1 reduced H2O2-induced increases in selected inflammation-associated mediators, including interleukin (IL)-2, IL-6, IL-12, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein (MCP)-1, and interferon-gamma (IFN-gamma). IMD-1 reduced apoptotic cell death and modulated apoptosis-related cellular and transcriptional responses. Molecular docking suggested a possible interaction between IMD-1 and caspase-8, providing hypothesis-generating support for the apoptosis-related findings. Overall, these findings suggest that IMD-1 attenuates H2O2-induced oxidative injury in SH-SY5Y cells as evidenced by changes in oxidative stress, mitochondrial dysfunction, ATP-associated bioenergetic impairment, inflammatory mediator release, and apoptosis-related responses. However, further protein-level, biochemical, and in vivo studies are required to determine the broader neurobiological and translational relevance of these findings.
Gliomas are the most prevalent primary malignant brain tumors with limited therapeutic targets. Aerobic glycolysis, a hallmark of glioma, depends on the SLC16 monocarboxylate transporter family, including established oncogenic members MCT1 and MCT4. SLC16A13, linked to systemic glucose homeostasis and cellular stress adaptation, remains uncharacterized in glioma. Given the critical role of metabolic flexibility in glioma pathophysiology, we hypothesized that SLC16A13 may represent a contributor to glioma metabolic reprogramming and malignant progression. This study systematically investigated SLC16A13 expression and clinical relevance using The Cancer Genome Atlas (TCGA) and a West China Hospital glioma cohort. Stable SLC16A13-knockdown models were established in U251 and U373 cells via lentiviral shRNA delivery. Cell proliferation, colony formation, apoptosis, and migration were assessed by CCK−8, colony formation, flow cytometry, and wound healing assays, respectively. A subcutaneous xenograft model was employed to evaluate tumor growth in vivo. Intracellular and extracellular metabolite concentrations were quantified by ELISA and HPLC. SLC16A13 was significantly upregulated in glioma tissues compared with non-tumor controls, and high expression was tightly correlated with advanced WHO grade, IDH wild-type status, TERT promoter mutation, and shorter overall survival (HR = 1.57, 95
Postoperative cognitive dysfunction (POCD) is a serious clinical complication and lacks effective therapeutic approaches. Recent studies demonstrate that targeting macrophage migration inhibitory factor (MIF) offers a novel strategy to cognitive impairment disorders. Here, we aim to investigate whether MIF inhibitor ISO-1 mitigates anesthesia/surgery-evoked cognitive defects via regulating NLRP3 inflammasome. C57BL/6 mice (18-month-old) were selected to establish a POCD model via unilateral nephrectomy under sevoflurane anesthesia. Cognitive and behavioral capabilities were evaluated by fear conditioning, Morris water maze and open field tests. On day 3 postsurgery, MIF levels in the serum and hippocampus were measured through ELISA, immunofluorescence and western blotting. Furthermore, to clarify whether elevated hippocampal MIF following nephrectomy contribute to cognitive decline, ISO-1 (30 mg/kg) was administered intraperitoneally 30 min before and after surgery to reduce hippocampal MIF expression. ELISA and immunofluorescence were used to gauge the levels of hippocampal MIF, IL-6, TNF-α, IL-1β and microglial activation. HE and TUNEL staining were used to assess the morphological alterations and apoptosis in hippocampal neurons. Western blotting was applied to determine the expression of hippocampal MIF, caspase-1, IL-1β, ASC, NLRP3, Bcl-2, Bax and Iba1. We found that surgery-treated mice exhibited pronounced cognitive impairment, accompanied by increased levels of MIF, neuronal apoptosis and neuroinflammation in the hippocampus, as well as the activation of microglia and NLRP3 inflammasome. Inhibition of MIF with ISO-1 can effectively reverse these detrimental changes. Our results reveal that ISO-1 exerts a neuroprotective effect against POCD, which may be associated with the inhibition of NLRP3 inflammasome activation.
Seizures trigger widespread molecular changes in the brain, but how these responses differ between surviving and degenerating regions remains unclear. Using the intrahippocampal kainic acid model, which is characterized by degeneration of the hippocampus, while the neocortex is less affected, we performed unbiased cytokine array screening and identified two functionally distinct systems that were prominently altered: the proteolytic tPA/PAI-1/uPAR axis and the trophic IGF/IGFBP-5 axis. Quantitative protein and mRNA analyses across five brain regions at 24 h post-seizures revealed distinct organizational patterns. The proteolytic axis showed a largely coordinated response: Serpine1 (PAI-1), Plat (tPA), and Plaur (uPAR) were coordinately upregulated across all studied structures, correlated with seizure severity, and showed minimal peripheral induction. The IGF system displayed a more region-dependent pattern, with Igfbp5 downregulation observed across all studied regions and divergent downstream trajectories. In the hippocampus, Igf2 and Igf1r were suppressed, consistent with reduced IGF signaling; in the neocortex, Igf1 and Igf1r were upregulated, mounting a compensatory response; the entorhinal cortex displayed an intermediate phenotype. Since IGFBP-5 may act as a co-activator of tPA and antagonist of PAI-1, its uniform downregulation together with the PAI-1 induction may create a coordinated shift that reduces proteolytic activity and alters IGF bioavailability across all regions. However, the neocortex appears to counteract this shift by upregulating Igf1 and Igf1r; the hippocampus does not, instead suppressing Igf2 and Igf1r. We propose that this region-specific coupling—between a universal proteolytic versus a trophic trigger and the capacity to mount a compensatory response—is one of the factors underlying the selective vulnerability of the hippocampus to seizure-induced neurodegeneration.
