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.
Protein Kinase C (PKC) dysregulation can affect Na⁺/K⁺-ATPase function, while alterations in Na⁺/K⁺-ATPase activity can conversely influence the PKC pathway. Therefore, this study investigated the interactions between Na⁺/K⁺-ATPase inhibition and PKC signaling, as well as the associated oxidative stress, using a translational approach that combines preclinical (in vitro and in vivo) models and clinical data from patients with bipolar disorder. In the in vitro model, cells were exposed to ouabain (OUA), a Na+/K+ ATPase inhibitor, and then treated with a PKC inhibitor (PKCi - tamoxifen). In the in vivo model, animals received intracerebroventricular OUA and were treated with PKCi. The animals underwent behavioral tests to evaluate manic- and depressive-like behaviors. The clinical study included a case-control protocol with 36 BD patients and 46 healthy controls. In both preclinical and clinical settings, the markers (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, and 3-nitrotyrosine [3-nitro]), as well as Na+/K+ ATPase and PKC activities, were assessed. In the in vivo and in vitro protocols, OUA increased PKC activity and reduced Na+/K+ ATPase activity. However, when combined with PKCi, OUA failed to inhibit Na+/K+ ATPase activity. Additionally, OUA was able to induce manic- and depressive-like behaviors and oxidative stress, which was also reversed by PKCi. Moreover, the clinical protocol identified increased PKC activity and reduced Na+/K+ ATPase activity, consistent with the preclinical protocols. Taken together, the data indicates that the interconnection between Na⁺/K⁺-ATPase and PKC signaling pathways represents an important component of BD pathophysiology.
Post-traumatic stress disorder (PTSD) is a severe psychiatric condition for which effective preventive strategies are lacking. Innate immune preconditioning has shown promise for the prevention of PTSD, yet the transient nature of such protection when induced in adulthood poses a substantial limitation. Using male C57BL/6J mice, we tested whether administration of macrophage colony-stimulating factor (M-CSF, 100 µg/kg, intraperitoneally) during adolescence, a developmental period characterized by heightened microglial plasticity, could establish enduring resilience against trauma-induced PTSD-like behaviors. Mice received a single M-CSF injection at postnatal day 28 (PND28) and were subsequently subjected to single prolonged stress (SPS/FS) at 4, 16, or 32 weeks thereafter, with behavioral and molecular assessments conducted at PND70, PND154, and PND266, respectively. Our results showed that adolescent M-CSF exposure substantially prevented SPS/FS-induced anxiety-like behaviors assessed by the elevated plus maze and open field test, and SPS/FS-induced fear-like behaviors evaluated by contextual and cued fear conditioning tests, at all three post-administration intervals. Concurrently, M-CSF pretreatment prevented SPS/FS-induced interleukin-1β (Il-1β), Il-6, and tumor necrosis factor-α (Tnf-α) mRNA expression within the hippocampus and medial prefrontal cortex across all time points examined. These protective phenotypes were eliminated when microglial function was pharmacologically inhibited or when microglia were depleted before M-CSF administration, establishing that microglial integrity at the time of adolescent immune challenge is required for the establishment of long-term resilience. Taken together, these findings demonstrate that a single developmental immune intervention confers lifelong protection against SPS/FS-induced PTSD-like behaviors through microglia-dependent mechanisms, introducing a vaccine-like paradigm for the prevention of PTSD.
