Brain Research Bulletin最新文献

Background: Glioblastoma (GBM) is an aggressive brain tumor with therapeutic resistance and poor prognosis. Mitochondrial dysfunction has emerged as a critical driver of tumor progression and immune modulation, yet mitochondrial gene alterations and their cellular specificity in GBM remain unclear.

Methods: Transcriptomic datasets (TCGA-GBM, GSE66354) were analyzed to identify differentially expressed mitochondria-associated genes using MitoCarta3.0. Prognostic mitochondrial DEGs (MitoDEGs) were determined by Cox regression, and a nomogram was constructed for survival prediction. Single-cell RNA sequencing was applied to explore mitochondrial gene expression in cellular populations, particularly macrophages. Functional enrichment and pseudotime analyses were conducted to define macrophage subpopulations, while in vitro assays validated the role of MTHFD2 in glioblastoma cell behavior, macrophage migration and the expression of IL-6 and CCL2.

Results: MTHFD2 was identified as a diagnosis mitochondrial hub gene strongly correlated with GBM diagnosis. Single-cell analysis revealed elevated mitochondrial activity and MTHFD2 expression in tumor-associated macrophages. A distinct MTHFD2-high macrophage subpopulation displayed immune-activated and metabolically reprogrammed pathways, representing a terminally differentiated state linked to tumor progression. Functional assays showed that silencing MTHFD2 suppressed glioblastoma cell proliferation, invasion, colony formation, and reduced macrophage migration and the expression of IL-6 and CCL2.

Conclusion: Mitochondrial dysfunction mediated by MTHFD2 in macrophages plays a key role in GBM progression and immune heterogeneity. MTHFD2 represents a potential diagnostic biomarker and therapeutic target for modulating GBM immune infiltration.

Chronic pain frequently coexists with emotional disorders such as anxiety and depression, thereby imposing a considerable global burden. This review aims to establish the central amygdala (CeA) as the primary neural hub regulating pain-related comorbidities. Existing evidence demonstrates that the CeA shapes both the sensory-discriminative and emotional-motivational dimensions of pain by integrating ascending pain inputs and descending regulatory outputs. At the cellular level, functionally antagonistic GABAergic neuronal populations within the central lateral capsular division (CeLC) exhibit abnormal plasticity during chronic pain, which disrupts emotional homeostasis. Key molecular mechanisms within the CeA include neuropeptide signaling, regulation of ionotropic and metabotropic glutamate receptors, and opioid receptor dynamics, all of which often display lateralization and state dependence. Moreover, neuroimmune dysregulation within the CeA and epigenetic modifications contribute substantially to the persistence of pain-emotion comorbidities. By integrating evidence across neural circuits, cells, molecules, immune responses, and epigenetics, this multi-level review positions the CeA as a critical convergence point and promising therapeutic target for alleviating the intertwined suffering of chronic pain and emotional disorders.

Neuropathic pain is a chronic condition often associated with damage to the somatosensory nervous system. The exact mechanistic understanding of neuropathic pain remains elusive. Metabolomics, an analytical approach used to assess metabolic alterations in various diseases, is a promising technique that can offer mechanistic insights into neuropathic pain. It may lead to the identification of novel therapeutic targets and biomarkers. Evidence from animal studies indicates that alterations in multiple metabolic pathways, including those involving amino acids, fatty acids, glycolysis intermediates, Krebs cycle metabolites, and eicosanoids, have been observed in models of neuropathic pain. Changes in several metabolites, including phosphatidylcholine, arachidonic acid derivatives, and amino acid levels, have also been found in models of neuropathic pain. These alterations have been associated with mitochondrial dysfunction, impaired maintenance of the myelin sheath, and increased pain signaling. In addition, clinical studies have demonstrated dysregulation of glutamate, choline, phospholipid, and glucose metabolism in patients with neuropathic pain. These metabolic disturbances contribute to neuronal hyperexcitability and persistent pain. Interestingly, modulation of specific metabolic pathways has been shown to alleviate neuropathic pain, as evidenced by both in vivo and clinical studies. Therefore, this comprehensive review aims to summarize and discuss the metabolomic alterations associated with neuropathic pain.

Background: Glial scarring is a major obstacle for axonal regeneration and neural repair in the late stage of ischemic stroke. Reactive astrocytes are the main component of the glial scar. Heat shock protein 47 (HSP47) is significantly expressed in reactive astrocytes and remains present in the glial scar. However, the role of HSP47 in glial scar formation in ischemic stroke remains unclear.

Methods: HSP47 was identified in the peri-infarct region of rats at 1, 7, and 14 days post middle cerebral artery occlusion (MCAO). The rats received daily tail vein injections of the HSP47 inhibitor Col003 from days 1-14 following MCAO. Glial scar, brain atrophy volume, neurological score was detected after ischemia.

Results: HSP47 levels were increased in the peri-infarct area at 1, 7, and 14 days post-MCAO, as did those in astrocytes subjected to oxygenglucose deprivation/reoxygenation (OGD/R). The HSP47 inhibitor Col003 enhanced neurological functional recovery and minimized glial scar formation. Col003 inhibited the proliferation and migration of OGD/R-induced astrocytes and reduced the expression of glial fibrillary acidic protein, neurocan, and phosphacan. RNA-seq analysis revealed that differentially expressed genes in the Col003 treatment group were enriched in the JAK2/STAT3 pathway, which is associated with astrogliosis and glial scar formation.

Conclusion: Our findings demonstrated that Col003 inhibited JAK2/STAT3 phosphorylation in OGD/R-induced astrocytes. The HSP47 inhibitor Col003 might suppress astrocyte proliferation, migration, and glial scar formation through the JAK2/STAT3 pathway following ischemic stroke, which suggests a novel therapeutic strategy for the chronic phase of ischemic stroke.