Journal of Neuropathology and Experimental Neurology最新文献

Glioblastoma (GBM) is the most common and lethal primary malignant tumor of the adult central nervous system, accounting for approximately half of all gliomas. Although RING finger and WD repeat domain 3 (RFWD3) has been implicated in the regulation of various cancers, its role and underlying mechanisms in GBM progression remain unclear. In this study, analysis of the GEPIA online database confirmed that RFWD3 expression is significantly elevated in GBM tumor tissues. We found increased RFWD3 protein levels in U87 and T98 GBM cell lines and that suppression of RFWD3 markedly reduced cell viability and increased apoptosis in the GBM lines. Moreover, RFWD3 knockdown significantly inhibited their migration and invasion. Flow cytometry analysis revealed that RFWD3 inhibition induced G2/M cell cycle arrest (U87: G1 phase from 69.03% to 50.48%, G2/M phase from 16.54% to 33.01%; T98: G1 phase from 67.31% to 48.32%, G2/M phase from 17.10% to 33.73%). Furthermore, suppression of RFWD3 downregulated the Wnt/β-catenin signaling pathway. These findings indicate that RFWD3 promotes GBM cell growth and migration by facilitating G2/M phase progression through the Wnt/β-catenin pathway. Targeting RFWD3 may represent a promising strategy for inhibiting GBM progression.

The mechanisms of cognitive impairment in small-for-gestational-age (SGA) infants remain unclear. We investigated clinical effects and mechanisms of sodium butyrate (NaB) treatment in a SGA rat model. Behavioral tests, immunohistochemistry, and molecular biology analysis were performed on controls and on SGA rats divided into SGA, SGA + NaB, and SGA + NaB + upadacitinib (a JAK1 inhibitor) groups. Compared to the controls, SGA rats showed weakened neuroreflexes, impaired short-term learning and memory, and manifestations of anxiety and depression. Hippocampal neurons were damaged and apoptotic, and expression of pro-inflammatory factors IL-6 and TNF-α and the JAK1/STAT3 inflammatory pathway were increased in the SGA rats. NaB improved neuroreflexes, learning and memory, anxiety and depressive behaviors, and apoptosis of hippocampal neurons in SGA rats whereas NaB + upadacitinib treatment did not significantly improve these indicators. NaB upregulated JAK1/STAT3 pathway expression in hippocampal neurons of SGA rats and downregulated IL-6 and TNF-α expression; NaB + upadacitinib treatment had the opposite effects. Thus, NaB improved the neurobehavioral performance of SGA rats and reduced damage of hippocampal neurons by activating the JAK1/STAT3 pathway. This study reveals a mechanism of cognitive impairment in SGA infants, providing possible new therapeutic targets.

Deubiquitinating enzymes are important regulators of cancer progression. We explored the role and regulatory mechanisms of the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22) in neuroblastoma (NB). USP22 expression was upregulated in NB patient tissue samples and its expression correlated with their overall survival. Knockdown of USP22 in NB cell lines suppressed cell proliferation, invasion and glycolysis, and enhanced apoptosis. A coimmunoprecipitation assay identified a relationship between USP22 and 3-phosphoinositide-dependent protein kinase 1 (PDK1). USP22 stabilized PDK1 expression via deubiquitination; PDK1 overexpression reversed the effects of USP22 knockdown on the malignant behaviors of NB cells. Dual-luciferase reporter assay and RNA immunoprecipitation were utilized to clarify the relationship between Yin Yang-1 (YY1) and USP22. Yin Yang-1 regulated PDK1 expression via promoting USP22 transcription. USP22 knockdown in a xenograft assay also inhibited tumor growth via regulating PDK1. Taken together, these results indicate that USP22 regulated by YY1 plays a promotional role in NB progression by mediating the deubiquitination of PDK1.

Given the known relationship between CDKN2A homozygous deletion (HD) and worsened outcomes in both meningiomas and IDH-mutant astrocytomas, it is paramount to identify CDKN2A HD for accurate risk stratification of patients. Multiple array platforms can detect CDKN2A HD. However, these methods are expensive and are not readily available at every institution. To address this, we conducted a meta-analysis and literature review to evaluate 5'-methylthioadenosine phosphorylase (MTAP) expression determined by immunohistochemistry (IHC) as a surrogate of CDKN2A HD. Our study analyzed 7 cohort studies, 3 of which focused on meningiomas encompassing a total of 87 patients; and 4 studies were conducted on infiltrating glioma patients, consisting of 423 patients. Our results show that despite utilizing different MTAP IHC clones, the results among all studies showed consistently good sensitivity and specificity. The overall sensitivity and specificity of MTAP IHC as a surrogate of CDKN2A HD was excellent with 92.3% and 97.5%, respectively. These results were maintained when MTAP IHC was evaluated in distinct tumor types. MTAP IHC is a good surrogate marker for identifying CDKN2A HD in infiltrating gliomas and meningiomas. MTAP IHC implementation would allow correct integrated diagnosis for institutions that lack DNA sequencing.