DDOST Correlated with Malignancies and Immune Microenvironment in Gliomas.

Among the most common types of brain tumor, gliomas are the most aggressive and have the poorest prognosis. Dolichyl-diphosphooligosaccharide protein glycosyltransferase non-catalytic subunit (DDOST) encodes a component of the oligosaccharide transferase complex and is related to the N-glycosylation of proteins. The role of DDOST in gliomas, however, is not yet known. First, we performed a pan cancer analysis of DDOST in the TCGA cohort. The expression of DDOST was compared between glioma and normal brain tissues in the GEO and Chinese Glioma Genome Atlas (CGGA) databases. In order to explore the role of DDOST in glioma, we analyze the impact of DDOST on the prognosis of glioma patients, with the CGGA 325 dataset as a test set and the CGGA 693 dataset as a validation set. Immunohistochemistry was performed on tissue microarrays to examine whether DDOST has an impact on glioma patient survival. Next, using single-cell sequencing analysis, GSEA, immune infiltration analysis, and mutation analysis, we explored how DDOST affected the glioma tumor microenvironment. Finally, we evaluated the clinical significance of DDOST for glioma treatment by constructing nomograms and decision curve analysis (DCA) curves. We found that DDOST was overexpressed in patients with high grade, IDH wild type, 1p19q non-codel and MGMT un-methylated, which was associated with poor prognosis. Patients with high levels of DDOST, regardless of their clinical characteristics, had a worse prognosis. Immunohistochemical analysis confirmed the results of the above bioinformatics analysis. Mechanistic analysis revealed that DDOST was closely associated with the glioma microenvironment and negatively related to tumor-infiltrating B cells and CD4+ T cells and positively related to CAFs and tumor-associated macrophages. In conclusion, these findings suggested that DDOST mediated the immunosuppressive microenvironment of gliomas and could be an important biomarker in diagnosing and treating gliomas.

Forkhead Box i2 Transcription Factor Regulates Systemic Energy Metabolism Via Neuropeptide AgRP.

The neuropeptide AgRP is essential for maintaining systemic energy homeostasis. In the current study, we show that hypothalamic Foxi2, as a novel regulator of nutrient sensing, controls systemic energy metabolism by specifically stimulating AgRP expression. Foxi2 was highly expressed in the hypothalamus, and its expression was induced by fasting. Immunofluorescence assays demonstrated that Foxi2 was localized in AgRP neurons. We stereotactically injected adeno-associated virus to selectively overexpress Foxi2 in AgRP-IRES-Cre mice and found that Foxi2 overexpression in AgRP neurons specifically increased AgRP expression, thereby increasing food intake and reducing energy expenditure, subsequently leading to obesity and insulin resistance. Mechanistically, Foxi2 stimulated AgRP expression by directly binding to it and activating its transcription. Furthermore, Foxi2 overexpression activated AgRP neuron activity, as revealed by whole-cell patch-clamp experiments. Conversely, global Foxi2-mutant mice became leaner with age and were resistant to high-fat diet-induced obesity and metabolic disturbances. Collectively, our data suggest that Foxi2 plays an important role in controlling energy metabolism by regulating AgRP expression.

Sleep Deprivation Aggravates Cognitive Impairment by the Alteration of Hippocampal Neuronal Activity and the Density of Dendritic Spine in Isoflurane-Exposed Mice.

Isoflurane contributes to cognitive deficits when used as a general anesthetic, and so does sleep deprivation (SD). Patients usually suffer from insomnia before an operation due to anxiety, fear, and other factors. It remains unclear whether preoperative SD exacerbates cognitive impairment induced by isoflurane. In this study, we observed the effects of pretreated 24-h SD in adult isoflurane-exposed mice on the cognitive behaviors, the Ca2+ signals of dorsal hippocampal CA1 (dCA1) neurons in vivo with fiber photometry, and the density of dendritic spines in hippocampal neurons. Our results showed that in cognitive behavior tasks, short-term memory damages were more severe with SD followed by isoflurane exposure than that with SD or isoflurane exposure separately, and interestingly, severe long-term memory deficits were induced only by SD followed by isoflurane exposure. Only the treatment of SD followed by isoflurane exposure could reversibly decrease the amplitude of Ca2+ signals when mice were freely moving and increase the duration of Ca2+ signals during the long-term memory behavior test. The density of dendritic spines with both SD and isoflurane exposure was lower than that with SD alone. This study suggests that SD should be avoided preoperatively in patients undergoing elective surgery under isoflurane anesthesia.