Clinical analysis of the efficacy of radiation therapy for primary high-grade gliomas guided by biological rhythms.

OBJECTIVE: High-grade glioma (HGG) patients frequently encounter treatment resistance and relapse, despite numerous interventions seeking enhanced survival outcomes yielding limited success. Consequently, this study, rooted in our prior research, aimed to ascertain whether leveraging circadian rhythm phase attributes could optimize radiotherapy results. METHODS: In this retrospective analysis, we meticulously selected 121 HGG cases with synchronized rhythms through Cosinor analysis. Post-surgery, all subjects underwent standard radiotherapy alongside Temozolomide chemotherapy. Random allocation ensued, dividing patients into morning (N = 69) and afternoon (N = 52) radiotherapy cohorts, enabling a comparison of survival and toxicity disparities. RESULTS: The afternoon radiotherapy group exhibited improved overall survival (OS) and progression-free survival (PFS) relative to the morning cohort. Notably, median OS extended to 25.6 months versus 18.5 months, with P = 0.014, with median PFS at 20.6 months versus 13.3 months, with P = 0.022, post-standardized radiotherapy. Additionally, lymphocyte expression levels in the afternoon radiation group 32.90(26.10, 39.10) significantly exceeded those in the morning group 31.30(26.50, 39.20), with P = 0.032. CONCLUSIONS: This study underscores the markedly prolonged average survival within the afternoon radiotherapy group. Moreover, lymphocyte proportion demonstrated a notable elevation in the afternoon group. Timely and strategic adjustments of therapeutic interventions show the potential to improve therapeutic efficacy, while maintaining vigilant systemic immune surveillance. A comprehensive grasp of physiological rhythms governing both the human body and tumor microenvironment can refine treatment efficacy, concurrently curtailing immune-related damage-a crucial facet of precision medicine.

Polydatin inhibits LPS-induced inflammatory response in BV2 microglia by disrupting the formation of lipid rafts.

OBJECTIVE: Polydatin has been used in the treatment of various inflammatory diseases. However, its role in the regulation of neuroinflammation has not been reported. In this study, we designed to investigate the anti-inflammatory effects of polydatin in LPS-stimulated BV2 microglia cells. METHODS: Inflammatory mediators TNF-α, IL-1ß, NO, and PGE2 production were measured by ELISA. The protein of signaling pathways were detected by western blot analysis. RESULTS: The results showed that polydatin significantly ameliorated the production of TNF-α, IL-1ß, NO, and PGE2 up-regulated by LPS. Polydatin also blocked LPS-induced NF-κB activation. In addition, PI3K and AKT, the up-stream molecules of NF-κB signaling pathway, were inhibited by the treatment of polydatin. Also, we found the formation of lipid rafts was inhibited by polydatin through attenuating the cholesterol content. Finally, polydatin was found to increase the expression of ABCA1 and ABCG1. CONCLUSION: In conclusion, the results of the present study suggested that polydatin exhibited its anti-inflammatory effects in BV2 cells through disrupting lipid rafts, which subsequently inhibiting PI3K/AKT signaling pathway.

Regional cerebral metabolic levels and turnover in awake rats after acute or chronic spinal cord injury.

Spinal cord injury (SCI) is a common cause of disability, which often leads to sensorimotor cortex dysfunction above the spinal injury site. However, the cerebral regional effects on metabolic information after SCI have been little studied. Here, adult Sprague-Dawley rats were divided into acute and chronic treatment groups and sham groups with day-matched periods. The Basso, Beatte, and Bresnahan scores method were utilized to evaluate the changes in behaviors during the recovery of the animals, and the metabolic information was measured with the 1 H-observed/13 C-edited NMR method. Total metabolic concentrations in every region were almost similar in both treated groups. However, the metabolic kinetics in most regions in the acute group were significantly altered (P < .05), particularly in the cortical area, thalamus and medulla (P < .01). After long-term recovery, some metabolic kinetics were recovered, especially in the temporal cortex, occipital cortex, and medulla. The metabolic kinetic changes revealed the alteration of metabolism and neurotransmission in different brain regions after SCI, which present evidence for the alternation of brain glucose oxidation. Therefore, this shows the significant influence of SCI on cerebral function and neuroscience research. This study also provides the theoretical basis for clinical therapy after SCI, such as mitochondrial transplantation.

PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/ß­catenin signaling pathway.

Glioblastoma is a highly malignant tumor that contains stem­like cells known as glioma stem cells (GSCs), which lare associated with an increased risk of glioma occurrence, recurrence and poor prognosis. Circadian clock gene, period circadian clock 2 (PER2) expression has been revealed to be inhibited in various types of cancer. However, the precise role and potential mechanisms of PER2 in GSCs remains unclear. The present study demonstrated that PER2 mRNA and protein expression was downregulated in GSCs compared with non­stem glioma cells, which indicated that PER2 could be involved in the malignant process of glioma. Furthermore, functional studies revealed that PER2 overexpression could induce GSC arrest at the G0/G1 phase and suppress their proliferation, stemness and invasion ability in vitro and in vivo. Subsequently, the Wnt/ß­catenin signaling pathway was identified as the target of PER2 in GSCs. These results indicated that PER2 plays a critical role in regulating the stemness of GSCs and provides a novel therapeutic target to overcome the effects of GSCs.

Plasma Erythropoietin, IL-17A, and IFNγ as Potential Biomarkers of Motor Function Recovery in a Canine Model of Spinal Cord Injury.

Traumatic spinal cord injury (SCI) is a devastating neurological disease for which an accurate, cost-effective prediction of motor function recovery is in pressing need. A plethora of neurochemical changes involved in the pathophysiological process of SCI may serve as a new source of biomarkers for patient outcomes. Five dogs were included in this study. We characterized the plasma cytokine profiles in acute phase (0, 1, and 3 days after SCI) and subacute phase (7, 14, and 21 days after SCI) with microarray analysis. The motor function recovery following SCI was monitored by Olby scores. The expression level of differentially expressed proteins (DEPs) was measured with enzyme-linked immunosorbent assay (ELISA). Then, correlations with the Olby scores and receiver operating characteristic curve (ROC) analysis were performed. We identified 12 DEPs including 10 pro-inflammatory and 2 anti-inflammatory cytokines during the 21-day study period. Among those, the expression levels of erythropoietin (EPO), IL-17A, and IFNγ significantly correlated with the Olby scores with R2 values of 0.870, 0.740, and 0.616, respectively. The results of the ROC analysis suggested that plasma EPO, IL-17A, and IFNγ exhibited a significant predictive power with an area under the curve (AUC) of 0.656, 0.848, and 0.800 for EPO, IL-17A, and IFNγ, respectively. Our results provide a longitudinal description of the changes in plasma cytokine expression in the acute and subacute stages of canine SCI. These data reveal novel panels of inflammation-related cytokines which have the potential to be evaluated as biomarkers for predicting motor function prognosis after SCI.

LINK-A lncRNA participates in the pathogenesis of glioma by interacting with survivin.

Long intergenic non-coding RNA for kinase activation (LINK-A) long non-coding RNA (lncRNA) has been characterized in triple negative breast cancer, but its potential involvement in glioma has not been investigated. In the present study, serum levels of LINK-A lncRNA and survivin in patients with glioma and healthy controls were determined by RT-qPCR and ELISA, respectively. The diagnostic value of serum LINK-A lncRNA for glioma was evaluated by receiver operating characteristic (ROC) curve analysis. Potential correlations between serum levels of LINK-A lncRNA and survivin were analyzed by Pearson correlation coefficient. LINK-A lncRNA siRNA, LINK-A lncRNA-carrying expression vector and survivin-carrying expression vector were transfected into glioma cells, and the effects on LINK-A lncRNA expression, survivin expression and cell apoptosis were explored by RT-qPCR, western blot analysis and annexin V/propidium iodide staining. It was observed that the serum levels of LINK-A lncRNA and survivin were significantly higher in patients with glioma compared with healthy controls. Increased levels of LINK-A lncRNA distinguished glioma patients from healthy controls, based on ROC curve analysis. Serum levels of LINK-A lncRNA and survivin were positively correlated in glioma patients, but not in healthy controls. Overexpression of LINK-A lncRNA led to increased survivin protein expression, while survivin overexpression had no effect on LINK-A lncRNA expression. LINK-A lncRNA and survivin overexpression each reduced glioma cell apoptosis, but LINK-A lncRNA siRNA-mediated knockdown increased apoptosis. Survivin overexpression attenuated the inducing effects of LINK-A lncRNA knockdown on apoptosis. In conclusion, LINK-A lncRNA inhibited glioma cell apoptosis potentially by the upregulation of survivin. The present study revealed that LINK-A may serve as possible diagnostic marker for glioma.

Deregulated expression of the Per1 and Per2 in human gliomas.

BACKGROUND: Growing evidence shows that the deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored. METHODS: Using reverse transcription polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, Per1 and Per2, in 33 gliomas. RESULTS: In this study, out of 33 gliomas, 28 were Per1-positive, and 23 were Per2-positive. The expression levels of Per1 and Per2 in glioma cells were significantly different from the surrounding non-glioma cells (P<0.01). The difference in the expression rate of Per1 and Per2 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was insignificant (P>0.05). While there was no difference in the intensity of immunoactivity for Per2 between high-grade gliomas and low-grade gliomas (r=-0.330, P=0.061), the expression level of Per1 in high-grade gliomas was significantly lower than that in low-grade gliomas(r=-0.433, P=0.012). CONCLUSIONS: In this study, we found that the expression of Per1 and Per2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in Per1 and Per2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.