Orexin-A mediates glioblastoma proliferation inhibition by increasing ferroptosis triggered by unstable iron pools and GPX4 depletion.

Glioblastoma (GBM) represents a prevalent form of primary malignant tumours in the central nervous system, but the options for effective treatment are extremely limited. Ferroptosis, as the most enriched programmed cell death process in glioma, makes a critical difference in glioma progression. Consequently, inducing ferroptosis has become an appealing strategy for tackling gliomas. Through the utilization of multi-omics sequencing data analysis, flow cytometry, MDA detection and transmission electron microscopy, the impact of orexin-A on ferroptosis in GBM was assessed. In this report, we provide the first evidence that orexin-A exerts inhibitory effects on GBM proliferation via the induction of ferroptosis. This induction is achieved by instigating an unsustainable increase in iron levels and depletion of GPX4. Moreover, the regulation of TFRC, FTH1 and GPX4 expression through the targeting of NFE2L2 appears to be one of the potential mechanisms underlying orexin-A-induced ferroptosis.

Dishevelled-associated antagonist of ß-catenin homolog 3 (DACT3) suppresses glioma progression though Notch1 signaling pathway in ß-catenin-dependent manner.

The disheveled-associated antagonist of ß-catenin homolog 3 (DACT3) has been recognized as a tumor suppressor in various cancers. However, the function of DACT3 on glioma malignant progression along with potential molecular mechanisms is poorly clarified. This research aimed to investigate how DACT3 contributes to suppressing the progression of glioma. In our investigation, a pronounced decrease in DACT3 expression was observed in glioma tissues. Through the overexpression of DACT3, we noted a significant suppression in the proliferation, invasion, and migration of glioma cells, while concurrently observing an increase in cell adhesion. Our exploration into the molecular mechanisms revealed that DACT3 executes its tumor-suppressive role by impeding the expression of notch 1 intracellular domain (NICD) and translocating into the nucleus by downregulating the expression of ß-catenin. Consequently, this process leads to the suppression of Notch1 signaling. To summarize, our findings reveal the function of DACT3 to inhibit glioma progression via the Notch1 signaling pathway in ß-catenin dependent manner. This study stands as the pioneer in examining the role of DACT3 in glioma progression and comprehensively elucidating its molecular mechanisms in glioma development. Therefore, our results suggest that DACT3 holds promise as both a prognostic factor and a potential biomarker for guiding treatment strategies in glioma patients (Graphical Abstract).

Hypocretin-1 suppresses malignant progression of glioblastoma cells through Notch1 signaling pathway.

Hypocretin-1 is a multifunctional neuropeptide that has been identified as a potential antitumor agent for its role in inhibiting tumor growth, including in colon cancer, neuroendocrine tumor, and prostate cancer. However, the role and mechanism of hypocretin-1 in the occurrence and development of malignant glioma have not been well studied. Therefore, we investigated the effect of hypocretin-1 on glioblastoma proliferation, apoptosis, migration and invasion and its mechanism. We found that the hypocretin-1 receptor was expressed in both glioma cell lines and glioma tissues. Hypocretin-1 treatment can inhibit glioblastoma cell proliferation, migration and invasion, and induce cell apoptosis. Meanwhile, hypocretin-1 treatment significantly reduces tumor growth rate and tumor weight. In addition, mechanistic studies have found that hypocretin-1 exerts antitumor effects by inhibiting NOTCH signaling pathway. Overexpression of NICD significantly reversed the antitumor effect of hypocretin on glioblastoma. Taken together, these findings suggest that hypocretin-1 inhibits glioblastoma proliferation, migration and invasion and induces apoptosis in vitro and in vivo through NOTCH signaling pathway.

Mast cell activation mediates blood-brain barrier impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway.

Introduction: Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction resulting from a systemic inflammatory response to infection; however, its pathophysiology remains unclear. Sepsis-induced neuroinflammation and blood-brain barrier (BBB) disruption are crucial factors in brain function disturbance in SAE. Mast cells (MCs) activation plays an important role in several neuroinflammation models; however, its role in SAE has not been comprehensively investigated. Methods: We first established a SAE model by cecal ligation puncture (CLP) surgery and checked the activation of MCs. MCs activation was checked using immumohistochemical staining and Toluidine Blue staining. We administrated cromolyn (10mg/ml), a MC stabilizer, to rescue the septic mice. Brain cytokines levels were measured using biochemical assays. BBB disruption was assessed by measuring levels of key tight-junction (TJ) proteins. Cognitive function of mice was analyzed by Y maze and open field test. Transwell cultures of brain microvascular endothelial cells (BMVECs) co-cultured with MCs were used to assess the interaction of BMVECs and MCs. Results: Results showed that MCs were overactivated in the hippocampus of CLP-induced SAE mice. Cromolyn intracerebroventricular (i.c.v) injection substantially inhibited the MCs activation and neuroinflammation responses, ameliorated BBB impairment, improved the survival rate and alleviated cognitive dysfunction in septic mice. In vitro experiments, we revealed that MCs activation increased the sensitivity of BMVECs against to lipopolysaccharide (LPS) challenge. Furthermore, we found that the histamine/histamine 1 receptor (H1R) mediated the interaction between MCs and BMVECs, and amplifies the LPS-induced inflammatory responses in BMVECs by modulating the TLR2/4-MAPK signaling pathway. Conclusions: MCs activation could mediate BBB impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway.

Multiomics integration reveals the effect of Orexin A on glioblastoma.

Objectives: This study involved a multi-omics analysis of glioblastoma (GBM) samples to elaborate the potential mechanism of drug treatment. Methods: The GBM cells treated with or without orexin A were acquired from sequencing analysis. Differentially expressed genes/proteins/metabolites (DEGs/ DEPs/ DEMs) were screened. Next, combination analyses were conducted to investigate the common pathways and correlations between the two groups. Lastly, transcriptome-proteome-metabolome association analysis was carried out to determine the common pathways, and the genes in these pathways were analyzed through Kaplan-Meier (K-M) survival analysis in public databases. Cell and animal experiments were performed to investigate the anti-glioma activity of orexin A. Results: A total of 1,527 DEGs, 52 DEPs, and 153 DEMs were found. Moreover, the combination analyses revealed that 6, 4, and 1 common pathways were present in the transcriptome-proteome, proteome-metabolome, and transcriptome-metabolome, respectively. Certain correlations were observed between the two data sets. Finally, 11 common pathways were discovered in association analysis, and 138 common genes were screened out in these common pathways. Six genes showed significant differences in terms of survival in both TCGA and CGGA. In addition, orexin A inhibited the proliferation, migration, and invasion of glioma in vitro and in vivo. Conclusion: Eleven common KEGG pathways with six common genes were found among different omics participations, revealing the underlying mechanisms in different omics and providing theoretical basis and reference for multi-omics research on drug treatment.

The Role of DACT Family Members in Tumorigenesis and Tumor Progression.

Disheveled-associated antagonist of ß-catenin (DACT), which ubiquitously expressed in human tissue, is critical for regulating cell proliferation and several developmental processes in different cellular contexts. In addition, DACT is essential for some other cellular processes, such as cell apoptosis, migration and differentiation. Given the importance of DACT in these cellular processes, many scientists are gradually interested in studying the role of DACT in tumorigenesis and cancer progression. This review article focuses on the latest research regarding the essential functions and potential DACT mechanisms in the occurrence and progression of tumors. Our study indicates that DACT may act as a tumor biomarker for cancer diagnosis and prognosis, as well as a promising therapeutic target in cancers.

Diffusion-weighted imaging lesions after endovascular treatment of cerebral aneurysms: A network meta-analysis.

Background: Thromboembolism is one of the common complications in endovascular treatments including coiling alone, stent-assisted coiling (SAC), balloon-assisted coiling (BAC), and flow-diverting (FD) stents. Such treatments are widely used in intracranial aneurysms (IAs), which usually present as positive lesions in diffusion-weighted imaging (DWI). Whether these adjunctive techniques increase postprocedural DWI-positive lesions after endovascular treatment remains unclear. Methods: A thorough electronic search for the literature published in English between January 2000 and October 2022 was conducted on PubMed, Medline, and EMBASE. Eighteen studies (3 cohort studies and 15 case-control studies) involving 1,843 patients with unruptured IAs (UIAs) were included. We performed a frequentist framework network meta-analysis (NMA) to compare the rank risks of cerebral thromboembolism of the above four endovascular treatments. The incoherence test was used to analyze the statistical disagreement between direct and indirect evidence. Funnel plots were used to analyze publication bias. Results: The incidences of DWI lesions in patients who received FD stents, SAC, BAC, and coiling alone were 66.1% (109/165), 37.6% (299/795), 31.1% (236/759), and 25.6% (236/921). The incidence of DWI lesions in patients who received FD stents was higher than that in patients who received SAC [OR: 2.40; 95% CI (1.15, 5.00), P < 0.05], BAC [OR: 2.62; 95% CI (1.19, 5.77), P < 0.05], or coiling alone [OR: 2.77; 95% CI (1.26, 6.07), P < 0.05]. The incoherence test showed preferable consistency in this NMA. No obvious publication bias was found in the funnel plot. Conclusion: FD stent placement brings more ischemic lesions identified by DWI than any other procedures for patients with UIA. The characteristics of FD stents may result in a high incidence of DWI lesions.

The safety and outcomes of acutely ruptured intracranial aneurysms with incomplete occlusion after coiling: a case-control study.

BACKGROUND: Incomplete aneurysmal occlusion is a common feature of immediate posttreatment angiography. The safety and outcomes of acutely ruptured intracranial aneurysms (RIAs) with incomplete occlusion after stent-assisted coiling (SAC) and no-stent coiling (NSC) have not been well clarified. Progressive occlusion of stents can promote the complete occlusion of intracranial aneurysms (IAs), but it remains to be determined if progressive occlusion in acutely RIAs with incomplete occlusion after coiling may be enhanced by protective stenting. This study aimed to evaluate the safety and outcomes of those aneurysms after SAC and NSC; And to discover whether the stents can promote progressive aneurysm occlusion in such lesions or not. METHODS: We reviewed 199 patients with acutely RIAs underwent endovascular coiling and developed incomplete occlusion in the past seven years. The patients' clinical and imaging information were recorded and analyzed. Univariate and multivariate analyses were performed to determine the association of recurrence rate with potential risk factors. RESULTS: SAC group had wider aneurysms neck (3.471 mm vs 2.830 mm, P = 0.009) and smaller dome-to-neck ratio (1.536 vs 2.111, P = 0.001) than in NSC group. There was no significant difference between the two groups in total procedure-related complications rate (31.7% vs 23.5%, P = 0.195), procedure-related mortality (6.9% vs 2.0%, P = 0.170) and modified Rankin Scale (mRS) score at 6-month follow-up (P > 0.05). However, SAC group had significantly higher ischemic complications rate (21.8% vs 8.2%, P = 0.007) and complete occlusion rate (65.6% vs 48.3%, P = 0.020), and lower recurrence rate (15.6% vs 28.1%, P = 0.042) than NSC group based on 6-month follow-up angiograms. Additionally, Multivariable analysis showed NSC was an independent risk factor for aneurysm recurrence (Odds Ratio [OR]: 4.061; P = 0.018). CONCLUSIONS: Acutely RIAs with incomplete occlusion after SAC is associated with higher complications rate and mortality, but has an acceptable safety profile and similar clinical outcome compared to NSC, as well as gives patients superior angiography outcome by progressive occlusion of stents.