Glioma-associated mesenchymal stem cells.

Recent studies have revealed that glioma-associated mesenchymal stem cells play instrumental roles in tumorigenesis and tumour progression and cannot be ignored as a cellular component of the glioma microenvironment. Nevertheless, the origin of these cells and their roles are poorly understood. The only relevant studies have shown that glioma-associated mesenchymal stem cells play a large role in promoting tumour proliferation, invasion and angiogenesis. This review provides a comprehensive summary of their discovery and definition, origin, differences from other tissue-derived mesenchymal stem cells, spatial distribution, functions and prognostic and therapeutic opportunities to deepen the understanding of these cells and provide new insight into the treatment of glioma.

Silencing of lncRNA LBX2-AS1 suppresses glioma cell proliferation and metastasis through the Akt/GSK3ß pathway in vitro.

Long non-coding RNAs (lncRNAs) have been proposed to play pivotal roles in the tumorigenesis of various malignant tumors. Previous studies have found that lncRNA LBX2-AS1 is involved in the progression of various tumors. However, currently, the expression and exact mechanism of LBX2-AS1 in glioma remain unclear. In this study, using online-available datasets combined with clinical glioma tissues collected, we found that LBX2-AS1 was significantly increased and negatively correlated with prognosis in glioma. In vitro functional assays such as CCK-8, Annexin V, transwell assay, and western blot analysis showed that silencing of LBX2-AS1 suppressed the proliferation, migration, and invasion of glioma cells and increased apoptosis. RNA sequencing and western blot analysis confirmed that LBX2-AS1 regulates the Akt/GSK3ß pathway. In conclusion, this study showed that lncRNA LBX2-AS1 depletion inhibits the proliferation, migration, and invasion of glioma cells and increases apoptosis through the Akt/GSK3ß pathway. lncRNA LBX2-AS1 is expected to become a new target for glioma therapy.

Downregulation of α-l-fucosidase 1 suppresses glioma progression by enhancing autophagy and inhibiting macrophage infiltration.

α-l-Fucosidase 1 (FUCA1), a lysosomal enzyme that catalyses the hydrolytic cleavage of the terminal fucose residue, has been reported to be involved in tumorigenesis. However, the clinical significance and biological roles of FUCA1 in glioma remain largely unknown. We analyzed FUCA1 expression according to data in Oncomine, The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases and further verified FUCA1 expression with immunohistochemistry and real-time PCR analysis in glioma tissues. The results showed that FUCA1 overexpression was significantly associated with high-grade glioma as well as high mortality rates in the survival analysis. Data analyzed in cBioPortal showed that alterations in FUCA1 (1.4%) were correlated with worse survival in glioblastoma multiforme patients. Functional experiments showed that downregulation of FUCA1 suppressed glioma growth in vitro and in vivo. Conversely, overexpression of FUCA1 had the opposite effects on glioma. Mechanistically, transient inhibition of FUCA1 promoted the formation of large acidic vacuoles, as revealed by staining with acridine orange, increased the ratio of LC3-B/LC3-A, and modified the expression of Beclin-1 and Atg12, which are autophagic markers. Upregulation of FUCA1 attenuated starvation-induced autophagy in glioma. In addition, lower levels of tumor-infiltrating macrophages, including CD68+ (-30%), F4/80+ (-50%), and CD11c+ macrophages (-50%), were identified in FUCA1-downregulated glioma tissues, and CCL2/CCL5 neutralizing Abs blocked this effect. These results show that FUCA1 could serve as a potential therapeutic target for the treatment of patients with glioma by enhancing autophagy and inhibiting macrophage infiltration.

Models for evaluating glioblastoma invasion along white matter tracts.

White matter tracts (WMs) are one of the main invasion paths of glioblastoma multiforme (GBM). The lack of ideal research models hinders our understanding of the details and mechanisms of GBM invasion along WMs. To date, many potential in vitro models have been reported; nerve fiber culture models and nanomaterial models are biocompatible, and the former have electrically active neurons. Brain slice culture models, organoid models, and microfluidic chip models can simulate the real brain and tumor microenvironment (TME), which contains a variety of cell types. These models are closer to the real in vivo environment and are helpful for further studying not only invasion along WMs by GBM, but also perineural invasion and brain metastasis by solid tumors.

Ultrasound-excited temozolomide sonosensitization induces necroptosis in glioblastoma.

Temozolomide (TMZ) has been determined to be the chemotherapeutic drug with efficacy for glioblastoma (GBM). Thus, potentiating the therapeutic effect of TMZ can undoubtedly yield twice the result with half the effort. In this study, we found for the first time that TMZ can produce reactive oxygen species (ROS) under the influence of ultrasound (US). This property allows TMZ-US therapy to have better efficacy in the treatment of GBM. Given that the increasing use of US in central nervous system (CNS) diseases and the importance of TMZ for GBM therapy, our results will facilitate the development of TMZ-associated glioblastoma therapies. Moreover, we found that chemotherapeutic drugs might have the ability to generate ROS under the excitation of US. On a larger scale, our findings may be applicable to a wide range of known drugs.

Low-intensity pulsed ultrasound-generated singlet oxygen induces telomere damage leading to glioma stem cell awakening from quiescence.

Cancer stem cells, quiescent and drug resistant, have become a therapeutic target. Unlike high-intensity focused ultrasound directly killing tumor, low-intensity pulsed ultrasound (LIPUS), a new noninvasive physical device, promotes pluripotent stem cell differentiation and is primarily applied in tissue engineering but rarely in oncotherapy. We explored the effect and mechanism of LIPUS on glioma stem cell (GSC) expulsion from quiescence. Here, we observed that LIPUS led to attenuated expression of GSC biomarkers, promoted GSC escape from G0 quiescence, and significantly weakened the Wnt and Hh pathways. Of note, LIPUS transferred sonomechanical energy into cytochrome c and B5 proteins, which converted oxygen molecules into singlet oxygen, triggering telomere crisis. The in vivo and in vitro results confirmed that LIPUS enhanced the GSC sensitivity to temozolomide. These results demonstrated that LIPUS "waked up" GSCs to improve their sensitivity to chemotherapy, and importantly, we confirmed the direct targeted proteins of LIPUS in GSCs.

Global research trends and hotspots on glioma stem cells.

Background: Glioma stem cells (GSCs) are a sub-population of cancer stem cells with capacity of self-renewal and differentiation. Accumulated evidence has revealed that GSCs were shown to contribute to gliomagenesis, distant metastasis as well as the resistance to radiotherapy and chemotherapy. As a result, GSCs were regarded as a promising therapeutic target in human glioma. The purpose of our study is to identify current state and hotspots of GSCs research by analyzing scientific publications through bibliometric methods. Methods: All relevant publications on GSCs during 2003-2021 were extracted from the Science Citation Index Expanded of Web of Science Core Collection (WoSCC), and related information was collected and analyzed using Microsoft Excel 2016, GraphPad Prism 8 and VOSviewer software. Results: A total of 4990 papers were included. The United States accounted for the largest number of publications (1852), the second average citations per item (ACI) value (67.54) as well as the highest H-index (157). Cancer Research was the most influential journal in this field. The most contributive institution was League of European Research Universities. RICH JN was the author with the most publications (109) and the highest H-index (59). All studies were clustered into 3 groups: "glioma stem cell properties", "cell biological properties" and "oncology therapy". The keywords "identification", "CD133" and "side population" appeared earlier with the smaller average appearing years (AAY), and the keywords"radiotherapy" and "chemotherapy" had the latest AAY. The analysis of top cited articles showed that "temozolomide", "epithelial-mesenchymal transition", and "immunotherapy" emerged as new focused issues. Conclusion: There has been a growing number of researches on GSCs. The United States has always been a leading player in this domain. In general, the research focus has gradually shifted from basic cellular biology to the solutions of clinical concerns. "Temozolomide resistance", "epithelial-mesenchymal transition", and "immunotherapy" should be given more attention in the future.

Oral Administration of Brain Protein Combined With Probiotics Induces Immune Tolerance Through the Tryptophan Pathway.

Excessive inflammation leads to secondary immune damage after traumatic brain injury (TBI). The intestinal mucosa is a key component of immune tolerance due to gut-brain axis regulation, but the curative effect is not optimal. Intestinal dysfunction impairs the establishment of immune tolerance in patients with TBI. Therefore, we orally administered brain protein (BP) combined with probiotics to induce immune tolerance and explored the mechanism by which the homeostasis of the microbiota contributes to the enhancement of curative effects by BPs. Herein, we demonstrated that patients with TBI and surgical brain injury (SBI) models of rats had obvious dysbiosis. Notably, the intestinal barrier, proinflammatory cytokines, and activation of microglia demonstrated that excessive inflammatory damage was better controlled in the combined group (oral administration of BP combined with probiotics) than in the BP group (oral administration of BP). Fundamentally, tandem mass tag (TMT)-based quantitative proteomics analysis revealed that BP and probiotics preferentially affect Try-related pathways. A series of experiments further confirmed that Indoleamine 2,3 dioxygenase (IDO)/Kynurenine (Kyn)/Aryl hydrocarbon receptor (AhR) expression was high in the BP group, while Tryptophan hydroxylase 1(TpH1)/5-hydroxytryptamine (5-HT) only changed in the combined group. This study suggests that probiotics can enhance the efficacy of oral BP-induced immune tolerance through the Try pathway.

Elevated GAS2L3 Expression Correlates With Poor Prognosis in Patients With Glioma: A Study Based on Bioinformatics and Immunohistochemical Analysis.

BACKGROUND: Growth arrest-specific 2 like 3 (GAS2L3) is a cytoskeleton-associated protein that interacts with actin filaments and tubulin. Abnormal GAS2L3 expression has been reported to be associated with carcinogenesis. However, the biological role of GAS2L3 in glioma remains to be determined. METHODS: The transcriptome level of GAS2L3 and its relationship with clinicopathological characteristics were analyzed among multiple public databases and clinical specimens. Bioinformatics analyses were conducted to explore biological functions and prognostic value of GAS2L3 in glioma. RESULTS: GAS2L3 was substantially expressed in glioma, and high GAS2L3 expression correlated with shorter overall survival time and poor clinical variables. Gene set enrichment analysis (GSEA), single-sample gene-set enrichment analysis, and CIBERSORT algorithm analyses showed that GAS2L3 expression was closely linked to immune-related pathways, inflammatory activities, and immune cell infiltration. Moreover, GAS2L3 was synergistic with T cell-inflamed gene signature, immune checkpoints, T-cell receptor diversities, and neoantigen numbers. CONCLUSION: This study suggests that GAS2L3 is a prognostic biomarker for glioma, providing a reference for further study of the potential role of GAS2L3 in the immunomodulation of glioma.

Current State and Future Directions of Intranasal Delivery Route for Central Nervous System Disorders: A Scientometric and Visualization Analysis.

Background: The management of various central nervous system (CNS) disorders has been challenging, due to highly compact blood-brain barrier (BBB) impedes the access of most pharmacological agents to the brain. Among multiple strategies proposed to circumvent this challenge, intranasal delivery route has sparked great interest for brain targeting in the past decades. The aim of this study was to apply scientometric method to estimate the current status and future trends of the field from a holistic perspective. Methods: All relevant publications during 1998-2020 were retrieved from the Web of Science Core Collection (SCIE, 1998-present). Two different scientometric software including VOS viewer and CiteSpace, and one online platform were used to conduct co-authorship, co-citation, and co-occurrence analysis of journals, countries, institutes, authors, references and keywords. Results: A total of 2,928 documents, including 2,456 original articles and 472 reviews, were retrieved. Our analysis revealed a significant increasing trend in the total number of scientific publications over the past 2 decades (R 2 = 0.98). The United States dominated the field, reflecting in the largest amount of publications (971), the highest H-index (99), and extensive international collaboration. Jamia Hamdard contributed to most publications. Frey WH and Illum L were key researchers with the highest number of publications and citations, respectively. The International Journal of Pharmaceutics was the most influential academic journal, and Pharmacology/Pharmacy and Neurosciences/Neurology were the hottest research categories in this field. Based on keywords occurrence analysis, four main topics were identified, and the current research focus of this field has shifted from cluster 4 (pathways and mechanisms of intranasal delivery) to cluster 2 (the study of nasal drug delivery systems), especially the nanostructured and nano-sized carrier systems. Keywords burst detection revealed that the research focus on oxidative stress, drug delivery, neuroinflammation, nanostructured lipid carrier, and formulation deserves our continued attention. Conclusion: To the authors' knowledge, this is the first scientometric analysis regarding intranasal delivery research. This study has demonstrated a comprehensive knowledge map, development landscape and future directions of intranasal delivery research, which provides a practical and valuable reference for scholars and policymakers in this field.

Therapeutic Effect of Enteral Nutrition Supplemented with Probiotics in the Treatment of Severe Craniocerebral Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Whether early enteral nutrition with probiotics can reduce the mortality and infection rate of patients with severe craniocerebral injury (SCI), improve their gastrointestinal function, and shorten the length of stay in the intensive care unit (ICU) has not been determined. METHODS: PubMed, China National Knowledge Infrastructure, and Embase were electronically searched for the purpose of identifying randomized controlled trials investigated the potential of early enteral nutrition supplemented with probiotics on patients with SCI from the establishment of databases to August 26, 2019. STATA software version 12.0 was used to perform meta-analysis. RESULTS: A total of 39 trials enrolling 3387 patients were included. Early enteral nutrition supplemented with probiotics was associated with decreased risk of infection (pooled risk ratio [RR], 0.486; 95% confidence interval [CI], 0.394-0.599), decreased risk of 7-, 14-, and 28-day mortality (pooled RRs, 0.415, 0.497, and 0.385; 95% CIs, 0.196-0.878, 0.297-0.833, and 0.197-0.751, respectively), and decreased risk of gastrointestinal complications (pooled RR, 0.363; 95% CI, 0.274-0.481). It also shortened the time course recovery of enteral function and shortened the length of stay in hospital and length of ICU stay (standardized mean differences, -3.327 and -1.461; 95% CIs, -6.213 to -0.440 and -2.111 to -0.811, respectively). CONCLUSIONS: Enteral nutrition supplemented with probiotics effectively decreases the risk of mortality, gastrointestinal complications, and infection, and shortens the stays in ICU; therefore, it should be extensively adopted to manage these given patients.