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Keywords = tumor-associated astrocytes

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15 pages, 2893 KiB  
Article
NRP1 and GFAP Expression in the Medulloblastoma Microenvironment: Implications for Angiogenesis and Tumor Progression
by Margarita Belem Santana-Bejarano, María Paulina Reyes-Mata, José de Jesús Guerrero-García, Daniel Ortuño-Sahagún and Marisol Godínez-Rubí
Cancers 2025, 17(15), 2417; https://doi.org/10.3390/cancers17152417 - 22 Jul 2025
Viewed by 227
Abstract
Background/Objectives: Medulloblastoma (MB) is the second leading cause of cancer-related death in children. Its tumor microenvironment (TME) includes endothelial, glial, and immune cells that influence tumor architecture and progression. Neuropilin-1 (NRP1), a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), is [...] Read more.
Background/Objectives: Medulloblastoma (MB) is the second leading cause of cancer-related death in children. Its tumor microenvironment (TME) includes endothelial, glial, and immune cells that influence tumor architecture and progression. Neuropilin-1 (NRP1), a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), is expressed in various cell types during oncogenesis, yet its role in MB progression remains unclear. This study aimed to evaluate the expression and localization of NRP1 and glial fibrillary acidic protein (GFAP) in MB tissue. Methods: We analyzed MB tissue samples using immunohistochemistry, immunofluorescence, and quantitative PCR. Samples were stratified by molecular subgroup (WNT, SHH, non-WNT/non-SHH). We assessed NRP1 expression in tumor-associated microglia/macrophages (TAMs) and endothelial cells, as well as GFAP expression in astrocytes and tumor cells. Histopathological correlations and survival analyses were also conducted. Results: NRP1 was consistently expressed by TAMs across all MB molecular subgroups. Tumor vasculature showed strong endothelial NRP1 expression, while perivascular astrocytic coverage was frequently absent. Astrocytic processes exhibited spatial differences according to tumor histology. In SHH-MBs, a subset of tumor cells showed aberrant GFAP expression, which correlated with tumor recurrence or progression. Conclusions: NRP1 and GFAP display distinct expression patterns within the MB microenvironment, reflecting subgroup-specific biological behavior. Endothelial NRP1 positivity combined with limited vascular-astrocytic interaction and aberrant GFAP expression in SHH-MB may contribute to dysregulated angiogenesis and tumor progression. These findings warrant further investigation to explore their prognostic and therapeutic implications. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Malignant Nervous System Cancers)
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23 pages, 2915 KiB  
Article
Analysis of the Expression Patterns of Tumor Necrosis Factor Alpha Signaling Pathways and Regulatory MicroRNAs in Astrocytic Tumors
by Klaudia Skóra, Damian Strojny, Dawid Sobański, Rafał Staszkiewicz, Paweł Gogol, Mateusz Miller and Beniamin Oskar Grabarek
Int. J. Mol. Sci. 2025, 26(12), 5892; https://doi.org/10.3390/ijms26125892 - 19 Jun 2025
Viewed by 1953
Abstract
Chronic inflammation is increasingly recognized as a driver of glioma progression, with tumor necrosis factor-alpha (TNF-α) playing a central role in modulating the tumor microenvironment. This study aimed to investigate the expression profiles and regulatory mechanisms of TNF-α and its downstream mediators—including interleukin-1 [...] Read more.
Chronic inflammation is increasingly recognized as a driver of glioma progression, with tumor necrosis factor-alpha (TNF-α) playing a central role in modulating the tumor microenvironment. This study aimed to investigate the expression profiles and regulatory mechanisms of TNF-α and its downstream mediators—including interleukin-1 beta (IL-1β), Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8), and Mitogen-activated protein kinase kinase 7 (MAP2K7)—in astrocytic tumors of varying malignancy. We conducted an integrative molecular analysis of 60 human astrocytic tumor samples (20 G2, 12 G3, 28 G4) using transcriptomic microarrays, Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), Enzyme-Linked Immunosorbent Assay (ELISA), Western blotting, immunohistochemistry, methylation-specific PCR, and miRNA profiling. Prognostic associations were evaluated using Kaplan–Meier survival and Cox regression analyses. TNF-α, IL-1β, and MAP3K8 were significantly upregulated in high-grade tumors, with log2 fold changes ranging from 5.56 to 8.76 (p < 0.001). High expression of TNF-α (HR = 2.10, 95% CI: 1.27–3.46, p = 0.004), IL-1β (HR = 2.35, 95% CI: 1.45–3.82, p = 0.001), and MAP3K8 (Hazard Ratio; HR = 1.88, 95% confidence interval; 95% CI: 1.12–3.16, p = 0.015) was associated with poorer overall survival. miR-34a-3p and miR-30 family members, predicted to target TNF-α and IL-1β, were markedly downregulated in G3/G4 tumors (e.g., miR-30e-3p fold change: –3.78, p < 0.01). Promoter hypomethylation was observed in G3/G4 tumors, supporting epigenetic activation. Our findings establish a multi-layered regulatory mechanism of TNF-α signaling in astrocytic tumors. These data highlight the TNF-α/IL-1β/MAP3K8 axis as a critical driver of glioma aggressiveness and a potential therapeutic target. Full article
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31 pages, 2278 KiB  
Review
Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH): A Promising Molecular Marker and Therapeutic Target for Hepatocellular Carcinoma
by Eva Davis, Ali Gawi Ermi and Devanand Sarkar
Cancers 2025, 17(8), 1375; https://doi.org/10.3390/cancers17081375 - 21 Apr 2025
Cited by 1 | Viewed by 889
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule. Full article
(This article belongs to the Special Issue Molecular Markers and Targeted Therapy for Hepatobiliary Tumors)
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12 pages, 3354 KiB  
Article
Polycystins Expression in Astrocytic Gliomas
by Martha Assimakopoulou, Konstantina Soufli and Maria Melachrinou
Biomedicines 2025, 13(4), 884; https://doi.org/10.3390/biomedicines13040884 - 5 Apr 2025
Viewed by 605
Abstract
Background: Polycystin 1 (PC1) and polycystin 2 (PC2) proteins are members of the transient receptor potential (TRP) channels family and are encoded from PKD1 and PKD2 genes, respectively. Until recently, the role of PKD1 and PKD2 has been associated with the pathogenesis of [...] Read more.
Background: Polycystin 1 (PC1) and polycystin 2 (PC2) proteins are members of the transient receptor potential (TRP) channels family and are encoded from PKD1 and PKD2 genes, respectively. Until recently, the role of PKD1 and PKD2 has been associated with the pathogenesis of the kidney since mutations in these genes cause autosomal dominant polycystic kidney disease (ADPKD). Recent data implicates polycystins in the pathogenesis of solid tumors. In this aspect, the expression of PKD1 and PKD2 in human astrocytomas is largely unknown. The aim of the present research study was to investigate the expression of PKD1 and PKD2 in astrocytic tumors and correlate it with clinicopathological characteristics such as the grade of malignancy, age, and gender of the patients. Methods: A total of 70 cases—corresponding to 8 grade II (diffuse fibrillary astrocytomas), 12 grade III (anaplastic astrocytomas), and 50 grade IV (glioblastomas multiforme)—were examined. The mRNA expression levels of PKD1 and PKD2 were determined through molecular qRT-PCR analysis using the relative quantification ΔΔCt method and the expression of PC1 and PC2 was detected through immunohistochemistry using the semi-quantitative H-score system. Results: Increased levels of PKD1 and PKD2 in astrocytomas were found compared with that of a normal brain (p < 0.05). Glioblastomas demonstrated the greatest increase in PKD1 and PKD2 expression compared to other grades of malignancy (p < 0.05). The same pattern of expression showed PC1 and PC2 proteins. A significant correlation between PKD1 and PKD2 as well as PC1 and PC2 expressions was found (p < 0.05). Although no association was detected between PC1 or PC2 and Ki67 expression (p > 0.05), a significant correlation between PC1 and p53 immunoexpressions, in grade III and between PC2 and p53 immunoexpressions, in grade II astrocytomas (p < 0.01) has emerged. PC1 expression was correlated with age of the patients (p < 0.05). PKD1 and PKD2 expression were negatively correlated with the prognosis of glioma patients. Conclusions: The results of this study indicate the potential involvement of polycystins in the pathogenesis of astrocytomas. However, further research is required to fully understand the mechanisms that these molecules are implicated. Full article
(This article belongs to the Section Cell Biology and Pathology)
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22 pages, 4256 KiB  
Article
Effects of Induced Pluripotent Stem Cell-Derived Astrocytes on Cisplatin Sensitivity in Pediatric Brain Cancer Cells
by Sonia Kiran, Yu Xue, Drishty B. Sarker and Qing-Xiang Amy Sang
Cancers 2025, 17(6), 997; https://doi.org/10.3390/cancers17060997 - 16 Mar 2025
Cited by 1 | Viewed by 1150
Abstract
Background: ATRTs and DIPGs are deadly pediatric brain tumors with poor prognosis. These tumors can develop resistance to chemotherapies, which may be significantly influenced by their microenvironment. Since astrocytes are the most abundant glial cell type in the brain microenvironment and may support [...] Read more.
Background: ATRTs and DIPGs are deadly pediatric brain tumors with poor prognosis. These tumors can develop resistance to chemotherapies, which may be significantly influenced by their microenvironment. Since astrocytes are the most abundant glial cell type in the brain microenvironment and may support tumor growth and chemoresistance, this study investigated the effects of induced pluripotent stem cell-derived astrocytes (iPSC-astrocytes) on cisplatin sensitivity in CHLA-05-ATRT and SF8628 (DIPG) cells. iPSCs provide an unlimited and standardized source of nascent astrocytes, which enables modeling the interaction between childhood brain tumor cells and iPSC-astrocytes within a controlled coculture system. Methods: To study the effects on tumor growth, the iPSC-astrocytes were cocultured with tumor cells. Additionally, the tumor cells were exposed to various concentrations of cisplatin to evaluate their chemosensitivity in the presence of astrocytes. Results: The paracrine interaction of iPSC-astrocytes with tumor cells upregulated astrocyte activation markers GFAP and STAT3 and promoted tumor cell proliferation. Moreover, the cisplatin treatment significantly decreased the viability of CHLA-05-ATRT and SF8628 cells. However, tumor cells exhibited reduced sensitivity to cisplatin in the coculture with iPSC-astrocytes. During cisplatin treatment, DIPG cells in particular showed upregulation of resistance markers, ERK1, STAT3, and MTDH, which are associated with enhanced proliferation and invasion. They also had increased expression of APEX1, which is involved in the base excision repair pathway following cisplatin-induced DNA damage. Conclusion: These findings underscore the significance of the tumor microenvironment in modulating tumor cell survival and chemosensitivity. Full article
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23 pages, 3717 KiB  
Article
Epidemiology and Outcome of Primary Central Nervous System Tumors Treated at King Hussein Cancer Center
by Maysa Al-Hussaini, Abdallah Al-Ani, Justin Z. Amarin, Sarah Al Sharie, Mouness Obeidat, Awni Musharbash, Amer A. Al Shurbaji, Ahmad Kh. Ibrahimi, Abdellatif Al-Mousa, Nasim Sarhan, Nisreen Amayiri, Rula Amarin, Tala Alawabdeh, Qasem Alzoubi, Dima Abu Laban, Bayan Maraqa, Khaled Jamal and Asem Mansour
Cancers 2025, 17(4), 590; https://doi.org/10.3390/cancers17040590 - 9 Feb 2025
Viewed by 1552
Abstract
Background and Objectives: Primary central nervous system (CNS) tumors are often associated with relatively poor outcomes. Data on the epidemiology and outcome of CNS tumors in Jordan are scarce. We aim to report the epidemiology and outcome of primary CNS tumors of patients [...] Read more.
Background and Objectives: Primary central nervous system (CNS) tumors are often associated with relatively poor outcomes. Data on the epidemiology and outcome of CNS tumors in Jordan are scarce. We aim to report the epidemiology and outcome of primary CNS tumors of patients managed at a comprehensive cancer care center in Jordan. Methods: We performed a retrospective chart review of all Jordanian patients with a primary CNS tumor diagnosis who were managed at the center between July 2003 and June 2019. We included all entities described in the 2021 CNS WHO classification system, in addition to pituitary neuroendocrine tumors (PitNETs). We used the Kaplan–Meier method to estimate the 1-year, 2-year, and 5-year overall survival (OS) rates for each entity. Results and Findings: We included 2094 cases. The numbers of pediatrics and adults were 652 (31.1%) and 1442 (68.9%), respectively. The three most common groups of tumors were “gliomas, glioneuronal tumors, and neuronal tumors” (n = 1200 [57.30%]), followed by meningiomas (n = 261 [12.5%]), embryonal tumors (n = 234 [11.2%]). The three most common tumor families were adult-type diffuse gliomas (n = 709 [33.8%]), medulloblastoma (n = 199 [9.5%]), and circumscribed astrocytic gliomas (n = 183 [8.7%]). The median survival for the entire cohort was 97 months (95CI; 81–112). Survival was significantly worse for males and adults compared to their respective counterparts. Among the most common tumor group, “gliomas, glioneuronal tumors, and neuronal tumors”, OS rates for adult-type diffuse gliomas were significantly lower than all other types. Overall, adult gliomas with IDH-mutations had a survival advantage over wildtype cases (IDH-mutant 1-year OS, 89% [82–97%] vs. IDH-wildtype 1-year OS, 60% [52–70%]; p < 0.001). Conclusions: We present a detailed analysis of the primary CNS tumors diagnosed in the largest cancer center in Jordan between 2003 and 2019. We compared the epidemiology and overall survival of these patients to worldwide estimates and found the epidemiology and outcome of these tumors comparable to worldwide trends. Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
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30 pages, 24558 KiB  
Article
In Vitro Functional Validation of an Anti-FREM2 Nanobody for Glioblastoma Cell Targeting
by Gloria Krapež, Neja Šamec, Alja Zottel, Mojca Katrašnik, Ana Kump, Jernej Šribar, Igor Križaj, Jurij Stojan, Rok Romih, Gregor Bajc, Matej Butala, Serge Muyldermans and Ivana Jovčevska
Antibodies 2025, 14(1), 8; https://doi.org/10.3390/antib14010008 - 24 Jan 2025
Viewed by 2239
Abstract
Background/Objectives: Glioblastomas are the most common brain malignancies. Despite the implementation of multimodal therapy, patient life expectancy after diagnosis is barely 12 to 18 months. Glioblastomas are highly heterogeneous at the genetic and epigenetic level and comprise multiple different cell subpopulations. Therefore, [...] Read more.
Background/Objectives: Glioblastomas are the most common brain malignancies. Despite the implementation of multimodal therapy, patient life expectancy after diagnosis is barely 12 to 18 months. Glioblastomas are highly heterogeneous at the genetic and epigenetic level and comprise multiple different cell subpopulations. Therefore, small molecules such as nanobodies, able to target membrane proteins specific to glioblastoma cells or specific cell types within the tumor are being investigated as novel tools to treat glioblastomas. Methods: Here, we describe the identification of such a nanobody and its in silico and in vitro validation. NB3F18, as we named it, is directed against the membrane-associated protein FREM2, overexpressed in glioblastoma stem cells. Results: Three dimensional in silico modeling indicated that NB3F18 and FREM2 form a stable complex. Surface plasmon resonance confirmed their interaction with moderate affinity. As we demonstrated by flow cytometry, NB3F18 binds to glioblastoma stem cells to a greater extent than to differentiated glioblastoma cells and astrocytes. Immunocytochemistry revealed surface localization of NB3F18 on glioblastoma stem cells, whereas cytoplasmic localization of NB3F18 was observed in other cell lines. NB3F18 was detected by transmission electron microscopy on the plasma membrane and in various compartments of the endocytic pathway, from endocytic vesicles to multivesicular bodies (endosomes) and lysosomes. Interestingly, NB3F18 was cytotoxic to glioblastoma stem cells. Conclusions: Collectively, NB3F18 has been qualified as an interesting tool to target glioblastoma cells and as a potential vehicle to deliver biological or pharmaceutical agents to these cells. Full article
(This article belongs to the Section Antibody Discovery and Engineering)
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29 pages, 1567 KiB  
Review
The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies
by Yuganthini Vijayanathan and Ivy A. W. Ho
Int. J. Mol. Sci. 2025, 26(2), 669; https://doi.org/10.3390/ijms26020669 - 14 Jan 2025
Cited by 3 | Viewed by 3260
Abstract
Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), [...] Read more.
Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), while glutamine and tryptophan metabolism further contribute to the aggressive phenotype of GBM. These metabolic alterations impair immune cell function, leading to exhaustion and stress in CD8+ and CD4+ T cells while favoring immunosuppressive populations such as regulatory T cells (Tregs) and M2-like macrophages. Recent studies emphasize the role of slow-cycling GBM cells (SCCs), lipid-laden macrophages, and tumor-associated astrocytes (TAAs) in reshaping GBM’s metabolic landscape and reinforcing immune evasion. Genetic mutations, including Isocitrate Dehydrogenase (IDH) mutations, Epidermal Growth Factor Receptor (EGFR) amplification, and Phosphotase and Tensin Homolog (PTEN) loss, further drive metabolic reprogramming and offer potential targets for therapy. Understanding the relationship between GBM metabolism and immune suppression is critical for overcoming therapeutic resistance. This review focuses on the role of metabolic rewiring in GBM, its impact on the immune microenvironment, and the potential of combining metabolic targeting with immunotherapy to improve clinical outcomes for GBM patients. Full article
(This article belongs to the Special Issue Targeting Glioblastoma Metabolism)
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18 pages, 3243 KiB  
Article
Integrated Transcriptome Profiling and Pan-Cancer Analyses Reveal Oncogenic Networks and Tumor-Immune Modulatory Roles for FABP7 in Brain Cancers
by Yool Lee, Carlos C. Flores, Micah Lefton, Sukanya Bhoumik, Yuji Owada and Jason R. Gerstner
Int. J. Mol. Sci. 2024, 25(22), 12231; https://doi.org/10.3390/ijms252212231 - 14 Nov 2024
Cited by 1 | Viewed by 2519
Abstract
Fatty acid binding protein 7 (FABP7) is a multifunctional chaperone involved in lipid metabolism and signaling. It is primarily expressed in astrocytes and neural stem cells (NSCs), as well as their derived malignant glioma cells within the central nervous system. Despite growing evidence [...] Read more.
Fatty acid binding protein 7 (FABP7) is a multifunctional chaperone involved in lipid metabolism and signaling. It is primarily expressed in astrocytes and neural stem cells (NSCs), as well as their derived malignant glioma cells within the central nervous system. Despite growing evidence for FABP7’s tumor-intrinsic onco-metabolic functions, its mechanistic role in regulating the brain tumor immune microenvironment (TIME) and its impact on prognosis at the molecular level remain incompletely understood. Utilizing combined transcriptome profiling and pan-cancer analysis approaches, we report that FABP7 mediates the expression of multiple onco-immune drivers, collectively impacting tumor immunity and clinical outcomes across brain cancer subtypes. An analysis of a single-cell expression atlas revealed that FABP7 is predominantly expressed in the glial lineage and malignant cell populations in gliomas, with nuclear localization in their parental NSCs. Pathway and gene enrichment analysis of RNA sequencing data from wild-type (WT) and Fabp7-knockout (KO) mouse brains, alongside control (CTL) and FABP7-overexpressing (FABP7 OV) human astrocytes, revealed a more pronounced effect of FABP7 levels on multiple cancer-associated pathways. Notably, genes linked to brain cancer progression and tumor immunity (ENO1, MUC1, COL5A1, and IL11) were significantly downregulated (>2-fold) in KO brain tissue but were upregulated in FABP7 OV astrocytes. Furthermore, an analysis of data from The Cancer Genome Atlas (TCGA) showed robust correlations between the expression of these factors, as well as FABP7, and established glioma oncogenes (EGFR, BRAF, NF1, PDGFRA, IDH1), with stronger associations seen in low-grade glioma (LGG) than in glioblastoma (GBM). TIME profiling also revealed that the expression of FABP7 and the genes that it modulates was significantly associated with prognosis and survival, particularly in LGG patients, by influencing the infiltration of immunosuppressive cell populations within tumors. Overall, our findings suggest that FABP7 acts as an intracellular regulator of pro-tumor immunomodulatory genes, exerting a synergistic effect on the TIME and clinical outcomes in brain cancer subtypes. Full article
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25 pages, 6163 KiB  
Article
A Human Brain-Chip for Modeling Brain Pathologies and Screening Blood–Brain Barrier Crossing Therapeutic Strategies
by Shek Man Chim, Kristen Howell, Alexandros Kokkosis, Brian Zambrowicz, Katia Karalis and Elias Pavlopoulos
Pharmaceutics 2024, 16(10), 1314; https://doi.org/10.3390/pharmaceutics16101314 - 10 Oct 2024
Cited by 3 | Viewed by 4663
Abstract
Background/Objectives: The limited translatability of preclinical experimental findings to patients remains an obstacle for successful treatment of brain diseases. Relevant models to elucidate mechanisms behind brain pathogenesis, including cell-specific contributions and cell-cell interactions, and support successful targeting and prediction of drug responses in [...] Read more.
Background/Objectives: The limited translatability of preclinical experimental findings to patients remains an obstacle for successful treatment of brain diseases. Relevant models to elucidate mechanisms behind brain pathogenesis, including cell-specific contributions and cell-cell interactions, and support successful targeting and prediction of drug responses in humans are urgently needed, given the species differences in brain and blood-brain barrier (BBB) functions. Human microphysiological systems (MPS), such as Organ-Chips, are emerging as a promising approach to address these challenges. Here, we examined and advanced a Brain-Chip that recapitulates aspects of the human cortical parenchyma and the BBB in one model. Methods: We utilized human primary astrocytes and pericytes, human induced pluripotent stem cell (hiPSC)-derived cortical neurons, and hiPSC-derived brain microvascular endothelial-like cells and included for the first time on-chip hiPSC-derived microglia. Results: Using Tumor necrosis factor alpha (TNFα) to emulate neuroinflammation, we demonstrate that our model recapitulates in vivo-relevant responses. Importantly, we show microglia-derived responses, highlighting the Brain-Chip’s sensitivity to capture cell-specific contributions in human disease-associated pathology. We then tested BBB crossing of human transferrin receptor antibodies and conjugated adeno-associated viruses. We demonstrate successful in vitro/in vivo correlation in identifying crossing differences, underscoring the model’s capacity as a screening platform for BBB crossing therapeutic strategies and ability to predict in vivo responses. Conclusions: These findings highlight the potential of the Brain-Chip as a reliable and time-efficient model to support therapeutic development and provide mechanistic insights into brain diseases, adding to the growing evidence supporting the value of MPS in translational research and drug discovery. Full article
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18 pages, 4374 KiB  
Article
Hepatocellular Carcinoma in Mice Affects Neuronal Activity and Glia Cells in the Suprachiasmatic Nucleus
by Mona Yassine, Soha A. Hassan, Lea Aylin Yücel, Fathima Faiba A. Purath, Horst-Werner Korf, Charlotte von Gall and Amira A. H. Ali
Biomedicines 2024, 12(10), 2202; https://doi.org/10.3390/biomedicines12102202 - 27 Sep 2024
Cited by 1 | Viewed by 1932
Abstract
Background: Chronic liver diseases such as hepatic tumors can affect the brain through the liver–brain axis, leading to neurotransmitter dysregulation and behavioral changes. Cancer patients suffer from fatigue, which can be associated with sleep disturbances. Sleep is regulated via two interlocked mechanisms: [...] Read more.
Background: Chronic liver diseases such as hepatic tumors can affect the brain through the liver–brain axis, leading to neurotransmitter dysregulation and behavioral changes. Cancer patients suffer from fatigue, which can be associated with sleep disturbances. Sleep is regulated via two interlocked mechanisms: homeostatic regulation and the circadian system. In mammals, the hypothalamic suprachiasmatic nucleus (SCN) is the key component of the circadian system. It generates circadian rhythms in physiology and behavior and controls their entrainment to the surrounding light/dark cycle. Neuron–glia interactions are crucial for the functional integrity of the SCN. Under pathological conditions, oxidative stress can compromise these interactions and thus circadian timekeeping and entrainment. To date, little is known about the impact of peripheral pathologies such as hepatocellular carcinoma (HCC) on SCN. Materials and Methods: In this study, HCC was induced in adult male mice. The key neuropeptides (vasoactive intestinal peptide: VIP, arginine vasopressin: AVP), an essential component of the molecular clockwork (Bmal1), markers for activity of neurons (c-Fos), astrocytes (GFAP), microglia (IBA1), as well as oxidative stress (8-OHdG) in the SCN were analyzed by immunohistochemistry at four different time points in HCC-bearing compared to control mice. Results: The immunoreactions for VIP, Bmal1, GFAP, IBA1, and 8-OHdG were increased in HCC mice compared to control mice, especially during the activity phase. In contrast, c-Fos was decreased in HCC mice, especially during the late inactive phase. Conclusions: Our data suggest that HCC affects the circadian system at the level of SCN. This involves an alteration of neuropeptides, neuronal activity, Bmal1, activation of glia cells, and oxidative stress in the SCN. Full article
(This article belongs to the Special Issue Understanding Diseases Affecting the Central Nervous System)
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14 pages, 2006 KiB  
Article
Brain Ischemic Tolerance Triggered by Preconditioning Involves Modulation of Tumor Necrosis Factor-α-Stimulated Gene 6 (TSG-6) in Mice Subjected to Transient Middle Cerebral Artery Occlusion
by Chiara Di Santo, Antonio Siniscalchi, Daniele La Russa, Paolo Tonin, Giacinto Bagetta and Diana Amantea
Curr. Issues Mol. Biol. 2024, 46(9), 9970-9983; https://doi.org/10.3390/cimb46090595 - 10 Sep 2024
Cited by 2 | Viewed by 1372
Abstract
Ischemic preconditioning (PC) induced by a sub-lethal cerebral insult triggers brain tolerance against a subsequent severe injury through diverse mechanisms, including the modulation of the immune system. Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, has recently been involved in [...] Read more.
Ischemic preconditioning (PC) induced by a sub-lethal cerebral insult triggers brain tolerance against a subsequent severe injury through diverse mechanisms, including the modulation of the immune system. Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, has recently been involved in the regulation of the neuroimmune response following ischemic stroke. Thus, we aimed at assessing whether the neuroprotective effects of ischemic PC involve the modulation of TSG-6 in a murine model of transient middle cerebral artery occlusion (MCAo). The expression of TSG-6 was significantly elevated in the ischemic cortex of mice subjected to 1 h MCAo followed by 24 h reperfusion, while this effect was further potentiated (p < 0.05 vs. MCAo) by pre-exposure to ischemic PC (i.e., 15 min MCAo) 72 h before. By immunofluorescence analysis, we detected TSG-6 expression mainly in astrocytes and myeloid cells populating the lesioned cerebral cortex, with a more intense signal in tissue from mice pre-exposed to ischemic PC. By contrast, levels of TSG-6 were reduced after 24 h of reperfusion in plasma (p < 0.05 vs. SHAM), but were dramatically elevated when severe ischemia (1 h MCAo) was preceded by ischemic PC (p < 0.001 vs. MCAo) that also resulted in significant neuroprotection. In conclusion, our data demonstrate that neuroprotection exerted by ischemic PC is associated with the elevation of TSG-6 protein levels both in the brain and in plasma, further underscoring the beneficial effects of this endogenous modulator of the immune system. Full article
(This article belongs to the Special Issue Advanced Research in Neuroinflammation)
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19 pages, 2121 KiB  
Article
A Pro-Inflammatory Stimulus versus Extensive Passaging of DITNC1 Astrocyte Cultures as Models to Study Astrogliosis
by Leonardo A. Pérez, Esteban Palacios, María Fernanda González, Ignacio Leyton-Rivera, Samuel Martínez-Meza, Ramón Pérez-Núñez, Emanuel Jeldes, Ana María Avalos, Jorge Díaz and Lisette Leyton
Int. J. Mol. Sci. 2024, 25(17), 9454; https://doi.org/10.3390/ijms25179454 - 30 Aug 2024
Cited by 1 | Viewed by 1638
Abstract
Astrogliosis is a process by which astrocytes, when exposed to inflammation, exhibit hypertrophy, motility, and elevated expression of reactivity markers such as Glial Fibrillar Acidic Protein, Vimentin, and Connexin43. Since 1999, our laboratory in Chile has been studying molecular signaling pathways associated with [...] Read more.
Astrogliosis is a process by which astrocytes, when exposed to inflammation, exhibit hypertrophy, motility, and elevated expression of reactivity markers such as Glial Fibrillar Acidic Protein, Vimentin, and Connexin43. Since 1999, our laboratory in Chile has been studying molecular signaling pathways associated with “gliosis” and has reported that reactive astrocytes upregulate Syndecan 4 and αVβ3 Integrin, which are receptors for the neuronal glycoprotein Thy-1. Thy-1 engagement stimulates adhesion and migration of reactive astrocytes and induces neurons to retract neurites, thus hindering neuronal network repair. Reportedly, we have used DITNC1 astrocytes and neuron-like CAD cells to study signaling mechanisms activated by the Syndecan 4–αVβ3 Integrin/Thy-1 interaction. Importantly, the sole overexpression of β3 Integrin in non-reactive astrocytes turns them into reactive cells. In vitro, extensive passaging is a simile for “aging”, and aged fibroblasts have shown β3 Integrin upregulation. However, it is not known if astrocytes upregulate β3 Integrin after successive cell passages. Here, we hypothesized that astrocytes undergoing long-term passaging increase β3 Integrin expression levels and behave as reactive astrocytes without needing pro-inflammatory stimuli. We used DITNC1 cells with different passage numbers to study reactivity markers using immunoblots, immunofluorescence, and astrocyte adhesion/migration assays. We also evaluated β3 Integrin levels by immunoblot and flow cytometry, as well as the neurotoxic effects of reactive astrocytes. Serial cell passaging mimicked the effects of inflammatory stimuli, inducing astrocyte reactivity. Indeed, in response to Thy-1, β3 Integrin levels, as well as cell adhesion and migration, gradually increased with multiple passages. Importantly, these long-lived astrocytes expressed and secreted factors that inhibited neurite outgrowth and caused neuronal death, just like reactive astrocytes in culture. Therefore, we describe two DITNC1 cell types: a non-reactive type that can be activated with Tumor Necrosis Factor (TNF) and another one that exhibits reactive astrocyte features even in the absence of TNF treatment. Our results emphasize the importance of passage numbers in cell behavior. Likewise, we compare the pro-inflammatory stimulus versus long-term in-plate passaging of cell cultures and introduce them as astrocyte models to study the reactivity process. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Neurobiology in Chile, 2nd Edition)
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14 pages, 3209 KiB  
Article
Therapeutic Effect of Padina arborescens Extract on a Cell System Model for Parkinson’s Disease
by Dong Hwan Ho, Hyejung Kim, Daleum Nam, Mi Kyoung Seo, Sung Woo Park, Dong-Kyu Kim and Ilhong Son
NeuroSci 2024, 5(3), 301-314; https://doi.org/10.3390/neurosci5030024 - 30 Aug 2024
Viewed by 1897
Abstract
Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are involved in the pathogenesis of Parkinson’s disease. The activity of LRRK2 in microglial cells is associated with neuroinflammation, and LRRK2 inhibitors are crucial for alleviating this neuroinflammatory response. α-synuclein contributes to oxidative stress in the [...] Read more.
Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are involved in the pathogenesis of Parkinson’s disease. The activity of LRRK2 in microglial cells is associated with neuroinflammation, and LRRK2 inhibitors are crucial for alleviating this neuroinflammatory response. α-synuclein contributes to oxidative stress in the dopaminergic neuron and neuroinflammation through Toll-like receptors in microglia. In this study, we investigated the effect of the marine alga Padina arborescens on neuroinflammation by examining LRRK2 activation and the aggregation of α-synuclein. P. arborescens extract inhibits LRRK2 activity in vitro and decreases lipopolysaccharide (LPS)-induced LRRK2 upregulation in BV2, a mouse microglial cell line. Treatment with P. arborescens extract decreased tumor necrosis factor-α (TNF-α) gene expression by LPS through LRRK2 inhibition in BV2. It also attenuated TNF-α gene expression, inducible nitric oxide synthase, and the release of TNF-α and cellular nitric oxide in rat primary microglia. Furthermore, P. arborescens extract prevented rotenone (RTN)-induced oxidative stress in primary rat astrocytes and inhibited α-synuclein fibrilization in an in vitro assay using recombinant α-synuclein and in the differentiated human dopaminergic neuronal cell line SH-SY5Y (dSH). The extract increased lysosomal activity in dSH cells. In addition, P. arborescens extract slightly prolonged the lifespan of Caenorhabditis elegans, which was reduced by RTN treatment. Full article
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61 pages, 1930 KiB  
Systematic Review
Association between the Anatomical Location of Glioblastoma and Its Evaluation with Clinical Considerations: A Systematic Review and Meta-Analysis
by Juan Jose Valenzuela-Fuenzalida, Laura Moyano-Valarezo, Vicente Silva-Bravo, Daniel Milos-Brandenberg, Mathias Orellana-Donoso, Pablo Nova-Baeza, Alejandra Suazo-Santibáñez, Macarena Rodríguez-Luengo, Gustavo Oyanedel-Amaro, Juan Sanchis-Gimeno and Héctor Gutiérrez Espinoza
J. Clin. Med. 2024, 13(12), 3460; https://doi.org/10.3390/jcm13123460 - 13 Jun 2024
Cited by 6 | Viewed by 3061
Abstract
Background: Glioblastoma is a primary malignant brain tumor; it is aggressive with a high degree of malignancy and unfavorable prognosis and is the most common type of malignant brain tumor. Glioblastomas can be located in the brain, cerebellum, brainstem, and spinal cord, originating [...] Read more.
Background: Glioblastoma is a primary malignant brain tumor; it is aggressive with a high degree of malignancy and unfavorable prognosis and is the most common type of malignant brain tumor. Glioblastomas can be located in the brain, cerebellum, brainstem, and spinal cord, originating from glial cells, particularly astrocytes. Methods: The databases MEDLINE, Scopus, Web of Science, Google Scholar, and CINAHL were researched up to January 2024. Two authors independently performed the search, study selection, and data extraction. Methodological quality was evaluated with an assurance tool for anatomical studies (AQUA). The statistical mean, standard deviation, and difference of means calculated with the Student’s t-test for presence between hemispheres and presence in the frontal and temporal lobes were analyzed. Results: A total of 123 studies met the established selection criteria, with a total of 6224 patients. In relation to the mean, GBM between hemispheres had a mean of 33.36 (SD 58.00) in the right hemisphere and a mean of 34.70 (SD 65.07) in the left hemisphere, due to the difference in averages between hemispheres. There were no statistically significant differences, p = 0.35. For the comparison between the presence of GBM in the frontal lobe and the temporal lobe, there was a mean in the frontal lobe of 23.23 (SD 40.03), while in the temporal lobe, the mean was 22.05 (SD 43.50), and for the difference in means between the frontal lobe and the temporal lobe, there was no statistically significant difference for the presence of GBM, p = 0.178. Conclusions: We believe that before a treatment, it will always be correct to know where the GBM is located and how it behaves clinically, in order to generate correct conservative or surgical treatment guidelines for each patient. We believe that more detailed studies are also needed to show why GBM is associated more with some regions than others, despite the brain structure being homologous to other regions in which GMB occurs less frequently, which is why knowing its predominant presence in brain regions is very important. Full article
(This article belongs to the Section Clinical Neurology)
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