Search Results (358)

Blood-based biomarkers offer a promising “biochemical imaging” approach for acute ischemic stroke (AIS) management, providing objective and accessible tools to complement conventional neuroimaging. This narrative review synthesizes recent advances in biomarkers derived from multiple neurovascular unit (NVU) compartments, including glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neuron-specific enolase (NSE), neurofilament light chain (NfL), matrix metalloproteinase-9 (MMP-9), Claudin-5, Occludin, brain-derived neurotrophic factor (BDNF), interleukin-33 (IL-33), tumor necrosis factor-alpha (TNF-alpha), PARK7/DJ-1, glycogen phosphorylase BB (GP-BB), and circulating microRNAs. We focus on their stage-specific clinical utility across three scenarios: (1) ultra-early differentiation between ischemic stroke and intracerebral hemorrhage in prehospital and emergency settings; (2) dynamic prediction and monitoring of hemorrhagic transformation after reperfusion therapies; and (3) assessment of infarct burden, neurorepair potential, and long-term functional outcomes. Despite their promise, clinical translation remains hindered by assay platform heterogeneity, lack of standardized cut-off values, limited cost-effectiveness data, and insufficient prospective validation adjusted for key covariates such as age and renal function. We further discuss multi-marker panel construction, including strategies to address biomarker collinearity and overfitting. Future directions emphasize stage-specific panels, point-of-care testing devices, and artificial intelligence algorithms to advance precision medicine in stroke care. Full article

Fatty acid-binding protein 7 (FABP7) is a multifunctional lipid chaperone that is enriched in radial glia and astrocytes within the central nervous system (CNS) and is frequently upregulated in glioma. Beyond its established roles in glial development, lipid homeostasis, and circadian regulation, growing evidence positions FABP7 at the intersection of tumor metabolism, neuronal activity, and immune modulation in the brain. In this review, we integrate the physiological functions of FABP7 in glial cells with its tumor-intrinsic and microenvironmental roles in glioma. We summarize how gliomas co-opt FABP7-dependent metabolic, transcriptional, and post-transcriptional programs to promote stemness, lipid remodeling (e.g., altered fatty acid composition, lipid droplet formation, and lipid peroxidation resistance), inflammatory signaling, and invasive growth, including nuclear FABP7-mediated transcriptional activation linked to oncogene status. Furthermore, we discuss the role of FABP7 in shaping the tumor–neuro–immune interface, including regulating immunosuppressive gene networks, pro-tumoral macrophage polarization, resistance to T-cell-induced ferroptosis and immunotherapy, and tumor microtube-mediated integration into neuronal circuits to support glioma progression. Finally, we highlight therapeutic opportunities and challenges, including small-molecule FABP7 inhibitors, brain-directed delivery strategies, chronotherapeutic considerations, and combination approaches with immunotherapy. Collectively, this work positions FABP7-centered metabolic, circadian, and neuro-immune networks as potential vulnerabilities in glioma, linking fundamental glial biology to glioma therapeutics. Full article

Objectives: To investigate the clinicopathologic characteristics and molecular biomarkers of atypical vasoproliferative retinal tumor (VPRT) with hemangioblastoma-like histopathologic features and concomitant von Willebrand factor (VWF) abnormalities. Methods: A 48-year-old woman undergoing phacoemulsification and 25-gauge pars plana vitrectomy with tumor resection was evaluated. Histopathological findings and immunohistochemical study of the resected tumor were performed using CD34, α-smooth muscle actin (αSMA), and glial fibrillary acidic protein (GFAP) markers. Preoperative plasma and intraoperative vitreous fluid VWF antigen levels, as well as ristocetin cofactor activity, were quantified using latex immunoturbidimetry. Results: Ultra-widefield imaging and angiography demonstrated a peripheral retinal tumor with intense vascular leakage and surrounding capillary nonperfusion. Histopathology showed hyalinized vascular components supportive of VPRT, along with abundant CD34/α-SMA-positive microvessels and scant GFAP-positive glial cells. Notably, numerous foamy vacuolated poorly differentiated cells suggested mixed hemangioblastoma-like features. Preoperative plasma VWF antigen (182.6%) and ristocetin cofactor activity (147.7%) were elevated, and vitreous VWF antigen was successfully detected at a low but distinct level (7.7%).and suggests that VWF abnormalities in the plasma and vitreous may reflect endothelial activation and/or blood–retinal barrier disruption in a subset of vascularized retinal tumors. Conclusions: Our findings demonstrate that VPRT may exhibit mixed clinicopathologic features, including hemangioblastoma-like components, which underscores the necessity of immunohistochemical assessment for definitive diagnosis. Furthermore, the quantification of VWF abnormalities in the plasma and vitreous suggests that VWF serves as a potential biomarker reflecting endothelial activation and/or blood–retinal barrier disruption in vascularized retinal tumors. Full article

Background/Objectives: Intramedullary tumors are uncommon spinal cord lesions that account for a small proportion of central nervous system neoplasms but are associated with a high risk of neurological morbidity. Accurate preoperative characterization is essential because therapeutic strategies, surgical planning, and functional prognosis depend strongly on tumor biology and growth behavior within the confined spinal cord environment. This study aims to characterize the radiological phenotype of intramedullary tumors and to identify imaging patterns that may assist in lesion characterization and diagnostic stratification. Methods: A retrospective analysis of preoperative MRI findings in patients with histopathologically confirmed intramedullary tumors was performed. Preoperative MRI examinations were systematically analyzed to describe imaging features according to tumor histology using conventional sequences (T1-weighted, T2-weighted, and contrast-enhanced imaging). Results: Distinct radiological phenotypes were observed across a wide spectrum of lesions. Glial tumors, including subependymoma, ependymoma, pilocytic astrocytoma, diffuse midline glioma H3K27M, glioblastoma, high-grade astrocytoma with piloid features, ganglioglioma, and diffuse leptomeningeal glioneural tumors, demonstrated variable combinations of cord expansion, margin definition, enhancement patterns, and tract involvement, reflecting differences between expansile and infiltrative growth. Secondary tumors such as metastases frequently exhibited aggressive imaging features, including extensive edema and intense or heterogeneous enhancement. Vascular lesions, including hemangioblastoma and cavernoma, showed characteristic vascular signatures, such as nodular enhancement with flow voids or susceptibility-related signal changes. Developmental lesions, such as epidermoid cysts, neurenteric cysts, and lipoma, displayed distinctive signal characteristics, especially on diffusion and T1, that aided differentiation from neoplastic processes. Conclusions: In conclusion, the structured radiological interpretation functions proposed herein are not only useful for diagnostic purposes, but could also be useful for risk stratification and therapeutic guidance. Full article

Background: Postmenopausal women are at high risk of Alzheimer’s disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose/AlCl₃ (60 and 10 mg/kg, respectively) for 42 days. Group III–V: Animals were exposed to MTN (10 mg/kg/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD/menopause treatment and prevention via modulating the TNF-α/p38 MAPK/PPAR-γ/NLRP3/GFAP pathway. Full article

Pesticide manufacturing industry wastewater is a complex mixture of potentially harmful components. If not properly treated, discharged effluents may pose serious risks to environment and organisms. In this study, influent and effluent wastewater samples from a pesticide factory were comprehensively non-screened by liquid chromatography high-resolution mass spectrometry, coupled with zebrafish embryo toxicity testing to assess whole effluent toxicity. A total of eight chemical groups were identified, including pesticides, antibiotics, nitrogen compounds, ketones, esters, amines and derivatives, other drugs, and other organic compounds. While wastewater treatment processes reduced most of the analyzed groups of compounds, compounds (e.g., 2-aminophenol, N-Nitrosodipropylamine, and carbamazepine) increased during the treatments. The influent samples were more toxic to zebrafish than the effluent samples in terms of lethality, teratogenic effects, developmental impacts, locomotor behavior, and neurotoxicity. The results showed that locomotor behavior was the most sensitive phenotypic toxicity endpoint, with significantly higher sensitivity than traditional acute lethal or teratogenic endpoints. Through a multi-dimensional assessment approach combining chemical screening, literature-based, risk ranking, and targeted quantification, we identified three predominant pesticide residues in the wastewater samples (both influents and effluents): hexaconazole, fenobucarb and isoprocarb. All three compounds exhibited additive or synergistic toxicity in zebrafish embryos. Exposure to ≥0.08% influent or ≥2% effluent increased inflammation (interleukin-1 beta, IL-1β), oxidative stress (copper/zinc superoxide dismutase, Cu/Zn-Sod), apoptosis (tumor protein p53, p53), and significantly impaired neurodevelopment in zebrafish larvae by altering the expression of sonic hedgehog a (shha), synapsin IIa (syn2a), and glial fibrillary acidic protein (gfap). This study suggests the necessity of incorporating non-apical endpoint (locomotor behavior) into whole effluent toxicity test, as this approach is essential for reducing the environmental risks posed by pesticide factory wastewater. Full article

Background and Objectives: The pathogenesis of liver steatosis is associated with obesity and systemic inflammation, particularly in subjects with body mass index (BMI) above 40 kg/m² and altered serum levels of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10). Recent evidence suggests that disruption of the blood–brain barrier (BBB) may be associated with the development of steatosis, although limited data are available in humans. Thus, we assessed serum levels of neuron-specific enolase (NSE), transglutaminase 2 (TGM2), and glial fibrillary acidic protein (GFAP) as indirect markers of BBB dysfunction and examined their associations with steatosis severity, TNF-α and IL-10 in patients with morbid obesity. Materials and Methods: We biopsied the liver during bariatric surgery to assess steatosis by histology and serum markers by ELISA. Results: Most study subjects were women aged 38.7 ± 9.9 years with an average BMI of 42.3 ± 7.9 kg/m² and a steatosis prevalence of 78.9%. After grading steatosis as none (n = 8), mild (n = 17), moderate (n = 8), or severe (n = 5), we found no differences in sex, age, BMI, comorbidities, or laboratory variables, including liver enzymes. One-way ANOVA showed that serum IL-10 was 4-fold less in severe steatosis than in mild steatosis (p = 0.038), whereas TNF-α levels increased twice in severe steatosis compared to no steatosis (p = 0.029). NSE and GFAP serum levels, but not TGM2, increased proportionally to steatosis stage, showing differences between severe steatosis and no steatosis (p = 0.012 and p = 0.0002, respectively). Pearson correlation coefficients showed that NSE and GFAP were significantly associated with TNF-α (r = 0.600 and r = 0.402, respectively), but not with IL-10. Conclusions: Steatosis severity is significantly associated with markers of BBB disruption and systemic inflammation in patients with morbid obesity, suggesting a link between the BBB and liver steatosis. Full article

Peripheral nerves provide a direct connection between the brain and the tumor microenvironment. This connection allows the nervous system to influence processes associated with the development, progression, and metastasis of different tumor types. Therefore, tumor innervation by peripheral nerve fibers is currently emerging as a characteristic that contributes to multiple hallmarks of cancer. Several experimental studies have shown that cancer progression involves actively inducing the ingrowth of autonomic and sensory nerve fibers into tumor tissue. In this process, known as neoaxonogenesis, cancer and other cells in the tumor microenvironment play an important role by synthesizing and releasing neurotrophic factors (e.g., nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor), axonal guidance molecules (netrins, semaphorins, ephrins, slits), exosomes (containing microRNA and axonal guidance molecules), and other molecules present in the tumor microenvironment (e.g., granulocyte colony-stimulating factor, leukemia inhibitory factor), which modulate the ingrowth of nerve fibers into the tumor. This results in an increased nerve supply to tumor tissue, which is primarily linked to its growth. However, there are also studies demonstrating the protective effects of increased nerve fiber density against processes associated with cancer progression in certain types of cancer. The findings from these studies contribute to the complexity of neuro-cancer interactions, which is probably based on the type of cancer and the physiological specializations of the nerve fibers in a given organ. Despite contrasting findings, the stimulatory effects of nerve fibers on cancer growth are supported by several studies that described reducing the negative impact of nerve fibers on tumors and thus inhibiting cancer progression. The most significant approaches to reducing neural effects appear to be denervation, the administration of neurotransmitter receptor antagonists, the administration of local anesthetics, and the administration of antibodies against neurotrophic factors. Other significant approaches include methods that improve quality of life, such as psychotherapy and heart rate variability biofeedback. Despite their therapeutic potential, there are several limitations to using approaches that manipulate cancer innervation in clinical practice. These limitations include impaired normal tissue function and nervous system function, as well as the problematic direct application of the therapeutic agent to the tumor site, dosage-dependent, cancer type-dependent, cancer stage-dependent, duration-dependent, and timing-dependent effects. Procedures that modify neoaxonogenesis and nerve fiber signaling appear to be a promising new therapeutic approach in oncology. However, more research is needed to better understand their effects on cancer progression. In the future, the assessment of the presence and density of nerve fibers in tumors, as well as the evaluation of approaches aimed at reducing their negative impact, could be part of personalized anticancer therapy. As part of this therapy, a fresh tumor sample would be collected from the patient to generate patient-derived organoid models to test and consider the possibility of using supportive therapy and to predict its efficacy. Based on these results, it would be possible to evaluate the applicability of nerve-fiber-targeted therapy for a given patient. This review article summarizes and describes the current knowledge concerning the significance of nerve fibers in cancer progression, with a particular emphasis on neoaxonogenesis in tumors and the various factors that influence this process. Full article

Background: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, in which neuroinflammation and blood–brain barrier (BBB) disruption are secondary pathophysiological events that drive progressive brain injury. Histone lysine demethylase JMJD3 (Jumonji C domain-containing protein 3) is a master epigenetic switch governing inflammatory signaling; however, its participation in ICH-induced vascular disruption and its possible mechanism remain elusive. Objective: To examine the expression patterns of JMJD3 in the context of ICH and to evaluate the therapeutic potential of its specific inhibitor, GSK-J4, in attenuating neuroinflammation and BBB disruption in a murine ICH model. Methods: Hemin treatment of a mouse C8-D1A astrocytic cell line was used to develop an in vitro ICH model. The transcript level of the Jmjd3 gene and its correlation with pro-inflammatory signaling were analyzed with or without GSK-J4 pretreatment. ICH in vivo was created experimentally in adult male C57BL/6 mice through stereotactic striatal injection of collagenase IV, and the mice were randomly assigned to sham, ICH + vehicle, and ICH + GSK-J4 (30 mg/kg intraperitoneally (i.p.), every other day starting three days before ICH) groups. At three days post-ICH, ipsilateral brain tissues were collected to detect JMJD3 cellular localization, pro-inflammatory mediator levels, tight junction protein expression, BBB ultrastructure, and hematoma volume. White matter integrity and neuronal recovery were assessed on day 7, and sensorimotor function was assessed longitudinally on days 1, 3, 5, 7, and 14. Results: Jmjd3 gene transcription was upregulated in hemin-treated astrocytes and correlated positively with IL-6 pro-inflammatory signaling activation. In vivo, the co-localization of JMJD3 with the astrocytic identifier glial fibrillary acidic protein (GFAP) was markedly increased in the area adjacent to the hematoma at three days post-ICH. GSK-J4 administration significantly suppressed the pro-inflammatory signaling cascade by decreasing the levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP-9), enhanced brain vascular structural and functional integrity by upregulating tight junction proteins zonula occludens protein-1 (ZO-1) and claudin-5, improved BBB ultrastructural integrity, and decreased hematoma volume at three days post-ICH. Furthermore, GSK-J4 administration promoted white matter integrity (increased myelin basic protein [MBP] expression) and neuronal recovery (increased neuron-specific nuclear protein [NeuN] expression) at seven days post-ICH and significantly improved the performance of ICH mice in sensorimotor behavioral tests. Conclusions: Astrocytic JMJD3 is upregulated following ICH and promotes neuroinflammation, which in turn mediates BBB disruption. Pharmacological inhibition of JMJD3 by GSK-J4 attenuates neuroinflammation and subsequent BBB damage, accelerates hematoma resolution, and promotes histological and functional recovery after ICH, likely by downregulating MMP-9 expression. These findings identify astrocytic JMJD3 as a novel epigenetic therapeutic target for acute ICH. Full article

Pinealectomy leads to melatonin deficiency, which is known to disrupt circadian clock regulation and may increase vulnerability of the hippocampus to oxidative stress and neuroinflammatory processes. The objective of this study was to examine the gene expression levels of circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period circadian regulator 1 (PER1), cryptochrome circadian regulator 1 (CRY1), brain-derived neurotrophic factor (BDNF), and interleukin-6 (IL-6) in the hippocampus to elucidate the impact of pinealectomy-induced circadian dysregulation on these gene expressions and to assess its association with hippocampal alterations. A total of 30 Wistar rats were randomly divided into three groups: Control, Sham, and Pinealectomy (PNX) (n = 10 per group). Gene expression levels were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis was performed to assess caspase-3 and glial fibrillary acidic protein (GFAP) immunoreactivity. In addition, oxidative stress parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), as well as the inflammatory marker tumor necrosis factor-alpha (TNF-α), were measured. The pinealectomy group showed a significant downregulation of BMAL1, BDNF, CLOCK, CRY1, and PER1 gene expression levels, with decreases ranging from approximately 60% to 83% compared with the sham and control groups, whereas IL-6 expression was significantly increased by approximately 185% (p < 0.05). Immunohistochemical analysis demonstrated significantly increased caspase-3 and GFAP immunoreactivity in the PNX group. Furthermore, pinealectomy resulted in a significant increase in MDA and TNF-α levels, accompanied by marked decreases in SOD, CAT, and GSH levels (p < 0.05). In conclusion, pinealectomy is associated with significant disruption of hippocampal circadian clock gene expression, accompanied by oxidative stress, neuroinflammation, and histopathological alterations. These findings highlight the critical role of circadian regulation in maintaining hippocampal cellular integrity. Full article

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly associated with dysregulated neuroimmune signaling and altered neurotrophic homeostasis. Tumor necrosis factor-alpha (TNF-α) has been implicated in ASD pathophysiology; however, the downstream effects of TNF-α blockade on cytokine–neurotrophin interactions during neurodevelopment remain insufficiently characterized. In this study, we evaluated the effects of infliximab (IFX), a monoclonal anti-TNF-α antibody, on behavioral performance, neuroinflammatory cytokine profiles, glial activation, and brain-derived neurotrophic factor (BDNF) signaling in a propionic acid (PPA)-induced experimental ASD rat model. Methods: Experimental ASD was induced by propionic acid administration in rats. Animals were divided into control and treatment groups. Behavioral performance was assessed using the Morris Water Maze, direct social interaction, and three-chamber sociability tests. Levels of TNF-α, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and BDNF were measured in serum, hippocampal, and cerebellar tissues. Microglial and astrocytic activation were evaluated using CD11 and GFAP immunohistochemistry. Results: PPA administration resulted in pronounced impairments in learning, memory, and social behaviors, accompanied by elevated proinflammatory cytokine levels, increased BDNF expression, and marked glial activation in the hippocampus and cerebellum. Although IFX treatment significantly reduced TNF-α levels in central tissues, it did not improve behavioral deficits and was associated with persistently elevated IL-1β and IL-6 levels, sustained glial reactivity, and further alterations in BDNF levels. Conclusions: These findings suggest that TNF-α suppression alone does not normalize the disrupted cytokine–neurotrophin axis and may differentially modulate BDNF-related neuroplastic signaling during development. In conclusion, this study indicates that non-selective TNF-α blockade during neurodevelopment fails to confer behavioral benefit in experimental ASD and highlights the importance of considering cytokine–BDNF pathway interactions when designing immunomodulatory strategies for neurodevelopmental disorders. Full article

Glial cells, particularly astrocytes and microglia, are central to maintaining CNS homeostasis and coordinating responses to injury through tightly regulated metabolic, inflammatory, and mechanosensitive processes. Emerging evidence identifies the Hippo signaling pathway and its downstream effectors YAP/TAZ as key regulators of glial functions, influencing proliferation, polarization, intercellular communication, and the balance between neuroprotection and neurotoxicity. This review discusses the Hippo signaling pathway and its transcriptional co-activators YAP/TAZ as context-dependent hubs integrating mechanical, metabolic, and immune cues in astrocytes and microglia. Particular attention is given to MST1/2- and YAP/TAZ-dependent signaling in microglia, which governs inflammatory states, redox balance, mitophagy, and mechanosensing. In astrocytes, Hippo–YAP signaling emerges as a bidirectional regulator of reactive gliosis and neuroprotection, capable of constraining excessive scar formation. However, when chronically suppressed, it impairs glutamate clearance, metabolic support, and resistance to neurodegeneration. Disruption of Hippo signaling in glial tumors is also considered, with YAP/TAZ–TEAD complexes driving glioblastoma stemness, infiltrative growth, immune evasion, and therapy resistance. Finally, therapeutic perspectives are outlined that emphasize context-selective modulation of Hippo signaling in the CNS. Overall, Hippo–YAP/TAZ signaling is presented as a highly context-dependent regulator at the interface of glial inflammation, neurodegeneration, and glioma biology and as a promising but demanding target for future CNS therapies. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Neuroinflammation is a hallmark of multiple sclerosis (MS). MS is marked by glial cell activation, autoreactive T cells, and the release of pro-inflammatory cytokines and free radicals. Current therapeutic strategies aim to modulate the immune response using disease-modifying therapies, to slow disease progression. The specific aims of this study were: (a) to investigate the effect of cannabinoid acids on the release of glial neuroinflammatory mediators, (b) to examine the effect of intraperitoneally administered cannabinoid acids on symptoms of MS, and (c) to evaluate their effects on microglial and astrocyte activation and CD4⁺ T cell infiltration into the spinal cords of MS mice. Exposure of BV2 microglia to cannabinoid acids attenuated lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase by 40–90% it also reduced the release of nitric oxide and interleukin-17A. Among the cannabinoid acids tested, cannabidiolic acid (CBDA) significantly increased tumor necrosis factor alpha (TNFα) secretion by up to 40% in LPS-stimulated BV2 cells. Intraperitoneal administration of CBDA also resulted in a twofold increase in TNFα secretion in splenocytes isolated from MS mice, compared to untreated MS controls. This study provides evidence that CBDA significantly reduces neurological scores, while both cannabinoid acids attenuate microgliosis, astrogliosis, and CD4+ T cell migration in lumbar spinal cord sections of MS mice. These compounds cross the blood–brain barrier (BBB) and act directly within the central nervous system. The consistent elevation of TNFα in the presence of CBDA across three experimental models suggests a distinctive immunomodulatory role for CBDA, with potential therapeutic implications in MS. Full article

Background: Extracranial metastasis (EM) from glioblastoma (GB), IDH-wildtype (WHO CNS 2021 grade 4) is rare and often under-recognized, yet it has immediate implications for staging and management. We report a case series integrating advanced neuroimaging, whole-body imaging, and pathology/biomarkers to characterize imaging–pathology correlates of EM and highlight practical clinical triggers that should prompt systemic evaluation. Case presentation: We report three patients with adult-type, IDH-wildtype GB who developed EM confirmed by cytology/histology and/or concordant multimodality imaging. Brain MRI (1.5T/3T) demonstrated aggressive primary tumors with qualitative elevation of DSC-perfusion and frequent tumor–surface contact (dural, ependymal/leptomeningeal contact). Intratumoral susceptibility signal reached grade 3 where assessed. All patients underwent surgical resection followed by temozolomide-based chemoradiation; two received fotemustine and bevacizumab, and one underwent re-irradiation. EM presented with clinical triggers including severe axial/back pain, palpable cervical masses, and/or cytopenias. Initial EM sites were bone marrow/vertebrae (n = 1) and cervical lymph nodes (n = 2); staging revealed additional osseous disease in both nodal cases and a small pulmonary nodule in one. Nodal and osseous lesions were FDG-avid on 18F-FDG PET/CT. OLIG2-positive cytology confirmed cervical nodal metastases, and bone marrow aspiration with GFAP/OLIG2 positivity confirmed medullary infiltration. All tumors shared a molecular profile of TERT-promoter mutation, ATRX wild-type, TP53 mutation, and MGMT-promoter methylation. Despite attempts at second- and third-line therapies, disease progression was rapid, and all patients succumbed within 8–16 months of diagnosis. Discussion: This series underscores that EM can occur despite MGMT-promoter methylation and supports the concept of heterogeneous metastatic phenotypes in GB. Our cases reinforce that new axial/back pain or hematologic abnormalities may signal osseous or marrow involvement, and necrotic cervical lymphadenopathy in GB patients warrants dedicated imaging and tissue confirmation with glial markers. Integrating brain MRI features (high perfusion, surface contact, susceptibility burden) with FDG-PET/CT and targeted cytology/pathology can expedite diagnosis and inform multidisciplinary care. Conclusions: EM can arise despite MGMT-promoter methylation in IDH-wildtype GBM. Imaging red flags (high perfusion, surface contact, necrotic/FDG-avid cervical nodes) and clinical cues (axial pain, cytopenias, neck masses) should prompt early systemic staging (CT/PET-CT) and targeted tissue confirmation to advance management. Full article