Purpose: This study aimed to elucidate the impact of brain tumors on cerebral edema and glymphatic drainage by leveraging advanced MRI techniques to explore the relationships among tumor characteristics, glymphatic function, and aquaporin-4 (AQP4) expression levels. Experimental Design: In a prospective cohort from March 2022 to April 2023, patients with glioblastoma, brain metastases, and aggressive meningiomas, alongside age- and sex-matched healthy controls, underwent 3.0T MRI, including diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index and multiparametric MRI for quantitative brain mapping. Tumor and peritumor tissues were analyzed for AQP4 expression levels via immunofluorescence. Correlations among MRI parameters, glymphatic function (DTI-ALPS index), and AQP4 expression levels were statistically assessed. Results: Among 84 patients (mean age: 55 ± 12 years; 38 males) and 59 controls (mean age: 54 ± 8 years; 23 males), patients with brain tumor exhibited significantly reduced glymphatic function (DTI-ALPS index: 2.315 vs. 2.879; P = 0.001) and increased cerebrospinal fluid volume (201.376 cm³ vs. 115.957 cm³; P = 0.001). A negative correlation was observed between tumor volume and the DTI-ALPS index (r: −0.715, P < 0.001), whereas AQP4 expression levels correlated positively with peritumoral brain edema volume (r: 0.989, P < 0.001) and negatively with proton density in peritumoral brain edema areas (ρ: −0.506, P < 0.001). Conclusions: Our findings highlight the interplay among tumor-induced compression, glymphatic dysfunction, and altered fluid dynamics, demonstrating the utility of DTI-ALPS and multiparametric MRI in understanding the pathophysiology of tumor-related cerebral edema. These insights provide a radiological foundation for further neuro-oncological investigations into the glymphatic system. See related commentary by Surov and Borggrefe, p. 4813

Background. Bone marrow-derived mesenchymal stem cells (BMSCs) have blossomed into an effective approach with great potential for the treatment of liver fibrosis. The aim of this study was to investigate the underlying antifibrosis mechanisms by which the BMSC inhibit activated hepatic stellate cells (HSCs) in vivo and in vitro. Methods. To study the effect of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) on activated HSCs, we used HSCs and the coculture systems to evaluate the inhibition of activated HSCs from the aspects of the apoptosis of activated HSCs. In addition, activation of NADPH oxidase pathway and the changes in liver histopathology were tested by using the carbon tetrachloride- (CCl₄-) induced liver fibrosis in mice. Results. Introduction of hBM-MSCs significantly inhibited the proliferation of activated HSCs by inducing the apoptosis process of activated HSCs. The effect of hBM-MSCs reduced the signaling pathway of NADPH oxidase in activated HSCs. Besides, the signaling pathway of NADPH oxidase mediated hBM-MSC upregulation of the expression of the peroxisome proliferator-activated receptor γ and downregulation of the expression of α1(I) collagen and alpha-smooth muscle actin (α-SMA) in activated HSCs. Moreover, the hBM-MSC-induced decrease in the signaling pathway of NADPH oxidase was accompanied by the decrease of the activated HSC number and liver fibrosis in a mouse model of CCl₄-induced liver fibrosis. Conclusion. The hBM-MSCs act as a promising drug source against liver fibrosis development with respect to hepatopathy as a therapeutic target.

Background: 17AAG has been extensively studied for its antitumor effects that protect cells from lethal stress by maintaining protein stability. The role of 17AAG in sevoflurane-induced neuronal injury has never been studied. We aim to investigate the effect of 17AAG on sevoflurane-induced neurotoxicity in vivo and in vitro. Methods: Sevoflurane-induced hippocampal neuron injury model was established in aged Sprague–Dawley rats. Pretreatment of vehicle or 17AAG was administered prior to sevoflurane inhalation. H4 neuroglioma cells were pretreated with vehicle or 17AAG and exposed to sevoflurane. Apoptosis, oxidative stress, expression of interleukin-6 (IL-6), and activation of the nuclear factor-κB (NF-κB) signaling pathway in H4 cells were examined by Hoechst assay, flow cytometry, Western blot, and immunofluorescent staining. RNA interference against HSPA1A was performed to test the function of HSP70 in neuroprotection. Results: Exogenous 17AAG reduced sevoflurane-induced apoptosis and oxidative stress in rat hippocampal neurons and in H4 cells. In H4 cells, 17AAG suppressed sevoflurane-induced upregulation of IL-6 and activation of NF-κB signaling. 17AAG enhanced sevoflurane-induced upregulation of HSP70 in rat hippocampal neurons and in H4 cells. Conversely, silencing of HSPA1A in H4 cells blocked the cytoprotective effect of 17AAG against sevoflurane-induced apoptosis and oxidative stress, and prevented upregulation of IL-6 and activation of NF-κB signaling. Conclusions: 17AAG protects against sevoflurane-induced neurotoxicity in vivo and in vitro via HSP70-dependent inhibition of apoptosis, oxidative stress, and pro-inflammatory signaling pathway.

Traumatic brain injury (TBI) affects millions of people worldwide and often results in significant extracranial complications, particularly acute respiratory distress syndrome (ARDS). The mechanisms underlying TBI-induced lung damage remain poorly understood, and current treatment options are limited. This study aimed to investigate the therapeutic potential and mechanisms of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation for alleviating TBI-induced lung injury and improving neurological function. Specifically, we sought to determine the role of neutrophil extracellular traps (NETs) in TBI-induced lung injury and whether hUC-MSCs improve acute lung injury (ALI) by inhibiting NET formation. TBI-associated ARDS in patients was diagnosed based on chest computed tomography (CT) imaging and relevant physiological and biochemical parameters. Bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) samples from TBI patients were collected to evaluate neutrophil activation and its correlation with the severity of pulmonary injury. A TBI mouse model was established using the Controlled Cortical Impact (CCI) method. 12 h post-injury, hUC-MSCs were administered via intravenous injection. Neurological function was assessed using the modified Neurological Severity Score (mNSS) and balance beam test. Lung and brain tissue injury were evaluated by histological staining, oxygen saturation monitoring, and micro-CT. Neutrophil infiltration and NET formation were detected in PB, BALF, and lung tissue by flow cytometry, immunofluorescence, and Western blotting. To further elucidate the direct regulatory effects of hUC-MSCs on neutrophils in vitro, neutrophils isolated from the PB of TBI patients were co-cultured with hUC-MSCs. The formation of NETs and reactive oxygen species (ROS) was subsequently quantified. We initially assessed neutrophil activation and NET formation in PB and BALF from TBI patients. The results revealed that neutrophils in PB were activated, with even more pronounced activation observed in BALF. Simultaneously, NET formation in PB was significantly elevated. A strong positive correlation was identified between the extent of neutrophil infiltration in BALF and the severity of pulmonary injury. In the CCI-induced TBI mouse model, hUC-MSC transplantation notably improved neurological function and alleviated pathological brain damage. Additionally, hUC-MSC administration increased SpO2, reduced lung injury scores, and partially restored the ultrastructural integrity of type II alveolar epithelial cells. Mechanistic studies demonstrated that hUC-MSC transplantation effectively suppressed neutrophil infiltration, NET formation, and the expression of peptidyl arginine deiminase 4 (PAD4), a crucial enzyme involved in NETosis. Remarkably, hUC-MSCs showed superior efficacy in mitigating TBI-induced ALI compared to pharmacological approaches targeting PAD4 inhibition or DNase-mediated NET degradation. Moreover, in vitro co-culture experiments confirmed that hUC-MSCs directly inhibited both NET production and ROS generation by peripheral neutrophils isolated from TBI patient. Our findings demonstrate that hUC-MSCs significantly alleviate TBI-induced lung injury by inhibiting neutrophil infiltration and NET formation, offering potential therapeutic benefits for treating TBI-associated lung complications. These results highlight the clinical potential of hUC-MSCs in addressing both neurological and pulmonary damage in TBI patients.

Background: Ischemic stroke, accounting for approximately 80% of all stroke cases, is a major public health challenge and a leading cause of death and disability worldwide. Current treatments primarily involve thrombolytic therapy, limited to a 4.5-hour window due to the risk of complications, underscoring the need for new therapeutic targets. Systemic inflammation plays a critical role in stroke progression, with immune cells infiltrating the brain and exacerbating damage. B cells, in particular, have been implicated in stroke pathogenesis, although their exact role remains contentious. This study examines anti-CD19 antibody (aCD19 Ab) treatment in a stroke model to determine if CD19⁺ B cell depletion can reduce infarct size and alleviate inflammation.Results: This study investigated whether temporary inhibition of B-cell activity using an aCD19 Ab could alleviate ischemic brain injury in a stroke mouse model by regulating cerebral and systemic immune reactions. Mice subjected to middle cerebral artery occlusion (MCAO) exhibited significant reductions in infarct size and brain edema, prolonged post-MCAO survival, and improved behavioral outcomes following aCD19 Ab treatment. Transmission electron microscopy (TEM) and Computed Tomography Angiography (CTA) results revealed a reduction in microvascular endothelial edema, decreased mitochondrial damage in neurons, reduced neuronal apoptosis, and a favorable reconstruction of the cerebral vascular network. Additionally, B cell inhibition reduced pro-inflammatory cytokines and immune cells in the brain and peripheral circulation. The immune response alterations observed in the MCAO/R group were consistent with the trends indicated by stroke patient data.Conclusions: Temporary inhibition of B-cell activity via aCD19 antibody injection alleviated ischemic brain injury in a mouse model of stroke by suppressing systemic immune reactions. Changes in immune cells within the meninges may play a role, and further investigation is needed to understand the mechanisms involved. These findings suggest that cerebral and systemic immune responses contribute to the pathogenesis of ischemic stroke, and temporary B cell depletion may represent a potential therapeutic target for stroke therapy.