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Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with high morbidity, mortality and disability, and early brain injury (EBI) after SAH is crucial for prognosis. Recently, stem cell therapy has garnered significant attention in the treatment of neurological diseases. Compared to other stem cells, dental pulp stem cells (DPSCs) possess several advantages, including abundant sources, absence of ethical concerns, non-invasive procurement, non-tumorigenic history and neuroprotective potential. Therefore, we aim to investigate whether DPSCs can improve EBI after SAH, and explore the mechanisms. In our study, we utilized the endovascular perforation method to establish a SAH mouse model and investigated whether DPSCs administered via tail vein injection could improve EBI after SAH. Furthermore, we used hemin-stimulated HT22 cells to simulate neuronal cell injury induced by SAH and employed a co-culture approach to examine the effects of DPSCs on these cells. To gain insights into the potential mechanisms underlying the improvement of SAH-induced EBI by DPSCs, we conducted bioinformatics analysis. Finally, we further validated our findings through experiments. In vivo experiments, we found that DPSCs administration improved neurological dysfunction, reduced brain edema, and prevented neuronal apoptosis in SAH mice. Additionally, we observed a decrease in the expression level of miR-26a-5p in the cortical tissues of SAH mice, which was significantly increased following intravenous injection of DPSCs. Through bioinformatic analysis and luciferase reporter assay, we confirmed the target relationship between miR-26a-5p and PTEN. Moreover, we demonstrated that DPSCs exerted neuroprotective effects by modulating the miR-26a-5p/PTEN/AKT pathway. Our study demonstrates that DPSCs can improve EBI after SAH through the miR-26a-5p/PTEN/AKT pathway, laying a foundation for the application of DPSCs in SAH treatment. These findings provide a theoretical basis for further investigating the therapeutic mechanisms of DPSCs and developing novel treatment strategies in SAH., Competing Interests: Declarations. Competing interest: The authors have no relevant financial or non-financial interests to disclose. Ethics Approval: All animal experiments complied with the guidelines established by the Chinese National Institutes of Health and Animal Care and were approved and supervised by the Institutional Animal Care and Use Committee of Renmin Hospital of Wuhan University (WDRM 20221001A)., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

C-X-C chemokine receptor type 4 (CXCR4) is critical for homeostasis of the adaptive and innate immune system in some CNS diseases. Bruton's tyrosine kinase (BTK) is an essential kinase that regulates inflammation in immune cells through multiple signaling pathways. This study aims to explore the effect of CXCR4 and BTK on neuroinflammation in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Our results showed that the expression of CXCR4 and p-BTK increased significantly at 24 h after SAH in vivo and in vitro. Ibrutinib improved neurological impairment, BBB disruption, cerebral edema, lipid peroxidation, neuroinflammation and neuronal death at 24 h after SAH. Inhibition of BTK phosphorylation promoted the in vitro transition of hemin-treated proinflammatory microglia to the anti-inflammatory state, inhibited the p-P65 expression and microglial pyroptosis. NLRP3 deficiency can significantly reduce pyroptosis in SAH mice. Moreover, CXCR4 inhibition can suppress NLRP3-mediated pyroptosis, NF-κB activation and NOX2 expression in vitro, and ibrutinib can abolish CXCR4-aggravated BBB damage and pyroptosis in EBI after SAH. The levels of CXCR4 in CSF of SAH patients is significantly increased, and it is positively correlated with GSDMD and IL-1β levels, and have a moderate diagnostic value for outcome at 6-month follow-up. Our findings revealed the effect of CXCR4 and P-BTK on NLRP3-mediated pyroptosis and lipid peroxidation after SAH in vivo and in vitro, and the potential diagnostic role of CXCR4 in CSF of SAH patients. Inhibition of CXCR4-BTK axis can significantly attenuate NLRP3-mediated pyroptosis and lipid peroxidation by regulating NF-κB activation in EBI after SAH., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background and Purpose: Neurogenic pulmonary edema (NPE) frequently arises as a complication subsequent to subarachnoid hemorrhage (SAH). Heterodimers of S100A8 and S100A9 are commonly formed, thereby initiating an inflammatory reaction through receptor binding on the cell surface. Paquinimod serves as a specific inhibitor of S100A9. The objective of this investigation is to assess the impact of Paquinimod administration and S100A9 knockout on NPE following SAH., Methods: In this study, SAH models of C57BL/6J wild-type (WT) and S100A9 knockout mice were established through intravascular perforation. These models were then divided into several groups, including the WT-sham group, S100A9-KO-sham group, WT-SAH group, WT-SAH + Paquinimod group, and S100A9-KO-SAH group. After 24 h of SAH induction, pulmonary edema was assessed using the lung wet-dry weight method and Hematoxylin and eosin (HE) staining. Additionally, the expression levels of various proteins, such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), occludin, claudin-3, Bax, Bcl-2, TLR4, MYD88, and pNF-κB, in lung tissue were analyzed using western blot and immunofluorescence staining. Lung tissue apoptosis was detected by TUNEL staining., Results: Firstly, our findings indicate that the knockout of S100A9 has a protective effect on early brain injury following subarachnoid hemorrhage (SAH). Additionally, the reduction of brain injury after SAH can also alleviate neurogenic pulmonary edema (NPE). Immunofluorescence staining and western blot analysis revealed that compared to SAH mice with wild-type S100A9 expression (WT-SAH), the lungs of S100A9 knockout SAH mice (S100A9-KO-SAH) and mice treated with Paquinimod exhibited decreased levels of inflammatory molecules (IL-1β and TNF-α) and increased levels of tight junction proteins. Furthermore, the knockout of S100A9 resulted in upregulated expression of the apoptotic-associated protein Bax and down-regulated expression of Bcl-2. Furthermore, a decrease in TLR4, MYD88, and phosphorylated pNF-κB was noted in S100A9-KO-SAH and Paquinimod treated mice, indicating the potential involvement of the TLR4/MYD88/NF-κB signaling pathway in the inhibition of the protective effect of S100A9 on NPE following SAH., Conclusion: The knockout of S100A9 not only ameliorated initial cerebral injury following subarachnoid hemorrhage (SAH), but also mitigated SAH-associated neurogenic pulmonary edema (NPE). Additionally, Paquinimod was found to diminish NPE. These findings imply a correlation between the central nervous system and peripheral organs, highlighting the potential of safeguarding the brain to mitigate harm to peripheral organs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ferroptosis, characterized by lipid peroxidation and intracellular iron accumulation, has been reported to be involving in the pathophysiological of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Although taurine reportedly yields neuroprotective effects in multiple central neurological diseases and can attenuated neuron damage after stroke, its role in EBI after SAH remains unclear. The present study indicated that taurine levels in cerebrospinal fluid were significantly reduced in SAH patients, which suggested that taurine treatment after SAH could improve neurological impairment, oxidative stress, iron accumulation, BBB integrity and neuronal ferroptosis in the SAH model in vivo. Taurine could attenuate MDA levels and ROS accumulation and regulate the expression of SLC7A11 and GPX4 and the AKT/GSK3β pathway in vitro. GABA B receptor inhibition and Ly294002 could reverse the therapeutic effects of taurine and significantly downregulate the levels of p-AKT, p-GSK3β, β-catenin, SLC7A11 and GPX4. The protective effects of taurine on SLC7A11 and GPX4 expression were reversed by ICG001 treatment in vitro. Taken together, our findings revealed that taurine could improve neurological function and alleviate cerebral edema, oxidative stress and BBB disruption after SAH, which reduced neuronal ferroptosis by regulating the GABA B /AKT/GSK3β/β-catenin signaling pathway., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest for the publication of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Subarachnoid hemorrhage (SAH) is a life -threatening cerebrovascular disease, where early brain injury (EBI) stands as a primary contributor to mortality and unfavorable patient outcomes. Neuronal ferroptosis emerges as a key pathological mechanism underlying EBI in SAH. Targeting ferroptosis for therapeutic intervention in SAH holds significant promise as a treatment strategy. Methods: SAH model was induced via intravascular puncture and quantitatively assessed the presence of neuronal ferroptosis in the early phase of SAH using FJC staining, Prussian blue staining, as well as malondialdehyde (MDA) and glutathione (GSH) measurements. Hyaluronic acid-coated ursolic acid nanoparticles (HA-PEG-UA NPs) were prepared using the solvent evaporation method. We investigated the in vivo distribution of HA-PEG-UA NPs in SAH model through IVIS and fluorescence observation, and examined their impact on short-term neurological function and cortical neurological injury. Finally, we assessed the effect of UA on the Nrf-2/SLC7A11/GPX4 axis via Western Blot analysis. Results: We successfully developed self-assembled UA NPs with hyaluronic acid to target the increased CD44 expression in the SAH-afflicted brain. The resulting HA-PEG-UA NPs facilitated delivery and enrichment of UA within the SAH-affected region. The targeted delivery of UA to the SAH region can effectively inhibit neuronal ferroptosis, improve neurological deficits, and prognosis in mice. Its mechanism of action is associated with the activation of the Nrf-2/SLC7A11/GPX4 signaling pathway. Conclusions: Brain-targeted HA-PEG-UA NPs was successfully developed and hold the potential to enhance SAH prognosis by limiting neuronal ferroptosis via modulation of the Nrf-2/SLC7A11/GPX4 signal. [ABSTRACT FROM AUTHOR]