The classical “vascular occlusion” model does not fully account for osteonecrosis of the femoral head (ONFH). Femoral head collapse may progress despite restored perfusion, and ischemia alone cannot adequately explain steroid-associated ONFH. We propose that ONFH involves disruption of bone-vascular-immune homeostasis, with macrophage immunometabolic reprogramming in response to hypoxic and lipotoxic stress acting as a potential driver of inflammatory repair failure. Among the metabolic mechanisms implicated in ONFH, the strongest disease-specific evidence supports roles for hypoxia, oxidative stress, disordered lipid metabolism, macrophage imbalance, and ferroptosis-associated injury. By contrast, macrophage-specific glycolytic reprogramming, remodeling of the tricarboxylic acid (TCA) cycle, epigenetic fixation, osteomac dysfunction, and cuproptosis remain less well established. Regulated cell death pathways, particularly ferroptosis and pyroptosis, may exacerbate local tissue injury by releasing damage-associated molecular patterns (DAMPs) and inflammatory mediators that disrupt type H vessel-osteogenesis coupling and shift repair toward fibrosis. Establishing causal relationships rather than correlative associations will require lineage-tracing experiments, spatial validation, metabolic flux analyses, and genetic loss-of-function studies in ONFH models. The translational potential of this article Viewing ONFH as an immunometabolic disorder identifies experimentally tractable targets beyond conventional anti-inflammatory strategies, including SLC7A11/GPX4-dependent ferroptosis defense, NLRP3 inflammasome signaling, and HIF-1α-associated macrophage metabolic adaptation. Extracellular vesicle- or biomaterial-based delivery systems designed for prolonged local retention should currently be considered experimental platforms for assessing lesion-specific target engagement in early-stage ONFH. Their clinical relevance must be established through ONFH-specific studies evaluating efficacy, safety, biodistribution, manufacturability, and long-term structural outcomes.

INTRODUCTION:The blood-brain barrier (BBB) maintains brain homeostasis, and its dysfunction is a critical pathological mechanism for many neurological disorders. However, current BBB models lack functional brain parenchyma, hindering mechanistic studies of BBB-parenchyma interactions and limiting drug evaluation for barrier penetration and neural targeting. OBJECTIVES:To develop an integrated human blood-brain barrier-brain organoid-on-a-chip (BBOC) model that replicates physiological interaction and pathological disruption between the BBB and brain parenchyma. METHODS:A bioengineered BBB model was constructed on a millifluidic plate using human brain microvascular endothelial cells and pericytes under dynamic flow. Human brain organoids (hBOs) derived from pluripotent stem cells were co-cultured to form the BBOC model. Parenchymal pathology was induced by Aβ42 oligomers (Aβ42O) to examine their effects on BBB function and integrity. RESULTS:Conditioned medium and dynamic flow improved endothelial cell viability. Co-culture with hBOs significantly enhanced the engineered BBB function, increasing TEER values and reducing molecular permeability. Aβ42O-treated hBOs exhibited the pathological phenotypes of brain parenchyma, including notable neurite loss, impaired stem cell proliferation, increased cell apoptosis, and transcriptional upregulation of cytokine genes. The pathological hBOs disrupted the BBB, including decreased tight junction protein expression, increased barrier permeability, and impaired barrier integrity. CONCLUSION:The BBOC model reproduced physiological and pathological interactions between parenchyma and the BBB, collectively confirming that brain parenchymal states can modulate BBB integrity. Functionally, hBOs strengthened endothelial barrier integrity, indicating that parenchymal-derived signals actively promote the BBB maturation and stability. In contrast, pathological hBOs induced pericyte degeneration and tight junction disruption of BBB, demonstrating that pathological brain environments can impair BBB function. By bridging neurobiology and bioengineering, the BBOC model will facilitate investigations into neurological mechanisms and drug discovery for barrier penetration and neural targeting.

Background/objective A fundamental translational impasse in musculoskeletal disorders—from osteoarthritis to bone metastases—is the “undruggability” of critical pathological drivers sequestered within anatomically restricted and avascular skeletal niches. While Targeted Protein Degradation (TPD) offers a revolutionary event-driven modality to eradicate these refractory targets, its clinical translation to orthopaedics is severely hindered by the physicochemical incompatibility of large degraders with dense extracellular matrices and the scarcity of bone-specific E3 ligases. Methods In this review, we present a transformative framework integrating deep learning (DL) with multimodal omics to circumvent these barriers. We systematically examine how emerging DL architectures—spanning geometric deep learning, protein language models, and generative design—are redefining the orthopaedic TPD pipeline. Results We highlight computational strategies for prioritizing cryptic pockets on “undruggable” skeletal transcription factors, identifying tissue-restricted E3 ligases via single-cell transcriptomics to minimize systemic toxicity, and optimizing degrader permeability (“penetrability-first” design) to navigate dense cartilage and bone matrices. Conclusion By bridging the gap between computational prediction and skeletal pathobiology, this roadmap outlines a shift in orthopaedic care from palliative symptom management to precise, mechanism-based microenvironmental reprogramming. The Translational Potential of this Article This review provides a timely, computationally-driven roadmap to translate Targeted Protein Degradation (TPD) from oncology to orthopaedics. By integrating deep learning with skeletal pathobiology to overcome matrix penetrability and off-target toxicity, this framework accelerates the development of precision degraders. Ultimately, it offers a tangible strategy to shift the clinical management of joint degeneration, osteoporosis, and bone tumors from palliative care to durable, mechanism-based microenvironmental reprogramming.

Genetic predisposition affects cataract severity and progression, but no specific genetic modifier has been identified to date. This study reveals Periaxin (Prx) gene variants that cause four amino acid substitutions in the cytoskeletal scaffold protein Periaxin (PRX) between C57BL/6J (B6) and 129S4 (129) mouse strains, modulating the severity of age-related cataracts in connexin 46 knockout (Cx46KO) mice. Expression of 129-PRX is significantly higher than B6-PRX in the lens. Additionally, 129-PRX is broadly distributed across lens fibers, accumulates at fiber cell tricellular vertices, and co-localizes with actin filaments at surface protrusions in inner fibers and cultured cells. Aberrant membrane/F-actin aggregates and irregular fibers appear only in the 129-Cx46KO lens core with severe nuclear cataracts. These findings suggest that Cx46 deficiency and the gain-of-function 129-Prx variant synergistically disrupt fiber cell homeostasis and promote membrane/F-actin aggregation, leading to severe age-related cataracts.

・Background: Malignant glioblastoma exhibits cellular senescence characterized by changing tumor microenvironment. Solute carrier family 6 member 6 (SLC6A6), a multichannel transmembrane protein, plays a crucial role in regulating cell proliferation, apoptosis, differentiation and cellular microenvironment. However, the molecular mechanism of SLC6A6 in the cellular senescence of glioblastoma remains unknown. Our study aimed to elucidate the regulatory role and molecular mechanisms of SLC6A6 in the proliferation and senescence of glioblastoma cells. ・Methods: Expression of SLC6A6 was examined in tumor samples from 50 patients with glioblastoma, and associations between SLC6A6 expression and survival outcome were evaluated using Kaplan–Meier survival and Cox regression analyses. To investigate the mechanism of SLC6A6, we used short hairpin RNA (shRNA) and overexpression vector to construct SLC6A6-knockdown and -overexpression glioblastoma cells, respectively. The role of SLC6A6 in glioblastoma was confirmed in vitro and in an orthotopic glioblastoma mouse model. ・Results: Patients with high expression of SLC6A6 had a worse prognosis. Downregulation of SLC6A6 protein inhibited malignant phenotypes of glioblastoma cells in vitro. In addition, SLC6A6 affected tumor senescence by directly binding to CSK with its N-terminal cytoplasmic domain, thereby enhancing AKT phosphorylation. Furthermore, SLC6A6 knockdown inhibited tumor growth and shortened survival in the glioblastoma xenograft mouse model. ・Conclusion: SLC6A6 can promote malignant progression and inhibit cellular senescence of glioblastoma cells by affecting the CSK/AKT/FoxO1 signaling pathway. SLC6A6 might be a valuable biomarker in the treatment of glioblastoma.

BACKGROUND:Ventriculoperitoneal (VP) shunt surgery is the primary treatment for patients with idiopathic normal pressure hydrocephalus (iNPH). This study compared the outcomes of VP shunt placement using electromagnetic (EM) navigation versus standard methods in patients with iNPH, focusing on catheter accuracy and postoperative complication rates. METHODS:This retrospective study included 31 patients with iNPH who underwent standard shunt placement using anatomical landmarks and 50 patients who underwent EM-guided shunt placement. Parameters assessed included shunt placement grade, catheter tip position, catheter angle, puncture attempts, operative duration, postoperative infection rates, intraparenchymal hemorrhage rates, and shunt malfunction rates. Patients had follow-ups at 3, 6, 12, and 24 months after surgery or until shunt failure. RESULTS:In the EM-guided group, a higher percentage of grade 1 shunt placements (92% vs. 71%, P = 0.03) and fewer grade 3 placements (2% vs. 13%, P = 0.068) were observed. The catheter tip position at the foramen of Monro was significantly more accurate (P < 0.001), with smaller lateral catheter deviation angles in both coronal (19.69° vs. 24.2°, P < 0.0001) and sagittal (21.75° vs. 39.3°, P < 0.01) sections. The EM-guided group had fewer puncture attempts, shorter operative durations, lower incidence of intraparenchymal hemorrhage (P < 0.01), and fewer shunt malfunctions over the 2-year follow-up period (2% vs. 26%, P = 0.0003). CONCLUSIONS:The use of EM navigation in VP shunt placement for patients with iNPH improves catheter placement accuracy, reduces postoperative complications and shunt malfunction rates, and provides precise and individualized surgical treatment.

Background Helicobacter pylori (H. pylori) infection promotes gastric cancer (GC) through various mechanisms. It causes inflammation and damage to the gastric mucosa, thereby increasing the risk of developing GC. Sphingolipids can act as signaling molecules that activate or inhibit intracellular signaling pathways, and abnormal sphingolipid metabolism may promote tumorigenesis and metastasis. This study aimed to explore the relationship among sphingosine kinase 2 (SphK2) expression, GC progression, and H. pylori infection. Methods Expression profile data for SphK2 were extracted from public datasets. Normal human gastric mucosal and GC cells were co-incubated with H. pylori, and SphK2 expression in these cells was detected using western blotting. GC cells with SphK2 overexpression and knockdown were established, and the effects of SphK2 and H. pylori on the proliferation, migration, and invasion abilities of GC cells were verified using CCK-8, EdU, and Transwell assays. The expression of Ras/MEK/ERK pathway-related proteins was detected using western blotting, and the secretion of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in GC cells was detected using ELISA. Results SphK2 is highly expressed in GC cells and is associated with a poor prognosis. The expression of SphK2 in GC cells is related to H. pylori infection. SphK2 overexpression promotes the proliferation, migration, and invasion of GC cells and enhances the pro-inflammatory effects of H. pylori. Conclusion SphK2 promotes the progression of H. pylori-positive GC by activating the Ras/MEK/ERK pathway.

ObjectiveThis study aims to investigate the impact of the offending vessel’s compression location on intraoperative lateral spread response (LSR) waveform parameters during microvascular decompression (MVD) for hemifacial spasm (HFS). Additionally, the study evaluates the clinical significance of LSR variations in intraoperative electrophysiological monitoring.MethodsA retrospective analysis was conducted on 72 patients with HFS who underwent MVD at Nanjing Brain Hospital between September 2021 and September 2023. Patients were categorized into two groups based on the compression site of the offending vessel on the facial nerve: the transitional zone (TZ) group and the attached segment (AS) group. General clinical characteristics, intraoperative LSR parameters, and postoperative outcomes were compared between groups. Statistical analyses focused on LSR latency, amplitude, and duration, as well as the patterns of LSR disappearance and postoperative complications.ResultsThe TZ group comprised 31 patients, while the AS group included 41. No significant differences were observed in baseline characteristics between groups. Intraoperative monitoring revealed that LSR disappearance was more frequently incomplete in the TZ group (11.1%) than in the AS group (p < 0.05). LSR latency was significantly longer in the AS group (p < 0.001), while the amplitude in the orbicularis oculi muscle was lower in the TZ group (p < 0.001). Additionally, LSR duration (T2) in the orbicularis oris (p < 0.05) and mentalis muscles (p < 0.01) was longer in the AS group, though the amplitude differences were not statistically significant. Postoperative outcomes showed no significant difference in effectiveness between the groups (AS: 92.7% vs. TZ: 93.5%, p = 0.882). Complications, such as facial palsy and hoarseness, were slightly more common in the AS group, whereas hearing loss and ataxia were more frequent in the TZ group. However, none of these differences reached statistical significance.ConclusionThe compression location of the offending vessel significantly influences LSR parameters, with longer latency and prolonged duration observed in the AS group. Despite these variations, postoperative outcomes and complications were comparable between groups. These findings highlight the importance of considering the compression location during MVD and the potential value of LSR monitoring in guiding surgical decision-making.

BACKGROUND:Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a poor prognosis largely due to its immunosuppressive microenvironment. Immunotherapy offers a promising approach by targeting this barrier to anti-tumor immunity. Despite growing research interest, an overview of the field's development is still lacking. This study uses bibliometric analysis to map trends and key advances in GBM immunotherapy research from 2005 to 2024. METHODS:A systematic bibliometric search was performed in the Web of Science Core Collection from 2005 to 2024, using a predefined search strategy combining terms related to "glioblastoma" and "immunotherapy". Only peer-reviewed articles and reviews in English were included. Bibliometric analysis was conducted using VOSviewer, CiteSpace, and Scimago Graphica to visualize research trends and collaboration networks. RESULTS:From 2005 to 2024, a total of 2064 publications on GBM immunotherapy were identified, with China and the United States as the leading contributors. Co-citation analysis highlighted Roger Stupp as the most influential author, while Frontiers in Oncology was the most prolific journal. Keyword burst analysis revealed increasing clinical interest in nivolumab and chemotherapy, with neoadjuvant immunotherapy emerging as a promising research direction. CONCLUSIONS:The analysis of 2,064 publications on GBM immunotherapy highlights a high level of collaborative effort aimed at advancing novel therapeutic approaches. The findings emphasize the importance of the tumor microenvironment and suggest that future efforts should focus on overcoming immune suppression and developing targeted combination therapies. This study provides a useful reference for guiding research and improving immunotherapy strategies in GBM.

BackgroundAlthough more risk prediction models are available for feeding intolerance in enteral-nourishment patients, it is still unclear how well these models will work in clinical settings. Future research faces challenges in validating model accuracy across populations, enhancing interpretability for clinical use, and overcoming dataset limitations.ObjectiveTo thoroughly examine studies that have been published on feeding intolerance risk prediction models for enteral nutrition patients.DesignConducted a systematic review and meta-analysis of observational studies.MethodsA comprehensive search of the literature was conducted using a range of databases, including China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), SinoMed, PubMed, Web of Science, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Embase. The search scope was confined to articles within the database from its inception until August 12th, 2024. The data from the selected studies should be extracted, including study design, subjects, duration of follow-up, data sources, outcome measures, sample size, handling of missing data, continuous variable handling methods, variable selection, final predictors, model development and performance, and form of model presentation. The applicability and bias risk were evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST) checklist.ResultsA total of 1,472 studies were retrieved. Following the selection criteria, 18 prediction models sourced from 14 studies were incorporated into this review. In the field of model construction, only one study employed the use of multiple machine-learning techniques for the development of a model. In contrast, the remaining studies used logistic regression to construct FI risk prediction models. The incidence of FI in enteral nutrition was 32.4–63.1%. The top five predictors included in the model were APACHE II, age, albumin levels, intra-abdominal pressure, and mechanical ventilation. The reported AUC, or area under the curve, exhibited a range of values between 0.70 and 0.921. All studies were identified as having a high risk of bias, primarily due to the use of inappropriate data sources and inadequate reporting within the analysis domain.ConclusionAlthough the included studies reported a certain degree of discriminatory power in their predictive models to identify feeding intolerance in patients undergoing enteral nutrition, the PROBAST assessment tool deemed all the included studies to carry a significant risk of bias. Future research should emphasize the development of innovative predictive models. These endeavors should incorporate more extensive and diverse sample sizes, adhere to stringent methodological designs, and undergo rigorous multicenter external validation to ensure robustness and generalizability.Systematic review registrationIdentifier CRD42024585099, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=585099.

BACKGROUND Glioblastoma (GBM) is the most common and aggressive malignant tumor in the central nervous system, with limited therapeutic options and poor prognosis. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor, has shown promise in treating various malignancies. This study systematically analyzed the treatment outcomes of 10 typical patients with progressive GBM in our institution who were treated with anlotinib. MATERIAL AND METHODS Ten progressive GBM patients treated with anlotinib between 2020 and 2022 were included. Tumor progression was assessed using modified Response Assessment in Neuro-Oncology (mRANO) criteria. Disease progression was evaluated via conventional MRI and physical examinations. Patient condition was measured using the Karnofsky performance status (KPS) scale and the European Organization for Research and Treatment Core Quality of Life Questionnaire (EORTC QLQ-C30). Median progression-free survival (PFS) and overall survival (OS) were calculated from anlotinib initiation. Adverse effects were graded using CTCAE 5.0. RESULTS According to the mRANO criteria, 3 patients had a complete response, 3 had a partial response, 1 had stable disease, and 3 had progressive disease, resulting in a 70% disease control rate and a 60% objective response rate. Median PFS was 5.42 months, and median OS was 6.30 months. KPS scores significantly improved after treatment (P<0.05), and QLQ-C30 scores were higher in 11 of 15 items (P<0.05). No grade 3 or 4 adverse events were observed. CONCLUSIONS Through small-sample real-world research, anlotinib, either as monotherapy or in combination with temozolomide, demonstrated promising therapeutic effects in patients with progressive GBM, suggesting its potential as a targeted treatment option.

BackgroundExosomes (EXO) play crucial roles in intercellular communication and glioma microenvironment modulation. Tumor-associated macrophages are more likely to become M2-like type macrophages in the immunosuppressive microenvironment. Here, we aimed to investigate the effects and molecular mechanisms of hypoxic glioma-derived exosomes mediated M2-like macrophage polarization.MethodsHighly expressed miRNAs in exosomes derived from glioma cells cultured under hypoxia condition compared to normoxic condition were identified through microRNA sequencing. The polarization status of macrophages was determined using qRT-PCR, Western blotting, flow cytometry, and immunohistochemistry. By using RNA-seq, we aimed to identify the downstream target genes regulated by miR-25-3p in macrophages and investigate the mechanistic pathways through which it exerts its effects. The proliferation and migration capabilities of glioma cells were assessed through EdU, Transwell assays, and in vivo experiments.ResultsWe found that miR-25-3p was upregulated in the exosomes derived from hypoxic glioma cells and can be transferred to the macrophage. In macrophages, miR-25-3p downregulates the expression of PHLPP2, thereby activating the PI3K-AKT-mTOR signaling pathway, ultimately leading to macrophage M2 polarization. As part of a feedback loop, M2-polarized macrophages can, in turn, promote malignant glioma progression.ConclusionOur study reveals that miR-25-3p from hypoxic glioma cells is delivered to macrophages via exosomes as a mediator, promoting M2 polarization of macrophages through the miR-25-3p/PHLPP2/PI3K-AKT signaling pathway. This study suggests that targeted interventions to modulate miR-25-3p expression, transmission, or inhibition of PI3K-AKT pathway activation can disrupt the immune-suppressive microenvironment, providing a novel approach for immunotherapy in gliomas.

BACKGROUND:Intracranial aneurysm (IA) is a severe cerebrovascular disease, and effective gene therapy and drug interventions for its treatment are still lacking. Oxidative stress (OS) is closely associated with the IA, but the key regulatory genes involved are still unclear. Through multiomics analysis and experimental validation, we identified two diagnostic markers for IA associated with OS. METHODS:In this study, we first analyzed the IA dataset GSE75436 and conducted a joint analysis of oxidative stress-related genes (ORGs). Differential analysis, functional enrichment analysis, immune infiltration, WGCNA, PPI, LASSO, and other methods were used to identify IA diagnostic markers related to OS. Next, the functions of TLR4 and ALOX5 expression in IA and their potential targeted therapeutic drugs were analyzed. We also performed single-cell sequencing of patient IA and control (superficial temporal artery, STA) tissues. 23,342 cells were captured from 2 IA and 3 STA samples obtained from our center. Cell clustering and annotation were conducted using R software to observe the distribution of TLR4 and ALOX5 expression in IAs. Finally, the expression of TLR4 and ALOX5 were validated in IA patients and in an elastase-induced mouse IA model using experiments such as WB and immunofluorescence. RESULTS:Through bioinformatics analysis, we identified 16 key ORGs associated with IA pathogenesis. Further screening revealed that ALOX5 and TLR4 were highly expressed to activate a series of inflammatory responses and reduce the production of myocytes. Methotrexate (MTX) may be a potential targeted drug. Single-cell analysis revealed a notable increase in immune cells in the IA group, with ALOX5 and TLR4 primarily localized to monocytes/macrophages. Validation through patient samples and mouse models confirmed high expression of ALOX5 and TLR4 in IAs. CONCLUSIONS:Bioinformatics analysis indicated that ALOX5 and TLR4 are the most significant ORGs associated with the pathogenesis of IA. Single-cell sequencing and experiments revealed that the high expression of ALOX5 and TLR4 are closely related to IA. These two genes are promising new targets for IA therapy.

AIMS:This study investigated the roles of lateral basal forebrain glial cell line-derived neurotrophic factor (GDNF) signaling and cholinergic neuron activity, apoptosis, and autophagy dysfunction in sleep deprivation-induced increased risk of chronic postsurgical pain (CPSP) in mice. METHODS:Sleep deprivation (6 h per day from -1 to 3 days postoperatively) was administered to mice receiving skin/muscle incision and retraction (SMIR) to determine whether perioperative sleep deprivation induces mechanical and thermal pain hypersensitivity, increases the risk of chronic pain, and causes changes of basal forebrain neurons activity (c-Fos immunostaining), apoptosis (cleaved Caspase-3 expression), autophagy (LC3 and p62 expression) and GDNF expression. Adeno-associated virus (AAV)-GDNF was microinjected into the basal forebrain to see whether increased GDNF expression could reverse sleep deprivation-induced changes in pain duration and cholinergic neuron apoptosis and autophagy. Cholinergic neurons were further depleted by mu p75-SAP to examine whether the pain-prolonging effects of sleep deprivation still exist. RESULTS:Perioperative sleep deprivation enhanced pain sensation and prolonged pain duration in SMIR mice, which was accompanied by decreased cholinergic neuron activity and GDNF expression, increased apoptosis, and autophagy dysfunction in the substantia innominata (SI), magnocellular preoptic nucleus (MCPO), and horizontal diagonal band Broca (HDB) (hereafter lateral basal forebrain). Normalizing cholinergic neuron GDNF expression by AAV-GDNF in the lateral basal forebrain inhibited apoptosis and autophagy dysfunction and mitigated sleep deprivation-induced pain maintenance. Mice with selective lesion of lateral basal forebrain cholinergic neurons were resistant to the pain-enhancing and prolonging effects of sleep deprivation and the pain-alleviating effects of AAV-GDNF therapy. CONCLUSIONS:Perioperative sleep deprivation promotes chronicity of postsurgical pain possibly through decreasing basal forebrain GDNF signaling and causing cholinergic neuronal apoptosis and autophagy dysfunction.

The purpose of this study is to explore the shared molecular pathogenesis of traumatic brain injury (TBI) and high-grade glioma and investigate the mechanism of propofol (PF) as a potential protective agent. By analyzing the Chinese glioma genome atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we compared the transcriptomic data of high-grade glioma and TBI patients to identify common pathological mechanisms. Through bioinformatics analysis, in vitro experiments and in vivo TBI model, we investigated the regulatory effect of PF on extracellular matrix (ECM)-related genes through Prrx1 under oxidative stress. The impact of PF on BBB integrity under oxidative stress was investigated using a dual-layer BBB model, and we explored the protective effect of PF on tight junction proteins and ECM-related genes in mice after TBI. The study found that high-grade glioma and TBI share ECM instability as an important molecular pathological mechanism. PF stabilizes the ECM and protects the BBB by directly binding to Prrx1 or indirectly regulating Prrx1 through miRNAs. In addition, PF reduces intracellular calcium ions and ROS levels under oxidative stress, thereby preserving BBB integrity. In a TBI mouse model, PF protected BBB integrity through up-regulated tight junction proteins and stabilized the expression of ECM-related genes. Our study reveals the shared molecular pathogenesis between TBI and glioblastoma and demonstrate the potential of PF as a protective agent of BBB. This provides new targets and approaches for the development of novel neurotrauma therapeutic drugs.

Rationale: Meningeal lymphatic vessels (MLVs) are essential for the clearance of subdural hematoma (SDH). However, SDH impairs their drainage function, and the pathogenesis remains unclear. Herein, we aimed to understand the pathological mechanisms of MLV dysfunction following SDH and to test whether atorvastatin, an effective drug for SDH clearance, improves meningeal lymphatic drainage (MLD). Methods: We induced SDH models in rats by injecting autologous blood into the subdural space and evaluated MLD using Gadopentetate D, Evans blue, and CFSE-labeled erythrocytes. Whole-mount immunofluorescence and transmission electron microscopy were utilized to detect the morphology of MLVs. Phosphoproteomics, western blot, flow cytometry, and in vitro experiments were performed to investigate the molecular mechanisms underlying dysfunctional MLVs. Results: The basal MLVs were detected to have abundant valves and play an important role in draining subdural substances. Following SDH, these basal MLVs exhibited disrupted endothelial junctions and dilated lumen, leading to impaired MLD. Subsequent proteomics analysis of the meninges detected numerous dephosphorylated proteins, primarily enriched in the adherens junction, including significant dephosphorylation of ERK1/2 within the meningeal lymphatic endothelial cells (LECs). Subdural injection of the ERK1/2 kinase inhibitor PD98059 resulted in dilated basal MLVs and impaired MLD, resembling the dysfunctional MLVs observed in SDH. Moreover, inhibiting ERK1/2 signaling severely disrupted intercellular junctions between cultured LECs. Finally, atorvastatin was revealed to protect the structure of basal MLVs and accelerate MLD following SDH. However, these beneficial effects of atorvastatin were abolished when combined with PD98059. Conclusion: Our findings demonstrate that SDH induces ERK1/2 dephosphorylation in meningeal LECs, leading to disrupted basal MLVs and impaired MLD. Additionally, we reveal a beneficial effect of atorvastatin in improving MLD.

To develop and validate a prediction model based on imaging data for the prognosis of mild chronic subdural hematoma undergoing atorvastatin treatment. We developed the prediction model utilizing data from patients diagnosed with CSDH between February 2019 and November 2021. Demographic characteristics, medical history, and hematoma characteristics in non-contrast computed tomography (NCCT) were extracted upon admission to the hospital. To reduce data dimensionality, a backward stepwise regression model was implemented to build a prognostic prediction model. We calculated the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model by a tenfold cross-validation procedure. Maximum thickness, volume, mean density, morphology, and kurtosis of the hematoma were identified as the most significant predictors of good hematoma dissolution in mild CSDH patients undergoing atorvastatin treatment. The prediction model exhibited good discrimination, with an area under the curve (AUC) of 0.82 (95

Azoospermia is a serious leading male-factor cause of infertility in couples of childbearing age. The two main azoospermia types, obstructive (OA) and non-obstructive (NOA) azoospermia, differ in their treatment approaches. Therefore, their clinical diagnosis is extremely important, requiring an accurate, efficient, and easy-to-use diagnostic model. This retrospective observational study included 707 patients with azoospermia treated between 2017 and 2021, 498 with OA, and 209 with NOA. Hematological and seminal plasma parameters, hormone levels, and testicular volume were used in logistic regression analysis to evaluate and compare their diagnostic performance, results showed that the optimal diagnostic model is constructed by five variables including semen volume, semen pH, seminal plasma neutral α-glucosidase activity, follicle-stimulating hormone in the serum, and testicular volume, compared with follicle-stimulating hormone-based and testicular volume-based models. The 5-factor diagnostic model had an accuracy of 90.4%, sensitivity of 96.4%, positive predictive value of 90.6%, negative predictive value of 89.8%, and area under the curve of 0.931, all higher than in the other two models. However, its specificity (76.1%) was slightly lower than in the other models. Meantime, the internal 5-fold cross-validation results indicated that the 5-factor diagnostic model had a good clinical application value. This study established an accurate, efficient, and relatively accessible 5-factor diagnostic model for OA and NOA, providing a reference for clinical decision-making when selecting an appropriate treatment.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. In investigating concerns brought up regarding the authenticity of the article, the editors reached out to the corresponding author for an explanation. The corresponding author failed to provide a satisfactory explanation. The editors therefore feel that the findings of the manuscript cannot be relied upon and that the article needs to be retracted.

Neural inflammatory response is a crucial pathological change in intracerebral hemorrhage (ICH) which accelerates the formation of perihematomal edema and aggravates neural cell death. Although surgical and drug treatments for ICH have advanced rapidly in recent years, therapeutic strategies that target and control neuroinflammation are still limited. Exosomes are important carriers for information transfer among cells. They have also been regarded as a promising therapeutic tool in translational medicine, with low immunogenicity, high penetration through the blood-brain barrier, and ease of modification. In our previous research, we have found that exogenous administration of miRNA-124-overexpressed microglial exosomes (Exo-124) are effective in improving post-injury cognitive impairment. From this, we evaluated the potential therapeutic effects of miRNA-124-enriched microglial exosomes on the ICH mice in the present study. We found that the gene-edited exosomes could attenuate neuro-deficits and brain edema, improve blood–brain barrier integrity, and reduce neural cell death. Moreover, the protective effect of Exo-124 was abolished in mice depleted of Gr-1+ myeloid cells. It suggested that the exosomes exerted their functions by limiting the infiltration of leukocyte into the brain, thus controlling neuroinflammation following the onset of ICH. In conclusion, our findings provided a promising therapeutic strategy for improving neuroinflammation in ICH. It also opens a new avenue for intranasal delivery of exosome therapy using miRNA-edited microglial exosomes.