Xingen Zhu

Crosstalk between the nervous and immune systems is responsible for ischemic cerebral injury. However, the molecular mechanism and regulatory network underlying this interaction still have not been completely illuminated. In this study, we found that the E3 SUMOylase Tripartite Motif-Containing Protein 28 (TRIM28) was primarily upregulated in astrocytes after ischemic stroke (IS), and elevated plasma TRIM28 levels correlated with poor prognosis in IS patients. Astrocyte-specific Trim28 knockout relieved IS-mediated cerebral injury. Conversely, in astrocyte-specific Trim28 knockout mice, AAV-mediated re-expression of TRIM28 in astrocytes aggravated IS-mediated neuroinflammation and cerebral injury. Mechanistically, TRIM28 catalyzed SUMO1 conjugation of interferon regulatory factor 3 (IRF3) at lysine 77, which stabilized intranuclear IRF3 by inhibiting K48-linked ubiquitination and subsequent proteasomal degradation. Stabilized IRF3 transcriptionally upregulated C-X-C motif chemokine ligand 1 (CXCL1), thereby enhancing CXCL1-CXCR2 signaling to promote CXCR2⁺ neutrophils chemotaxis and infiltration into the ischemic brain. Importantly, virtual screening of the FDA-approved drug library identified Acarbose as a pharmacological inhibitor of TRIM28-IRF3 axis, and Acarbose administration relieved neutrophils brain infiltration and cerebral injury after IS. Our findings highlight the critical role of TRIM28 in regulating crosstalk between astrocytes and neutrophils and nominate TRIM28 as a tractable therapeutic target for ischemic cerebral injury.

Background Plasma D-dimer levels are independently associated with poor prognosis following aneurysmal subarachnoid hemorrhage (aSAH). However, the underlying mechanisms contributing to early D-dimer elevation remain unclear. This study aimed to evaluate the association between admission D-dimer levels and total bleeding volume (TBV) and to further explore their combined predictive power for functional outcomes using interpretable machine learning approaches. Methods We analyzed data from 473 patients with aSAH enrolled in the retrospective PROSAH-MPC cohort, including clinical, radiological, and laboratory parameters. Patients were stratified by D-dimer quartiles. Multivariable logistic regression was employed to assess associations between D-dimer, TBV, and 12-month modified Rankin scale (mRS) outcomes. Boruta algorithm was applied for feature selection, identifying D-dimer, TBV, age, Hunt–Hess grade, and modified Fisher score (mFS) as top predictors. Subsequently, seven machine learning models were developed for outcome prediction. SHapley Additive exPlanations (SHAP) analysis was used to interpret the contribution of these features. Results Unfavorable outcomes occurred in 125 patients (26.4%). Elevated D-dimer levels were significantly associated with unfavorable outcomes (adjusted OR 1.08; 95% CI 1.02–1.16). A significant interaction between TBV and D-dimer was observed in relation to functional outcome (P for interaction = 0.032). Combined D-dimer + TBV + Hunt–Hess yielded the highest area under the curve (AUC; 0.867; 95% CI 0.764–0.856), outperforming D-dimer (0.735), TBV (0.783), and Hunt–Hess (0.833). Among machine learning models, XGBoost achieved the highest discriminative performance (AUC = 0.904), with SHAP confirming D-dimer and TBV as major contributors. Conclusions Admission D-dimer levels are a key biomarker associated with long-term functional outcomes after aSAH, and their prognostic value is significantly influenced by total bleeding volume. Integrating machine learning and SHAP interpretability enhances our understanding of these relationships and may inform early risk stratification in clinical practice.

Background: Glioma is the most common primary intracranial tumor in adults. As a subunit of immune proteasome, proteasome subunit beta type-8 (PSMB8) may regulate the progression of glioma via participating in degradation and presentation of tumor antigenic peptides, but its prognostic and clinical applicant usage is under investigation. Therefore, this study aimed to comprehensively evaluate the prognostic significance of PSMB8 in low-grade glioma (LGG) and to elucidate its association with the tumor immune microenvironment and potential as a predictor for immunotherapy response. Methods: Transcriptome data were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Gene Expression Omnibus (GEO) repositories. The correlations between PSMB8 expression and the clinicopathological features of LGG were investigated in our study, and the prognostic role of PSMB8 in LGGs was assessed fully and comprehensively. Furthermore, we evaluated the correlation between PSMB8 expression and LGG immune environment via the experiments and bioinformatic analysis. Results: Our results indicated that, PSMB8 were highly expressed in most tumor tissues, including LGG. Lower expression of PSMB8 was significantly correlated with lower World Health Organization (WHO) grade and isocitrate dehydrogenase (IDH) mutation status. Moreover, PSMB8 showed a promising prognostic ability for LGG patients via nomogram model and receiver operating characteristic (ROC) curves. Association analysis showed that PSMB8 expression was associated with immune cell infiltration in a variety of tumors, including LGG. Our experiments validated the positive correlation between PSMB8 expression and M2-macrophage infiltration level in clinical LGG tissues and invasive ability of LGG cell. Conclusions: PSMB8 could be used as one of the prognostic indicators of LGG and it could regulate the LGG cell migratory and invasive ability. Besides, PSMB8 is expected to be a promising biomarker of cancer immunotherapy.

Temozolomide (TMZ) resistance remains a major obstacle in glioblastoma (GBM) therapy. Here, we identified E2F6 as a critical driver of TMZ resistance in GBM. E2F6 expression was significantly elevated in glioma tissues and correlated with advanced tumor grade, recurrence, and poor prognosis. Functionally, E2F6 depletion sensitized GBM cells to TMZ, suppressing proliferation and promoting apoptosis both in vitro and in vivo. Mechanistically, E2F6 directly bound to the SH3GL2 promoter and transcriptionally repressed its expression. SH3GL2 acted as a key downstream effector of E2F6, as SH3GL2 silencing abolished the chemosensitizing effects induced by E2F6 knockdown. Further investigation revealed that SH3GL2 promoted HMGB1 secretion through BAR domain-mediated interaction with CHMP4B and SH3 domain-dependent binding to HMGB1. Enhanced HMGB1 secretion reduced intracellular HMGB1 retention, impaired DNA damage repair, and increased TMZ-induced DNA damage. In addition, extracellular HMGB1 promoted M1 macrophage polarization, thereby enhancing anti-tumor immune responses. Collectively, our findings identify the E2F6/SH3GL2/HMGB1 axis as a previously unrecognized mechanism linking DNA repair and tumor immune regulation during TMZ resistance, and suggest that targeting this pathway may represent a promising therapeutic strategy for GBM.

While the central dogma outlines DNA-to-protein information flow, existing gene regulators mainly target transcription. Here, we developed the λN-Guided RNA Targeting System (λGRTS), a CRISPR-independent platform enhancing mammalian mRNA translation via specific translation-guiding RNAs (tgRNAs). λGRTS integrates λN (high-affinity BoxB binder), mutated eIF4E1 (ablated non-specific 5' cap binding, retains TIC recruitment), and auxiliary factors (HuR for dsRNA stabilization, PABP and RRM2-RRM3 for mRNA closed loops). Optimized 22-nt tgRNAs (targeting 58 bp upstream of mRNA ATG in 5' UTR) and NES-tagged proteins maximized efficacy. λGRTS outperformed dCasRX (smaller ~ 50 kDa vs. ~ 150 kDa, single tgRNA vs. crRNA-tracrRNA), boosting functional proteins (e.g., GFP). It activated P53/PTEN, suppressing GBM cell proliferation, inducing G1 arrest, and reducing invasion in vitro. In vivo, lentiviral λGRTS inhibited orthotopic GBM in nude mice, extended survival by approximately 35-40 days, with IHC confirming P53/PTEN upregulation. Mass spectrometry showed no off-target effects. Cross-species tests (human, mouse, bovine cells) validated broad applicability via conserved eIF4E1. λGRTS offers a specific, safe translation-centric tool for gene regulation and oncology research.

The TPD strategy has been attracting increasing attention since it was proposed, with related technologies continuously evolving to the extent that it is considered a drug development method with i...

BACKGROUND: Endothelial dysfunction has emerged as early and pivotal event in Alzheimer's disease (AD), yet the molecular mechanisms linking vascular aging to neuroinflammation remain elusive. METHODS: We used APP/PS1 mice and amyloid beta (Aβ)–challenged brain endothelial cells (BECs) to understand the mechanisms of nicotinamide adenine dinucleotide (NAD ⁺ ) deficiency, and its relationship with endothelial senescence and neuroinflammation in AD pathology. Nicotinamide riboside supplementation was administered to APP/PS1 mice to determine whether restoration of NAD ⁺ homeostasis mitigates AD‐related vascular and inflammatory pathology. RESULTS: NAD ⁺ deficiency induced voltage‐dependent anion channel 1 (VDAC1) oligomerization, mitochondrial DNA (mtDNA) leakage, and cGAS/STING‐IRF3 activation, promoting endothelial senescence and SASP production with NAD ⁺ ‐consuming enzyme CD38 upregulation. Senescent BECs triggered IL‐6‐dependent microglial activation. NR treatment restored mitochondrial integrity, suppressed cGAS‐STING signaling, and reduced neuroinflammation, improving vascular function and cognition. DISCUSSION: Aβ‐driven NAD ⁺ deficiency initiates a VDAC1‐mtDNA‐cGAS/STING cascade that promotes endothelial senescence and neurovascular inflammation in AD pathology, and amplifies neuroinflammation through BEC–microglia crosstalk, highlighting NAD ⁺ restoration as a promising AD therapeutic strategy.

Despite advances in embolization techniques and neurocritical care, patients with severe aneurysmal subarachnoid hemorrhage (SaSAH) continue to face substa

The interaction between tumour-associated neutrophils (TANs) and angiogenesis plays a crucial role in tumour progression. However, the specific regulatory mechanisms by which different TANs populations influence angiogenesis in colorectal cancer (CRC) remain poorly understood. The study integrates our own dataset with publicly available single-cell RNA sequencing (scRNA-seq) data to analyze the infiltration of various single-cell types in colorectal cancer (CRC). Using in vitro experiments, immunofluorescence, and animal models treated with anti-VEGFR antibodies, we investigated the role of tumor-associated neutrophils (TANs) in CRC and angiogenesis. We conducted RAB31 knockdown cell line, RNA sequencing, Western blotting, quantitative PCR, ELISA, tube formation assays, CCK8, and clonogenic assays, combined with in vivo experiments, to elucidate the impact of RAB31 in the tumor microenvironment (TME) and the mechanism by which tumor-derived RAB1 regulates TANs recruitment. Single-cell analysis revealed a significant infiltration of myeloid cells, particularly TANs, in CRC tumour tissue compared to normal tissue. RAB31 was found to be involved in malignant cell pathways, promoting CRC progression. Depletion of TANs substantially suppressed tumour growth and angiogenesis, while VEGFR blockade inhibited tumour growth and altered TANs infiltration in response to angiogenesis status. In vitro, knockdown of RAB31 expression inhibited tumour cell proliferation, and CXCL2 protein secretion was significantly reduced in shRab31-transfected tumour cells. In vivo, tumour tissue from shRab31 models showed decreased angiogenesis and reduced Neutrophil Extracellular Traps (NET) production, alongside reduced TANs infiltration. Moreover, CXCR4 expression was significantly elevated in TANs, and tumour cells influenced TANs through the CXCL2–CXCR4 axis. RAB31 regulated the PI3K–Akt signalling pathway, which is linked to neutrophil recruitment in CRC. Our findings suggest that tumour-derived RAB31 regulates the CXCL2–CXCR4 signalling pathway in CRC. RAB31 promotes CXCL2 secretion through the PI3K-Akt signalling pathway, facilitating TANs recruitment and angiogenesis, thereby driving tumour growth. This work enhances our understanding of the complex role of TANs and RAB31 in CRC progression and provides new insights into potential therapeutic strategies targeting the tumour microenvironment. The online version contains supplementary material available at 10.1186/s12967-026-07908-6.