Hangzhou First People's Hospital

Obesity can lead to various forms of brain damage and cognitive impairments. The neuropathological mechanism may involve brain iron deposition and changes in cerebral blood flow perfusion. This study aims to use Quantitative Susceptibility Mapping (QSM) and Arterial Spin Labeling (ASL) to quantitatively assess brain iron deposition and Cerebral Blood Flow (CBF) in patients with obesity, and to explore their patterns of alteration and association with cognitive impairment. 37 patients with obesity and 45 controls underwent 3.0 T MRI and cognitive assessment. We compared susceptibility and cerebral blood flow values within automatically segmented regions of the interest and analyzed associations with cognition using partial correlations. Patients displayed increased iron in the left nucleus accumbens and bilateral red nuclei (p = 0.001, p = 0.001, p < 0.001) and abnormal perfusion in the right cerebellum, right middle frontal gyrus, left putamen, and right anterior cingulate gyrus (p < 0.001). Furthermore, iron deposition correlated with cognitive impairment. This study suggests that obese patients may exhibit iron deposition and perfusion abnormalities in certain areas of the brain. Bilateral red nuclei iron deposition is closely related to cognitive impairment. The multimodal combined application of QSM and ASL provides imaging evidence for revealing the impact of obesity on brain structure and function, and also provides potential biomarkers for targeted interventions in the future.

Trigeminal neuralgia (TN) is a debilitating neuropathic facial pain disorder in which current treatments often provide incomplete or poorly tolerated relief. Microglia-driven neuroinflammation in the trigeminal system, particularly Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88) signaling, is increasingly recognized as a key driver of neuropathic pain, and network pharmacology suggests that Liquiritin, a major licorice flavonoid with anti-inflammatory actions, may target this pathway. We aimed to determine whether Liquiritin alleviates infraorbital nerve injury (IONI)-induced TN-like neuropathic pain by suppressing microglial M1-like polarization via the TLR4/MyD88 pathway, and to characterize its effects on head-withdrawal thresholds, conditioned place preference, inflammatory and pain mediators and TLR4/MyD88 signaling in vivo and in LPS-stimulated BV2 microglia. Adult female ICR mice (8-10weeks) underwent infraorbital nerve injury (IONI) or sham surgery and were randomly assigned to Sham + vehicle, IONI + vehicle, IONI + Liquiritin (200mg/kg, oral) or IONI + Pregabalin (10mg/kg) groups (n=10 per group) treated once daily for 18days. Mechanical allodynia (head-withdrawal thresholds to von Frey stimulation) and conditioned place preference were assessed, trigeminal tissues were analyzed by Western blotting, immunofluorescence and flow cytometry for microglial markers, inflammatory cytokines, pain mediators and TLR4/MyD88, and TLR4 antagonist/agonist administration, LPS-stimulated BV2 microglia and network pharmacology plus molecular docking were used to interrogate Liquiritin's TLR4/MyD88-dependent actions. In IONI mice, Liquiritin significantly attenuated mechanical allodynia and increased conditioned place preference compared with IONI + vehicle, yielding head-withdrawal threshold and conditioned place preference improvements. Network pharmacology identified 92 Liquiritin-related components, 194 candidate targets, and 41 neuropathic-pain-related overlapping genes enriched in Toll-like receptor signaling, and molecular docking showed favorable binding to IL-1β (-11.2kcal/mol), TNF-α (-8.35kcal/mol) and TLR4 (-8.76kcal/mol). Blocking TLR4/MyD88 signaling with LRU alleviated IONI-induced pain behaviors and reduced trigeminal IL-1β, TNF-α, Iba1, CD32, CGRP and TRPV1 expression, whereas TLR4 agonist TEA partially reversed Liquiritin-induced behavioral and molecular changes, supporting pathway involvement. In trigeminal tissues, Liquiritin decreased TLR4 and MyD88 expression and suppressed microglial M1-like markers together with IL-1β, TNF-α, TRPV1 and CGRP; in LPS-stimulated BV2 microglia, Liquiritin (100μM) and LRU (10μg/mL) reduced the production of iNOS, Iba1, CD32 and IL-1β/TNF-α, and serum alanine aminotransferase and aspartate aminotransferase activities were not significantly altered at 200mg/kg, while serum creatinine increased. Liquiritin alleviated IONI-induced TN-like neuropathic pain in mice, concomitant with reduced microglial M1-like activation, decreased IL-1β/TNF-α and TRPV1/CGRP levels, and down-regulation of TLR4/MyD88 signaling in trigeminal tissues. These in vivo, in vitro and in silico data support Liquiritin as a promising neuroinflammation-modulating candidate targeting TLR4/MyD88 in trigeminal neuropathic pain, warranting further pharmacokinetic, long-term safety and translational studies.

BackgroundAlthough Upadacitinib has proven success in inflammatory bowel diseases (IBD), there is less data on its efficacy and safety in Asian patients with refractory IBD.MethodsThis multicenter study evaluated the real-world effectiveness and safety of UPA in patients with refractory IBD. This multicenter retrospective cohort analysis included adult refractory IBD patients who received UPA therapy at three tertiary hospitals from January 2023 to March 2025. Clinical, endoscopic, and laboratory outcomes were effectiveness goals. Safety measures included AEs and and rates of discontinuation.ResultsA total of 80 eligible patients were enrolled, including 52 with CD and 28 with UC. During the induction period, for CD: steroid-free clinical remission: 59.6%; clinical response: 61.5%; endoscopic remission: 30.8%; endoscopic response: 57.7%. For UC, steroid-free clinical remission: 67.9%; clinical response: 71.4%; endoscopic remission: 46.4%; endoscopic response: 60.7%. In the maintenance phase (12 months), CD had 78.8% steroid-free clinical remission and 75.0% endoscopic remission. UC had 85.7% steroid-free clinical remission and 78.6% endoscopic remission. Inflammatory indicators and nutritional parameters improved significantly. The incidence of adverse events in CD and UC was 23.1% and 14.3%, respectively, and the discontinuation rates during the 12-month maintenance treatment period were 7.1% and 21.5%, respectively. The most common adverse reaction is acne (8.75%).ConclusionUPA demonstrated robust real-world effectiveness and an acceptable safety profile in Asian patients with refractory IBD.

Abstract Background Hepatocellular carcinoma (HCC) is characterized by pronounced hypoxia and suboptimal response to sorafenib, but how hypoxia in defined malignant cell subsets drives metabolic adaptation and drug tolerance remains unclear. This study aimed to identify hypoxia-dominant tumor populations, derive a hypoxia-related risk signature, and determine whether a HIF1A-HK2 axis mediates glycolytic reprogramming and sorafenib resistance through tumor cell-intrinsic mechanisms. Methods Single-cell RNA sequencing from ten HCC samples was integrated with bulk transcriptomic cohorts to define a hypoxia-enriched epithelial subcluster, construct a seven-gene hypoxia-related risk model, and screen for a stable metabolic node, followed by hypoxia modelling (1% O₂/CoCl₂), HK2 knockdown/overexpression, co-immunoprecipitation, promoter-focused structural modelling, and functional assays of glycolysis, sorafenib sensitivity and endothelial tube formation. Results The analysis identified a hypoxia-high malignant subcluster whose gene set generated a seven-gene signature that stratified survival and reflected activation of hypoxia and glycolysis pathways; HK2 was consistently retained across subcluster screening, risk modelling and pathway annotation, and in vitro HIF1A stabilization increased HK2 expression, glycolytic flux and sorafenib survival, while HK2 knockdown reduced glycolysis and partially restored sorafenib sensitivity and HK2 overexpression in normoxia reproduced a hypoxia-like metabolic and drug-response profile without major effects on endothelial tube formation. Conclusions These findings indicate that a hypoxia-associated HIF1A-HK2 axis acts as a tumor cell-intrinsic driver of glycolytic support for sorafenib tolerance and suggest that hypoxia- and glycolysis-related features may refine risk stratification and inform metabolic co-targeting strategies in HCC.

Bone regeneration of oral and maxillofacial defects in situ remains a significant clinical challenge. This study investigates the synergistic effects of phosphorus (P) and zinc (Zn) co-doping in wollastonite bioceramics to enhance osteogenic activity and antibacterial potential for bone repair. Cylindrical bioceramic granules with varying P/Zn ratios (CSi-P8: CSi-Zn6 = 3:0, 2:1, 1:2 and 0:3) were fabricated via co-precipitation and evaluated for in-vitro bioactivity, cell proliferation, osteogenic differentiation, and antibacterial performance. The experimental results demonstrated that the co-doped groups (8P/6Zn-2:1 and 8P/6Zn-1:2) exhibited superior hydroxyapatite formation in simulated body fluid (SBF), sustained Ca²⁺/Si⁴⁺ ion release, and synergistic osteogenic effects, as evidenced by elevated RUNX2/β-catenin expression and BMSC proliferation. Zn doping conferred dose-dependent antibacterial activity against Staphylococcus aureus (93% inhibition for 8P/6Zn-0:3). In vivo cranial defect experiments in rabbits revealed that the 8P/6Zn-2:1 granules significantly promoted new bone trabeculae formation and defect closure within 16 weeks, outperforming single-doped and control groups. Histological and micro-CT analyses confirmed enhanced bone volume fraction (BV/TV%) and trabecular density (Tb.N) in the co-doped groups. These findings highlight the dual functionality of P/Zn co-doped wollastonite (e.g. 8P/6Zn-2:1), where P enhances osteogenesis via increasing the expression of RUNX2/β-catenin and apatite deposition, while Zn provides antibacterial protection, offering more promising implants for infected oral bone defects.