AIM:To investigate the effect of fibroblast growth factor 21(FGF21)on high glucose-induced oxidative stress in retinal pigment epithelial(RPE)cells and to clarify the underlying molecular mechanisms.METHODS:Single-cell sequencing data from the GEO database were analyzed to determine the expression profile of the FGF21 receptor FGFR1 in RPE cells. Human ARPE-19 cells were cultured and randomly assigned to control, high glucose(30 mmol/L), and high glucose+FGF21 analog treatment groups, with additional siFGFR1 and PI3K inhibitor groups. Cell viability in different treatment groups was assessed using CCK-8 assay, intracellular reactive oxygen species(ROS)levels were quantified using DCFH-DA fluorescent probing combined with immunofluorescence staining and flow cytometry. Transcriptome sequencing was performed on cells from the high glucose group and high glucose+FGF21 group to analyze the enrichment level of the PI3K/Akt signaling pathway. Western blotting was performed to detect phosphorylation levels of PI3K/Akt pathway components.RESULTS:Single-cell sequencing revealed specific expression of FGFR1 in RPE cells of retinal tissues from diabetic model mice. Under In vitro experiments, high glucose(30 mmol/L)exposure reduced ARPE-19 cell viability by 49.7% and increased ROS levels by approximately 2-fold. Whereas treatment with the FGF21 analog(60 ng/mL)restored cell viability and attenuated high glucose-induced ROS accumulation. Mechanistic studies demonstrated that FGFR1 knockdown inhibited the antioxidative stress of FGF21. Further validation of the molecular mechanism revealed that high glucose significantly suppressed the PI3K/Akt pathway activation(the levels of p-Akt and p-PI3K were decreased by 33.9% and 36.6%, respectively), while FGF21 effectively reversed this inhibitory effect and restored the expression of p-Akt and p-PI3K. Treatment with the PI3K inhibitor LY294002 inhibited the cytoprotective effect of FGF21 and significantly increased the ROS-positive cells, these findings confirm that PI3K/Akt signaling is indispensable downstream mechanism for FGF21 to exert its effects.CONCLUSION:FGF21 alleviates high glucose-induced oxidative stress and cellular injury in RPE cells by activating the PI3K/Akt signaling pathway through its receptor FGFR1.

Liver cancer, one of the most common primary malignancies in humans, is a malignant tumor characterized by multifactorial induction, polygenic involvement, and intricate molecular mechanisms. This disease is characterized by its treatment challenges and poor prognosis, which are closely related to its unique tumor microenvironment composition. The tumor microenvironment of liver cancer is a dynamic ecosystem composed of heterogeneous cellular populations, soluble cytokines, and remodeled extracellular matrix. In recent years, significant progress has been made in the study of the tumor microenvironment of liver cancer, revealed an important role in the occurrence, development, and treatment of liver cancer. The key regulatory elements of the tumor microenvironment in liver cancer were systematically summarized, such as activation of hepatic stellate cells, dysfunction of immune cells, abnormalities of platelet, and remodeling of the extracellular matrix, which provided theoretical foundations for prevention and treatment strategies against liver cancer.

ObjectiveTo develop an assessment tool for apraxia of speech (AOS) of Chinese Putonghua speakers and test its reliability and validity. MethodsThe Chinese Apraxia of Speech Assessment and Diagnostic Tool (CAADT) was developed based on the Apraxia of Speech Rating Scale 3.5, combined with the linguistic characteristics of Chinese and clinical experience. The tool consistsed of eleven items across three sections: articulation, prosody and alternating motion rates. Six experts evaluated the content validity. From November, 2024 to May, 2025, 51 patients with post-stroke AOS (experimental group) and ten patients with post-stroke aphasia without AOS (control group) were recruited from Anhui Wannan Rehabilitation Hospital (the Fifth People's Hospital of Wuhu), and tested with CAADT. Reliability was assessed using Cronbach's α coefficient, Kendall's coefficient of concordance W and Pearson correlation coefficient. Validity was evaluated using the content validity index (CVI) and Spearman correlation coefficient. Discriminative effect was analyzed using the receiver operating characteristic (ROC) curve. ResultsThe Cronbach's α coefficients for the articulation and prosody sections and the total scale were all > 0.9, while it was 0.454 for the alternating motion rates. Inter-rater reliability was good (W ≥ 0.598, P < 0.001). Test-retest reliability showed high positive correlations for the three sections and the total score between the two assessments (r ≥ 0.84, P < 0.001). The scale-level CVI was 0.95, and the item-level CVI ≥ 0.83. The Spearman correlation coefficients among the sections ranged from 0.30 to 0.70. ROC analysis revealed an area under the curve of 0.953, with a cut-off value of 11, yielding a sensitivity of 0.92 and a specificity of 0.90. ConclusionCAADT demonstrates good reliability, validity and discriminative effect, which can be used for clinical assessment and auxiliary diagnosis of Chinese Putonghua speaking patients with post-stroke AOS.

The primary intravenous anesthetics employed in clinical practice encompass dexmedetomidine (Dex), propofol, ketamine, etomidate, midazolam, and remimazolam. Apart from their established sedative, analgesic, and anxiolytic properties, an increasing body of research has uncovered neuroprotective effects of intravenous anesthetics in various animal and cellular models, as well as in clinical studies. However, there also exists conflicting evidence pointing to the potential neurotoxic effects of these intravenous anesthetics. The role of intravenous anesthetics for neuro on both sides of protection or toxicity has been rarely summarized. Considering the mentioned above, this work aims to offer a comprehensive understanding of the underlying mechanisms involved both in the central nerve system (CNS) and the peripheral nerve system (PNS) and provide valuable insights into the potential safety and risk associated with the clinical use of intravenous anesthetics.
Animals ; Humans ; Anesthetics, Intravenous/adverse effects* ; Neuroprotective Agents/pharmacology* ; Propofol ; Neurotoxicity Syndromes/prevention & control* ; Central Nervous System/drug effects* ; Dexmedetomidine

This study employed Mendelian randomization (MR) analysis to confirm the association between breast cancer and the risk of anxiety and depression, and to explore the molecular mechanisms by which lipid nanoparticles of ketamine (LNP@Ket) modulate these behaviors in a mouse model of breast cancer. Through single-cell transcriptomic analysis, the study aimed to clarify nuclear factor erythroid 2-related factor 2 (Nrf2)'s role in the development of anxiety and depression in these mice. Analysis of patient data from genome-wide association study (GWAS) databases supported the link between breast cancer, anxiety, and depression. In vivo experiments demonstrated that treating breast cancer mice with LNP@Ket significantly reduced anxiety and depression behaviors. The synthesis of LNP@Ket and its subsequent analysis highlighted its inhibitory effects on these behaviors. Single-cell transcriptomic sequencing identified key cells and genes affected by LNP@Ket treatment, particularly emphasizing Nrf2. Upregulation of Nrf2 in astrocytes increased the expression of antioxidant enzymes and reduced pro-inflammatory cytokines, alleviating anxiety and depression symptoms by inhibiting neuroinflammation and neurodegeneration. This comprehensive study highlights the pivotal role of Nrf2 in the therapeutic efficacy of LNP@Ket for treating anxiety and depression in breast cancer mice.

Objective To investigate the role of low-density lipoprotein receptor-related protein 1(LRP1),the key gene of epithelial-mesenchymal transition,in silicosis fibrosis progression,and to preliminarily explore its regulatory mechanisms.Methods Gene set variation analysis(GSVA)was employed on GSE70866 and GSE49072 from Gene Expression Omnibus(GEO)database to assess the activity of the epithelial-mesenchymal transition gene set.LRP1 was screened via Venn diagram intersection.A multivariable Cox proportional hazards regression model(adjusted for age and sex)was constructed to validate the independent prognostic value of LRP1.Patients were grouped based on LRP1 expression,and its function mechanisms in pulmonary were explored through differential analysis,enrichment analysis,correlation analysis,and immune infiltration analysis.The silicosis model was established by a single intratracheal injection of 10 mg SiO2 suspension in C57BL/6J mice,with 100 μL of 0.9%saline administered as the control group.Pathological changes were assessed by hematoxylin-eosin staining in lung tissues.EMT model was induced in A549 cells by TGF-β1 at varying time points.LRP1 mRNA levels were measured by qPCR in lung tissues and A549 cells of TGF-β1-induced EMT model.Protein expression of LRP1,E-Cadherin,α-SMA,collagen I,p-PI3K,PI3K,p-mTOR and mTOR were detected by Western blot in lung tissues and A549 cells.Results The epithelial-mesenchymal transition gene set score was significantly higher in patients than in healthy control,with high-score patients showing reduced survival time(P<0.01).Bioinformatics analysis revealed that LRP1 primarily acts through the mTOR signaling pathway.Immune infiltration analysis demonstrated enhanced activities of activated dendritic cells,effector memory CD4+T cells,and Th17/Th2 cells in LRP1 high-expression patients,suggesting its potential regulatory role in adaptive immune responses.Histopathological observation confirmed obvious silica nodule formation in lung tissues of mouse silicosis model.RT-qPCR and Western blot analyses showed that the expression levels of LRP1 mRNA and protein were significantly downregulated in both silicosis mouse lungs and A549 cells(P<0.05).E-cadherin protein expression was downregulated,while α-SMA and collagen I expression were upregulated(P<0.05).Furthermore,the phosphorylation ratios of PI3K(p-PI3K/PI3K)and mTOR(p-mTOR/mTOR)were significantly increased(P<0.05).Conclusion LRP1 downregulation may activate the PI3K/mTOR signaling pathway,promoting the EMT process and fibrosis in silicosis.Targeting LRP1 regulation might become a new therapeutic strategy for silicosis.

Objective:To analyze the epidemiological information of oral leukoplakia and explore the relationship between clinical characteristics and different degrees of epithelial dysplasia.Methods:A total of 430 patients with oral leukoplakia confirmed by pathology in the Department of Oral Medicine, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine from February 2013 to May 2021 were enrolled. Epidemiological information was recorded, and univariate and multivariate Logistic regression analysis were performed on age, gender, smoking, drinking, lesion size, lesion site and lesion type to evaluate the correlation between the risk factors and the degree of epithelial dysplasia in oral leukoplakia.Results:A total of 430 valid samples were included in this study, among which 23 patients were diagnosed with oral leukoplakia with concurrent cancer. The age of all patients was (52.9±12.9) years (22-85 years); 213 were male and 217 were female. One hundred and seventy-six cases (40.9%) had lesions on the lateral and ventral tongue, and 254 cases (59.1%) had lesions in other locations. Three hundred and two cases (70.2%) had homogeneous lesions, and 128 cases (29.8%) had heterogeneous lesions. The degrees of epithelial dysplasia included none [11.9% (51/430)], mild [51.9% (223/430)], moderate [24.4% (105/430)], severe [6.5% (28/430)], and concurrent cancer [5.3% (23/430)]. Smoking, drinking, and gender were correlated with the degree of epithelial dysplasia in some binary classification systems, while tongue (border and ventral) and non-homogeneous damage were significantly correlated with higher degrees of epithelial dysplasia in all binary classification systems ( P<0.05). Conclusions:Lesions on the lateral or ventral tongue and heterogeneous lesions are significantly associated with higher degrees of dysplasia, suggesting that clinicians should pay more attention to these types of oral leukoplakia during the follow-up monitoring process.

Objective:To investigate the mechanisms of baicalin in treating septic acute liver injury through a combination of network pharmacology and animal experiments.Methods:Thirty male C57BL/6 mice (6 weeks old) were divided into five groups ( n=6): control group (normal saline), model group [lipopolysaccharide (LPS) 10 mg/kg, intraperitoneal injection], low-dose baicalin group (10 mg/kg), high-dose baicalin group (20 mg/kg), and baicalin-only group (20 mg/kg, without LPS). Baicalin was administered orally for 14 consecutive days prior to modeling. Mice were sacrificed 24 h after LPS injection. Alanine transaminase, aspartate transaminase liver tissue histopathology were measured; neutrophil infiltration was visualized using immunofluorescence; mRNA expression levels of interleukin (IL)-1β, IL-17, IL-6, and tumor necrosis factor (TNF)-α were detected by RT-qPCR; and the expression of Toll-like receptor 4 (TLR4) and phosphorylated nuclear factor (NF)-κB proteins were analyzed by Western blotting. Results:In the LPS model group, the ALT, AST, and histopathological injury score were (148.60±22.02) U/L, (81.58±11.59) U/L, and 8.50(7.75, 9.25), respectively. These indicators were significantly reduced in the high-dose baicalin group with (77.90±16.79) U/L, (49.92±14.89) U/L, and 1.00(1.00, 2.25) (all P<0.05). Compared with the LPS group, neutrophil infiltration in the liver of high-dose baicalin group was also significantly reduced [1.18%(0.98%, 1.22%) vs. 6.13%(5.41%, 8.69%), P<0.05]. RT-qPCR results showed that the relative mRNA expression levels of inflammatory cytokines IL-1β [(1.03±0.06) vs. (2.60±0.34)], IL-17 [(1.21±0.12) vs. (2.94 ± 0.39)], IL-6 [(1.37±0.26) vs. (2.73±0.18)], and TNF-α [(1.18±0.10) vs. (3.30±0.92)] were significantly decreased in the high-dose baicalin group compared with the LPS group (all P<0.05). Western blot analysis revealed that the relative protein expression levels of TLR4 [(1.25±0.13) vs. (1.73±0.06)] and phosphorylated NF-κB [(1.25±0.25) vs. (1.79±0.12)] were also significantly lower in the high-dose baicalin group (both P<0.05). Conclusion:Baicalin reduces liver injury in septic mice by downregula-ting the expression of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and IL-17, potentially through the inhibition of the TLR4/NF-κB signaling pathway.

Objective To investigate the effect of active muscle response on mechanical responses and injuries of human neck under high Gx loading.Methods A refined finite element model of the head and neck with active muscle response was established and validated based on the existing post-crash volunteer experiments.The effects of active muscle action on the kinematic and biomechanical responses of the neck were investigated under different G-value loads and at each tilting angle using this model.Results The stress distribution of vertebrae under high Gx load was dispersed from C4-7 to the whole vertebrae,and the active muscle action reduced the stress change,and the effect was significant under 8 G acceleration,which reduced the peak vertebral bone stress by 23.6％and 11.6％,and the peak intervertebral disc stress by 42.3％and 63.4％under 8 G and 10 G conditions,respectively.The maximum stress difference of 34.3 MPa was achieved by the active muscle action at 15° backward tilting.Conclusions The neck showed better stability by the active muscle action under the impact of high Gx loading.At different tilting angles,the active muscle action was more obvious in the backward tilting posture compared with the forward tilting and upright seated postures,and the backward tilting posture was safer to meet the impact when the same active muscle action was applied.The results can provide a reference for the subsequent studies related to the neck injury.