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关键词： Airway inflammation   Asthma   Santonin   Ovalbumin   Dexamethasone   IL-4/IL-13 signalling  

摘要： Airway inflammation is a hallmark of asthma and is characterised by swelling of the lung airways and excessive mucus production. Enhanced oxidative stress, immune cell activation, increased specific IgE antibodies and Th2-mediated inflammation are the underlying causes of asthma. Santonin (SANT), a sesquiterpene lactone, exhibits therapeutic potential for the treatment of inflammatory diseases. It is a compound of interest due to its potential therapeutic benefits against allergic airway inflammation, a condition for which traditional therapies have limited efficacy and serious side effects. The study aimed to assess the impact of Santonin on ovalbumin (OVA)-induced allergic airway inflammation in a mouse model, focusing on allergy symptoms, immune response, oxidative stress, and underlying molecular pathways. Male mice were sensitised with OVA and alum, and then nebulisation was used to induce airway inflammation. The mice were administered SANT at doses of 10, 20, and 40 mg/kg to assess its therapeutic effect on airway inflammation. Allergic symptoms like rhinorrhoea and serum IgE levels of inflammatory cells in blood and BLAF are measured. Furthermore, oxidative stress and gene expression were targeted using RT-qPCR. Histopathological changes and DNA damage were performed using a comet assay. SANT alleviated allergic symptoms such as rhinorrhoea. It enhanced the levels of antioxidant enzymes (GST, GSH, CAT) and decreased oxidative stress markers (MDA and NO), improved disease-induced DNA damage, and decreased IgE levels in BALF. Lung histopathology showed reduced collagen deposition and improved inflammatory scores. The qRT-PCR results demonstrated that Santonin inhibits the IL-4/IL-13 pathway in OVA-induced airway inflammation. The findings suggest that by lowering IgE levels, reducing oxidative stress, and altering immunological pathways, specifically the IL-4/IL-13 pathway-Santonin can be used as a therapeutic drug to treat allergic airway inflammation.

关键词： Bile acid   Fibroblast growth factor 15   Farnesoid X receptor   Metabolic dysfunction–associated steatohepatitis   Peroxisome proliferator–activated receptor   α   ALP   alkaline phosphatase   ALT   alanine aminotransferase   AST   aspartate aminotransferase   BA   bile acid   Bsep   bile salt export pump   CD   control chow diet   CK   cytokeratin   Cyp7a1   cholesterol 7   α   hydroxylase   FA   fatty acid   FGF   fibroblast growth factor   Gsta1   glutathione S-transferase   α   1   GTT   glucose tolerance test   HFD   high-fat diet   Ho   heme oxygenase   HSC   hepatic stellate cell   IL   interleukin   Lcn   lipocalin   LW   liver weight   MASH   metabolic dysfunction–associated steatohepatitis   MASLD   metabolic dysfunction–associated steatotic liver disease   Mt1   metallothionein 1A   Nqo   NAD(P)H:quinone oxidoreductase   Ost   organic solute transporter   PPAR   peroxisome proliferator–activated receptor   TBA   total bile acids   TBARS   thiobarbituric acid reactive substances   TC   total cholesterol   Tg   transgenic   TG   triglyceride   TNF   tumor necrosis factor   WAT   white adipose tissue   WT   wild-type   WY   WY-14643  

摘要： Metabolic dysfunction–associated steatohepatitis (MASH) is increasing worldwide along with the obesity epidemic. However, there are limited treatments. Fibroblast growth factor (FGF)19 and its mouse ortholog FGF15, act as hormones to repress bile acid synthesis and increase energy expenditure. Activation of peroxisome proliferator–activated receptor (PPAR) α increases fatty acid oxidation in hepatocytes. However, a combined role of FGF19/15 with activation of PPAR α in the treatment of MASH is unknown. Wild-type and Fgf15 transgenic ( Fgf15 Tg) mice were fed a high-fat diet (HFD) to induce MASH, then a PPAR α agonist was subsequently administered to a subcohort of HFD groups to study the synergistic effect of Fgf15 overexpression and PPAR α activation. HFD feeding diminished glucose tolerance and increased liver fat accumulation in both wild-type and Fgf15 Tg mice. However, Fgf15 Tg mice demonstrated resistance to weight gain, displayed improved glucose tolerance, and attenuated liver steatosis. Fgf15 overexpression alone reduced liver injury and the expression of genes involved in inflammation and fibrosis. The activation of PPAR α , both individually and in conjunction with FGF15 overexpression, led to weight loss and reduced liver steatosis. However, the combined approach with PPAR α activation and FGF15 overexpression resulted in an increase in liver injury and upregulation of gene expression associated with inflammation and fibrosis. In summary, Overexpression of FGF15 alone, with or without a combined activation of PPAR α , effectively reduces hepatic steatosis. However, the combined treatment leads to increased oxidative stress and ductular reactions, indicating a complex interplay in the pathogenesis of MASH. Significance Statement Fibroblast growth factor (FGF)15 overexpression and peroxisome proliferator–activated receptor (PPAR) α activation ameliorates high-fat diet–induced hepatic steatosis. Combined PPAR α activation and FGF15 overexpression exacerbate

关键词： 白细胞介素12   前体蛋白mRNA   脂质纳米颗粒   免疫治疗   抗肿瘤作用  

摘要： 针对白细胞介素12(IL-12)抗肿瘤效果不佳、免疫毒性严重的问题,采用IL-12β1受体作为“保护域”经肿瘤微环境(TME)特异性水解的肽段连接到IL-12前体结构中,设计了一种可以在TME中特异性切割释放的IL-12前体蛋白mRNA(Pro-IL-12 mRNA),通过物理包载的方式与可离子化脂质构建成脂质纳米粒(Pro-IL-12 LNPs)。采用微流控工艺制备的纳米粒呈均一的球形结构,粒径为(93.07±1.02)nm,PDI为0.18±0.05,Zeta电位为(3.13±0.70)mV,且稳定性良好。体内药效研究显示,在MC38荷瘤小鼠模型上,Pro-IL-12 LNPs单药的抑瘤率为64.0%,与抗PD-1单抗联合治疗后,抑瘤率升至85.9%。抑瘤效果和生存期均显著提升,且各组小鼠的体重无显著差异,耐受性较好。进一步开展安全性研究,对健康小鼠给药后,检测血清中炎症细胞因子和肝毒性指标,结合组织病理切片分析,结果显示Pro-IL-12 LNPs降低了IL-12诱导的免疫毒性,无明显肝损伤,提示安全性良好。综上,本研究构建的TME响应释放的前体蛋白mRNA可为开发高效低毒的IL-12递送新策略提供理论依据。

关键词： Brain   IL-17   Precuneus   Psoriasis  

关键词： Trehalose   Icariin   Microparticle   Copd   Inhalation   M2 macrophage  

摘要： Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disorder with limited therapeutic strategies capable of addressing its underlying immunopathology. Icariin (ICA), a flavonoid with documented anti-inflammatory and antioxidant activity, exhibits mechanistic relevance to COPD pathology but is limited in clinical utility due to poor aqueous solubility and low systemic bioavailability. This study reports the development of a dry powder inhalation system comprising DSPE-PEG2000/DPPC micelle-in-microparticles stabilized with trehalose for targeted pulmonary delivery of ICA. Spray-drying produced respirable microparticles with a mass median aerodynamic diameter of 2.36 +/- 0.3 mu m, an emitted dose of 93 %, and a fine particle fraction of 44 %, consistent with efficient deposition in the lower respiratory tract. Physicochemical characterization confirmed ICA encapsulation in an amorphous state, with preservation of micellar structure upon rehydration, supporting formulation stability. In vitro studies demonstrated enhanced uptake of ICA-loaded micelles by RAW 264.7 macrophages and a 73 % reduction in IL-4-induced CD206 expression, indicative of inhibition of M2 macrophage polarization. These findings support the potential applicability of this inhalable system for modulating macrophage-mediated inflammation in COPD. In vivo studies are required to evaluate pharmacokinetic behaviour, pulmonary distribution, and therapeutic efficacy in validated models of chronic obstructive pulmonary disease.

关键词： mouse   liver transplantation   surgical model   ischemia-reperfusion injury   liver regeneration   allograft rejection   transplant tolerance   AR   Amphiregulin   CEACAM1   Carcinoembryonic antigen-related cell adhesion molecule 1   DC   Dendritic cells   IFN   Interferon   IL   Interluekin   IRI   Ischemia-reperfusion injury   MHC   Major histocompatibility complex   RAI   Rejection activity index   RSLT   Reduced-size liver transplantation   TIM   T cell immunoglobulin mucin   Treg   Regulatory T cell  

摘要： The surgically challenging mouse orthotopic liver transplant model has provided numerous insights into liver immunobiology, cellular and molecular regulation of liver transplant ischemia-reperfusion injury, liver regeneration, the influence of major histocompatibility complex antigens on transplant outcome, spontaneous transplant tolerance, and regulation of allograft immunity. Nonarterialized and arterialized models have been established. Reduced-size liver transplant models have also been developed and used to determine critical mass and factors that determine tissue injury and regeneration. Since its first description 3 decades ago, the surgical demands of the model have limited its application to a relatively small number of centers focused on basic liver transplant research. Dissemination of and commitment to acquisition of the required technical skills will facilitate the application of cutting-edge experimental approaches to which the mouse model is well-suited and allow important key basic and translational questions in transplant immunology to be addressed.

摘要： The TBK1 image for the PANC-1 cell line. The author regrets that in Fig. 3D, the DAPI images for the GP group, after contrast adjustment, were mistakenly uploaded as those of the control group. The DAPI images for the GP group. The TBK1 image for ...

关键词： HLA-specific antibody   Machine learning   Risk factors  

摘要： Introduction The development of de novo donor-specific antibodies (DSAs) against HLA is associated with premature graft failure in kidney transplantation. However, reported rates and contributing factors vary widely. We aimed to identify pre-transplant factors influencing de novo HLA-specific antibody development using machine learning (ML). Methods Data from 460 kidney transplant recipients at a single centre (2009–2014) was analysed. Pre-transplant clinical and immunological variables were collected, and post-transplant sera were screened for HLA antibodies. Positive samples underwent Single Antigen Bead (SAB) testing. ML models (CART, RF, XGBoost, CatBoost) were trained on a set of pre-transplant data to predict dn DSA formation, with and without SMOTE oversampling. Model performance was evaluated using F1 scores, and feature importance was assessed using SHAP. Results In the full cohort, 115 patients (25 %) developed dn HLA-specific antibodies, including 36 (31 %) with dn DSAs. XGBoost achieved the best performance (F1 0.54–0.59 without SMOTE; 0.72–0.79 with SMOTE). Univariate analysis identified significant predictors: pre-transplant HLA-specific antibodies ( p  < 0.001), prior transplantation (p < 0.001), cold ischaemia time (CIT) ( p  = 0.02), female gender ( p  = 0.01), younger age ( p  = 0.03), HLA mismatch (p = 0.01), aminoacid mismatch (p = 0.01), and depleting induction (p = 0.01). SHAP plots confirmed the importance of pre-existing antibodies and re-transplantation. Extremes of CIT and age ≥ 65 was associated were associated with reduced predicted risk. Model performance in the unsensitised subgroup was limited (F1 < 0.2). Conclusion ML models can be used to identify pre-transplant risk factors for de novo HLA-specific antibody development. Monitoring and risk-stratification based on these factors may inform immunological strategies and recipient selection to improve long-term allograft outcomes. Translational statement This study identified pre-transpl

摘要： BACKGROUND:While cervical cancer (CC) is increasingly detected at earlier stages due to improved screening, clinical dilemmas persist in stratifying precancerous lesions and managing advanced disease. Major histocompatibility complex-related genes (MHCRGs), which regulate antigen presentation and immune surveillance, may serve as promising biomarkers for prognosis and therapeutic guidance in CC. METHODS:We identified MHCRGs via literature review and constructed a prognostic signature using LASSO and multivariate Cox regression based on TCGA-CESC data. Bioinformatic analyses assessed associations between the MHCRG signature, immune cell infiltration, immunotherapy response, and drug sensitivity. Validation was conducted using external GEO datasets (GSE29570, GSE63514), and further confirmed through qRT-PCR and Western blot in clinical CC samples. Functional assays, including gene knockdown in CC cell lines, were performed to explore the biological roles of key MHCRGs in tumor progression. RESULTS:A five-gene signature (CANX, HLA-DMB, HLA-DPB1, PSMB6, PSMB7) was identified as predictive of prognosis, immune infiltration, and therapeutic responsiveness. CANX was significantly upregulated, while HLA-DMB and HLA-DPB1 were downregulated in high-risk groups across all datasets and clinical tissues. qRT-PCR and WB results aligned with bioinformatic predictions. Functional experiments demonstrated that silencing CANX suppressed CC cell proliferation and invasion. These findings support the oncogenic role of CANX and the immune-regulatory potential of the other MHCRGs. The MHCscore remained an independent prognostic factor in multivariate analysis. CONCLUSIONS:We propose a robust MHCRG-based gene signature, validated through both bioinformatic analyses and in vitro functional experiments. These findings offer translational potential for improving risk stratification and guiding immunotherapy in CC patients.