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关键词： 细胞因子   合成免疫学   信号重编程   模块化重组   JAK-STAT信号通路   核酸适配体  

摘要： 细胞因子作为免疫调控的核心介质，在肿瘤、自身免疫病等疾病的治疗中具有重要潜力，但其临床应用长期受限于多效性强、半衰期短、毒性大和靶向性不足等问题。近年来，合成生物学和蛋白质工程的发展为细胞因子的人工改造提供了全新策略。研究者通过配体结构域定向进化与从头设计，成功构建具有延长血浆半衰期和增强靶向特异性的新型细胞因子变体；利用计算生物学指导的重组受体工程，实现下游信号通路的正交性激活与可编程信号输出；更有基于模块化生物元件开发的智能调控系统，能够通过生物传感器介导的反馈回路精确控制细胞因子时空释放。这些创新技术体系正在推动细胞因子治疗从传统的天然分子替代向人工智能驱动的精准调控范式跃迁，为肿瘤微环境重编程、自身免疫稳态重建等重大医学挑战提供变革性解决方案。

关键词： Oral lichen planus   DnaK   BAG3   Outer membrane vesicles   NF-kappa B  

摘要： BackgroundOral lichen planus (OLP) is one of the most frequent oral mucosal diseases associated with chronic inflammation, despite a profoundly limited understanding of its underlying pathogenic *** microbiome analysis was conducted on buccal and lip mucosae, tongue dorsum, and saliva in nonerosive/erosive OLP patients and healthy individuals. Significant variations were observed in the oral microbiome of OLP patients, particularly in the buccal mucosa. Network, random forest, and NetShift analysis collectively indicated that Parvimonas micra (P. micra) emerged as a crucial bacterium in OLP. In vivo analysis further demonstrated that P. micra was abundant at the junction of epithelial and connective tissue layers in OLP lesions. Single-cell RNA sequencing data implicated fibroblasts as potential targets, characterized by upregulation of the NF-kappa B pathway linked to TNF-alpha. Co-culturing of P. micra or its extracellular vesicles (EVs) with fibroblasts showed that P. micra and EVs could activate the NF-kappa B signaling pathway and suppress autophagy in buccal mucosal fibroblasts. Among the pathogenic effectors, DnaK from P. micra EVs was identified to interact with BAG3 in fibroblasts. The interaction of DnaK with BAG3 subsequently activated the NF-kappa B pathway and decreased autophagy flux. Additionally, we identified that IKK-gamma was the key downstream protein that could bind with DnaK-BAG3, thereby inhibiting autophagy and promoting TNF-alpha *** initially revealed that P. micra was a crucial pathogen in the development of OLP and demonstrated that P. micra's EVs induce the inhibition of autophagy and enhanced TNF-alpha secretion in OLP fibroblasts via the DnaK-BAG3-IKK-gamma axis. This study offers novel insights into the pathogenic mechanisms underlying ***5rDVDWHDqRPSqZHTVideo AbstractConclusionsWe initially revealed that P. micra was a crucial pathogen in the development of OLP and demonstrated that P. mic

关键词： 麦芽酚   心肌纤维化   炎症反应   NOD样受体热蛋白结构域相关蛋白3   半胱氨酸天冬氨酸蛋白酶1   白细胞介素1β  

摘要： 目的：探讨麦芽酚对心肌纤维化小鼠的影响及其潜在机制。方法：构建异丙肾上腺素（ISO）诱导的心肌纤维化小鼠模型，并随机分为正常对照组、模型对照组、麦芽酚50 、100 mg/kg组。采用超声心动图评估心功能；苏木精-伊红（HE）染色观察心肌组织病理学改变；马松（Masson）和免疫组织化学染色观察胶原沉积和纤维化；酶联免疫吸附测定法（ELISA）检测血清肌酸激酶同工酶（CK-MB）、N末端脑钠肽前体（NT-pro BNP）、肿瘤坏死因子α（TNF-α）、白细胞介素1β（IL-1β）和IL-6的水平；转录组学分析潜在作用机制，并通过蛋白免疫印迹对相关机制进行验证。结果：与正常对照组比较，模型对照组心脏重量指数（CWI）、心胫比（HW/TL）、平均心肌细胞横截面积、血清CK-MB、NT-pro BNP、TNF-α、IL-1β和IL-6含量显著升高（P＜0.01），左室射血分数（EF）和左室短轴缩短分数（FS）显著降低（P＜0.01），心肌组织中NLRP3、Caspase-1、GSDMD、TNF-α、IL-1β和IL-6的蛋白表达明显升高（P＜0.05或P＜0.01）；与模型对照组比较，麦芽酚50、100 mg/kg组CWI、HW/TL、平均心肌细胞横截面积、血清CK-MB、NT-pro BNP、TNF-α、IL-1β和IL-6含量显著降低（P＜0.01），EF和FS显著升高（P＜0.01），心肌组织中NLRP3、Caspase-1、GSDMD、TNF-α、IL-1β和IL-6的蛋白表达明显降低（P＜0.05或P＜0.01）。结论：麦芽酚通过NLRP3/Caspase-1/IL-1β通路，抑制炎症反应，改善ISO诱导的心肌纤维化。

关键词： Newcastle disease virus   DU145   oncolytic   apoptosis  

摘要： Background/Objectives: Prostate cancer is the second most common type of cancer diagnosed in men. Various treatments for this cancer, such as radiation therapy, surgery, and systemic therapy, can cause side effects in patients;therefore, there is a need to develop new treatment alternatives. One promising approach is virotherapy, which involves using oncolytic viruses (OVs), such as the recombinant Newcastle disease virus (rNDV). Methods: We used the lentogenic rNDV rLS1 strain (the control virus) as our backbone to develop two highly fusogenic rNDVs: rFLCF5nt (the parental virus) and rFLCF5nt-IFN-gamma (rFLCF5nt expressing human interferon-gamma (IFN-gamma)). We evaluated their oncolytic properties in a prostate cancer cell line (DU145). Results: The results showed the expression and stability of the IFN-gamma protein, as confirmed using Western blotting after ten passages in specific pathogen-free chicken embryo eggs using the IFN-gamma-expressing virus. Additionally, we detected a significantly high oncolytic activity in DU145 cells infected with the parental virus or the IFN-gamma-expressing virus using MTS (a cell viability assay) and Annexin V-PE assays compared with the control virus (p < 0.0001 for both). Conclusions: In conclusion, our data show that IFN-gamma-expressing virus can decrease cell viability and induce apoptosis in human prostate cancer in vitro.

关键词： factor Xa   IL-6   proteinase-activated receptor   pulmonary arterial hypertension   pulmonary hypertension  

摘要： Activated factor X (FXa) induces inflammatory response and cell proliferation in various cell types via activation of proteinase-activated receptor-1 (PAR(1)) and/or PAR(2). We thus aimed to investigate the impact of FXa on the development of pulmonary arterial hypertension (PAH) and the mechanisms involved. The effects of edoxaban, a selective FXa inhibitor, on hemodynamic, right ventricular (RV) hypertrophy, and vascular remodeling were evaluated in a monocrotaline (MCT)-exposed pulmonary hypertension (PH) rat model. At 21 days after a single subcutaneous injection of MCT of 60 mg/kg, right ventricular systolic pressure (RVSP) and total pulmonary vascular resistance index (TPRI) were elevated concomitant with the increased plasma FXa and lung interleukin-6 (IL-6) mRNA. Daily administration of edoxaban (10 mg/kg/day, by gavage) starting from the day of MCT injection for 21 days ameliorated RVSP, TPRI, RV hypertrophy, pulmonary vascular remodeling, and macrophage accumulation. Edoxaban reduced nuclear factor-kappa B (NF-kappa B) activity and IL-6 mRNA level in the lungs of MCT-exposed rats. mRNA levels of FXa, PAR(1), and PAR(2) in cultured pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with PAH were higher than those seen in normal PASMCs. FXa stimulation increased cell proliferation and mRNA level of IL-6 in normal PASMCs, both of which were blunted by edoxaban and PAR(1) antagonist. Moreover, FXa stimulation activated extracellularly regulated kinases 1/2 in a PAR(1)-dependent manner. Inhibition of FXa ameliorates NF-kappa B-IL-6-mediated perivascular inflammation, pulmonary vascular remodeling, and the development of PH in MCT-exposed rats, suggesting that FXa may be a potential target for the treatment of PAH.

关键词： HMPV   RSV   macrophages   MDMs   proinflammatory   innate immunity   IFN   cytokines  

摘要： Macrophages are a principal pulmonary source of type I and III interferons (IFNs), initiating and coordinating the early antiviral response to respiratory viral infections. Yet the contribution of macrophage-derived IFNs to host defense during human metapneumovirus (HMPV) infection remains poorly defined. Here, we use human primary monocyte-derived macrophages (MDMs) and THP-1-derived macrophages to analyze the IFN responses induced by HMPV compared to its closely related human pneumovirus, respiratory syncytial virus (RSV). We show that HMPV induced a robust response of type I and type III IFNs and ISGs, whereas RSV elicited only a modest, delayed IFN response despite strong IRF activation;instead, RSV preferentially activates NF-kappa B and exhibits a pronounced proinflammatory cytokine output. Our results highlight the role of macrophages as key modulators of the IFN and proinflammatory responses during HMPV and RSV infection.

关键词： cystatin C   sepsis-associated   acute kidney injury   serum creatinine   tumor necrotizing factor-alpha  

摘要： Sepsis-associated acute kidney injury (S-AKI) represents a significant health problem associated with adverse outcomes. Our study aimed to assess the value of serum cystatin-C (sCysC) and TNF-alpha (rs361525) in combination for diagnosing S-AKI patients and predicting their adverse outcomes. The study included 100 critically ill neonates and 100 controls. Patients were categorized into an S-AKI group and a non-AKI group. TNF-alpha (-238, rs361525) genotyping was performed using RT-PCR, and sCysC was assessed using ELISA. Our study showed a fundamental difference in the genotype frequencies of TNF-alpha (-238, rs361525) and SNP between S-AKI and non-AKI patients. Furthermore, there was a significant relationship between cystatin C and TNF-alpha (-238, rs361525), where cystatin C was higher in patients with AA alleles than in patients with GA and GG alleles. Combining GA + AA genotypes with elevated serum cystatin-C levels can serve as a potential diagnostic and prognostic biomarker for AKI development in this population. The GA/AA genotypes independently predicted S-AKI risk (OR = 6.64, p < 0.001). At the same time, elevated sCysC (>9.4 mg/L) emerged as a sensitive biomarker (AUC = 0.848) and independent predictor of adverse outcomes. Collectively, these findings contribute to the growing field of personalized medicine and represent a strategic advantage, enabling prevention-focused care rather than the treatment of established disease.

关键词： RBD   neurofilament   inflammation   biomarkers   Parkinson's  

摘要： Background: Isolated RBD (iRBD) is a prominent early marker of Parkinson's disease and related disorders. Objectives: Evaluate biomarkers of inflammation and axonal damage people with iRBD for disease *** samples from 27 video-polysomnography confirmed iRBD patients and 25 controls were analyzed for inflammatory biomarkers (CRP, IL-6, TNF-alpha, IFN-gamma, IL-1 beta) and NfL using the Meso Scale Discovery platform. Results: People with iRBD had elevated plasma TNF-alpha and IL-6 (p = 0.013 and p = 0.051). In the iRBD group, plasma NfL was associated with objective motor tests: Timed Up and Go (R-2 = 0.292, p = 0.027) and 10-m walk (R-2 = 0.355, p = 0.034) and plasma TNF-alpha was associated with the Timed Up and Go test (R-2 = 0.277, p = 0.025). Conclusions: We report evidence of peripheral inflammation in early synuclein-related disease processes, and association of plasma NfL and TNF-alpha with motor dysfunction in iRBD patients, suggesting possible association with increased risk of phenoconversion.

关键词： Immunoinformatics   immunoproteomics   MHC   epitope prediction   MHC binding prediction   machine learning   artificial intelligence   cancer immunotherapy   multi-omics integration  

摘要： Immune responses depend on the identification and prediction of peptides that bind to MHC (major histocompatibility complex) class I molecules, especially when it comes to the creation of vaccines, cancer immunotherapy, and autoimmune disorders. The ability to predict and evaluate MHC class immunoproteomics have completely transformed I epitopes in conjunction with immunoinformatics technologies. However, precisely identifying epitopes across various populations and situations is extremely difficult due to the complexity and diversity of MHC class I binding peptides. The most recent developments in immunoinformatics technology that have improved MHC class I epitope prediction are examined in this article. The sensitivity and specificity of epitope prediction have been greatly enhanced by recent developments that have concentrated on bioinformatics algorithms, artificial intelligence, and machine learning models. Potential epitopes are predicted using large-scale peptide-MHC binding data, structural characteristics, and interaction dynamics using tools like NetMHC, IEDB, and MHCflurry. Additionally, the integration of proteomic, transcriptomic, and genomic data has improved prediction accuracy in real-world scenarios by enabling more accurate identification of naturally occurring peptides. Furthermore, newer techniques like deep learning and multi-omics data integration have the potential to overcome peptide binding prediction constraints. Utilizing these technologies is expected to speed up the identification of new epitopes, improve the accuracy of immunotherapy techniques, and enable customized vaccine development. These innovative techniques, their uses, and potential future developments for improving MHC class I epitope prediction in immunoproteomics are highlighted in this study.

关键词： protozoan vaccine   serological markers   Th1 immunity   T-cell activation   protective efficacy  

摘要： Toxoplasma gondii, a parasitic protozoan, causes zoonotic infections with severe health impacts in humans and warm-blooded animals, underscoring the urgent need for effective vaccines to control these infections. In this study, a DNA vaccine encoding TgROP5, TgROP18, TgGRA7, TgGRA15, and TgMIC6 was formulated using the eukaryotic expression vector pVAX I. IL-24 was delivered as a molecular adjuvant using plasmid pVAX-IL-24. BALB/c, C57BL/6, and Kunming mouse strains received the DNA immunization, after which antibody levels, cytokine production, and lymphocyte surface markers were analyzed to assess immune responses. Additionally, survival rates and brain cyst counts were measured 1 to 2 months post-vaccination in experimental models of toxoplasmosis. As a result, compared to controls, the DNA vaccine cocktail significantly increased serum IgG levels, Th1 cytokine production, and proportions of CD4+/CD8+ T cells, leading to extended survival and reduced brain cyst counts post-challenge with T. gondii ME49. Furthermore, the five-gene DNA vaccine cocktail conferred greater protection compared to single-gene immunizations. Co-administration of IL-24 significantly enhanced the immune efficacy of the multi-gene DNA vaccination. Our findings suggest that IL-24 is an effective molecular adjuvant, enhancing the protective immunity of DNA vaccines against T. gondii, supporting its potential role in vaccine strategies targeting other apicomplexan parasites.