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关键词： biomaker   diagnostic   neutrophils   pyroptosis   systemic lupus erythematosus  

摘要： Systemic lupus erythematosus (SLE) is closely associated with neutrophils and pyroptosis, but the pyroptosis related genes (PRGs) with neutrophils in SLE have been less studied. Based on public databases, key genes associated with neutrophil pyroptosis in SLE were identified through immune infiltration analysis and differential analysis. Subsequently, three machine learning algorithms were utilised to derive biomarkers. Additionally, based on the logistic regression model, we constructed a weighted score formula and determined the optimal cut-off value through receiver operating characteristic (ROC) analysis. Gene set enrichment analysis (GSEA) and localization analysis were performed on the biomarkers. The expression of the biomarkers in SLE was verified by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. Through a series of screenings, two biomarkers (PYCARD and IL1B) were obtained. The weighted score based on biomarkers could better distinguish SLE patients from healthy individuals with high diagnostic accuracy. These two biomarkers were found to be involved in the same pathways, including 'toll-like receptor signaling pathway', 'NOD-like receptor signaling pathway' and 'chemokine signaling pathway'. Subcellular localization analyses showed that both biomarkers were mainly localised in the cytoplasm. The results of RT-qPCR and western blotting showed that PYCARD and IL1B were highly expressed in SLE samples, which was consistent with our transcriptome results. In conclusion, we filled a knowledge gap in the area of central granulocyte-associated pyroptosis in SLE. These findings provide a reference for the potential targeting of neutrophil-associated pyroptosis genes in the treatment of patients with SLE.

关键词： 桂枝芍药知母汤   椎间盘   髓核细胞退变   铁死亡   PI3K/AKT/FOXO3a  

摘要： 目的:探讨桂枝芍药知母汤含药血清对大鼠椎间盘髓核细胞退变的影响及其作用机制。方法:20只雄性SD大鼠分别灌胃生理盐水、桂枝芍药知母汤（12.6g/kg）,连续给药7d后收集血清。另取10只雄性大鼠,分离髓核细胞。（1）采用IL-1β处理来构建髓核细胞退变模型,分别加入不同浓度桂枝芍药知母汤含药血清和铁死亡抑制剂去铁胺（DFO）,探究桂枝芍药知母汤含药血清对退变髓核细胞存活率的影响。（2）加入DFO,研究铁死亡在IL-1β诱导髓核细胞退变中的作用。（3）采用IL-1β和20%桂枝芍药知母汤含药血清处理,研究桂枝芍药知母汤含药血清对IL-1β处理髓核细胞PI3K/AKT/FOXO3a信号通路的影响。（4）在IL-1β和20%桂枝芍药知母汤含药血清处理的同时,加入PI3K/AKT激活剂740Y-P进行干预,研究PI3K/AKT/FOXO3a通路在桂枝芍药知母汤含药血清调控髓核细胞铁死亡中的作用。CCK-8法检测细胞存活率,比色法检测细胞Fe2+、MDA、GSH水平;细胞与胶原的黏附实验检测CollagenⅡ与大鼠髓核细胞结合能力;免疫荧光检测p-PI3K、p-AKT、p-FOXO3a蛋白表达;WesternBlot检测p-PI3K、p-AKT、pFOXO3a、SLC7A11、GPX4、MMP-13、CollagenⅡ蛋白表达。结果:与模型组比较,桂枝芍药知母汤含药血清组和DFO组细胞存活率和CollagenⅡ结合能力显著升高,Fe2+、MDA水平和p-PI3K、p-AKT、p-FOXO3a、MMP-13蛋白表达显著降低,SLC7A11、GPX4、CollagenⅡ蛋白表达显著升高,桂枝芍药知母汤含药血清组FOXO3a蛋白表达显著升高（P<0.05）。740Y-P能逆转桂枝芍药知母汤含药血清的作用（P<0.05）。结论:桂枝芍药知母汤含药血清能激活PI3K/AKT/FOXO3a信号通路,抑制IL-1β诱导的大鼠髓核细胞铁死亡,延缓椎间盘髓核细胞的退变。

关键词： CD30   IL-4   Th2 cytokines   brentuximab vedotin   combination therapy   lymphoma   mycosis fungoides   therapeutic resistance   tumor microenvironment  

摘要： BACKGROUND:Mycosis fungoides (MF), the most prevalent cutaneous T cell lymphoma, features clonal CD4⁺ T cell proliferation within a Th2-dominant microenvironment. Interleukin-4 (IL-4) promotes disease progression while Brentuximab Vedotin (BV), an anti-CD30 antibody-drug conjugate, shows efficacy but faces resistance challenges. METHODS:We conducted a narrative literature review (2010-2024) synthesizing evidence on IL-4 signaling and BV's efficacy in MF to develop a theoretical framework for combination therapy. RESULTS:IL-4 may modulate CD30 expression and compromise BV's effectiveness through immunosuppressive microenvironment remodeling. Theoretical mechanisms suggest that IL-4 pathway inhibition could reprogram the microenvironment toward Th1 dominance and restore BV sensitivity. However, no direct experimental evidence validates this combination, and safety concerns including potential disease acceleration require careful evaluation. CONCLUSIONS:The proposed IL-4/BV combination represents a biologically compelling but unproven hypothesis requiring systematic preclinical validation and biomarker-driven clinical trials. This framework could guide future research toward transforming treatment approaches for CD30-positive MF by targeting both malignant cells and their immunologically permissive microenvironment.

关键词： IL-37   IL-38   rheumatoid arthritis   precision medicine   pathogenesis  

摘要： Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disorder that primarily affects the joints, and in severe cases, can damage other major organs, particularly in susceptible individuals. Management of RA primarily relies on disease-modifying anti-rheumatic drugs (DMARDs) often used in conjunction with low-dose steroids;however, outcomes are frequently suboptimal, resulting in significant physical and psychological impact. Biological agents have shown promise for non-responsive RA patients. Nevertheless, the precise underlying mechanism of RA remains unclear. Systemic and local levels of IL-37 and IL-38, anti-inflammatory cytokines, are elevated in RA patients. Intriguingly, these levels decrease in individuals experiencing remission, correlating with the Disease Activity Score (DAS28) and histopathological findings. In animal models, exogenous IL-37 and IL-38 demonstrate protective effects against RA development, while depletion of either cytokine exacerbates the disease in vivo. These findings suggest that the elevated IL-37 and IL-38 represent a compensatory response to the substantial inflammation in affected joints, attempting to mitigate dysregulated host immunity, albeit unsuccessfully. These data offer potential insights for developing novel, more effective RA therapies through precision medicine approaches.

摘要： Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1, 2-3. However, the molecular mechanisms that regulate CAR-NK cell activity remain unclear. Here we identify the transcription factor cyclic AMP response element modulator (CREM) as a crucial regulator of NK cell function. Transcriptomic analysis revealed a significant induction of CREM in CAR-NK cells during the peak of effector function after adoptive transfer in a tumour mouse model, and this peak coincided with signatures of both activation and dysfunction. We demonstrate that both CAR activation and interleukin-15 signalling rapidly induce CREM upregulation in NK cells. Functionally, CREM deletion enhances CAR-NK cell effector function both in vitro and in vivo and increases resistance to tumour-induced immunosuppression after rechallenge. Mechanistically, we establish that induction of CREM is mediated by the PKA-CREB signalling pathway, which can be activated by immunoreceptor tyrosine-based activation motif signalling downstream of CAR activation or by interleukin-15. Finally, our findings reveal that CREM exerts its regulatory functions through epigenetic reprogramming of CAR-NK cells. Our results provide support for CREM as a therapeutic target to enhance the antitumour efficacy of CAR-NK cells.

关键词： HLA   HY antigen   allogeneic hematopoietic stem cell transplantation   graft-versus-host disease   relapse  

摘要： Background Minor histocompatibility antigens play an important role in eliciting an alloimmune response in allogeneic hematopoietic stem cell transplantation (allo-HSCT). HY antigens, minor histocompatibility antigens originating from distinct regions of the Y chromosome, serve as immunogenic targets in female-to-male (FtoM) allo-HSCT, potentially increasing the risk of graft-vs-host disease (GVHD) and the development of allogeneic HY antibodies. Moreover, extensive HLA polymorphism and diverse peptide-binding specificities of HLA molecules can lead to varying alloimmunity and subsequent clinical risks/benefits among patients upon exposure to the HY antigen. Objective In the current study, we investigated the clinical implications of HY molecular disparity using the predicted indirectly recognizable HY epitopes (PIRCHyE) score (PS) in 712 patients undergoing allo-HSCT from an HLA-matched related donor, including 336 gender-mismatched HSCT. Results In FtoM (N=194) allo-HSCT, higher PS-I, which theoretically reflects CD8+ T-cell alloreactivity triggered by HY antigens, was associated with a significantly higher rate of grade III-IV acute GVHD (P=0.005) and an increased relapse rate (P=0.01). In contrast, high PS-II correlated with reduced progression (P=0.04) and a higher risk of chronic GVHD (P=0.01). To further explore the interplay between CD4 T-helper cell responses (PS-II) and CD8 cytotoxic effects (PS-I), we simultaneously assessed the impact of the PS-I and PS-II and found high PS-I/low PS-II was associated with a significantly higher relapse rate (P=0.002) and a lower progression-free survival (PFS) (P=0.02). Conversely, a low PS-I/high PS-II was significantly associated with a higher chronic GVHD rate (P=0.02) and a favorable trend in PFS (P=0.2) in multivariate analysis. No such effects were observed in the male-to-female allo-HSCT group. Conclusion These findings indicate that molecular assessment of HY antigens enables quantitative prediction of HY allorea

关键词： Adoptive cell therapy - ACT   Chimeric antigen receptor - CAR   Cytokine   Tumor microenvironment - TME   Natural killer - NK  

摘要： Background Adoptive transfer of chimeric antigen receptor (CAR)-expressing natural killer (NK) cells has demonstrated success against hematological malignancies. Efficacy against solid tumors has been limited by poor NK cell survival and function in the suppressive tumor microenvironment (TME). To enhance efficacy against solid tumors, stimulatory cytokines have been incorporated into CAR-NK cell therapeutic approaches. However, current cytokine strategies have limitations, including systemic toxicities, exogenous dependencies, and unwanted TME bystander effects. Here, we aimed to overcome these limitations by modifying CAR-NK cells to express a constitutively active interleukin (IL)-7 receptor, termed C7R, capable of providing intrinsic CAR-NK cell activation that does not rely on or produce exogenous signals nor activate bystander *** We examined persistence, antitumor function, and transcriptional profiles of CAR-NK cells coexpressing C7R in a novel tumor immune microenvironment (TiME) co-culture system and against hematologic and solid tumor xenografts in *** Peripheral blood NK cells expressing a CAR directed against the solid tumor antigen GD2 and modified with C7R demonstrated enhanced tumor killing and persistence in vitro compared with CAR-NK cells without cytokine support and similar functions to CAR-NK cells supplemented with recombinant IL-15. ***-NK cells exhibited enhanced survival and proliferation within neuroblastoma TiME xenografts in vivo but produced poor long-term tumor control compared with CAR-NK cells supplemented with IL-15. Similar results were seen using C7R-expressing ***-NK cells against CD19+leukemia xenografts. Gene expression analysis revealed that chronic signaling via C7R induced a transcriptional signature consistent with intratumor stressed NK cells with blunted effector function. We identified gene candidates associated with chronic cytokine-stressed NK cells that could be targeted to reduce CAR-NK cel

关键词： IL-33   ST2   Foxp3   IL-10   CREB   CREM  

摘要： Introduction Regulatory T-cells (Tregs) are characterized by the expression of Foxp3, a master regulator involved in the development and function of Tregs. Foxp3 expression is dependent on activity of the Treg specific demethylated site (TSDR), which contains a CREB binding site. We aimed to find out how Foxp3 specific CREB deletion affects Treg expression and *** Tregs from Foxp3creCREBfl/fl mice and wild type (CREBfl/fl ) mice were analyzed by flow cytometry. Cytokine analysis was performed by flow cytometry, ELISA and RT-qPCR. Gene expression analysis was performed using Affymetrix HTA2 assays, ATAC-sequencing, and Methylation-assays. For functional relevance, a CD4 T cell mediated transfer colitis was *** and discussion Foxp3creCREBfl/fl mice showed increased frequencies of Tregs (CD25+/Foxp3+) in thymus, spleen and peripheral lymph nodes and in nonlymphoid organs including lung and colon, but decreased Foxp3 expression at the single cell level. Despite decreased Foxp3 expression, enhanced expression of the IL- 33 receptor (ST-2), IL-10, IL-13, and CREM was observed. CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in a CD4 T cell mediated transfer colitis in an IL-10 dependent way. Mechanistically CREB fulfils dual roles in Tregs: (1) it promotes Foxp3 expression under Steady state conditions and (2) in cooperation with CREM, CREB restricts chromatin accessibility at the ST2 locus, thereby modulating IL-33 driven immune responses. This dual regulation balances FoxP3-dependent Treg stability with IL-10 mediated suppression of inflammation.

关键词： 槲皮素   活性氧(ROS)/NOD样受体蛋白3(NLRP3)/白细胞介素1β(IL-1β)信号通路   痛风性关节炎   NLRP3炎性小体  

摘要： 目的：探究槲皮素通过抑制活性氧（ROS）/NOD样受体蛋白3（NLRP3）/白细胞介素-1β（IL-1β）信号通路对急性痛风性关节炎（GA）大鼠的影响。方法：将60只雄性SPF级SD大鼠随机分为六组（n=10）：空白组、模型组、秋水仙碱组(0.3 mg·kg-1)和槲皮素低(25 mg·kg-1)、中(50 mg·kg-1)、高剂量组(100 mg·kg-1)。给药组大鼠每天按10 mL·kg-1的剂量经口灌胃给予对应药物，连续7天，空白组与模型组均通过同样途径接受等量生理盐水。第5天给药后1 h造模，采用尿酸钠混悬液对非空白组的各组大鼠实施右后侧踝关节腔注射，以此构建急性痛风性关节炎病理模型。在造模后6、12、24、48 h检测各组大鼠的关节肿胀度和步态评分，苏木素-伊红（HE）染色法观察各组大鼠踝关节组织病理改变，丙二醛（MDA）、黄嘌呤氧化酶（XOD）、总超氧化物歧化酶（T-SOD）试剂盒分别检测血清中MDA、XOD、T-SOD活性，酶联免疫吸附测定法（ELISA）法检测大鼠血清中白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、IL-1β以及踝关节中ROS水平，蛋白免疫印迹法（Western blot）测定踝关节中NLRP3、硫氧还蛋白相互作用蛋白（TXNIP）、凋亡相关斑点样蛋白（ASC）、半胱氨酸蛋白酶-1（Pro-Caspase-1）、活化的半胱氨酸蛋白酶-1（Caspase-1 p20）、IL-1β的蛋白表达水平，采用实时荧光定量逆转录聚合酶链式反应（RT-qPCR）对踝关节组织中TXNIP、NLRP3、ASC、IL-1β、TNF-α的mRNA转录水平进行测定。结果:与空白组大鼠比较，模型组大鼠自主活动度下，精神倦怠，踝关节肿胀度及步态评分升高（P<0.01），滑膜组织明显水肿、炎性细胞浸润程度明显升高（P<0.01），血清中XOD、MDA、TNF-α、IL-1β、IL-6以及关节组织中ROS水平均明显升高（P<0.01），T-SOD活性显著降低（P<0.01），踝关节组织中NLRP3、TXNIP、ASC、Pro-Caspase-1、Caspase-1 p20、IL-1β蛋白表达水平均显著升高（P<0.01），踝关节组织中NLRP3、TXNIP、ASC、IL-1β、TNF-α mRNA表达水平升高（P<0.01）。与模型组大鼠相比，槲皮素中、高剂量组大鼠一般情况改善，步态评分降低（P<0.05，P<0.01），关节肿胀度减轻（P<0.01），滑膜组织水肿情况减轻、炎性细胞浸润程度减轻（P<0.05，P<0.01），血清中XOD、MDA、TNF-α、IL-1β、IL-6以及关节组织中ROS水平降低（P<0.01），T-SOD活性升高（P<0.01），踝关节组织中TXNIP、NLRP3、ASC、Pro-Caspase-1、Caspase-1 p20、IL-1β蛋白表达水平均降低（P<0.05，P<0.01），踝关节组织TXNIP、NLRP3、ASC、IL-1β、TNF-α mRNA表达水平降低（P<0.01），槲皮素低剂量组也能改善部分上述指标的水平/活性（P<0.05，P<0.01）。结论：槲皮素通过阻断ROS/NLRP3/IL-1β信号通路，下调NLRP3炎性小体活化并抑制TNF-α、IL-1β及IL-6等促炎因子生成，从而介导其抗痛风性关节炎作用。

关键词： Immune checkpoint inhibitor   PD-1/PD-L1   Triple-negative breast cancer   NOG mouse   Humanized mouse  

摘要： Although triple-negative breast cancers are still challenging to treat, the development of novel neoadjuvant chemotherapy combined with immune checkpoint antibodies is promising. Our group developed the small compound-based anti-PD-1/PD-L1 inhibitor SCL-1 and reported its potent anti-tumor effects on various syngeneic mouse tumors. We herein investigated the efficacy of SCL-1 using an in vivo humanized NOG mouse system. We established a humanized mouse system using double major histocompatibility complex-knockout NOG mice transplanted with MDA-MB231 breast cancer cells and HLA-matched human PBMCs. Tumor-infiltrating lymphocytes (TILs) were analyzed using flow cytometry and real-time PCR. An RNA-sequencing analysis (RNA-seq) of SCL-1-treated MDA-MB231 tumors was performed to identify differentially expressed genes. Orally administered SCL-1 exerted potent anti-tumor effects with > 50% reduction in tumor sizes, which were dependent on PD-L1 expression and T-cell infiltration. Its effects were significantly stronger than those of nivolumab or atezolizumab. A TIL analysis revealed effector CD8+ T cells expressing cytotoxic markers and exhausted markers as well as increases in NK cells and B cells. RNA-seq showed the up-regulated expression of tumor-specific long non-coding (lnc) RNAs in SCL-1-treated tumor tissues, some of which exhibited high HLA-binding activity. SCL-1 exerted strong tumor growth inhibitory effects that were mediated by effector T-cell induction inside tumors and the up-regulated expression of lncRNAs as neoantigens leading to CTL activation. The up-regulated expression of lncRNAs in SCL-1-treated MDA-MB231 tumors is a novel result and may be one of the mechanisms responsible for the anti-tumor efficacy of SCL-1.