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关键词： arsenic   pyroptosis   IL-17   NLRP3   HSCs  

摘要： Long-term exposure to arsenic, a prevalent environmental contaminant, has been implicated in the pathogenesis of various hepatic conditions. Hepatic stellate cells (HSCs) are central to the development of liver fibrosis. Recently, the involvement of interleukin-17 (IL-17) and the NOD-like receptor protein 3 (NLRP3) inflammasome in hepatic pathologies has attracted significant research interest. Hepatocyte pyroptosis, a form of programmed cell death, is a critical factor in the occurrence of inflammation. The objective of this study was to investigate the specific roles of IL-17 and NLRP3 in the arsenic-induced activation of HSCs through hepatocyte pyroptosis. We pretreated MIHA cells with MCC950 (1 and 5 mu M) and secukinumab (10 and 100 nM) for 4 h, then with NaAsO2 (25 mu M) for 24 h at 37 degrees C under 5% CO2. After incubation, the cell-culture supernatant was collected and mixed with serum-free high-glucose DMEM medium in a 1:1 ratio to prepare the conditioned medium, which was subsequently used for the culture of LX-2 cells. The results showed that exposure to NaAsO2 induced hepatocellular pyroptosis, which led to the release of the inflammatory cytokines IL-18 and IL-1 beta and subsequent activation of HSCs. Treatment with the inhibitors MCC950 and secukinumab significantly reduced the secretion of Extracellular matrix (ECM) components and attenuated HSC activation. These results demonstrate that blocking the IL-17 and NLRP3 signaling pathways significantly reduces HSC activation and attenuates hepatic fibrogenesis. These results provide novel molecular targets for the prevention and treatment of arsenic-related liver fibrosis.

摘要： BACKGROUND:Pemphigus is a life-threatening autoimmune disease mediated by anti-desmoglein(Dsg) autoantibodies. Ectopic lymphoid-like structures (ELSs) are frequently found in chronic skin lesions and are thought to contribute to local autoantibody production. However, the mechanisms driving ELS formation at lesion sites remain unclear. OBJECTIVES:To investigate the role of myeloid cells in the formation of ELSs in pemphigus lesions and to identify potential therapeutic targets by better understanding the underlying mechanisms that contribute to this process. METHODS:We used single-cell RNA sequencing to identify the myeloid subpopulation in pemphigus lesions and study their functions. Immunohistochemistry(IHC), immunofluorescence, and flow cytometry were used to validate the presence of interleukin (IL)-1β-producing myeloid cells. Culture, bulk RNA sequencing and trans-well chemotaxis experiments were conducted to assess the effects of IL-34 and tumor Necrosis Factor (TNF)-α on monocytes. Additionally, the high expression of IL-34 in pemphigus keratinocytes was validated by IHC. RESULTS:We first confirmed the abundant presence of myeloid cells within ELSs in pemphigus skin lesions, including PV and PF. Single-cell RNA sequencing revealed that IL1B_Macro is the dominant myeloid subpopulation in pemphigus lesions, originating from classical monocytes. These cells have a strong inflammatory and chemotactic transcriptomic profile, expressing high levels of IL1B, IL6, and chemokines such as CCL20, CCL3, CCL5, and CXCL5, promoting leukocyte infiltration. Ex-vivo experiments showed that IL1B_Macro differentiation is enhanced by the synergistic action of IL-34 and TNF-α, and this can be attenuated by a CSF-1R inhibitor. IL-34 alone also promotes IL1B and CCL20 expression, and keratinocytes were found to be the major source of elevated IL-34 in pemphigus lesions. Bulk RNA sequencing data indicated that high IL-34 expression in pemphigus keratinocytes correlates with increase

摘要： In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery;deep responses were enriched at higher PRAME expression;and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203

关键词： Gastric injury   Indomethacin   Neutrophil extracellular traps (NETs)   Gastric epithelial cells (GECs)   IL-17  

摘要： The homeostasis of gastric mucosa is extremely delicate. Neutrophils, the most abundant immune cells in human circulation, are regarded crutial in the regulation of gastric mucosal immune response. Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury is the second major reason for gastric ulcers. The relations between neutrophils and Indomethacin-induced gastric injury are not fully understood. A mouse model of gastric injury was established using Indomethacin, followed by proteomic analysis (raw data are available via ProteomeXchange with identifier PXD058482). GO functional annotations and KEGG pathway enrichment analysis were conducted on significant differential proteins. The formation of neutrophil extracellular traps (NETs) was observed using ELISA and immunofluorescence. TEM, Western blot and Real-time PCR were applied to observe programmed death of gastric epithelial cells (GECs), and ELISA was conducted to measure levels of TNF-alpha and IL-1 beta in the gastric tissue. Deoxyribonuclease 1 (DNase 1), a NETs inhibitor, was administered intraperitoneally to inhibit NETs formation. In vitro, neutrophils were isolated from peripheral blood of mice and co-cultured with mouse GECs cell line, different dosage of Indomethacin were added to the culture dish, the levels of inflammatory factors, formation of NETs and GECs programmed death were assessed in vitro. Poly morphonuclear neutrophils (PMN) were extracted from mouse peripheral blood and single-cell RNA-sequencing (scRNA-seq) was further applied (raw data are available via Genome Sequence Archive with identifier CRA020950) to explore the intracellular mechanism of NETs formation. ELISA and immunofluorescence were performed to validate expression of IL-17 signaling pathway. After Indomethacin gavage, obvious gastric injury was observed. Proteomic analysis indicated that NETs formation played a crucial role in Indomethacin-induced gastric injury. Compared to control group, Indomethacin treatment

关键词： Active Immunotherapy   Anti-PD-1   Breast Cancer   Macbecin II   MHC-I  

摘要： We aimed to restore MHC-I expression on the surface of solid tumors including breast cancer and melanoma cells to regain sensitivity to immunotherapy and suppress metastatic progression. We screened a natural compound library and identified macbecin II as a reagent that upregulates MHC-I expression and induces antigen-dependent cell death in pre-invasive and invasive breast cancer models. Furthermore, we employed active immunotherapy using engineered small extracellular vesicles from dendritic cells (DCs) as a tumor vaccine (IL2-ep13nsEV) in combination with macbecin II for personalized breast cancer treatment. We found that macbecin II induced MHC-I-dependent antigen presentation and that IL2-ep13nsEV synergized with macbecin II inducing cell death, reducing metastasis, and boosting immune cell infiltration. In addition, macbecin II potentiated the effects of anti-PD-1 immunotherapy in suppressing tumor growth and metastasis. Mechanistically, macbecin II upregulated MHC-I expression post-translationally by rescuing it from lysosomal degradation. Our findings revealed a strong efficacy of macbecin II in regulating MHC-I expression and following antigen-dependent cell death. Therefore, combining active immunotherapies and macbecin II represents an effective strategy to prevent growth and progression of solid tumors including breast cancer and melanoma.

关键词： Dried ginger essential oil   Gut microbiota   Indole-3-acetic acid   Mucositis   Epithelial barrier function  

摘要： Ethnopharmacological relevance: 5-Fluorouracil (5-FU) commonly induces severe mucositis, causing pain, inflammation, and gastrointestinal dysfunction, which significantly increases patient morbidity and reduces quality of life. In Ayurveda, Traditional Chinese Medicine, and other ethnopharmacological practices, dried ginger has been widely used to alleviate symptoms such as nausea, vomiting, diarrhea, and inflammation, highlighting its important role in traditional medicine. Aim of the study: This study explored the potential of dried ginger essential oil (DGEO) in mitigating intestinal epithelial barrier damage in mice with mucositis induced by 5-FU. Methods: The therapeutic effects of DGEO were evaluated by measurements of weight changes, diarrhea scores, ELISA, and H&E. Further investigations included 16S rRNA sequencing, untargeted metabolomics, molecular docking, and HPLC-MS/MS to explore its underlying mechanisms, with validation performed using western blotting and ELISA. Results: The results demonstrated that DGEO was effective in alleviating mucositis symptoms. It also improved the gut microbiota, enhanced the biotransformation of tryptophan to indole-3-acetic acid (IAA), and elevated the protein expressions of the AHR, CYP1A1, and p-STAT3, as well as level of IL-22. Moreover, DGEO improved the expressions of tight junction (TJ) proteins and anti-apoptotic proteins, enhancing intestinal barrier integrity. Conclusion: These findings indicated that DGEO ameliorated 5-FU-induced mucositis by modulating gut microbiota and the tryptophan metabolite IAA-AHR/IL-22/STAT3 signaling axis, providing new insights into its therapeutic applications, particularly its ability to regulate gut microbiota and related signaling pathways.

关键词： hepcidin   IL-6/STAT3 pathway   ferulic acid   hypoferremia   anemia  

摘要： Background/Objectives: Hepcidin is a negative regulator of iron absorption that is released by hepatocytes. It is one of the main contributors to hypoferremia and anemia in inflammatory and oncological disorders that are mediated by the proinflammatory cytokine IL-6/STAT3 pathway. Ferulic acid (FA) is a phenolic compound with pleiotropic biological activities, including anti-inflammatory activity. However, its effect on hepcidin secretion is still unknown. Thus, this study aimed to explore the impact of FA on hepcidin levels and the underlying mechanism. Methods: HepG2 cells were treated with different log percentages of FA, and their viability was determined via the MTT assay. The relative expression of IL-6 and HAMP in treated and untreated cells was measured via qRT-PCR, and the protein levels of hepcidin, IL-6 and STAT3 were measured using ELISA. Results: The MTT test showed an inverse relationship between FA concentrations and HepG2 cell proliferation;FA's IC50 value was 0.07669%. The expression levels of IL-6 and HAMP were significantly increased in HepG2 cells following 24 h of culture with 4 mu g/mL LPS. Meanwhile, the addition of FA significantly decreased the relative expression levels of these two genes and the secretion levels of IL-6, STAT3 and hepcidin compared to the cells treated with LPS alone. Conclusions: Overall, these findings show that FA modifies inflammatory pathways, affecting hepcidin levels via the IL-6/STAT3 pathway. Thus, this suggests FA as a potential therapeutic agent against the hypoferremia and anemia developed due to dysregulated hepcidin levels in diseases such as inflammatory and oncological disorders.

关键词： influenza virus   virus-host interactions   cell-intrinsic antiviral responses   interferon   interferon-stimulated genes   CIC   IFN   ISG   ATXN1L   IAV  

摘要： Early detection of viral infection and rapid activation of host antiviral defenses through transcriptional upregulation of interferons (IFNs) and IFN-stimulated genes (ISGs) are critical for controlling infection. However, aberrant production of IFN in the absence of viral infection leads to auto-inflammation and can be detrimental to the host. Here, we show that the DNA-binding transcriptional repressor complex composed of Capicua (CIC) and Ataxin-1 like (ATXN1L) binds to an 8-nucleotide motif near IFN and ISG promoters and prevents erroneous expression of inflammatory genes under homeostasis in humans and mice. By contrast, during respiratory viral infection, activation of the mitogen-activated protein kinase (MAPK) pathway results in rapid degradation of the CIC-ATXN1L complex, thereby relieving repression and allowing for robust induction of IFN and ISGs. Together, our studies define a new paradigm for host regulation of IFN and ISGs through the evolutionarily conserved CIC-ATXN1L transcriptional repressor complex during homeostasis and viral infection.

关键词： HLA-DQA1   肺腺癌   肿瘤免疫浸润   预后  

摘要： 目的 探讨主要组织相容性复合体Ⅱ类DQ alpha 1(major histocompatibility complex,class II,DQ alpha 1,HLA-DQA1)在肺腺癌中的表达及其预后意义。方法 通过构建受试者工作特征（receiver operating characteristic,ROC）曲线和Kaplan-Meier曲线确定HLA-DQA1在肺腺癌中的预后意义，并通过基因本体论（gene ontology,GO）富集、京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes,KEGG）通路和基因集富集分析（gene set enrichment analysis,GSEA）进行功能分析。应用CIBERSORT和Spearman相关性分析评估免疫细胞浸润水平与HLA-DQA1表达之间的关联。收集2022—2023年就诊于华北理工大学附属医院并住院行手术治疗的肺腺癌患者的临床病理资料，对患者的术后标本进行逆转录聚合酶链反应（reverse transcriptionpolymerase chain reaction,RT-PCR）和免疫组织化学体外实验，分析HLA-DQA1表达与肺腺癌患者临床病理特征的关系。结果 最终入组患者30例，其中女17例、男13例，年龄≥60岁20例、<60岁10例。与正常组织相比，HLA-DQA1在肺腺癌中的表达水平明显较低，这一点在肺腺癌和正常肺组织的实时荧光定量PCR(quantitative real-time PCR,qRT-PCR)和免疫组织化学中得到证实。CancerSEA、GO和KEGG分析表明，HLA-DQA1与肿瘤细胞的免疫浸润密切相关。药物敏感性分析表明，HLA-DQA1高表达的肺腺癌患者可能对克唑替尼治疗耐药，而对顺铂、紫杉醇、多西他赛和表皮生长因子受体抑制剂相对敏感。结论 HLA-DQA1是肺腺癌患者预后的重要标志物。