课程文献中心 更多>>

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

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-α and IL-1β 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 resulted

关键词： Axial spondyloarthritis   Early treatment   Early diagnosis   Giant cell arteritis   IL-17A   IL-17A inhibition   Polymyalgia rheumatica   Psoriasis   Psoriatic arthritis   Rheumatic and musculoskeletal diseases  

摘要： Interleukin-17A (IL-17A) plays a pivotal role in many rheumatic immune-mediated inflammatory diseases. Targeting the IL-17 pathway has transformed the way psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are managed, with a number of IL-17A inhibitors now available for treating rheumatic and musculoskeletal diseases. This narrative review will describe the opportunities presented by novel imaging techniques in understanding the metabolic and mechanical changes that characterize the pathogenesis of PsA and axSpA. It will look at the current consensus definitions of early disease in PsA and axSpA, present evidence for the benefit of early treatment, and highlight the gaps in current knowledge. Finally, it will describe novel treatment targets to address the unmet needs in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) and discuss the potential role of IL-17A inhibition in treating GCA and PMR.

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： Nile tilapia fingerlings   ammonia detoxication   functional amino acids   gut health   inflammatory cytokine   microbiota   nutrigenomics  

摘要： This study aimed to evaluate the effects of dietary glutamine (Gln) and glutamic acid (Glu) blend on growth performance, plasmatic biochemical parameters, intestinal bacteriome composition, short-chain fatty acids (SCFAs) production, digestive enzyme activity, and histomorphometry of Nile tilapia fingerlings. The study also aimed to evaluate the effects of this blend on liver antioxidant status and gene expression of anti-inflammatory interleukin 10 (IL-10), pre-inflammatory interleukin 1β (IL-1β), glutamine synthetase (GS), and peroxisome proliferator-activated receptor alpha (PPAR-α). Fish (n = 408; 1.0 ± 0.0 g) were randomly distributed into eight aquaria (51 fish each) and fed micro-extruded diets either unsupplemented (CON) or supplemented with 20 g kg of Gln and Glu (1:1) blend (AMG). Fish were hand-fed six times daily until apparent satiety for 30 days. Fish fed the AMG diet showed higher body weight gain (+3.0%) than those fed the CON diet. Additionally, these fish exhibited a higher abundance of Staphylococcus saprophyticus, a SCFA-producing bacterium known for its probiotic-like potential in fish. Consequently, fish fed AMG diet exhibited higher intestinal butyric acid production and increased intestinal fold height relative to fish fed CON diet. The upregulation of PPAR-α and GS genes suggested that fish fed AMG diet exhibited improved energy metabolism and ammonia excretion, respectively. Furthermore, the upregulated expression of the anti-inflammatory cytokine IL-10 gene in fish fed AMG diet indicated enhanced immune responses. Fish fed AMG diet showed increased activity of superoxide dismutase and glutathione-S-transferase and decreased malondialdehyde concentration in the liver. Dietary supplementation with 20 g kg of Gln plus Glu promoted fish growth and survival through beneficial modulation of the bacteriome, improving intestinal health and function, supporting nutrient absorption and metabolism, strengthening innate immunity, and reducing oxidativ

摘要： Tumor cell death shapes tumorigenesis and antitumor immunity in complex ways. Recently, Hänggi et al. revealed that necrotic-like death releases interleukin-1α (IL-1α), driving myeloid-mediated immunosuppression. Lamorte et al. demonstrated that medullary sinus macrophage (MSM) efferocytosis of apoptotic tumor cells activates the IL-33-regulatory T cell (Treg) axis, accelerating tumor growth. Blocking these pathways enhances the efficacy of cancer immunotherapy.

摘要： With the aim of isolating immunomodulatory compounds from the -butanol extract of leaves, nine megastigmane compounds were identified. Among these, the structure of the new compound 1, namely, "boehmegaside A", was established using NMR and HR-ESI-MS, and its absolute configurations were established through ECD calculations and DP4+ analysis using DFT-NMR chemical shift calculations. Furthermore, eight of these compounds were discovered for the first time in the genus, marking this the first report on megastigmane compounds isolated from this genus. Regarding their immunomodulatory activity, the isolated megastigmane compounds 3, 2, and 6 exhibited pro-inflammatory cytokine IL-1β secretion inhibitory activity. Compounds 3 and 6 significantly increased anti-inflammatory cytokine IL-10 secretion in LPS-activated RAW264.7 cells. Furthermore, the study on the mechanism of the immunomodulatory and other biological activities of megastigmane compounds through molecular docking simulations revealed that the planar structures of 3, 2, and 6 were critical in their ability to directly suppress TLR4 signalling. Instead, they attached to a nearby smooth area in TLR4. This interference likely disrupted the ability of TLR4 and MD-2 to form their primary contact interface and recognize LPS. These findings highlight the significant role of TLR4 in inflammation and immunity, indicating that these megastigmane compounds may be beneficial in treating various inflammatory disorders associated with immunological issues.