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摘要： Interleukin-1 (IL-1)/IL-1 receptor family consists of activators and inhibitors which play a key role in inflammation, emergency myelopoiesis, and myeloid cell activation. The latter includes the IL-1R2 decoy receptor. To investigate the expression and significance of IL-1R2 in sepsis, we conducted high-dimensional flow cytometry of circulating cells from patients stratified according to the Sequential Sepsis-Related Organ Failure Assessment (SOFA) score. Here we report that the IL-1 decoy receptor is selectively upregulated on the plasma membrane of leukocytes and, in particular, monocytes from septic patients, and downregulated in septic shock. Flow cytometry combined with transcriptomic analysis of publicly available datasets indicated that IL-1R2 is associated with the differentiation of monocytes to a population of circulating monocytic cells with macrophage features (Mono/Mφ). In vitro stimulation of monocytes from healthy donors with Colony Stimulating Factors (CSFs), in particular GM-CSF and Lipopolysaccharides (LPS), induced IL-1R2 Mono/Mφ, which recapitulated the characteristics of sepsis-associated monocytic cells, including low expression of HLA-DR, high levels of macrophage markers such as MS4A4A and CD63, immune checkpoints, immunosuppressive molecules and selected scavenger receptors. Membrane-associated IL-1R2 and MS4A4A correlated with immunological markers, cytokine storm, and clinical parameters (e.g., SOFA score, creatinine, survival), reflecting the infection severity in hospitalized ***, in sepsis IL-1R2 is expressed in a subset of circulating monocytes co-expressing mature macrophage and immune dysfunction features with clinical significance.

关键词： B-cells   Lymphopenia   NK cells   Sarcoidosis   T-cells   TNF-α   Treatment  

摘要： BACKGROUND:Severe sarcoidosis has been associated with peripheral blood (PB) total lymphopenia and high tumour necrosis factor α (TNF-α) levels, and the lymphopenia phenotype seems to respond poorly to conventional treatment. However, the mechanisms behind PB lymphopenia and its correlation with TNF-α levels remain unclear. Understanding the connections among PB lymphocyte subsets, TNF-α and clinical phenotype including treatment status could offer insights into how to individualize therapy. METHODS:PB samples from 65 consecutive sarcoidosis patients were collected at the Department of Respiratory Medicine, Karolinska University Hospital. Total lymphocyte, T-, B- and natural killer cell and TNF-α serum concentrations were measured and correlated to clinical parameters. Penias were defined as values below the lower limit of normal. The medical charts were retrospectively searched for the first PB total lymphocyte count, mostly recorded at time around diagnosis. RESULTS:PB total lymphopenia was observed in 35% of patients, was present since time around diagnosis, and associated with a need for treatment later (p = 0.005). Lymphocyte counts did not change by therapy, except for an increase in patients receiving TNF-α inhibitors (TNFi) (p < 0.05). B-cell penia, observed in 37% of patients, was the most common abnormality, also in patients with normal total lymphocyte counts, while T-cell penia mainly occurred in patients with total lymphopenia (91 vs 5%, p < 0.001). CONCLUSIONS:B-cell penia is common in sarcoidosis patients while T-cell penia is mainly a feature of the sarcoidosis PB lymphopenia phenotype. Increased lymphocyte counts during TNFi treatment suggests that TNF-α signaling is of importance for sarcoidosis associated lymphopenia.

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： 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.

摘要： BACKGROUND:Hantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. Here, we investigated a potential role for IL-6 trans-signaling in hantavirus pathogenesis. METHODS:Effects of IL-6 trans-signaling during in vitro hantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to severity. FINDINGS:In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did not. INTERPRETATION:IL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of severe HFRS and perhaps also HPS.

关键词： Colitis-associated colorectal cancer   Traditional Chinese medicine   Network pharmacology   Transcriptomics   Inflammation-to-cancer transformation   IL-17RA/ACT1/NF-kappa B signaling axis  

摘要： Ethnopharmacological relevance: Inflammation-to-cancer transformation is critical for the progression of ulcerative colitis to colitis-associated colorectal cancer (CAC). Aim of the study: To explore the role and potential mechanisms of Qingre Huayu Jianpi prescription (QHJ) treatment in the development of CAC. Materials and methods: Combined network pharmacology and transcriptome analyses were used to investigate QHJ-associated targets and pathways in the context of CAC. Using clinical data and a murine CAC model, we examined QHJ effects on pathological morphology, inflammatory factors, and key target pathways. Results: Network pharmacology analysis identified the interleukin 17 receptor A (IL-17RA)/ACT1/nuclear factor kappa B (NF-kappa B) axis as critical in the inflammation-to-CAC transformation and for QHJ effects in CAC. Western blot and multiplex immunofluorescence analyses revealed significant upregulation of the IL-17RA/ACT1/NF-kappa B axis along with matrix metalloproteinase (MMP)7, MMP9, and chemokine ligand 2 (CCL2) in human tumor tissues. QHJ significantly ameliorated CAC-related symptoms in mice in vivo by downregulating the IL-17RA/ ACT1/NF-kappa B axis. This reduced the number of colorectal adenomas, increased colorectal length, and improved the structure of colonic mucosal glands. Additionally, QHJ inhibited the expression of pro-inflammatory factors and decreased the levels of MMP7, MMP9, and CCL2, ultimately suppressing the inflammation-to-cancer transformation. Conclusion: QHJ exhibited significant therapeutic effects on CAC in mice, likely due to its inhibitory action on the IL-17RA/ACT1/NF-kappa B axis. This study lays the foundation for research into the pathogenesis of CAC and the clinical application of QHJ.

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.