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关键词： Agmatine   Sepsis   Intestinal injury   AhR   Anti-inflammation  

摘要： Background: Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. However, no reports of AGM alleviating sepsis-related intestinal injury have been found. Therefore, this study intends to investigate the protective effects of AGM on sepsis-related intestinal injury and its potential mechanism. Methods: We first established a sepsis model by lipopolysaccharide (LPS) or cecum ligation perforation (CLP), and then used H&E staining, transmission electron microscopy (TEM), and TUNEL to examine the pathological changes in rat intestines after AGM treatment. ELISA was used to detect expression levels of inflammatory factors in ileal tissues and biochemical indexes of infectionin in serum. TNF-alpha induced Caco-2 cell inflammation model was established in vitro, and cell activity and proliferative capacity were detected by CCK8 and EdU after AGM treatment. The Caco-2 cell inflammation model with high or low expression of Aryl hydrocarbon receptor (AhR) was established, and whether AGM exerts anti-inflammatory effects via AhR/STAT3/IL-10 pathway was investigated using molecular docking, Co-IP, and Western Blot. Results: The histopathological staining demonstrated that AGM significantly reduced intestinal injury and the content of inflammatory factors IL-1(3, IL-6, and TNF-alpha, improved systemic infection and the survival rate of septic mice, and restored intestinal barrier function in CLP rats. In vitro, AGM improved cell viability and proliferative capacity of the Caco-2 cell inflammation model. AGM inhibits inflammatory factor expression by activating AhR, decreasing HIF-1 protein expression, and activating the STAT3/IL-10 signaling pathway. Discussion and conclusion: AGM has the potential to ameliorate sepsis-related intestinal injury via the AhR-STAT3IL-10 pathway, thereby offering theoretical basis for clinical treatm

关键词： Allergy   Contact hypersensitivity   Inflammatory skin diseases   T cells   Transcription factors  

摘要： A plethora of data supports a major role of CD4+ and CD8+ T lymphocytes for the initiation, progression, and maintenance of allergic contact dermatitis. However, in-depth understanding of the molecular mechanisms is still limited. NFATc1 plays an essential role in T-cell activation. We therefore investigated its impact on contact hypersensitivity, the mouse model for allergic contact dermatitis. The contact hypersensitivity response to 2,4,6-trinitrochlorobenzene was diminished in Nfatc1fl/flxCd4-cre mice (Nfatc1-/-) compared with that in wild-type mice and associated with a lower percentage of IL-17-producing CD8+ T (Tc17) cells in both inflamed skin and draining lymph nodes. In vitro Tc17 polarization assays revealed that Nfatc1-/- CD8+ T cells have a reduced capacity to polarize into Tc17 cells. Applying single-cell RNA sequencing, we realized that NFATc1 controls the T-cell differentiation fate. In the absence of NFATc1, CD8+ T cells favor the development of IFN-g-secreting CD8+ T (Tc1) lymphocytes, whereas in its presence, they turn into Tc17 cells. Finally, the adoptive transfer of 2,4,6-trinitrochlorobenzene-sensitized wild-type CD8+ T cells restored the contact hypersensitivity response in na & imath;ve Nfatc1-/- mice. Our data demonstrate that NFATc1 contributes to the development of Tc17 cells and might present a promising target to alleviate CD8+ T-cell-mediated allergic responses.

关键词： antigen presentation   food allergy   IL-9   MHC class II   mucosal mast cell  

摘要： Background IgE-mediated food allergy is accompanied by mucosal mast cell (MMC) hyperplasia in the intestinal mucosa. Intestinal MMC numbers correlate with the severity of food allergy symptoms. However, the mechanisms by which MMCs proliferate excessively are poorly understood. Here, we clarify the role of newly identified MHC class II (MHCII)-expressing MMCs in the effector phase of IgE-mediated food *** Mice reconstituted with MHCII-deficient or wild-type MMCs were used to generate a mouse mode of IgE-mediated food allergy. We assessed the extent of intestinal MMC hyperplasia and the severity of hypothermia in these mice. In addition, we performed in vitro antigen presentation assay using induced MHCII-expressing MMCs generated from bone marrow cells to evaluate the effect of CD4+ T cell activation on MMC *** In food-allergic mice, we identified the appearance of MHCII-expressing MMCs in the intestinal mucosa and showed that MMC hyperplasia was suppressed in mice with MHCII-deficient MMCs compared to mice with wild-type MMCs. In vitro assays demonstrated that MHCII-expressing MMCs incorporate food antigens directly and through the high-affinity IgE receptor Fc epsilon RI-mediated endocytosis and activate antigen-specific CD4+ T cells from food-allergic mice by antigen presentation. Activated CD4+ T cells secrete IL-4 and large amounts of IL-5, which enhance production of the mast cell growth factor IL-9 by IL-33-activated MMCs. Excess IL-9 causes excessive MMC proliferation, leading to the development of MMC *** Antigen presentation to CD4+ T cells by MHCII-expressing MMCs triggers intestinal MMC hyperplasia and exacerbates IgE-mediated food allergy.

关键词： Acute kidney injury   Multi-omics integration   Therapeutic target discovery   Drug repurposing  

摘要： Acute kidney injury (AKI) remains a critical condition with limited pharmacological options. Bioactive molecules, including cytokines, receptors, and enzymes, play central roles in AKI pathogenesis, but systematic efforts to identify translational targets remain limited. In this study, we implemented a multi-omics integrative framework to nominate and validate candidate targets for AKI. Using genetically informed screens anchored on a curated set of potentially actionable genes, we identified five prioritized candidates, CD46, IL6R, KLRC1, LEAP2, and SMOX, with strong biological plausibility and therapeutic potential. Bulk and single-cell RNA sequencing data revealed cell-type-specific enrichment, particularly in proximal tubules, immune subsets, and endothelium under AKI conditions. Pathway enrichment highlighted shared involvement in cytokine signaling, antigen presentation, and metabolic stress responses. In silico drug repurposing revealed several clinically approved compounds (e.g., tacrine, raloxifene hydrochloride, tretinoin) with strong predicted binding to CD46, IL6R, and SMOX. In vivo experiments demonstrated that pharmacological inhibition of SMOX significantly alleviated tubular injury, preserved renal function, and reduced oxidative stress. In vitro studies further confirmed the protective effects of SMOX inhibition by maintaining epithelial cell integrity and viability in renal tubular cells, while suppressing oxidative damage.

关键词： Pulmonary arterial hypertension   Broiler   Transcriptomics   Network pharmacology   Piperine  

摘要： Pulmonary arterial hypertension (PAH) is a chronic, progressive vasculopathy characterized by a sustained elevation in pulmonary vascular resistance and remodeling of pre-capillary pulmonary arterioles, leading to right ventricular failure and often death. This study explores the potential of piperine, a bioactive dietary alkaloid, in mitigating PAH pathogenesis using a broiler chicken model. Network pharmacology analysis identified the IL-6/ STAT3 signaling pathway as key anti-PAH targets of piperine. In vivo experiments demonstrated that piperine treatment significantly reduced PAH-associated mortality, suppressed inflammatory cytokine production, and attenuated pulmonary vascular remodeling in the chicken model. Mechanistically, the observed protective effects were linked to the downregulation of IL-6 expression and STAT3 phosphorylation, along with the suppression of NF-kappa B p65 activation. Furthermore, piperine inhibited hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) in vitro, reinforcing its role in preventing vascular remodeling. Collectively, these findings underscore the potential of piperine as a functional food component with cardiopulmonary protective properties, proposing its utility as a potential dietary intervention for the management of PAH.