Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1292352 | ENA |
REPOSITORIES: ENA
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Project description:Single-Atom Catalysts Ameliorate Sepsis-Induced Intestinal Barrier Damage
| PRJNA1292362 | ENA
Project description:Tumor microenvironment (TME)-induced nanocatalytic therapy is a promising strategy for cancer treatment, but the low catalytic efficiency limits its therapeutic efficacy. Single-atom catalysts (SACs) are a new type of nanozyme with incredible catalytic efficiency. Here we construct a single-atom manganese (Mn)-N/C nanozyme. Mn-N/C catalyzes the conversion of cellular H2O2 to ∙OH through a Fenton-like reaction and enables the sufficient generation of reactive oxygen species (ROS), which induces immunogenic cell death (ICD) of tumor cells and significantly promotes CD8+T anti-tumor immunity. Moreover, RNA sequencing reveals that Mn-N/C treatment activates type I interferon (IFN) signaling which is critical for Mn-N/C-mediated anti-tumor immune response. Mechanistically, Mn-N/C-triggered releasing of cytosolic DNA from ICD tumor cells activates cGAS-STING pathway, consequently stimulating type I IFN induction. We propose a new promising single-atom nanozyme with extraordinary catalytic activity, which enhances anti-tumor immune response and exhibits synergistic therapeutic effects when combined with anti-PD-L1 blockade.
2024-04-24 | GSE249852 | GEO
Project description:Group 3 innate lymphoid cells (ILC3s) are key regulators of mucosal immunity,yet their role in sepsis-associated colon injury remains unclear.Peripheral blood from healthy volunteers and septic patients was analyzed for ILC subset alterations.A LPS-induced murine sepsis model,combined with ILC3-deficient mice,was employed to assess ILC3 dynamic,function,metabolic features and impact on colon barrier interity using flow cytometry,histopathology,ELISA,RT-qPCR and in vitro co-culture experiments.Septic patients exhibited significantly reduced circulating ILC3 proportions.In mice,sepsis decreased colonic ILC3 numbers but enhanced IL-22 and GM-CSF production.ILC3 deficiency increased mortality and exacerbated intestinal barrier disruption,while exogenous IL-22/GM-CSF administration ameliorated colonic pathology.Mechanistically,sepsis induced metabolic reprogramming in ILC3,characteristiced by enhanced glycolysis,reduced mitochondrial mass and ATP producton,which led to mitochondrial ROS accumulation.ROS activated the NF-κB pathway to drive IL-22 and GM-CSF production.However,ROS scavening or NF-κB inhibition unexpectedly increased ILC3 apoptosis,revealing that ROS-NF-κB axis also conveys pro-survival signals.Despite enhanced function,the repair capacity of residual ILC3s was outpaced by ongoing intestinal destruction.Our finding provided insight into the relation of ROS-NF-κB axis with IL-22/GM-CSF production and the survival of remaining colonic ILC3s in sepsis.Thereby targeting this metabolic-immune crosstalk may present a therapeutic strategy to sepsis associated intestinal injury.
2026-09-02 | GSE322583 | GEO
Project description:<p>The intestinal microflora and metabolites produced by these microbes serve as important regulators of the development of sepsis. Accordingly, this study was designed to systematically explore the relationships between the regulation of septicemia and both the intestinal flora and fecal metabolites by examining the functional roles of metabolites in the protection against sepsis-associated intestinal damage. To that end, fecal and peripheral blood mononuclear cell (PBMC) samples were collected from sepsis patients and healthy controls. A series of longitudinal multi-omics analyses were then used to assess the links between the intestinal flora or associated metabolites and PBMCs in sepsis patients, while animal model studies were further used to probe the protective effects of intestinal flora-derived metabolites on intestinal damage and immunity in the context of sepsis. These analyses revealed that intestinal dysbiosis was a common finding in sepsis patients, which commonly exhibited higher levels of deleterious bacteria and/or reductions in beneficial bacteria. A machine learning approach was used to identify samples from sepsis patients, revealing that at the genus level, sepsis samples could be distinguished by the presence of Bifidobacterium, Bacteroides, Porphyromonas, Prevotell, Enterococcus, Anaerococcus and Veillonella species. Metabolomics analyses indicated that there were significant differences in the levels of intestinal flora-derived metabolites including L-serine, L-valine and L-tyrosine when comparing samples from the sepsis and control groups, while corresponding transcriptomic analyses of PBMC samples using an ImmunecellAI analytical approach revealed a significant sepsis-related increase in the abundance of T cells and Th17 cells. Single-cell sequencing data from sepsis-associated PBMCs was also downloaded from the GEO database, confirming the observation that Th17 cell levels and those of other immune cells rose significantly in the context of septicemia. Animal model experiments revealed that intestinal microbiota-derived L-valine was able to alleviate inflammation and protest against sepsis-induced intestinal damage by inhibiting Th17 cell activation. Overall, these results thus highlight the successful application of machine learning to distinguish between sepsis and control samples based on the composition of the intestinal flora while demonstrating the potential therapeutic benefits of L-valine as an inhibitor of Th17 cell activity that may offer value as a means of alleviating or preventing intestinal damage in treated individuals. </p>
2023-07-28 | MTBLS7866 | MetaboLights
Project description:Paneth cells, critical sentinels of the innate immune system within the intestinal epithelium, play a vital role in maintaining intestinal homeostasis and defending against pathogens. Their dysfunction is implicated in the pathogenesis of sepsis. However, the specific mechanisms by which Paneth cells communicate with and regulate the surrounding intestinal microenvironment, particularly via extracellular vesicles (EVs), remain poorly understood. This study aims to characterize the global miRNA expression profile of intestinal epithelial cell-derived EVs (IEC-EVs) in a mouse model of acute Paneth cell loss, to identify key intercellular signaling molecules that may mediate intestinal barrier response to injury. We employed a well-established model of Paneth cell ablation by a single intraperitoneal injection of dithizone in C57BL/6 mice. Control mice received a vehicle solution. Intestinal epithelial cells were isolated six hours post-injection, and IEC-EVs were subsequently purified from these cells. Small RNA from the purified IEC-EVs was extracted and subjected to next-generation sequencing to comprehensively profile the miRNA cargo. Our comparative analysis reveals a distinct set of miRNAs that are differentially expressed in IEC-EVs following Paneth cell ablation. These candidate miRNAs are predicted to target signaling pathways crucial for epithelial cell proliferation, apoptosis, and inflammatory responses. We hypothesize that the alteration of the miRNA landscape in IEC-EVs represents a novel mechanism of intercellular communication that orchestrates the intestinal epithelial response to damage. This dataset provides the comprehensive resource of miRNA expression in IEC-EVs under conditions of Paneth cell deficiency. The findings are expected to elucidate novel pathways in intestinal pathophysiology and may identify potential miRNA biomarkers or therapeutic targets for conditions involving intestinal barrier dysfunction, such as sepsis.
2025-12-01 | GSE311914 | GEO
Project description:Chronic inflammatory bowel diseases (IBD), including Crohn's disease, are characterized by relapsing-remitting intestinal inflammation associated with a dysfunctional intestinal epithelial barrier. Existing preclinical in vitro models of IBD have limitations in accurately reproducing the dynamic processes of epithelial barrier dysfunction and repair, which hinders the translation of research findings into new therapeutic approaches. Here, we established a scalable, microarrayed 3D human intestinal organoid platform that enables high-throughput, single-organoid resolution modeling of inflammation-induced epithelial damage and subsequent regenerative responses, recapitulating both morphological and transcriptional signatures of biopsy-derived mucosal tissues from Crohn’s disease patients. Employing time-resolved morphological imaging, transcriptomics, and a novel quantitative epithelial recovery metric, introduced as the 'Intestinal Organoid Recovery Score (IORS),' we distinguished responder organoids to preventive and therapeutic bioactives, notably dexamethasone (DEX), nicotinamide (NAM), and β-hydroxybutyrate (BHB). These interventions effectively mitigated inflammation-induced barrier disruption and promoted regenerative epithelial barrier programs to restore barrier function. Transcriptomic analysis further revealed differential modulation of pathways associated with epithelial integrity and inflammatory responses in DEX and NAM interventions, highlighting distinct regenerative mechanisms of action that may be utilized for future combinatorial therapies. Collectively, this robust, single-organoid resolution approach offers an unprecedented opportunity for precision medicine-driven screening and therapeutic development in the context of chronic gastrointestinal diseases.
2026-08-10 | GSE294920 | GEO
Project description:Effective therapeutic strategies for myocardial ischemia/reperfusion (I/R) injury are still lacking. Targeting reactive oxygen species (ROS), the major cause of I/R injury, provides a practical approach to alleviate myocardial damage after reperfusion procedure. Herein, we synthesized an innovative antioxidant nanozyme equipped with single-platinum-atom (PtsaN-C) for protecting against I/R injury. PtsaN-C exhibited potent multiple enzyme-mimicking activities with high-efficiency ROS-scavenging. Mechanistic studies demonstrated that excellent ROS-elimination performance in single platinum atom center was prior to that of platinum cluster center attributing to good synergistic effect and metallic electronic property with nitrogen-doping coordination structure. Systematic in vitro and in vivo studies confirmed that PtsaN-C counteracted ROS efficiently to restore cellular homeostasis and prevented apoptotic progress after I/R injury. PtsaN-C presented excellent biocompatibility and biosafety, making it promising for future clinical application. Current study broadens the horizon of single-atom nanomedicine against ROS-induced damage, offering a promising therapeutic avenue for treatment of I/R injury.
2024-01-16 | PXD048584 |
Project description:Malnutrition is a major global health challenge that increases intestinal permeability and susceptibility to sepsis, yet the mechanisms driving barrier dysfunction remain poorly defined. We aimed to identify how the gut microbiome and microbiota-derived metabolites regulate intestinal barrier integrity during malnutrition. We used a low-protein, low-fat diet (LPLFD) to induce malnutrition in specific pathogen-free (SPF) and germ-free (GF) mice. Colonic permeability and mucus thickness were quantified. Metabolomics identified microbiota-derived metabolites altered by malnutrition. Human colonoids were used to test mechanistic effects of candidate metabolites. Barrier restoration was evaluated following colonic administration of isovalerate or oral supplementation with its precursor amino acid, leucine. LPLFD-induced malnutrition increased colonic permeability and reduced mucus thickness in male, but not female, SPF mice. These defects were absent in malnourished GF mice, indicating a microbiota-dependent and sexually dimorphic mechanism of barrier disruption. Metabolomic analysis revealed reduced colonic levels of branched-chain fatty acids (BCFAs) in malnourished mice. Supplementation of human colonoids with the BCFA isovalerate improved barrier function and altered expression of genes associated with epithelial junctional complexes. Restoring isovalerate levels, either directly via colonic administration or indirectly through oral leucine supplementation, partially rescued barrier defects in malnourished male mice. These findings identify BCFAs, particularly isovalerate, as essential microbiota-derived regulators of intestinal barrier integrity during malnutrition. This work reveals a sex-specific, microbiota-dependent pathway of barrier dysfunction and highlights microbial metabolites as promising therapeutic targets for mitigating sepsis risk in undernourished populations.
2026-07-24 | GSE316703 | GEO