Mediators of Inflammation最新文献

Background: This study aimed to investigate the role and mechanism of long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) in macrophage ferroptosis during atherosclerosis (AS).

Methods: The clinical characteristics and disease severity were assessed in 84 patients with coronary heart disease (CHD). The role of NEAT1 in high-fat diet-induced AS and the impact of exercise were examined in APOE^-/- and NEAT1^-/- mice. Human monocyte THP-1 cells were utilized to explore cellular mechanisms underlying AS. Quantitative real-time PCR, immunofluorescence staining, and Western blot analysis were employed to analyze gene expression. Transmission electron microscopy and fluorescence in situ hybridization were used to examine cellular and tissue-level changes. Bioinformatics analyses were conducted to explore protein interactions and functional networks.

Results: NEAT1 expression and iron levels were correlated with disease severity in CHD patients. In THP-1 cells, oxidized low-density lipoprotein (ox-LDL) induced NEAT1 expression, ferroptosis marker ACSL4, reactive oxygen species (ROS), and mitochondrial abnormalities. Knockdown of NEAT1 reversed these effects. NEAT1 overexpression increased pSTAT3, ACSL4, and ROS production, reversed by STAT3 inhibitor. NEAT1 physically interacted with STAT3 via FBXW11. Knockdown of NEAT1 promoted pSTAT3 ubiquitination, reduced ACSL4 expression, and reversed ox-LDL effects. NEAT1 deletion attenuated macrophage ferroptosis and AS in APOE^-/- mice. Exercise reduced NEAT1 and ferroptosis indicators in mice and CHD patients.

Conclusions: NEAT1 plays a crucial role in macrophage ferroptosis during AS. Targeting NEAT1 or exercising may provide therapeutic interventions against AS.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder marked by immune dysregulation and multiorgan involvement. This study investigates the role of the ubiquitination-related gene EEF1A1 in SLE pathogenesis, focusing on T cell dysfunction.

Methods: Single-cell RNA sequencing (scRNA-seq) data from the GSE135779 dataset was analyzed to characterize the cellular composition of SLE samples. Clustering analysis identified 15 T cell subpopulations, with seven clusters notably depleted in SLE. Trajectory analysis indicated progressive transcriptional dysregulation during T cell differentiation. High-dimensional weighted gene coexpression network analysis (hdWGCNA) and LASSO regression highlighted EEF1A1 as a key ubiquitination-related hub gene. EEF1A1 expression was significantly elevated in SLE T cells, while its ubiquitinated form was reduced, suggesting impaired proteasomal degradation.

Results: Functional assays demonstrated that EEF1A1 overexpression enhances STAT1 phosphorylation (p-STAT1) without altering total STAT1 protein levels, leading to T cell dysfunction. In vitro and in vivo experiments revealed that EEF1A1 overexpression skews the T helper 1 (Th1)/T helper 2 (Th2) balance towards a Th1-dominant phenotype. In MRL/lpr mouse models, EEF1A1 overexpression exacerbated renal pathology, including increased proteinuria and immune complex deposition.

Conclusions: These findings suggest that EEF1A1 contributes to SLE pathogenesis by promoting STAT1-mediated T cell dysfunction and Th1/Th2 imbalance. EEF1A1 emerges as a potential biomarker and therapeutic target, offering new insights into the post-translational regulatory mechanisms underlying SLE.

Background: Due to the complex pathogenesis of sequelae of pelvic inflammatory disease (SPID), targeted therapeutic agents are still lacking. Here, we investigated the interactions between neutrophils and uterine fibroblasts (FBs) in developing tissue fibrosis in SPID.

Methods: A rat model of SPID was constructed to assess the roles of autophagy and neutrophil extracellular traps (NETs) in SPID rats. Single-cell sequencing data from the public database GSE223639 were utilized to identify the specific cell cluster FBs where NETs act. A DMSO-induced HL-60-driven neutrophil-like (dHL-60) cell model was established, and neutrophil-like cells were treated with rapamycin and MHY1485 to activate and inhibit autophagy, respectively, to observe the differences in the production of NETs. NETs were cocultured with FBs to observe the effects on FB proliferation, migration, apoptosis, and phenotypic transformation.

Results: In vivo experiments revealed that there was a consistency in the expression of autophagy and NETs in the adherent tissues of rats with the SPID model and that autophagy promotes the generation of NETs, which are collectively involved in the fibrosis of pelvic tissues in SPID. Single-cell sequencing identified FBs, the cells in which NETs play a major role in aseptic inflammation. Further in vitro studies confirmed that NETs inhibit FB apoptosis while promoting horizontal and longitudinal migration, phenotypic transformation, and hyperproliferation of FBs, thereby exacerbating tissue fibrosis.

Conclusions: Autophagy promotes the generation of NETs, which facilitates FB transformation and hyperproliferation and exacerbates the degree of adhesion and fibrosis in the pelvic tissue of SPID.

Background: Rheumatoid arthritis (RA) is a growing public health concern with rising incidence worldwide. The C-reactive protein-triglyceride-glucose index (CTI), a composite marker of inflammation and insulin resistance, has been linked to various metabolic disorders, but its role in RA remains unclear. This study aimed to examine the association between CTI and RA risk and assess whether body mass index (BMI) mediates this relationship.

Methods: We analyzed data from 4292 participants using the 2005-2010 National Health and Nutrition Examination Survey (NHANES). CTI was computed and stratified into quartiles. Multivariable logistic regression models assessed the association between CTI and RA after adjusting for demographic, socioeconomic, lifestyle, and clinical confounders. Restricted cubic spline (RCS) functions were employed to test for nonlinear patterns. Additionally, subgroup analyses examined effect modification, and mediation analysis quantified the indirect effect through BMI.

Results: Elevated CTI values were independently linked to higher odds of RA. After full adjustment, each one-unit rise in CTI corresponded to a 45% increase in RA odds (OR = 1.45, 95% CI: 1.22-1.73, p  < 0.001). The RCS analysis demonstrated a significant nonlinear association (p for nonlinearity = 0.048). Stratified analyses indicated consistent patterns across sex, ethnicity, and other variables, with a more pronounced effect among individuals without diabetes (p for interaction = 0.036). Mediation findings showed that BMI accounted for 32.31% of the total CTI-RA effect (p  < 0.001).

Conclusions: CTI is nonlinearly and independently associated with RA risk, partly through BMI, highlighting its potential as a biomarker linking metabolic and inflammatory pathways.

Spinal cord injury (SCI) triggers severe neuroinflammation, impeding recovery. While microglial M1 polarization and pyroptosis are key drivers, their upstream regulators are incompletely understood. This study investigated the role of the ubiquitin ligase tripartite motif-containing protein 14 (TRIM14) in regulating neuroinflammation following SCI. Using rat SCI models and BV2 microglia exposed to lipopolysaccharide (LPS), we assessed TRIM14 expression and its functional impact via knockdown and overexpression, alongside pharmacological neurofilament (NF)-κB inhibition (pyrrolidine dithiocarbamate [PDTC]). TRIM14 was upregulated in injured spinal cords and microglia, associated with injury severity. TRIM14 knockdown in microglia stabilized IκBα by inhibiting its ubiquitination, thereby suppressing NF-κB activation, M1 polarization, and NLRP3-mediated pyroptosis. Conversely, TRIM14 overexpression exacerbated inflammation, effects markedly reversed by PDTC. In SCI rats, intralesional AAV-CRISPR/CasRx-mediated TRIM14 silencing significantly attenuated neuroinflammation and neuronal apoptosis, enhanced axonal regeneration, and improved locomotor function. Mechanistically, TRIM14 knockdown suppressed NF-κB/NLRP3 signaling, promoting a prorepair microenvironment. These results identify TRIM14 as a critical regulator of microglial activation and pyroptosis post-SCI, suggesting its therapeutic targeting could be a viable strategy to promote neural repair.

[This retracts the article DOI: 10.1155/2016/8467849.].

Background: Chronic kidney disease (CKD) imposes significant global health burdens. Shengqing Jiangzhuo (SQJZ) capsule possesses potential to alleviate CKD via gut-kidney axis, with the specific role and mechanisms involving CHAC glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) and hypoxia-inducible factor 1 (HIF-1) signaling remaining unclear.

Methods: Adenine-induced CKD rats were treated with SQJZ capsule for 4 weeks. The levels of blood urea nitrogen (BUN), serum creatinine (SCR), urine albumin/creatinine ratio (ACR), and inflammatory markers in colon tissues, including proinflammatory cytokines and oxidative markers, were assessed via enzyme-linked immunosorbent assay (ELISA). The renal pathology was estimated by histopathology. Transcriptomic sequencing combined with bioinformatics analysis identified the downstream pathway regulated by SQJZ in colon tissues. In vitro, after treatment with CHAC1 knockdown or HIF-1α activation, lipopolysaccharide (LPS)-treated NCM460 cells were analyzed for apoptosis, detected by flow cytometry, and inflammatory marker levels, determined by ELISA.

Results: SQJZ significantly reduced serum BUN, SCR, and urinary ACR in CKD rats, ameliorating histopathological damage. In colon tissues, SQJZ suppressed proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), and oxidative markers, reactive oxygen species (ROS), and malondialdehyde (MDA), while elevating superoxide dismutase activity. Transcriptomics revealed SQJZ-mediated regulation of HIF-1. CHAC1 knockdown in vitro reduced LPS-induced apoptosis and inflammation, while HIF-1α activation reversed these effects. Additive suppression of inflammation was observed in NCM460 cells with combined CHAC1 knockdown and SQJZ treatment.

Conclusion: SQJZ alleviates intestinal inflammation in CKD, potentially mediated by downregulation of CHAC1 and subsequent inactivation of the HIF-1 pathway, positioning SQJZ as a promising gut-targeted therapy in CKD.

Background: PANoptosis is implicated in immunoinflammatory diseases, but its role in cerebral ischemia-reperfusion injury (CIRI) remains unclear.

Methods: We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk RNA-sequencing (bulk RNA-seq) datasets to explore PANoptosis-related molecular signatures in ischemic stroke. scRNA-seq identified cellular subpopulations; ST revealed spatial expression. Multimodal intersection analysis (MIA) and high-dimensional weighted gene coexpression network analysis (hdWGCNA) detected PANoptosis-related differently expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA)-identified biomarkers were validated in GSE35338 and GSE137482. Analyses characterized spatiotemporal microglial dynamics. TNFRSF1A expression was validated by Western blot.

Results: Nine stromal cell subtypes were mapped across 14 brain regions. Stroke-associated microglial clusters showed microglia-specific dysregulation of PANoptosis regulators (MCL1, TNFRSF1A, and STAT3), with TNFRSF1A upregulated in the ischemic core. Altered intercellular communication via SPP1, MIF, FN1, and TNF pathways were observed. Pseudotime analysis revealed dynamic microglial reprogramming. TNFRSF1A showed time-dependent upregulation post-CIRI, validated at the protein level.

Conclusions: TNFRSF1A acts as a key PANoptosis-related biomarker and suggests microglial subclusters as therapeutic targets in ischemic stroke.

Gout is a common autoinflammatory disease that clinically manifests as recurrent joint redness, swelling, and pain, but the molecular mechanism of recurrent gouty inflammation remains unclear. Circular RNAs (circRNAs) might exert their function by regulating autophagy. Our previous studies revealed that autophagy-related genes (ATGs) are differentially expressed in patients with acute gout. The aim of this study was to investigate the molecular mechanism by which circ_0058051 regulates autophagy as a competitive endogenous RNA (ceRNA) in recurrent gouty inflammation. Real-time quantitative PCR was used to measure the expression of circ_0058051, miR-129-5p, ATG7, LC3, and IL-1β. Western blotting was used to assess the protein levels of ATG7, LC3, and IL-1β. Enzyme-linked immunosorbent assay (ELISA) was used to measure the IL-1β, IL-6, and TNF-α levels. A dual-luciferase reporter assay was used to confirm the interaction between circ_0058051, miR-129-5p, and ATG7. The gout group expressed significantly more circ_0058051 and ATG7 and significantly less miR-129-5p than the HC group. In the 20 paired cases, compared with stable gout cases, the expression of circ_0058051 and ATG7 was significantly greater during a gout attack and even greater in patients with gout recurrence. The significant decrease in miR-129-5p expression was more pronounced in patients with gout recurrence. In the simulation model of gout recurrence in the peripheral blood of intercritical gout patients stimulated with MSU, circ_0058051 peaked 2 h after MSU stimulation, ATG7 peaked 1 h after MSU stimulation, and miR-129-5p expression was lowest 1 h after MSU stimulation. In addition, the expression levels of circ_0058051, ATG7, IL-1β, TNF-α, IL-6, and LC3 significantly increased after THP-1 macrophages were treated with MSU, and the expression of miR-129-5p significantly decreased. In MSU-stimulated THP-1 macrophages, circ_0058051 sponges miR-129-5p to promote the expression of the miR-129-5p target gene ATG7, leading to acute gout attack. Our findings suggest that circ_0058051 is involved in the recurrence of acute gout by targeting miR-129-5p to regulate ATG7-mediated autophagy.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC), involves chronic gastrointestinal inflammation, with tumor necrosis factor alpha (TNF-α) playing a key role. Anti-TNF therapy is widely used, but not all UC patients respond, suggesting additional contributing factors. Gut microbiota alterations, particularly dysbiosis, may influence treatment outcomes. This study examines the relationship between Fusobacterium nucleatum (F. nucleatum) density and TNF-α expression in UC patients receiving anti-TNF therapy. Biopsy samples from responders (n = 10), nonresponders (n = 10), and healthy controls (n = 10) were analyzed using real-time PCR. Fusobacterium nucleatum density was significantly higher in nonresponders than in responders (3.2-fold, p  < 0.05) and controls (fivefold, p  < 0.05). TNF-α expression was elevated in both UC groups. These findings suggest F. nucleatum may contribute to anti-TNF therapy resistance by modulating intestinal inflammation, highlighting its potential as a biomarker for treatment prediction.