Mediators of Inflammation最新文献

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.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with a poor prognosis and limited effective treatment options. Our study comprehensively explores the complex role of programed cell death (PCD) mechanisms in PDAC development, examining 18 distinct PCD pathways and their genetic underpinnings. Using an advanced machine learning framework incorporating 429 algorithmic variations, we have developed an innovative PCD-based molecular signature that demonstrates robust prognostic capabilities. This signature exhibits superior performance across diverse patient cohorts, significantly outperforming traditional clinicopathological indicators. Through integrated pathway analysis, we revealed that high-risk patients show distinct activation of oncogenic pathways and significant alterations in the tumor immune microenvironment. These alterations include reduced infiltration of cytotoxic T lymphocytes and increased levels of immunosuppressive regulatory T cells (Tregs). Furthermore, leveraging the TISCH (Tumor Immune Single Cell Hub) database, we conducted detailed single-cell expression profiling of our signature genes across different cell populations within the tumor microenvironment (TME). This analysis uncovered cell-type-specific expression patterns of key PCD-related genes. Our results highlight the critical involvement of PCD in PDAC progression and introduce a promising tool for clinical risk stratification. The integration of bulk and single-cell transcriptomic analyses not only validates our molecular signature but also reveals potential cellular targets for therapeutic intervention. This PCD-focused approach may support the development of personalized therapeutic strategies and ultimately improve outcomes for PDAC patients.

Background: Clinical evidence indicates that inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) often co-occur, but their genetic mechanisms remain unclear. Our objective is to explore the genetic relationship between IBD and AS.

Methods: Using large-scale summary statistics from genome-wide association study (GWAS), we investigated the shared genetic architecture between IBD, including ulcerative colitis (UC) and Crohn's disease (CD), and AS. Starting with genetic correlation, we then examined shared genetic structures and genes, followed by causal inference, and explored potential functional genes and biological pathways in tissue and cell types.

Results: We observed a positive genetic correlation between IBD and AS (IBD-AS: r _g  = 0.252, p=3.78e - 06; CD-AS: r _g  = 0.268, p=5.19e - 06; UC-AS: r _g  = 0.171, p=6.64e - 03). Multitrait analysis of GWAS (MTAG) and cross-phenotype association analysis (CPASSOC) identified 24 pleiotropic single-nucleotide polymorphisms (SNPs) across three trait pairs. Gene association analysis from three methods collectively identified eight shared functional genes for IBD and AS. Shared tissue-specific genetic enrichment was found in lung, spleen, small intestine, and whole blood tissues. Additionally, common enrichment was observed in specific cell types, such as T and B cells. Bidirectional Mendelian randomization (MR) analysis revealed no causal relationship between the two conditions.

Conclusions: This study confirms the genetic correlation between IBD and AS, identifies their shared genetic architecture and biological pathways, providing strong evidence for the genetic comorbidity of IBD and AS. These findings offer directions for future research.

Depression and cardiovascular disease (CVD) frequently coexist, significantly impacting patient prognosis and quality of life. Research indicates that inflammatory responses play a crucial role in the pathogenesis of both conditions. The NLRP3 inflammasome, a key inflammatory signaling platform of the innate immune system, mediates the maturation and release of IL-1β and IL-18 and induces pyroptosis, playing a significant role in both depression and CVD. To explore the mechanisms and therapeutic potential of the NLRP3 inflammasome in the comorbidity of depression and CVD, we systematically reviewed recent literature. Our focus was on its activation pathways, expression changes in animal models and clinical samples, and intervention studies. The results indicate that NLRP3 inflammasome is persistently activated in patients with both depression and CVD, and this activation correlates with disease severity. Furthermore, various pharmaceutical drugs and natural compounds have demonstrated synergistic effects by inhibiting the NLRP3 inflammasome pathway. In conclusion, the NLRP3 inflammasome represents a critical molecular mechanism linking depression and CVD, as well as a potential target for combined therapeutic strategies. This area holds significant research and clinical translational value.