Mediators of Inflammation最新文献

Background: There is currently little research on the association between immune traits and urethral stricture, and the diversity of immune cell subtypes leads to an unclear association with urethral stricture. This study investigated the relationship between immune cells and urethral stricture using the Mendelian randomization (MR) technique.

Methods: We assessed the causative relationships between urethral stricture (N = 341,285) and 731 immunological characteristics (N = 3757). The main technique was the inverse-variance weighted (IVW) approach, which was supplemented by MR-Egger and weighted median (WM). The robustness of MR results was assessed using sensitivity analyses, primarily the Egger intercept, Cochran's Q test, MR-PRESSO, and leave-one-out test.

Results: Our findings revealed that 37 immune phenotypes have suggestive causal relationships with urethral stricture, including 13 subtypes of B cells, four classical dendritic cells, three myeloid cells, five monocytes, four TBNK, five Treg cells, and three maturation stages of T cells. Sensitivity analyses revealed neither heterogeneity nor pleiotropy.

Conclusions: Our findings supported a potential causal relationship between immune cells and urethral stricture. This may guide the management and treatment of urethral stricture in the future.

Background: Long noncoding RNAs (lncRNAs) are involved in regulating inflammatory responses in sepsis. This study aimed to investigate the potential roles of lncRNA SNHG5 in the pathogenesis of sepsis-induced coronary artery injury.

Methods: Cecal ligation and puncture were used to establish a sepsis mouse model. Serum and coronary artery tissues were collected to assess inflammatory markers and lncRNA expression using enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qPCR). In vitro, mouse aortic endothelial cells were exposed to septic serum. The SNHG5/miR-377-3p/methionyl aminopeptidase 2 (METAP2) axis was investigated using dual-luciferase reporter gene experiments. Loss-of-function, gain-of-function, and rescue assays were performed to elucidate the functions of these genes in sepsis.

Results: Septic mice exhibited elevated systemic tumor necrosis factor alpha and interleukin (IL)-6 levels, as well as dysregulated endothelial markers (eNOS downregulation and ET-1 upregulation). Among the inflammation-related lncRNAs, SNHG5 was the most significantly upregulated in septic coronary arteries and serum. Bioinformatic and experimental analyses revealed that SNHG5 acts as a competitive endogenous RNA (ceRNA) for miR-377-3p, thereby upregulating (METAP2). Silencing SNHG5 or METAP2 reduced IL-8 secretion and endothelial apoptosis; these effects were reversed by miR-377-3p inhibition. Conversely, METAP2 overexpression increased IL-8 secretion and apoptosis, which were attenuated by miR-377-3p mimics.

Conclusion: We identified the SNHG5/miR-377-3p/METAP2 axis as a novel regulatory pathway in sepsis-induced endothelial inflammation and apoptosis. SNHG5 promotes METAP2 expression by sponging miR-377-3p, leading to increased IL-8 secretion and endothelial dysfunction. These findings provide new insights into lncRNA-mediated mechanisms in sepsis.

Much evidence has demonstrated that the association between sepsis and diabetes can result in comorbidity effects. The endotoxin lipopolysaccharide (LPS) is a damaging factor that penetrates through the intestinal wall and into circulation in patients with diabetes. Benzydamine is a clinical drug widely used for pharyngitis and periodontitis with local anesthetic and analgesic properties. The purpose of this study was to investigate the anti-matrix degradative effects of benzydamine and its mechanisms on matrix metalloproteinase (MMP)-9 activation in LPS-stimulated THP-1 human monocytic cells under high-glucose condition. In this study, it was found that benzydamine could attenuate LPS-induced MMP-9-mediated gelatinolysis and protein expression in THP-1 cells under the normal-glucose condition. On the other hand, LPS induced higher MMP-9 gelatinolytic activity under the high-glucose condition than under the normal-glucose condition. Under the high-glucose condition, benzydamine also significantly inhibited LPS-induced MMP-9-mediated gelatinolysis and MMP-9 protein in THP-1 cells in a concentration-dependent manner. However, enzyme-linked immunosorbent assay (ELISA) showed that benzydamine partially affect TIMP-1 levels. Under the normal-glucose condition, benzydamine also inhibited tumor necrosis factor (TNF)-α-induced MMP-9-related gelatinolysis and its protein or mRNA expression. Among the signaling pathways, LPS-mediated phosphorylation of p38 or JNK MAPK was not affected by benzydamine. Surprisingly, it was strongly shown that benzydamine could significantly attenuate LPS-mediated phospho-ERK MAPK expression and translocation. Also, phosphorylation of p65 as NF-κB activation was markedly inhibited. Moreover, LPS-induced surface expression of TLR-4 and COVID-19 S1 protein-induced MMP-9-related gelatinolysis were abrogated by benzydamine under the high-glucose condition. In conclusion, benzydamine exerted anti-MMP-9 actions through inhibition of ERK MAPK and NF-κB activation under the high-glucose condition. This study revealed additional anti-monocytic properties of benzydamine in its potential for novel anti-inflammatory therapy.

Objective: Necrotizing enterocolitis (NEC) is a severe inflammatory disease of the intestine. Although previous studies have demonstrated that APOL1 plays an important role in regulating macrophage polarization and immune-mediated inflammatory diseases, its specific function in NEC remains unclear. We aim to further explore the role of APOL1 in NEC and its efficacy as a diagnostic biomarker.

Methods: We performed tissue transcriptomic and plasma proteomic analyses based on clinical samples from preterm infants with NEC patients and conducted multilevel experimental validations. An in vitro macrophage polarization model was established to further investigate the regulatory role of APOL1 in macrophage differentiation. The diagnostic potential of APOL1 for NEC was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: Multiomics analyses revealed a significant upregulation of APOL1 expression in NEC, which was further confirmed by qPCR, immunofluorescence, and ELISA. Pathway enrichment and immune infiltration analyses indicated that APOL1 is positively associated with M1 macrophage infiltration and the expression of multiple proinflammatory cytokines. Immunofluorescence staining further demonstrated that APOL1 is highly expressed in M1 macrophage-enriched regions. In vitro experiments showed elevated APOL1 expression in M1 macrophages, while its inhibition significantly reduced intracellular reactive oxygen species (ROS) accumulation and NF-κB p65 activation, thereby suppressing M1 polarization. Moreover, the combination of plasma APOL1 and lymphocyte count (LYM) demonstrated high diagnostic efficacy for NEC, with an AUC value of 0.96 (sensitivity 93.3% and specificity 93.3%).

Conclusions: Our findings reveal a marked upregulation of APOL1 in preterm infants with NEC. Mechanistically, we propose that the APOL1-ROS-NF-κB axis constitutes a novel and promising therapeutic target for NEC intervention. Furthermore, the combined detection of plasma APOL1 and LYM demonstrates high efficacy.

Glioblastoma (GBM) is a highly aggressive central nervous system malignancy with a dismal 5-year survival rate of less than 5%, and poorly understood environmental factors complicate its treatment. One such factor is bis(2-ethylhexyl) phthalate (DEHP, also known as di-2-ethylhexyl phthalate), a common plasticizer with documented neurotoxicity, yet its potential role in GBM pathogenesis remains elusive. In this study, we employed an integrative computational framework that combined network toxicology, single-cell transcriptomics, proteome-wide and metabolome-wide Mendelian randomization (MR), and molecular dynamics (MD) simulations to systematically investigate the interplay between DEHP and GBM risk. Cross-dataset targets were identified by mining toxicogenomic and disease databases, followed by the construction of a protein-protein interaction (PPI) network. This approach identified 76 overlapping targets between DEHP and GBM, which were refined to 24 hub genes through topological analysis. Notably, MR analyses revealed putative causal associations between higher genetically predicted plasma levels of three hub proteins-CD63, CTSS, and S100A4-and an increased risk of GBM, with S100A4 showing the strongest effect (odds ratio [OR] = 2.03, 95% confidence interval [CI] 1.15-3.58, p = 0.0149). This association was consistently validated across 11 independent cohorts, including TCGA, GTEx, and GEO datasets. Molecular docking and dynamics simulations identified S100A4 as the predominant binding target of DEHP, revealing a high-affinity interaction that may stabilize a metastasis-associated conformation. A two-step MR mediation analysis further indicated that S100A4 partially influences GBM risk by altering plasma lipid metabolites, with erucic acid mediating ~17% of the total effect. In conclusion, our analysis provides converging computational and genetic epidemiological evidence for a novel DEHP-S100A4-lipid metabolic axis that may contribute to GBM development. This pathway conceptually bridges environmental toxicology and neuro-oncology and highlights S100A4 and associated lipid disturbances as potential targets for preventive intervention. However, the proposed mechanistic links remain inferential, and definitive confirmation will require future in vitro and in vivo experiments to directly test the impact of DEHP on S100A4 expression, function, and downstream metabolic reprogramming in GBM models.

Objectives: Cerebrovascular disease (CeVD), the second leading global cause of death, has an incompletely understood pathogenesis. This study aimed to investigate causal relationships among gut microbiota, inflammatory cytokines, and CeVD, specifically examining inflammatory cytokine-mediated pathways.

Methods: Genome-wide association study (GWAS) summary statistics for 209 gut microbial taxa, 91 inflammatory cytokines, and three CeVD subtypes were obtained from publicly available datasets. Causal effects were estimated by applying four complementary two-sample Mendelian randomization (MR) methods. Reverse MR and comprehensive sensitivity analyses were performed to validate the robustness of the findings. Multivariable MR (MVMR) analyses were conducted to account for potential confounders. Mediation analysis was conducted to elucidate the pathways from gut microbiota to CeVD, mediated by inflammatory cytokines.

Results: Our study identified 33 gut microbiota significantly associated with CeVD, including nine with ischemic stroke (IS), 14 with intracerebral hemorrhage (ICH), and 10 with subarachnoid hemorrhage (SAH). Eighteen inflammatory cytokines showed significant associations with different CeVD subtypes. Mediation analysis revealed 10 causal pathways from gut microbiota to CeVD mediated by inflammatory cytokines; among these, three inflammatory cytokines mediated more than two pathways.

Conclusions: This study demonstrated that inflammatory cytokines mediated the gut microbiota-CeVD causal pathway through genetic evidence, elucidating novel disease mechanisms, thereby providing actionable insights for developing CeVD prevention and treatment strategies.

Background: Pulmonary hypertension (PH) is a serious disease that manifests itself as elevated pressure within the pulmonary arteries. The onset of PH is usually insidious, and if left untreated, it may lead to heart failure and even life-threatening conditions. Recent studies have shown that sophocarpine (SOP) has significant effects on antioxidant, anti-inflammatory, antifibrotic, and hemodynamic improvement, and it may become an emerging drug for the treatment of PH. However, the specific mechanism of action of SOP still requires further experimental validation.

Methods: We established in vivo and in vitro models of PH and treated them with varying concentrations of SOP. To visualize the changes in rats and cells, we used scratch assay, flow cytometry, Western blotting, pulmonary artery pressure measurement, biochemical analysis, enzyme-linked immunosorbent assay (ELISA), ultrasound scanning, hematoxylin and eosin (HE) staining, and Masson's trichrome staining.

Results: Our results showed that SOP significantly alleviated the inflammatory response and apoptosis induced by PH, reduced pulmonary artery pressure, and restored the balance of pulmonary artery remodeling. These effects were found to be effective in alleviating PH.

Conclusion: Our study provides clear evidence that SOP has a significant protective effect in the PH model and is expected to be a promising therapeutic agent for PH.

Background: This study aimed to investigate the association between systemic inflammatory biomarkers-specifically the systemic inflammatory response index (SIRI), systemic immune inflammation index (SII), and aggregate index of systemic inflammation (AISI)-and the prevalence of diabetic foot ulcer (DFU).

Method: We conducted a cross-sectional analysis using data from three cycles of the National Health and Nutrition Examination Survey (NHANES), supplemented by a single-center retrospective clinical study. Initially, 31,126 participants were screened from NHANES. Binary logistic regression models (both unadjusted and adjusted for covariates) were employed to evaluate the associations between ln SIRI, ln SII, and ln AISI and DFU prevalence. Restricted cubic spline (RCS) analysis was applied to assess nonlinear relationships, and subgroup analyses were performed to examine the stability of associations across strata defined by age, gender, race, body mass index (BMI), smoking status, and hypertension. Additionally, a clinical validation study was conducted from January to December 2023, comprising 34 DFU patients and 68 diabetic controls. We performed multivariable binary logistic regression analyses to assess the independent associations between systemic inflammatory indices and the presence of DFU, adjusting for age, sex, diabetes duration, BMI, and albumin levels. Receiver operating characteristic (ROC) curve analysis was used to preliminarily assess the discriminatory ability of SII, SIRI, and AISI for DFU status.

Results: The cross-sectional analysis included 135 participants with DFU and 1560 without DFU. Logistic regression revealed consistent positive associations between ln SIRI, ln SII, and ln AISI and DFU prevalence in both unadjusted and adjusted models. RCS analysis indicated linear dose-response relationships for all three biomarkers. Subgroup analyses confirmed that these associations remained stable across demographic and clinical subgroups. In the retrospective clinical study, ln SIRI, ln SII, and ln AISI were significantly associated with DFU prevalence, with odds ratios (ORs) as follows: ln SIRI: OR = 2.51 (95% CI: 1.39-4.54), ln SII: OR = 5.44 (95% CI: 2.48-11.91), and ln AISI: OR = 2.75 (95% CI: 1.59-4.74). After adjusting for key confounders, the associations between these biomarkers and DFU remained consistent in both direction and statistical significance. ROC analysis showed that SII was more reliable than the other two for predicting DFU.

Conclusion: By integrating a cross-sectional NHANES-based analysis with a clinical retrospective study, this research demonstrates that elevated levels of SIRI, SII, and AISI are significantly associated with an increased prevalence of DFU. These systemic inflammatory biomarkers may serve as valuable tools for risk assessment in patients with DFU.

About 25% of patients with myelodysplastic syndromes (MDS) have combined autoimmune diseases (AIDs). However, the relationships between MDS and AIDs, especially a causal relationship and the underlying shared pathophysiological mechanisms, remain largely unknown. We aimed to evaluate the association between MDS and AIDs using a multicenter retrospective study, Mendelian randomization (MR), and bioinformatics analysis. About 26.6% of patients with MDS from all centers presented with AIDs. Compared to MDS patients without AIDs, MDS with AIDs was less likely to progress to acute myeloid leukemia (AML) (6.6% vs. 15.1%, p = 0.037), and the pre-existing AIDs could be used as an independent protective factor of survival (HR: 0.504, p = 0.048). Bidirectional MR results showed that MDS could cause the risk of systemic lupus erythematosus (SLE, OR: 1.09, p = 0.015), although with no significant causal relationship in other AIDs. The effect of MDS on SLE may be partially mediated by naïve CD4+ T-cells (median proportion 6.9%) and CD45RA-CD4+ T memory cells (median proportion 9.0%). Furthermore, two hub genes (IFI27 and VSIG4) were identified by machine learning and curve analysis as potential diagnostic markers for MDS with SLE. Our study suggested that the impact and mechanisms of AIDs in MDS need to be taken seriously, which could provide more accurate treatment guidance.

Background: Coronary heart disease (CHD) remains the leading global cause of death; concomitant diabetes mellitus (DM) doubles short-term mortality, largely through chronic low-grade inflammation. Inexpensive, bedside complete blood count (CBC)-derived inflammatory indices (NLR, MLR, PLR, SII, SIRI, and AISI) predict outcomes in CHD or DM alone, but their utility in comorbid patients is unclear.

Methods: Retrospective cohort study of CHD-DM patients from Medical Information Mart for Intensive Care-IV (MIMIC-IV; 2008-2022), split into training (2017-2022, n = 1607) and validation (2008-2016, n = 1145) sets. Six indices (NLR, MLR, PLR, SII, SIRI, and AISI) were calculated from initial ICU CBC (48-h mean for sensitivity analysis). Primary outcome: 28-day mortality, Cox regression, restricted cubic splines (RCSs), receiver operating characteristic (ROC) curves, calibration plots, and SHAP-based variable importance were used.

Results: Mortality was 10.6% (training) and 11.9% (validation). All indices showed independent, dose-dependent associations with mortality (e.g., training MLR per 1-SD: HR = 1.49, 95% CI = 1.37-1.61), discrimination was good (training AUC 0.767, C-index 0.752; validation AUC 0.755, C-index 0.746), and calibration was excellent. Spearman correlation showed moderate-to-strong interindex correlations (e.g., MLR-SIRI: r = 0.84). SHAP analysis ranked PLR and MLR as top predictive indices. Sensitivity analysis confirmed robustness.

Conclusions: Six CBC-derived indices independently predict 28-day mortality in critically ill CHD-DM patients, with PLR and MLR showing superior predictive weight, and can be used for rapid, cost-free bedside risk stratification.