Mediators of Inflammation最新文献

Background: Macrophages are central to innate immune responses and are crucial in maintaining homeostasis and managing inflammatory diseases. Forkhead box J2 (Foxj2) is a member of the forkhead/hepatocyte nuclear factor 3 transcription factor family and is essential for multiple biological functions. However, the involvement of Foxj2 in the inflammatory process in macrophages remains unclear.

Objective: The present study aimed to explore the role of Foxj2 in the inflammatory processes of macrophages activated through lipopolysaccharide (LPS) stimulation.

Methods: The modulation of Foxj2 expression in macrophages in response to LPS stimulation was investigated via reverse-transcription quantitative (RT-q) PCR, Western blot, and immunofluorescence staining assays. Macrophages were infected with adenovirus vectors to upregulate the expression of the Foxj2 gene. Luciferase reporter gene assay and chromatin immunoprecipitation (ChIP)-PCR analysis were used to determine the regulatory relationship between Foxj2 and Tak1 (transforming growth factor-β-activated kinase 1).

Results: LPS stimulation of peritoneal macrophages led to a significant decrease in Foxj2 expression. In addition, LPS treatment led to Foxj2 depletion in several mouse tissues, including the heart, liver, spleen, lungs, kidneys, adipose tissue, blood vessels, and peritoneal macrophages. Furthermore, Foxj2 overexpression ameliorated the mRNA expression of TNF, IL-1β, IL-6, IL-12, IFN-stimulated gene 15, and IFN-β in macrophages treated with LPS. Additionally, Foxj2 overexpression attenuated phosphorylation of Stat1, p65, Erk1/2, Jnk, and p38. Subsequent experiments confirmed the binding of Foxj2 to the promoter region of Tak1, led to the suppression of Tak1's transcriptional activity. Moreover, a reduction in Foxj2 levels was observed during the pathological processes of numerous diseases characterized by inflammation, including high-fat diet (HFD)-induced obesity, HFD-induced nonalcoholic fatty liver disease (NAFLD), doxorubicin-induced cardiomyopathy, acute myocardial infarction (AMI) and D-galactose induced aging conditions.

Conclusion: The present findings indicated that Foxj2 is crucial in mitigating macrophage inflammation induced by LPS and might be considered a target for treating sepsis and other inflammatory diseases.

Background and aim: Biologic disease-modifying antirheumatic drugs (bDMARDs) are effectively used to relieve symptoms in inflammatory bowel diseases (IBD). The study aimed to examine the rate of non-responders to bDMARD treatment in Australian population.

Method: Cohort studies using a 10% random sample of the population dispensing medicines under the Australian Pharmaceutical Benefits Scheme (PBS). People aged 18 years and over who initiated bDMARD for IBD in 2019 or 2020 were followed for 12 months. The proportion of non-responders (people who discontinued initial therapy by Week 16 and 40) was determined using Kaplan-Meier survival analysis.

Results: There were 522 initiators of bDMARD for Crohn's disease (mean age of 42 years). By Week 16, 15% discontinued initial therapy (primary non-responders); 22% of initial responders discontinued bDMARD by Week 40 (secondary non-responders). The primary non-responder rate was lowest amongst infliximab initiators (6%), and highest for ustekinumab (24%). Infliximab had the lowest (17%) secondary non-responder rate compared to the other biologics, suggesting less loss of response over time.There were 390 initiators of bDMARD for ulcerative colitis (UC) (mean age of 44 years). By Week 16, 25% discontinued initial therapy; 21% of people with initial response discontinued by Week 40. The non-responder rates were lowest amongst vedolizumab initiators (5% for primary and 8% for secondary) and highest amongst adalimumab (50% for primary and 48% for secondary).

Conclusion: Comparison between bDMARD agents showed lowest initial non-response and lowest loss of sustained response in infliximab initiators with Crohn's disease and in vedolizumab initiators with UC.

Background: Previous studies have found that some indices derived from preoperative complete blood count (CBC) are closely related to the prognosis of glioma, but the results are inconsistent. This study comprehensively discussed the prognostic significance of the preoperative CBC index in patients with glioblastoma (GBM) through a multicenter study.

Methods: In this multicenter study, we retrospectively analyzed clinical data from 143 GBM patients to evaluate the prognostic value of 12 preoperative CBC-derived indicators: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), red cell distribution width (RDW), platelet distribution width (PDW), RDW-to-PDW (RPR), systemic inflammation index (SII), systemic inflammation response index (SIRI), hemoglobin-to-red cell distribution width ratio (HRR), platelet-to-basophil ratio (PBR), lymphocyte-to-basophil ratio (LBR), and eosinophil-to-lymphocyte ratio (ELR). Optimal cut-off values for each indicator were determined using maximally selected rank statistics (MSRS). Survival outcomes were assessed by Kaplan-Meier analysis, and univariate and multivariate Cox regression were employed to identify independent prognostic factors. Furthermore, a nomogram was developed by integrating significant prognostic indicators to facilitate individualized prediction of survival in GBM patients.

Results: The results showed that higher levels of NLR, PLR, MLR, RDW, PDW, and RPR were associated with shorter survival in GBM patients. In contrast, lower levels of ELR were associated with shorter survival in GBM patients. Among these, RDW (HR 1.905, 95% CI 1.114-3.258, p = 0.019), MLR (HR 1.603, 95% CI 1.029-2.496, p = 0.037), and ELR (HR 0.380, 95% CI 0.193-0.747, p = 0.005) emerged as an independent prognostic factors. The prognostic nomogram was constructed according to the three independent factors, which improved the accuracy of prognosis prediction (AUC = 0.702).

Conclusion: Routine preoperative CBC parameters, particularly RDW, MLR, and ELR, serve as valuable complementary prognostic indicators for GBM patients. These accessible biomarkers warrant further validation through large-sample, multicenter studies to solidify their clinical utility.

[This retracts the article DOI: 10.1155/2019/8709583.].

Nontraumatic intracerebral hemorrhage (ICH), characterized by bleeding into the brain parenchyma, is a major cause of adult disability and mortality. The pathophysiology of ICH involves complex processes, including mass effect and subsequent inflammatory responses, which cause severe primary and secondary brain damage. As the first responders in neuroinflammatory reactions, neutrophils are rapidly recruited to the hemorrhage site. They interact with other immune cells, release cytotoxic molecules, and significantly exacerbate neuroinflammation. In the acute phase, neutrophils secrete cytokines, chemokines and neutrophil extracellular traps (NETs), which are particularly detrimental to brain tissue. However, in later stages, infiltrated neutrophils can adopt an immunosuppressive phenotype, exerting beneficial effects. Emerging evidence reveals that neutrophils play a multifaceted role in ICH progression, shifting between anti-inflammatory or pro-inflammatory phenotypes depending on brain tissue niche. Hence, tuning neutrophils into a beneficial phenotype represents a promising therapeutic strategy for ICH. We conducted a comprehensive literature search in PubMed and Web of Science databases for relevant studies published up to July 2025, using keywords including "intracerebral hemorrhage (ICH)," "neutrophil," "inflammation," "neuroinflammation," " neutrophil extracellular traps (NETs)," "treatment," "therapy," and "therapeutics." In this article, we explore the roles of neutrophils in ICH, encompassing their recruitment, activation mechanisms, interactions with other immune cells, and impact on neuroinflammation and neuronal injury. Furthermore, we discuss therapeutic strategies targeting neutrophil-mediated pathways in ICH, highlighting potential avenues for future research and clinical intervention.

Some natural remedies in traditional Chinese medicine (TCM) inhibit tumor progression and increase sensitivity in the treatment of patients who have received radiation therapy. However, the specific synergistic effect of the active ingredients in the traditional Chinese therapeutic Rongbei Maimendong decoction (RBMD) on sensitivity to radiation therapy for non-cell lung cancer (NSCLC) is still unclear. RBMD inhibited transplanted tumor cell growth in mice, showing a dose-dependent effect in tumor growth inhibition following radiotherapy. Our study utilized bioinformatics analysis and liquid chromatography with tandem mass spectrometry to identify the presence of β-thymidine (β-thy) in Phellodendron bark, the primary component of RBMD. This compound modulated mRNA and protein levels of SOD1 by interacting with SOD1, inhibiting the malignant characteristics (proliferation, apoptosis, migration, and invasion) of NSCLC cells. Furthermore, apoptosis assays demonstrated that β-thy attenuated tumor growth in mice following radiotherapy. Single-cell gel electrophoresis assays demonstrated the ability of SOD1 to mitigate DNA damage in irradiated (IR) NSCLC cells, suppressing apoptosis, and that β-thy attenuated this SOD1 protective effect, mitigating NSCLC cells resistance to radiation. We propose that the consumption of RBMD, which is rich in β-thy, may enhance NSCLC radiosensitivity by hindering DNA repair mechanisms and facilitating apoptosis through DNA damage augmentation.

Background: Inflammatory cytokines have been implicated in monoclonal gammopathy of undetermined significance (MGUS), but their causal mechanisms remain unclear. Metabolites play pivotal roles in plasma cell dysregulation, however, their potential mediation effects between cytokines and MGUS are unexplored. We aimed to elucidate causal relationships between inflammatory cytokines and MGUS and identify metabolite-mediated pathways.

Methods: Using genome-wide association study (GWAS) summary statistics, we performed bidirectional two-sample Mendelian randomization (MR) to assess causality between 91 inflammatory cytokines and MGUS. A two-step MR approach was employed to investigate metabolite mediation using data from 1400 blood metabolites. Sensitivity analyses addressed pleiotropy and reverse causality (IVs: p < 1 × 10^-5, F-statistic > 10).

Results: MR analysis identified CXCL10 (OR = 2.12, 95% CI: 1.06-4.23, p = 0.034) and IL-6 (OR = 3.61, 95% CI: 1.22-10.65, p = 0.020) as causal risk factors for MGUS. We also found Threonate (OR = 2.24, 95% CI: 1.06-4.75, p = 0.035), X-22776 (OR = 3.45, 95% CI: 1.37-8.67, p = 0.009) and glucose to sucrose ratio (OR = 2.89, 95% CI: 1.18-7.07, p = 0.020) were associated with increased MGUS risk, while N-acetylputrescine to (N(1) + N(8))-acetylspermidine ratio (OR = 0.65, 95% CI: 0.43-0.98, p = 0.039) showed protective effects. Mediation analysis revealed 2 metabolites Threonate and X-22776 mediating CXCL10's effect on MGUS. Threonate mediated 11.2% (β = 0.08, p = 0.014) and X-22776 mediated 17.7% (β = 0.13, p = 0.028) of CXCL10's total effect. Sensitivity analyses confirmed robustness (no pleiotropy: MR-Egger intercept p > 0.05; Cochran's Q p > 0.05).

Conclusion: This study deeply reveals the mechanism by which inflammatory cytokines affect the pathogenesis of MGUS through metabolite-mediated pathways, providing new potential targets for the early diagnosis and treatment of MGUS. In the future, other inflammatory cytokines and metabolites that may be related to the pathogenesis of MGUS can be further explored, and the interactions and potential mechanisms between them can be further studied to provide a more comprehensive theoretical basis and practical guidance for the prevention and treatment of MGUS.

Objection: Pulmonary arterial hypertension (PAH) was a cancer-like disease. It shared several mechanisms, including perivascular inflammation. But the genes common and different between cancer and PAH was still unclear. We aimed to analyze the genes common in the two diseases, especially the N7-methylguanosine (m7G) genes.

Methods: We acquired dataset GSE1519, GSE113439, and GSE81089 and recognized differentially expressed genes (DEGs) and investigated their functions utilizing R software. m7G-related genes were identified using a online tool RMvar. The extent of immune cell infiltration in the normal and PAH tissues, nonsmall cell lung cancer (NSCLC) tissues was determined using ImmuneCellAI and CIBERSORT. Additionally, the association between diagnostic markers and immune cells was analyzed. Single cell analysis and Cellchat were used to analyze the role of SPP1 in the PAH.

Results: Among five DEGs overlapped by the differently datasets about NSCLC, CD163, and SPP1 were m7G genes. The immune cell infiltration results suggested that PAH and NSCLC shared different immune cell infiltration. SPP1 was significantly correlated to the macrophage cells and activated mast cells in NSCLC. Higher expression of CD163 and SPP1 might be related to the progression of monocrotaline (MCT) induced rats in the dataset GSE229361. The KM survival analysis suggested that higher expression of CD163 and SPP1 related to poor prognosis of NSCLC. The important role of SPP1 in PAH was verified using single cell anslysis.

Conclusion: Different T cells infiltration contributed to the development of PAH and NSCLC. SPP1 might be vital for the cancer-like characteristics of PAH.

Colorectal adenomas (CRA) represent critical precursors to colorectal cancer (CRC), yet reliable transcriptomic biomarkers for early detection and therapeutic targeting remain limited. Integration of gut microbiota (GM) genetics with transcriptomics offers a novel approach to identify disease-associated molecular signatures. We sought to identify GM-associated molecular signatures that could serve as early intervention targets. We integrated transcriptomic data with Mendelian randomization (MR) analysis to establish causal relationships between GM and CRA development. Machine learning algorithms identified robust biomarkers, which we validated through expression analysis and receiver operating characteristic (ROC) analysis to construct predictive nomogram models. Comprehensive molecular characterization included Gene Set Enrichment Analysis (GSEA), immune profiling, and regulatory network analysis. Single-cell RNA sequencing (scRNA-seq) analysis further validated biomarker expression patterns across distinct cell populations in the tumor microenvironment. We discovered 12 GM species with significant causal relationships to CRA risk. Two biomarkers, TMOD2 and DOCK4, emerged as powerful predictive indicators with strong correlation (r = 0.66, p  < 0.001). These biomarkers demonstrated excellent diagnostic performance in ROC analysis and revealed previously unrecognized connections to cell adhesion pathways critical for adenoma progression. Single-cell analysis revealed TMOD2 expression across multiple cell clusters with notable exclusion in mast cells, while DOCK4 expression was predominantly restricted to fibroblasts, myeloid, and epithelial cells. Notably, we identified distinct immune cell infiltration patterns, including altered naive B cells and macrophage populations, suggesting immune dysregulation as a key mechanism. GSEA revealed enrichment in cell adhesion molecule (CAM) pathways. Regulatory network analysis uncovered complex control by 18 microRNAs (miRNAs), 40 long noncoding RNAs (lncRNAs), and 10 transcription factors (TFs), with EIF3A emerging as a key m6A reader protein. Drug screening identified 22 potential therapeutic compounds, with trichostatin A showing optimal binding affinity. These findings establish TMOD2 and DOCK4 as novel biomarkers linking GM dysbiosis to CRA development, opening new avenues for microbiome-targeted early intervention strategies.

Purpose: Evidence is accumulating that links gut microbiota, a crucial component of the immune environment, to Sjogren's syndrome (SS). The mechanisms underlying the influence of gut microbiota on the onset and development of SS are still not completely understood. To this end, we applied a Mendelian randomization (MR) framework to investigate whether inflammatory cytokines mediate the association of gut microbiota with SS.

Methods: Our MR analysis leveraged publicly available GWAS data, including information on 211 gut microbiota taxa sourced from the MiBioGen consortium (18,340 participants), summary statistics for 91 inflammatory cytokines obtained from a study of 14,824 individuals, and genetic data for SS derived from the UK Biobank (407,746 participants). To investigate causal associations between gut microbiota and SS, we primarily employed the inverse variance weighted method, supported by additional techniques such as MR-Egger, simple mode, weighted median, and weighted mode for validation. The potential mediating effect of inflammatory cytokines in the gut microbiota-SS relationship was investigated using both mediation MR and multivariable MR (MVMR) analyses.

Results: MR analysis identified five microbiota taxa causally associated with SS. Particularly, class Gammaproteobacteria (OR = 3.468, 95% CI = 1.139-10.557, p=0.029) and genus Peptococcus (OR = 1.722, 95% CI = 1.082-2.471, p=0.022) were significantly associated with an increased risk of developing SS. Six inflammatory cytokines were identified as potentially causal, with Axin-1 (OR = 2.556, 95% CI = 1.072-6.096, p=0.034) and C-X-C motif chemokine 10 levels (CXCL10) (OR = 3.049, 95% CI = 1.428-6.513, p=0.004) being the most critical contributors. Mediation MR analysis showed that Axin-1 levels mediated 16.96% of the causal effect of class Gammaproteobacteria on SS, CXCL10 levels mediated 36.78% of the causal effect of genus Coprococcus3 on SS.

Conclusion: The findings suggest that certain gut microbiota is sociated with an increased risk of SS, mediated by specific inflammatory cytokines.