Mediators of Inflammation最新文献

[This corrects the article DOI: 10.1155/2023/8533476.].

Background: Efferocytosis, the phagocytic clearance of apoptotic cells, plays a key role in tumor progression and immune regulation, but its prognostic significance and molecular mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear.

Methods: Four efferocytosis-related pathways were curated, and the pathway activities were quantified in ccRCC. Prognostic genes were identified by univariate Cox regression and used to construct linear survival models with multiple algorithms, with the optimal model selected by cross-validation. Associations between the risk score and tumor mutational burden (TMB), mutation profiles, and copy number variation (CNV) were subsequently evaluated. Multiomics integration highlighted RAC1 as a key risk gene, which was further examined using single-cell and spatial transcriptomics (ST) to characterize expression patterns, tumor microenvironment interactions, and pathway enrichments. Protein-level validation was performed using immunohistochemistry (IHC) data from the Human Protein Atlas.

Results: Efferocytosis pathway activity was upregulated in ccRCC, increased with disease stage, and correlated with poorer survival. The ridge regression-based prognostic model demonstrated consistent predictive performance across independent datasets and was associated with higher TMB, specific mutation patterns, and increased CNV. Notably, RAC1, identified as the top weighted gene in the model, was overexpressed in association with copy number amplification, showing preferential enrichment in malignant core regions and strong links to oncogenic signaling.

Conclusion: Efferocytosis activation characterizes aggressive ccRCC. The developed prognostic model and identification of RAC1 as a central effector link efferocytosis-related risk to immune remodeling and oncogenic signaling, providing potential biomarkers and therapeutic targets.

Exercise is crucial for postmenopausal osteoporosis (PMOP) management, yet the comparative efficacy of different exercise modalities and the underlying mechanisms remain unclear. This study investigated the differential effects of distance-matched high-intensity interval training (HIIT) and moderate-intensity continuous exercise (MICE) on ovariectomy (OVX)-induced osteoporosis (OP) in mice. After 12 weeks of training, micro-CT analysis revealed that MICE, but not HIIT, significantly attenuated OVX-induced bone loss and microstructural deterioration. Crucially, only MICE suppressed osteoclastogenesis and reduced proinflammatory factors (interleukin [IL]-6, IL-1β, and tumor necrosis factor-alpha [TNF-α]) expression in the femur, serum, and colon. Mechanistically, MICE uniquely restored gut microbiota (GM) diversity, mitigated dysbiosis, and enhanced intestinal barrier integrity by upregulating the expression of tight junction proteins (TJPs; ZO-1, occludin, and claudin-1), thereby reducing systemic inflammation. In contrast, HIIT failed to ameliorate GM imbalance and intestinal permeability. Our findings demonstrate that the protective effect of MICE on OVX-induced OP is mediated through the gut-bone axis by modulating GM, repairing the intestinal barrier, and suppressing inflammatory osteoclast activation. This study provides novel evidence that the benefits of exercise on PMOP are modality-dependent, highlighting MICE as a superior strategy and offering mechanistic insights for optimizing exercise prescriptions.

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.