Journal of Inflammation Research最新文献

Purpose: To develop and externally validate an interpretable machine learning model for preoperative prediction of Gangrenous cholecystitis (GC) using multicenter clinical data.

Patients and methods: This retrospective multicenter study included 744 patients with cholecystitis who underwent cholecystectomy at one institution, split into training (n=521) and testing (n=223) cohorts, and a temporal external validation cohort of 300 patients from a second center. Twenty preoperative variables were screened by LASSO regression and Boruta algorithm; predictors selected by both were used to construct six machine learning models. Model performance was assessed via AUC, calibration, and decision curve analysis. SHAP analysis provided model interpretability.

Results: The Random Forest (RF) model demonstrated superior predictive performance, achieving an AUC of 0.893 in the training set, 0.875 in the testing set, and 0.818 in external validation. Calibration and decision curve analyses indicated excellent agreement and clinical benefit. SHAP analysis identified gallbladder wall thickening, C-reactive protein, pericholecystic fluid, white blood cell count, and impacted stone as the most influential predictors, ensuring transparency of model decisions.

Conclusion: In our multicenter cohorts, this interpretable machine learning model showed good discrimination for preoperative risk stratification of gangrenous cholecystitis and acceptable generalizability between centers. By integrating clinical, laboratory, and imaging features and providing explainability, the approach may assist perioperative decision-making when used alongside clinical judgment. Prospective, multicenter evaluations and clinical impact studies are warranted before routine clinical adoption.

Background: Perianal Abscess is an inflammatory disease caused by infection in the perianal area, characterized by inflammatory cell infiltration and imbalance of intestinal flora. The herbal medicine anti-inflammatory combination (KYHJ) has therapeutic effects in acute and chronic soft tissue infections, but the specific therapeutic mechanism in perianal inflammatory diseases is unclear. There is a literature evidence showing the role of OSM gene in inflammatory conditions, however this was not previously studied in perianal abscess.

Methods: A perianal inflammation model was constructed in SD rats using 75% glacial acetic acid and treated with different doses of KYHJ; genome-wide changes were detected by RNA sequencing. H&E staining observed pathological states, TUNEL kit detected apoptosis, WB measured apoptotic protein levels, ELISA detected inflammatory factors in serum, and 16S rRNA sequencing analyzed intestinal flora abundance. In vitro, an anal epithelial cell inflammation model induced by LPS was treated with 10% KYHJ-containing serum; EDU assay, flow cytometry, WB, and ELISA were used to detect cell proliferation, apoptosis, related protein levels, and inflammatory factor secretion. Oncostatin M gene was knocked down in rats and overexpressed in epithelial cells for mechanism exploration.

Results: Results showed that KYHJ ameliorated perianal tissue inflammatory infection, inhibited apoptosis, and restored intestinal flora abundance. Initial transcriptome analysis, RT-qPCR and WB performed in this study have additionally supported the role of OSM gene. RNA sequencing linked the tested anti-inflammatory effects of KYHJ to reduced Oncostatin M (OSM) gene expression. RNA transcriptome sequencing showed high Oncostatin M expression in inflamed rats and low expression in the KYHJ group; in vivo knockdown improved perianal inflammation and increased flora abundance. In vitro, KYHJ - containing serum inhibited LPS - induced apoptosis, promoted proliferation, and reduced inflammatory factor secretion, which were reversed by Oncostatin M overexpression.

Conclusion: KYHJ ameliorates perianal inflammatory diseases by targeting Oncostatin M, restoring intestinal flora imbalance, promoting cell proliferation, and inhibiting apoptosis.

Purpose: Dupilumab is known to cause transient, asymptomatic eosinophilia, but in rare cases it can present as eosinophilic pneumonia accompanied by cough. This study reports a distinct manifestation of dupilumab-related eosinophilia presenting as a severe dry cough despite the absence of radiological or clinical evidence of eosinophilic pneumonia.

Patients and methods: A retrospective analysis of clinical data from patients with severe eosinophilic asthma (SEA) treated with dupilumab at the Guangzhou Institute of Respiratory Disease between August 2020 and February 2025 was conducted. Data on clinical manifestations, objective indicators and subjective questionnaires were collected at four time-points: before dupilumab initiation, preceding dupilumab-related cough, during the cough episode, and after cough resolution.

Results: Five patients treated with dupilumab (three males and two females with a mean age of 65.6 ± 9.2 years) developed a severe dry cough and marked eosinophilia (1,130-4,050 cells/μL) without radiologic or clinical evidence of eosinophilic pneumonia. The cough began after one to eleven dupilumab courses. Despite the increase in eosinophils, all patients achieved their personal best FEV1 versus baseline. The symptoms resolved with a short course of systemic corticosteroids (in four patients) or antitussive therapy alone (in one patient).

Conclusion: Dupilumab-related eosinophilia can manifest as a severe, steroid-responsive coughing despite the absence of parenchymal eosinophilic disease.

Biologic therapies such as infliximab and adalimumab have transformed the management of inflammatory bowel disease. However, many patients experience primary or secondary loss of response, often due to the development of anti-drug antibodies. The cause of anti-drug antibody formation is thought to be influenced by genetic variations, with human leukocyte antigen alleles-particularly HLA-DQA1*05-emerging as consistent risk factors for immunogenicity, but other candidate variants may also be of importance. To explore the role of genetic predictors in anti-drug antibody development, we systematically reviewed the literature. A search of Medline, Embase, and the Cochrane Library identified 1944 records, of which 27 studies met inclusion criteria. Across these studies, HLA-DQA1*05 carriage was repeatedly associated with higher antibody formation, lower drug levels, treatment failure, and secondary loss of response. Other HLA alleles and FCGR3A variants were also linked to increased risk, while some haplotypes appeared protective. Findings varied depending on the drug, genetic background, and patient population. The role of concomitant immunomodulator therapy was inconsistent, though some genotypes appeared to benefit. Overall, HLA-DQA1*05 and FCGR3A variants are the most reliable predictors of immunogenicity, particularly in infliximab-treated patients. Future work should prioritize large, multi-ethnic prospective studies with standardized antibody measurements and integrated pharmacogenomic approaches to establish clinical utility.

Background: Endothelial cells (ECs) senescence has emerged as a critical factor in the pathogenesis of atherosclerosis, contributing to vascular aging and plaque formation. However, the molecular mechanisms underlying endothelial senescence in atherosclerosis remain poorly understood.

Methods: Single-cell RNA sequencing (scRNA-seq) data from atherosclerotic core plaques and adjacent normal tissues were analyzed using the Seurat package to identify cell subpopulations and senescence markers. RNA-seq data from early and late atherosclerotic plaques were used for differential gene expression analysis. Subsequently, the candidate gene was identified and validated in the atherosclerotic plaques of ApoE^-/- mice and ox-LDL-treated human aortic ECs (HAECs) through siRNA knockdown, Western blot, RT-qPCR, and β-galactosidase staining in vitro.

Results: Single-cell analysis revealed elevated levels of senescence markers in ECs within atherosclerotic plaques. Combined with bulk RNA-seq analysis, SULF1 was identified as a key gene associated with EC senescence. Increased Sulf1 expression was uncovered in the ECs of atherosclerotic plaques in high-fat-fed ApoE^-/- mice. In vitro, SULF1 expression was found significantly upregulated in senescent HAECs. Knockdown of SULF1 reversed ox-LDL-induced senescence in HAECs, as shown by reduced expression of senescence markers and improved cell migration in wound healing assays.

Conclusion: This study highlights the critical role of endothelial senescence in atherosclerosis and identifies SULF1 as a key contributor to endothelial senescence and atherogenesis. Targeting SULF1 may be a potential therapeutic strategy for mitigating EC senescence and atherosclerosis.

Purpose: Chronic heart failure (CHF) is a major public health issue with high morbidity and mortality, where inflammation plays a key role in its progression. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and NOD-like receptor protein 3 (NLRP3) regulate inflammatory responses, but their prognostic value in CHF remains unclear. This study aims to investigate the association between serum levels of TNFAIP3 and NLRP3 and the risk of major adverse cardiovascular events (MACEs) in patients with CHF.

Patients and methods: A cohort study was conducted involving 318 patients with CHF and 122 controls. Serum levels of TNFAIP3 and NLRP3 were measured using enzyme-linked immunosorbent assay method. Propensity score matching (PSM) was used to control for confounders. Multivariable logistic regression, restricted cubic spline, threshold effect, and receiver operating characteristic (ROC) analyses were employed to evaluate the associations between biomarker levels and MACEs over a 6-month follow-up.

Results: After PSM, patients with CHF had significantly higher TNFAIP3 and NLRP3 levels than controls (both p < 0.001). Compared to CHF patients without MACEs, those with MACEs exhibited significantly lower levels of TNFAIP3 and higher levels of NLRP3. Multivariable analysis confirmed TNFAIP3 as an independent protective factor [odds ratio (OR)= 0.61, 95% confidence interval (CI): 0.40-0.93) and NLRP3 as an independent risk factor (OR = 1.24, 95% CI: 1.17-1.31) for MACEs. ROC analysis demonstrated NLRP3 (AUROC = 0.756) had better predictive ability than TNFAIP3 (AUROC = 0.611).

Conclusion: TNFAIP3 and NLRP3 are significantly associated with the risk of MACEs in patients with CHF and NLRP3 demonstrates stronger predictive performance than TNFAIP3.

Purpose: Previous studies have highlighted a strong association between programmed cell death and ulcerative colitis (UC). Banxia Xiexin decoction (BXD) is a thoroughly validated formula with an extensive history of clinical application for treating UC. However, it remains unclear whether BXD regulates pyroptosis and necroptosis in UC. This study focused on pyroptosis and necroptosis to investigate the underlying mechanisms of BXD on UC.

Material and methods: The therapeutic effects of BXD were evaluated in a dextran sulfate sodium (DSS)-induced colitis mouse model. To identify key signaling pathways, transcriptomics and proteomics were performed, followed by the validation of these pathways using Western blotting, immunohistochemistry, and immunofluorescence in vivo and in vitro. The bioactive components of BXD were screened through pharmacodynamic experiments, molecular docking, and surface plasmon resonance (SPR) analysis.

Results: BXD significantly alleviated UC symptoms by reducing inflammatory levels and improving intestinal barrier function. Multi-omics analyses demonstrated a significant alteration in pyroptosis- and necroptosis-related signaling pathways following BXD intervention. BXD suppressed pyroptosis through the P2RX7/NEK7 pathway and necroptosis via the TNFR1/RIPK3 pathway in the colons of UC model mice and in LPS+TNF-α-induced NCM460 cells. The screening of active ingredients revealed that baicalin and glycyrrhizic acid significantly affected LDH release and IL-1β levels. Molecular docking and SPR analyses demonstrated that baicalin targeted P2RX7 with high affinity and that glycyrrhizic acid targeted TNFR1 with moderate affinity.

Conclusion: BXD ameliorates inflammation and intestinal barrier dysfunction in UC by suppressing pyroptosis through the P2RX7/NEK7 pathway and necroptosis via the TNFR1/RIPK3 pathway. Baicalin and glycyrrhizic acid are identified as the pharmacodynamic components responsible for these therapeutic effects. These findings can provide molecular mechanisms and a material basis for the clinical application of BXD in the treatment of UC.

Background: Early in-hospital mortality remains an important concern after coronary artery bypass grafting. Existing risk scores, such as EuroSCORE and STS, rely mainly on demographic and clinical parameters and do not adequately incorporate routine hematological markers. This study aimed to develop and validate the Hematological Inflammatory Gradient Score (HIGS), a novel model derived from routinely available hematological indices, to predict early postoperative mortality after coronary artery bypass grafting (CABG).

Methods: A retrospective, single-center cohort of 202 patients undergoing elective isolated CABG between January 2022 and March 2024 was analyzed. HIGS was calculated using standardized z-scores of red cell distribution width (RDW), platelet distribution width (PDW), and immature granulocyte percentage (IG%). Discrimination was assessed with ROC curve analysis, while logistic regression identified independent predictors of mortality.

Results: In-hospital mortality occurred in 10.9% (22/202) of patients. Compared with survivors, non-survivors had significantly higher HIGS values (1.02 ± 0.74 vs -0.12 ± 0.43, p < 0.001). HIGS demonstrated the highest discriminative ability for mortality prediction among tested parameters (AUC = 0.862, 95% CI: 0.794-0.931), with 86.4% sensitivity and 78.9% specificity at the optimal cut-off (>0.44). When added to the base model consisting of age, ejection fraction, and urea, HIGS provided a modest improvement in discrimination (AUC increase from 0.639 to 0.665). In multivariate analysis, lower ejection fraction, higher IG%, and elevated urea were independent predictors of mortality, and inclusion of HIGS improved model performance.

Conclusion: HIGS is a simple, inexpensive, and biologically plausible score derived from routine blood tests that reliably stratifies early mortality risk after CABG. If confirmed in larger, prospective multicenter studies, HIGS may serve as a practical adjunct to conventional risk models in perioperative decision-making. Given the retrospective, single-center design and limited event count, these findings should be interpreted cautiously, and external validation is required.

Background: Although increasing evidence implicates circular RNAs (circRNAs) in the pathogenesis of various autoimmune diseases, the potential role of circRNAs in rheumatoid arthritis (RA) remains poorly understood.

Methods: Utilizing a two-phase study design, we performed high-throughput RNA sequencing on peripheral blood mononuclear cells (PBMCs) from three treatment-naïve RA patients and three healthy controls (HCs), followed by validation in an independent cohort of 32 RA patients and 32 HCs using real-time quantitative polymerase chain reaction (RT-qPCR).

Results: A total of 157 circRNAs were differentially expressed between RA patients and HCs, including 91 upregulated and 66 downregulated circRNAs. Six circRNAs, including hsa_circ_0001394, hsa_circ_0001998, hsa_circ_0009172, hsa_circ_0006732, circRNA2842, and circRNA8330, were further confirmed to be upregulated in RA. Among them, hsa_circ_0001394 demonstrated perfect sensitivity (100%), and hsa_circ_0001998 exhibited perfect specificity (100%) in distinguishing RA from HCs. All six circRNAs showed considerable diagnostic performance, with area under the curve (AUC) values ranging from 0.794 to 0.993. Additionally, specific circRNAs correlated significantly with established serological markers: hsa_circ_0009172 expression was negatively associated with anti-cyclic citrullinated peptide (anti-CCP) antibody titers, whereas hsa_circ_0001998 expression correlated positively with rheumatoid factor (RF). Pathway enrichment analysis suggested that these differentially expressed circRNAs may participate in RA pathogenesis through key pathways like Wnt, calcium and VEGF signaling.

Conclusion: Our study identifies several novel circRNAs with high diagnostic utility for RA, highlighting their potential as promising biomarkers and therapeutic targets.

Background: The role of ITGB7 in pancreatic ductal adenocarcinoma (PDAC) remains unreported. This study aims to investigate the effects of ITGB7 on inflammation and immune microenvironment, and its correlation with the response to immune checkpoint inhibitors (ICIs).

Methods: The correlation between ITGB7 expression and the response to ICIs treatment was evaluated in our clinical cohort and in the TCGA dataset. TMT and PRM proteomic analysis identified ITGB7-associated proteins, biological processes, and signal pathways. The role of ITGB7 in macrophage polarization was explored both in vivo and in vitro. Additionally, ITGB7-associated immune and inflammatory regulatory molecules, and immune cells infiltration in PDAC were assessed using TCGA dataset. An ITGB7-associated ceRNA network was constructed to explore post-transcriptional regulation.

Results: Clinical sample analysis and TCGA analysis showed that ITGB7 was significantly overexpressed in PDAC compared to normal pancreatic tissue. Patients with high ITGB7 expression demonstrated a better response to ICIs blockade therapy and exhibited a favorable prognosis. Proteomic analysis indicated that ITGB7 regulates immune- and inflammation- related proteins. ITGB7 expressed in pancreatic tumor cells promoted M2 macrophage polarization. ITGB7 modulated immune-related signaling pathways and was positively correlated with expression of immune checkpoint molecules, inflammatory cytokines, and immune-stimulating molecules. ITGB7 correlated with increased immune cell infiltration.

Conclusion: We provide the first evidence that ITGB7 expression correlates with immune regulation, inflammatory modulation, and immune cell infiltration in PDAC. ITGB7 is associated with enhanced immunotherapy response and improved prognosis. This study provides novel insights into the regulation of PDAC immune responses.