Journal of Inflammation Research最新文献

Background: Rejection hinders long-term survival in lung transplantation, and no widely accepted biomarkers exist to predict rejection risk. This study aimed to develop and validate a prognostic model using laboratory data to predict the time to first rejection episode in lung transplant recipients.

Methods: Data from 160 lung transplant recipients were retrospectively collected. Univariate Cox analysis assessed the impact of patient characteristics on time to first rejection episode. Kaplan-Meier survival analysis, LASSO regression, and multivariate Cox analysis were used to select prognostic indicators and develop a riskScore model. Model performance was evaluated using Kaplan-Meier analysis, time-dependent ROC curves, and multivariate Cox regression.

Results: Patient characteristics were not significantly associated with the time to the first rejection episode. Six laboratory indicators-Activated Partial Thromboplastin Time, IL-10, estimated intrapulmonary shunt, 50% Hemolytic Complement, IgA, and Complement Component 3-were identified as significant predictors and integrated into the riskScore. The riskScore demonstrated good predictive performance. It outperformed individual indicators, was an independent risk factor for rejection, and was validated in the validation dataset.

Conclusion: The riskScore model effectively predicts time to first rejection episode in lung transplant recipients.

Purpose: Genome-wide association studies (GWAS) have identified multiple genetic loci associated with primary open-angle glaucoma (POAG). However, the mechanisms by which these loci contribute to POAG progression remain unclear. This study aimed to identify potential causative genes involved in the development of POAG.

Methods: We utilized multi-dimensional high-throughput data, integrating proteome-wide association study(PWAS), transcriptome-wide association study (TWAS), and summary data-based Mendelian randomization (SMR) analysis. This approach enabled the identification of genes influencing POAG risk by affecting gene expression and protein concentrations in the bloodstream. The key gene was validated through enzyme-linked immunosorbent assay (ELISA) analysis.

Results: PWAS identified 86 genes associated with altered blood protein levels in POAG patients. Of these, eight genes (SFTPD, CSK, COL18A1, TCN2, GZMK, RAB2A, TEK, and GNLY) were identified as likely causative for POAG (P _SMR < 0.05). TWAS revealed that GNLY was significantly associated with POAG at the gene expression level. GNLY-interacting genes were found to play roles in immune dysregulation, inflammation, and apoptosis. Clinical and cell-based validation confirmed reduced GNLY expression in POAG groups.

Conclusion: This study reveals GNLY as a significant potential therapeutic target for managing primary open-angle glaucoma.

Background: Patients with transfusion-dependent thalassemia experience iron dysregulation, which affects the immune response. Surface proteins such as FcγRIII (CD16), lipopolysaccharide receptor (CD14), and human leukocyte antigen (HLA-DR) on monocytes are crucial for innate and adaptive responses. Blood monocytes, identified by their CD14 and CD16 expression, show functional diversity during injury or inflammation. Considering the mechanisms of vitamin D activation and its potential interaction with monocytes, further investigation of its immunomodulatory role in transfusion-dependent thalassemia is essential.

Purpose: This study evaluated monocyte subsets, population, and surface receptor expression (CD14, CD16, and HLA-DR), and their association with iron status and vitamin D levels in patients with transfusion-dependent thalassemia.

Patients and methods: Fifty lysed erythrocyte-heparinized whole blood samples from transfusion-dependent thalassemia patients were analyzed by flow cytometry and classified into three monocyte subsets: CD14++CD16- (classical), CD14++CD16+ (intermediate), and CD14+CD16++ (non-classical). Cell percentage referred to the monocyte subset population. Median fluorescence intensity (MFI) indicated surface protein expression. The 25(OH)vitamin D level was used to measure vitamin D levels. Iron status was assessed using ferritin and serum iron levels. A correlational study was performed.

Results: We did not find a correlation between low vitamin D levels (22.9 ng/mL ± 3.9) and monocyte characteristics, iron status, or hematology profile. However, we observed a negative correlation between the percentage of intermediate and non-classical monocytes and hemoglobin and ferritin levels (P = 0.02, r = -0.3; P = 0.04, r = -0.3). Additionally, we found a positive correlation between the median fluorescence intensity (MFI) of CD14 in non-classical monocytes and serum iron (P = 0.04, r = 0.3).

Conclusion: Our findings suggest that iron overload and anemia may influence the function of inflammatory monocyte subsets. Considering the immunomodulatory role of vitamin D through monocyte modulation during pathogen insult, further research utilizing a whole-blood stimulation assay is imperative.

Purpose: Kuiyangling is a traditional Chinese medicine formula used for the treatment of ulcerative colitis, but the specific mechanism remains unclear. Imbalance in NETs regulation is one of the important factors contributing to the onset of ulcerative colitis (UC). The HuR/VDR signaling pathway plays a significant role in restoring the intestinal mucosal barrier in UC. The aim of this study is to explore the mechanism of Kuiyangling in the treatment of ulcerative colitis.

Methods: A mouse model of ulcerative colitis using 3% DSS water was considered, and model, normal, Kuiyangling medium- (5 g·kg^-1) and high-dose (10 g·kg^-1), and mesalazine (50 mg·kg^-1) groups were created. Measurements of colon length, spleen index, histopathological variances, subcellular structure observations, ROS content, and NET-related proteins (PAD4, MPO, citH3) were obtained through HE staining, electron microscopy, live imaging, and Western blotting assays. Immunohistochemistry and immunofluorescence analyses were conducted to assess the levels of HuR/VDR protein complex, ZO-1, Occludin, Claudin-7, and intestinal NETs. An ELISA kit was utilized to determine cytokine levels, LC-MS was performed to analyze the composition of Kuiyangling, and next-generation sequencing was conducted for detection of the intestinal mucosal transcriptome.

Results: Kuiyangling reduced DAI, splenic index, and ROS content; maintained mucosal structure; decreased inflammation; and increased colon length and body mass index. Western blotting indicated that Kuiyangling reduced PAD4,MPO, and citH3 levels. Kuiyangling decreased NETs and increased the expression levels of ZO-1, Occludin, and Claudin-7, as well as up-regulating HuR, VDR, and HuR/VDR proteins. Kuiyangling reduced IL-1β, IL-6, and TNF-α levels while increasing TGF-β, IL-10, and IL-37 levels. Kuiyangling reduced inflammatory response proteins and elevated the levels of anti-inflammatory and intestinal barrier proteins, possibly inhibiting the TNF and oxidative phosphorylation signaling pathways.

Conclusion: Kuiyangling enema in treating ulcerative colitis in mice, associated with a reduction in intestinal NETs and enhancement of HuR-mediated intestinal barrier signaling pathways.

Purpose: This study aimed to evaluate the prognostic value of C-reactive protein to albumin (CRP/Alb) ratio in hepatocellular carcinoma (HCC) treated with transcatheter intra-arterial therapy combined with molecular targeted agents (MTAs) and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors.

Methods: Medical records of 271 consecutive patients with HCC receiving this combination therapy in China between 2019 and 2023 were retrospectively analyzed. Prognostic factors for progression-free survival (PFS) and overall survival (OS) were identified using univariate and multivariate Cox regression analyses. The discriminatory capability of inflammation-based prognostic scores-including the CRP/Alb ratio, C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) score, modified Glasgow prognostic score (mGPS), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)-was assessed using the area under the curve (AUC).

Results: A total of 133 patients met the inclusion criteria. The optimal cutoff value for the binary classification of CRP/Alb ratio in predicting OS, as determined using X-tile software, was 0.02. Multivariate analysis identified the CRP/Alb ratio (hazard ratio [HR] = 2.61, p < 0.001), tumor size (HR = 2.45, p = 0.018), and extrahepatic metastases (HR = 1.93, p = 0.015) as independent predictors of OS. For PFS, significant factors included Eastern Cooperative Oncology Group Performance Status (HR = 1.55, p = 0.033) and macrovascular invasion (HR = 1.48, p = 0.046). Patients with higher CRP/Alb ratios were more likely to experience fever and fatigue. The CRP/Alb ratio demonstrated significantly higher AUCs than PLR and SII at 24 months (all p < 0.05) and showed comparable AUCs to CRAFITY score and mGPS at 12, 24, and 36 months.

Conclusion: The CRP/Alb ratio is a valuable prognostic marker for predicting OS and treatment-related adverse events in HCC patients receiving transcatheter intra-arterial therapy combined with MTAs and PD-1/PD-L1 inhibitors. This ratio can be used as a simple and reliable biomarker for assessing prognosis and guiding patient selection in clinical practice.

Purpose: Previous studies have reported that infection-induced fever is associated with improved breast cancer prognosis, potentially through the modulation of cytokines. However, the key cytokines and the underlying mechanisms through which fever exerts its anti-tumor effects remain unclear.

Patients and methods: A total of 794 breast cancer patients were recruited between 2008 and 2017, with follow-up extending until October 31st, 2023. Infection-induced fever was assessed using questionnaires, while a multiplex assay evaluated a panel of 27 cytokines. The mediation effects of various cytokines were analyzed through model-based causal mediation analysis. Additionally, we explored modifications to these mediation effect by examining interactions among the cytokines themselves as well as their interactions with infection-induced fever. Bioinformatic analyses were conducted to elucidate the biological pathways mediating infection-induced fever.

Results: The relationship between infection-induced fever and improved breast cancer prognosis was mediated by a decrease in interleukin-8 (IL-8) levels. Furthermore, our findings revealed that the downregulation of IL-8, which mediates the beneficial effects of fever, was antagonized by IL-2, IL12p70 and IL-7. By intersecting the biological pathways influenced by IL-8, alongside those affected by IL-2, IL12p70, or IL-7, we found that these latter cytokines antagonized the mediation effects of IL-8 via regulating critical pathways such as neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation.

Conclusion: Infection-induced fever may improve breast cancer prognosis through IL-8 downregulation and the mediation mechanisms may be involved in neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation. Such findings not only provide valuable insights into effectively managing febrile responses for breast cancer patients, but also underscore the therapeutic potential of cytokines in breast cancer patients.

Background: Osteoarthritis (OA) is a leading cause of pain, disability, and reduced mobility worldwide, characterized by metabolic imbalances in chondrocytes, extracellular matrix (ECM), and subchondral bone. Emerging evidence highlights the critical role of long non-coding RNAs (lncRNAs) in OA pathogenesis. This study focuses on lncRNA PTS-1, a novel lncRNA, to explore its function and regulatory mechanisms in OA progression.

Methods: The expression profile of lncRNAs was assessed using RNA sequencing and qRT-PCR. The expression of lnc-PTS-1 was further validated by qRT-PCR in degenerated cartilage tissues, degenerative primary chondrocytes, and IL-1β-treated C28/I2 cells. Cell viability, proliferation, and apoptosis rates, along with the mRNA and protein levels of apoptosis-related markers (cleaved Caspase 3, cleaved Caspase 9, Bcl-2, Bax), ECM metabolism markers (MMP-3, MMP-13, aggrecan, collagen II), and inflammation-related markers (IL-1β, IL-6, TNF-α) were evaluated using Cell Counting Kit-8, Toluidine Blue staining, Alcian Blue staining, flow cytometry, qRT-PCR, immunofluorescence, and Western Blot. The interaction between miR-8085 and lnc-PTS-1 or E2F2 was investigated through dual luciferase reporter assays and RNA immunoprecipitation (RIP) analyses.

Results: Lnc-PTS-1 expression was significantly downregulated in degenerated cartilage tissues, IL-1β-induced degenerative primary chondrocytes and C28/I2 cells. Functional experiments showed that lnc-PTS-1 knockdown aggravated IL-1β-induced ECM degradation, chondrocyte apoptosis, and inflammation, while its overexpression provided protective effects. Mechanistically, lnc-PTS-1 acted as a competing endogenous RNA (ceRNA) by sponging miR-8085, thereby upregulating E2F2 expression. Notably, miR-8085 upregulation diminished the protective effects of lnc-PTS-1 on ECM degradation, apoptosis, and inflammation, while E2F2 upregulation partially alleviated IL-1β-induced damage. However, these mitigating effects were reversed by miR-8085 overexpression.

Conclusion: These findings identify lnc-PTS-1/miR-8085/E2F2 axis as a novel regulatory mechanism in OA pathogenesis, providing theoretical basis and experimental evidence for the potential clinical application of new lncRNA molecules in the treatment of OA.

Background: Dupilumab is a safe and effective treatment for moderate to severe atopic dermatitis (AD), but real-world data in pediatric patients in China are limited. Currently, there is no exploration of changes in blood cell counts derived indexes in pediatric patients, especially under 6 years old.

Purpose: To investigate the changes in blood cell counts derived indexes before and after dupilumab treatment in Chinese children with AD, the relationship with clinical scores, and the potential role of these indexes on treatment efficacy.

Patients and methods: We conducted a retrospective study of 109 children with moderate to severe AD treated with dupilumab. Derived inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-lymphocyte ratio (ELR), eosinophil-to-neutrophil Ratio (ENR), monocyte-to-lymphocyte ratio (MLR), inflammation response index (SIRI), systemic inflammation index (SII), and aggregate inflammation systemic index (AISI) were calculated. The correlation between clinical scores and inflammatory indexes at different treatment time points were analyzed. Logistic regression and ROC curve was employed to explore factors associated with treatment efficacy.

Results: Baseline ELR and ENR were positively correlated with the baseline Eczema Area and Severity Index (EASI) and the Scoring Atopic Dermatitis (SCORAD). Additionally, baseline ENR levels showed a positive correlation with the baseline Peak Pruritus Numeric Rating Scale (PP-NRS). At 4 and 16 weeks of treatment, the percentage reduction in ELR was significantly associated with the percentage reduction in EASI and PP-NRS. Logistic regression results indicated that high baseline ELR could predict a poor response to dupilumab treatment.

Conclusion: ELR was significantly correlated with disease severity score during the treatment with dupilumab. Baseline ELR could act as a predictor of the efficacy of dupilumab in the treatment of children with atopic dermatitis under 6 years of age.

Background: Lung transplantation is the only effective therapeutic option for patients with end-stage lung disease. However, ischemia/reperfusion injury (IRI) during transplantation is a leading cause of primary graft dysfunction (PGD). Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, has been implicated in IRI across various organs. This study aims to explore the role of ferroptosis in lung transplantation-related ischemia/reperfusion injury and to identify its potential molecular mechanisms through bioinformatics analysis.

Methods: Transcriptome data from lung transplant patients were obtained from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (FRGs) were identified by analyzing gene expression profiles before and after reperfusion. Weighted gene co-expression network analysis (WGCNA) was used to identify module genes, and overlapping genes were further analyzed using two machine learning algorithms. The CIBERSORT algorithm was applied to assess immune cell infiltration, while Mendelian randomization (MR) analysis was used to investigate causal relationships between candidate genes and PGD. Finally, Consensus clustering based on FRGs was performed to identify subtypes.

Results: We identified four candidate genes associated with ferroptosis during lung reperfusion: tumor necrosis factor alpha-induced protein 3 (TNFAIP3), C-X-C motif chemokine ligand 2 (CXCL2), neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L), and sestrin 2 (SESN2). These genes were closely associated with immune cell infiltration. MR analysis suggested that SESN2 might play a protective role against PGD. Additionally, consensus clustering revealed distinct immune infiltration patterns across subtypes, providing insights for personalized therapeutic approaches to lung ischemia/reperfusion injury (LIRI).

Conclusion: This study highlights TNFAIP3, CXCL2, NEDD4L, and SESN2 as candidate genes associated with ferroptosis during LIRI, with SESN2 potentially protecting against PGD. These findings offer promising therapeutic targets for preventing LIRI and improving outcomes in lung transplantation.