Journal of Inflammation Research最新文献

Background: Lactylation has emerged as a novel post-translational modification, and genes linked to both lactylation and macrophage polarization may play a role in inflammatory bowel disease (IBD). However, the connection between these genes and TNF-α inhibitor response in IBD remained unclear.

Methods: This study used bioinformatic tools including weighted gene co-expression network analysis (WGCNA), immune infiltration analysis, and machine learning algorithms to identify correlations between lactylation and macrophage-related genes and TNF-α inhibitor response in IBD.

Results: Significant differential expression of MNDA, CALD1, RECQL, and RBM10 was identified between the remission and non-remission groups in the pre-treatment data. Based on these findings, we established a predictive model for TNF-α inhibitor response, achieving an ROC performance with training AUC reaching 0.894 and validation AUC reaching 0.883. Furthermore, MNDA, LGALS1, ZYX, ADAR, and WAS were significantly elevated in the non-remission group 4-6 weeks after initial treatment. Immune infiltration analysis further indicated strong correlations between hub genes expression and immune cell proportions. In addition, GSEA identified signaling pathways associated with TNF-α inhibitor response. To validate these observations, TNF-α inhibitor was administered to mice with TNBS-induced colitis, and the expression of hub genes was confirmed by RT-qPCR. Importantly, combination therapy with lactate supplementation enhanced the efficacy of TNF-α inhibitor treatment compared with monotherapy. Finally, analysis of lactylation levels indicated intergroup differences associated with TNF-α inhibitor treatment in IBD.

Conclusion: Overall, we identified lactylation and macrophage-related genes as potential biomarkers for TNF-α inhibitor response. Lactate supplementation was found to enhance the efficacy of TNF-α inhibitor based on animal experimental validation. Nevertheless, the findings were based on secondary analyses of public datasets, and the animal experiments remained preliminary. Further studies should be conducted to validate these findings and explore the molecular pathways involved.

Purpose: Atrial fibrillation (AF) is a leading cause of stroke, heart failure, and mortality, yet the molecular mechanisms remain incompletely defined.

Patients and methods: We integrated bulk transcriptomes from GEO with weighted gene co-expression network analysis, consensus clustering, and a 12-algorithm machine-learning pipeline (66 model combinations) to map programmed cell death (PCD) pathways and pinpoint diagnostic genes. Immune infiltration was profiled by CIBERSORT, xCell, and ssGSEA. Hub-gene expression was validated in an HL-1 atrial pacing model and in peripheral blood mononuclear cells (PBMCs) from patients with persistent AF.

Results: Four hub genes-SGPL1, NPC2, PTGDS, and RCAN1-were identified and incorporated into a nomogram and a PCD-based risk score (PCDscore). The nomogram showed robust discrimination in the training cohort and two independent validation datasets. Patients with a high PCDscore exhibited markedly increased immune-cell infiltration and dysregulated immune modulators, with macrophages consistently enriched across algorithms. qRT-PCR confirmed up-regulation of SGPL1, NPC2, and RCAN1 and down-regulation of PTGDS in AF cell models; NPC2 and SGPL1 were further elevated in PBMCs from AF patients.

Conclusion: Our integrative framework reveals PCD-linked remodeling in AF and nominates SGPL1, NPC2, PTGDS, and RCAN1 as candidate diagnostic biomarkers, providing a PCD-based nomogram and risk score that may inform patient stratification and hypothesis-generating targeted interventions.

Background: Ulcerative colitis (UC), a chronic inflammatory bowel disease with rising global incidence, involves neutrophil-driven mucosal damage. The precise mechanisms remain elusive, hindering targeted therapies. Therefore, this study aims to integrate single-cell transcriptomics with in vivo experiments to reveal the key signaling axes driving pathogenic neutrophil activation in UC.

Methods: Single-cell transcriptomics characterized UC inflammatory microenvironments, focusing on neutrophil functional states and intercellular interactions. Based on key findings from bioinformatics analysis, we hypothesize that the eNAMPT-integrin α5β1 signaling axis drives abnormal neutrophil-endothelial cell communication and functionally validate this hypothesis in in vivo models.

Results: Neutrophils exhibited aberrant activation and significant NAMPT overexpression in UC. Extracellular eNAMPT functioned as a signaling molecule binding endothelial integrin α5β1, mediating pathological neutrophil-endothelial crosstalk. Pharmacological blockade of the eNAMPT/integrin α5β1 axis inhibited neutrophil mucosal infiltration, reducing inflammation and tissue damage in UC mouse models.

Conclusion: The eNAMPT-integrin α5β1-mediated neutrophil-endothelial communication axis represents a novel pathogenic pathway in UC, providing a foundation for precision therapies targeting this mechanism.

Background: Allergic rhinitis (AR) is a prevalent chronic inflammatory disease characterized by immune dysregulation and epithelial barrier dysfunction. Conventional therapies are often limited by side effects and insufficient efficacy in addressing the underlying pathophysiology. To explore alternative approaches, this study investigated the potential of YuPingTongQiao (YPTQ), a novel Traditional Chinese Medicine (TCM) formulation, as a multi-target treatment for AR.

Methods: An ovalbumin-induced AR rat model was established. Nasal allergic symptoms were assessed using a standardized scoring system. Histopathology, FC, RT-qPCR, and ELISA were performed to assess epithelial integrity, cell infiltration, cytokine expression, and immune cell phenotypes.

Results: YPTQ significantly alleviated AR symptoms, including nasal rubbing, sneezing, and rhinorrhea, in a dose-dependent manner. The high-dose YPTQ (YPTQ-H) group demonstrated superior efficacy compared to Loratadine. Mechanistically, YPTQ suppressed T_H2 cytokines (IL-4, IL-5, IL-13) and IL-33, restored follicular regulatory T (T_FR) cell balance, and increased CTLA4 expression, thus mitigating IgE-mediated immune responses. Additionally, YPTQ enhanced epithelial barrier integrity by upregulating Claudin1 and reduced mucus hypersecretion by suppressing MUC2 expression. Histological analysis revealed decreased infiltration of eosinophils, mast cells, and goblet cells in the nasal mucosa.

Conclusion: YPTQ offers a safe, effective, and multi-target therapeutic option for AR, addressing both immune dysregulation and epithelial dysfunction. Its superior efficacy compared to Loratadine and excellent safety profile highlight its potential as a novel alternative or adjunct to conventional treatments for AR.

Background: Acute lung injury (ALI), as a respiratory condition triggered by various internal and external factors, is characterized clinically by high rates of incidence and mortality. In the current context where respiratory system diseases are on the rise, the incidence of ALI has been increasing annually. Previous research has established the efficacy of traditional Chinese medicine (TCM) in inhibiting ALI. Siji Kangbingdu Mixture (SJM), has demonstrated a clear clinical therapeutic effect in managing respiratory infections. Nevertheless, its mechanism of action in treating ALI is still lacking.

Purpose: To clarify the mechanism by which SJM exerts its therapeutic effects in the treatment of ALI.

Materials and methods: In our study, we initially elucidated the chemical constituents of SJM by the UHPLC-Q-Orbitrap HRMS (LC-MS), and established an ALI model. Next, we evaluated how SJM inhibited ALI by measuring the weight curve of mice, the wet-to-dry lung weight ratio (W/D), the HE lung tissue pathological change score, along with the inflammatory factor expression. Then, by employing transcriptomics and network pharmacology approaches, the mechanism of SJM acting on ALI were predicted and analyzed. Finally, the expression and regulatory interactions of the differentially expressed target proteins in the key pathways were verified by qRT-PCR analysis, Western blotting (WB), immunofluorescence and immunohistochemistry.

Results: The LC-MS analysis identified 148 active ingredients. In vitro experiments indicated that SJM could significantly reduce the W/D index, pulmonary tissue pathological score, and the inflammatory factor levels. The findings from transcriptomics and network pharmacology suggested that SJM may alleviate ALI as a TNF and IL-17 signaling pathway. Further, through WB, immunofluorescence and immunohistochemistry, we noted significant downregulations in the pulmonary tissue expression of keys proteins in the SJM-H group.

Conclusion: SJM has the potential to inhibit the progression of ALI, and its mechanism of action may involve the TNF and IL-17 signaling downregulation.

Purpose: A common complication observed in septic patients under intensive care is acute kidney injury (AKI), which is characterized by acute onset and strong inflammation, resulting in poor clinical outcomes for patients. This study aims to explore the expression status of PCED1B-AS1 in sepsis-induced AKI and to preliminarily investigate the molecular mechanism by which PCED1B-AS1 affects AKI.

Patients and methods: This study included 105 healthy individuals and 220 patients with sepsis (110 patients with AKI and 110 non-AKI patients). The levels of PCED1B-AS1 were examined by RT-qPCR. Macrophage polarization was induced by LPS treatment of RAW264.7 cells, and an in vitro renal injury model was established using HK-2 cells. Cell proliferation ability was evaluated by CCK-8 assay, apoptosis was detected by flow cytometry, and the levels of inflammatory factors were assessed using ELISA kits. The dual-luciferase assay was used to verify the interrelationship among the PCED1B-AS1/miR-361-3p/SOCS1 axis.

Results: PCED1B-AS1 was downregulated in sepsis patients without AKI and further reduced in AKI patients. PCED1B-AS1 could differentiate healthy individuals from non-AKI sepsis patients and identify AKI patients. Additionally, low PCED1B-AS1 expression correlated with poor AKI prognosis. Overexpression of PCED1B-AS1 promoted the polarization of M1 macrophages to M2 by regulating the miR-361-3p/SOCS1 axis, thereby inhibiting apoptosis and inflammatory responses in HK-2 cells.

Conclusion: PCED1B-AS1 may serve as a potential diagnostic and prognostic marker and inhibit sepsis-induced AKI by promoting transformation of macrophages from M1 to M2 type via regulating the miR-361-3p/SOCS1 axis.

Background: Endometriosis is frequently treated with Paeoniae Radix. It contains Tellimagrandin II, which has the role of modulating immunity and anti-tumor. Therefore, we will explore the effects of Tellimagrandin II on the apoptosis and invasion/migration of ectopic endometrial cells (EECs).

Methods: Tellimagrandin II was used to treat EECs, and transcriptomics and bioinformatics techniques were used to identify its main pathways and targets of Tellimagrandin II. Western blotting was used to confirm the expression of essential targets. Flow cytometry was applied, the impact of tellimagrandin II on EECs apoptosis was identified. Transwell assays were conducted the effects of Tellimagrandin II on EECs invasion and migration. Finally, the binding of tellimagrandin II to key targets was confirmed using molecular docking techniques.

Results: Tellimagrandin II may inhibit pathways like beta-alanine metabolism and ECM-receptor interaction while activating JAK-STAT, NF-κB, and apoptotic pathways, according to transcriptomics and GSEA enrichment analysis. Tellimagrandin II can inhibit ALDH7A1 expression in EECs as well as increase SMOX expression, which may facilitate the accumulation of 3-Aminopropanal. This action becomes more pronounced as the dosage is increased. By upregulating the expression of NLRP3, TIMP-1, Caspase-3, BAX, and Caspase-1 in EECs while decreasing the expression of β-catenin and MMP2, tellimagrandin II can prevent EECs invasion and migration and encourage EECs apoptosis. Tellimagrandin II exhibited good docking with ALDH7A1 and SMOX, according to molecular docking.

Conclusion: Tellimagrandin II may stimulate inflammasomes by encouraging 3-aminopropanal accumulation within EECs. The increase in inflammasomes may promote EECs apoptosis and inhibit EECs invasion and migration. However, its in vivo inhibitory effects on endometriosis require further investigation.

Background: ANCA-associated vasculitis (AAV) is a group of autoimmune diseases characterized by necrotizing inflammation and fibrinoid necrosis of small- and medium-sized blood vessels. Renal involvement is common in AAV; however, renal hemorrhage is extremely rare, particularly in cases of eosinophilic granulomatosis with polyangiitis (EGPA). Spontaneous renal hemorrhage often presents as acute abdomen.

Case presentation: We report a 51-year-old male with a prior diagnosis of EGPA who presented to the emergency department with acute left-sided abdominal pain and signs of hypovolemic shock. Imaging revealed a massive left perirenal hematoma without active contrast extravasation, suggestive of renal rupture. Initial management focused on hemostasis and stabilization, but recurrent contralateral renal hemorrhage occurred during hospitalization. Further immunological, histopathological, and bone marrow evaluations confirmed EGPA complicated by renal involvement. The patient was treated with corticosteroids, cyclophosphamide, and rituximab, but recurrent hemorrhage indicated rapid disease progression or insufficient therapeutic response. Due to financial constraints, the patient was discharged prematurely, precluding long-term follow-up.

Discussion: This case highlights the complexity of diagnosing and managing AAV-associated renal hemorrhage, particularly in EGPA patients. While the renal vascular changes observed, such as inflammation and potential necrosis, may be linked to the underlying vasculitis in EGPA, causality should be interpreted with caution, as other factors like coagulopathy, concurrent infections, or iatrogenic effects could contribute. Current literature suggests that ANCA-associated mechanisms, including NETs formation, play a role in vascular damage, but direct causation in rare complications like renal hemorrhage remains uncertain and requires further investigation. While EGPA treatment primarily involves immunosuppressive therapy targeting vasculitis and eosinophilia, spontaneous renal hemorrhage requires an integrated approach, including conservative management, interventional embolization, or surgical exploration in life-threatening cases. Reports of AAV-associated renal hemorrhage are rare, and large-scale studies are lacking, necessitating further research to optimize treatment strategies.

Purpose: Sepsis continues to pose a significant threat to global health, characterized by elevated mortality rates. Pulmonary complications frequently develop in septic patients, with endothelial dysfunction correlating with adverse clinical outcomes. While overproduction of neutrophil extracellular traps (NETs) is implicated in vascular damage, their specific influence on the regenerative potential of pulmonary endothelial cells requires further elucidation. Our investigation aims to address this critical knowledge gap.

Patients and methods: Clinical samples from sepsis patients and healthy controls were analyzed to establish the correlation between NETs and pulmonary endothelial injury. An in vivo sepsis model was generated through cecal ligation and puncture (CLP) in mice, with sham surgery animals serving as reference group. Human umbilical vein endothelial cells (HUVECs) were employed for in vitro assessment of NETs-mediated cell cycle modulation.

Results: Elevated NETs formation was observed in septic patients, showing positive association with inflammatory damage. CLP-induced mice demonstrated substantially increased NETs levels, pronounced pulmonary vascular permeability, and notable endothelial cell depletion. DNase I-mediated NETs degradation alleviated pulmonary inflammation and promoted endothelial recovery. Both experimental models revealed that excessive NETs release during sepsis compromises endothelial proliferation via polo-like kinase 1 (PLK1) pathway inhibition and subsequent G2/M phase arrest.

Conclusion: This study establishes that NETs accumulation in septic pulmonary injury hinders endothelial regeneration and vascular repair through PLK1 signaling suppression and G2/M cell cycle blockade.

Background: To assess whether baseline serum high density lipoprotein (HDL) levels predict the effectiveness of infliximab in patients with Crohn's disease (CD).

Methods: This was a retrospective single-center study evaluating CD patients baseline data and effectiveness of infliximab at the Xiangya Hospital, Central South University, between January 2016 and September 2021. The primary endpoint was composite adverse outcome during 52 weeks, defined as clinical activity, changes in treatment, surgical treatment, or unexpected readmission.

Results: Among the 166 enrolled patients, 37 (22.3%) experienced adverse events within the 52-week follow-up period. HDL was identified as a predictor of adverse outcomes at 52 weeks (AUC 0.661, p < 0.05), with an optimal cut-off value of 0.85. Patients with higher HDL levels not only exhibited elevated total cholesterol but were also associated with better nutritional status and lower inflammatory burden. HDL was negatively correlated with white blood cell count and C-reactive protein, and positively correlated with albumin level (p < 0.05). Baseline HDL level was an independent risk factor for adverse events within 52 weeks in CD patients treated with infliximab (p = 0.022). Moreover, the high-HDL group demonstrated a significantly lower risk of developing adverse events (p = 0.0017).

Conclusion: The identification of HDL as an independent risk factor for 52-week adverse events in infliximab-treated CD patients suggests its potential utility as a predictive biomarker.

Trial registration: The study adhered to the Declaration of Helsinki. All participants provided written informed consent, and the study was approved by the Ethics Committee of Xiangya Hospital, Central South University with approval No. 202108158.