Journal of Inflammation Research最新文献

Objective: This study aimed to explore potential molecular targets and pathways of Hyp in LN using integrative bioinformatics and network pharmacology, and to provide in vitro validation of key mechanistic hypotheses in an IFN-α-induced mesangial-cell injury model.

Methods: Differential expression analysis was performed on multiple datasets to identify LN-related target genes. Integrative approaches including machine learning algorithms, network pharmacology, and molecular docking were employed to explore the binding interactions between Hyp and target proteins. In vitro experiments were conducted to validate the mechanism by which Hyp intervenes in glomerular mesangial cell apoptosis.

Results: A total of 18 genes were identified as potential targets involved in Hyp-induced modulation of LN progression. Machine learning SHAP analysis identified 5 core genes (STAT1, RSAD2, OAS3, GBP1, XAF1) as key regulators. Molecular docking simulations revealed specific binding between Hyp and each target protein, with particularly strong binding affinity between Hyp and XAF1. Cellular experimental results demonstrated that Hyp could inhibit the P53/XAF1 signaling pathway, downregulate the expression of apoptosis-related proteins, and thereby alleviate glomerular mesangial cell apoptosis.

Conclusion: Hyp attenuated IFN-α-induced glomerular mesangial cell apoptosis by suppressing the P53/XAF1 signaling pathway, suggesting a potential therapeutic mechanism in LN. These integrative bioinformatics and in vitro findings provide a rationale for future in vivo validation and clinical translation.

Background: Chronic spontaneous urticaria (CSU) is a debilitating inflammatory skin disorder with a significant impact on quality of life. Current treatment algorithms are ineffective for a substantial portion of patients, highlighting an urgent need to elucidate its underlying pathological mechanisms for the development of novel therapies.

Methods: Microarray datasets (GSE72540 and GSE57178) from CSU lesional skin (LS), non-lesional skin (NLS), and healthy controls (HC) were analyzed using weighted gene co-expression network analysis (WGCNA) and differential expression to identify characteristic genes. Functional enrichment, transcription factor networks, protein-protein interactions (PPI), and immune cell deconvolution via CIBERSORT were performed. Hub genes were correlated with immune infiltrates, and expression was validated in IgE-stimulated RBL-2H3 basophil cells via RT-qPCR.

Results: WGCNA identified six modules (3,114 genes) correlated with LS status. Differential analysis revealed 101 characteristic DEGs enriched in inflammatory, cytokine, and metabolic pathways. Fifteen transcription factors, including STAT1 and JUN, regulated these DEGs. PPI networks identified 10 hub genes (CXCL2, MYC, THBS1, EGR1, SOCS3, CXCL1, ICAM1, IL6, PTGS2, CCL2). LS showed increased activated mast cells, eosinophils, neutrophils, and monocytes, with depleted regulatory T cells and plasma cells. Hub genes positively correlated with activated mast cells and eosinophils. Validation confirmed biphasic hub gene expression: early downregulation (2 hours) and late upregulation (8 hours) post-stimulation.

Conclusion: This study reveals a multifaceted inflammatory and metabolic landscape in CSU, identifying hub genes as candidates warranting further investigation for the development of targeted therapeutic strategies. These findings require validation in larger, clinically characterized cohorts.

Extracellular Adenosine triphosphate (ATP), acting as both an energy signal and damage-associated molecular pattern (DAMP), plays a critical role in the progression of degenerative bone diseases (DBD) and cardiovascular diseases (CVD). Through activation of purinergic receptors, particularly P2X7, ATP induces a cascade of events leading to ATP-induced cell death (AICD), characterized by calcium influx, mitochondrial dysfunction, oxidative stress, and inflammasome activation, culminating in pyroptosis, apoptosis, and ferroptosis. These processes are implicated in osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and cardiovascular conditions such as myocardial infarction and heart failure. The ATP-P2X7-NLRP3 axis emerges as a shared molecular mechanism linking these diseases, driven by energy imbalance and chronic inflammation. This review explores the molecular mechanisms of AICD in DBD and CVD, evaluates experimental and clinical evidence, and discusses potential therapeutic strategies targeting the ATP-purinergic-mitochondrial axis, offering insights into integrated treatment approaches for both disease types.

Background: Acute pancreatitis (AP) is characterized by early acinar injury followed by rapid inflammatory amplification, yet the upstream molecular triggers linking tissue stress to cytokine escalation remain incompletely defined. Interleukin-34 (IL-34), a ligand of colony-stimulating factor-1 receptor (CSF-1R), regulates inflammatory signaling, but its role in AP has not been elucidated. Celastrol is a bioactive triterpenoid with established anti-inflammatory properties; however, whether it modulates IL-34-associated signaling in AP remains unclear.

Methods: Experimental AP was induced in rats by retrograde sodium taurocholate infusion. Celastrol (6 mg/kg, i.p.) was administered 1 h prior to AP induction. In vitro, caerulein-stimulated AR42J acinar cells and IL-34 overexpressing cells were employed to evaluate functional relevance. ERK/NF-κB activation and inflammatory mediator production were assessed by Western blotting, ELISA, and immunofluorescence. Molecular docking was performed as an exploratory structural analysis of celastrol and the IL-34/CSF-1R complex.

Results: Celastrol significantly attenuated pancreatic injury in vivo, reducing serum amylase activity by approximately 34% and improving histological scores (both P < 0.01). IL-34 protein expression was markedly increased in experimental AP (P < 0.001), accompanied by activation of CSF-1R-dependent ERK and NF-κB signaling. IL-34 overexpression enhanced inflammatory outputs, whereas celastrol suppressed IL-34 expression and downstream signaling activation (P < 0.05). Docking analysis suggested structural compatibility between celastrol and IL-34/CSF-1R. Targeting IL-34 signaling may represent a potential therapeutic approach for acute pancreatitis.

Conclusion: These findings identify IL-34 as a previously unrecognized contributor to inflammatory amplification in experimental AP. Celastrol treatment was accompanied by reduced IL-34 expression and attenuation of ERK/NF-κB activation. Although further loss of function studies are required to establish direct causality, modulation of IL-34-related signaling may represent a potential therapeutic direction for AP.

Purpose: To determine whether neutrophil extracellular trap (NET) predicts prognosis and response to neoadjuvant immunotherapy in gastric cancer (GC) and explore the associated mechanisms.

Patients and methods: Transcriptomic data from a GEO dataset (GSE62254) comprising 300 GC patients were analyzed. Patients were clustered based on 69 predefined NET-related genes (NRGs) summarized in previous studies, and clinical characteristics and immune cell infiltration between clusters were compared. An NRG signature was constructed. Retrospective clinical data and tissue samples from 243 surgically resected GC patients without neoadjuvant therapy and 49 patients receiving neoadjuvant chemotherapy combined with immunotherapy were collected. RNA sequencing, immunohistochemistry, and immunofluorescence were performed to assess NET density and its clinical relevance.

Results: Two NET-related subtypes in GC (NT1 and NT2) with distinct clinical features and survival time were identified. A risk model based on five NRGs demonstrated that NT2 had lower risk scores, correlating with favorable outcomes. High NET density was associated with advanced TNM stage and short recurrence-free survival time in the surgery cohort. In the immunotherapy cohort, low pre-treatment NET density correlated with more T cells predicted superior response rates (45.8% vs. 16.0%, P = 0.032) and pathological complete response (29.2% vs. 4.0%, P = 0.023).

Conclusion: Low NET density is linked to better prognosis and may identify patients with GC who could benefit from immunotherapy. These findings highlight the important role of NET in GC.

Purpose: Although inflammatory markers have been implicated in the prognosis of intracerebral hemorrhage (ICH), their associations with peak perihematomal edema (PHE) and hematoma clearance remain unclear. This study evaluated inflammatory markers, focusing on the neutrophil percentage-to-albumin ratio (NPAR), to determine their prognostic relevance in supratentorial ICH.

Patients and methods: We retrospectively analyzed patients with supratentorial ICH who arrived at Beijing Tiantan Hospital within 24h of symptom onset between January 2021 and December 2022. Both inflammatory and imaging markers were measured at multiple time points. Hematoma and PHE volumes were quantified using 3D Slicer software. The primary outcome was 90-day functional outcome assessed with the modified Rankin Scale (mRS). LASSO regression was used to identify inflammation-related indices most strongly associated with 90-day functional outcome. Multivariable logistic and linear regression analyses were then performed to examine associations between inflammatory markers, 90-day outcomes, peak PHE, and the maximum hematoma clearance percentage (MHCP).

Results: A total of 470 patients were included. LASSO regression identified NPAR as the strongest inflammation-related predictor of 90-day outcome. Higher admission NPAR independently related with greater peak PHE (r = 0.15, P = 0.001), and poor functional outcome (adjusted OR 1.15, 95% CI 1.03-1.30), with a 2.52-fold increased risk in the highest quartile versus lowest quartile. Elevated NPAR levels at 1-3, 4-7, and >7 days after admission remained associated with poor outcome (all p<0.05). Admission NPAR was also associated with MHCP (adjusted OR 0.85, 95% CI 0.75-0.97). Restricted cubic spline analysis revealed a nonlinear relationship, with optimal clearance observed at moderate NPAR levels.

Conclusion: NPAR was independently associated with poor functional outcome and greater peak PHE, while also being associated with hematoma clearance dynamics, highlighting the complex relationship between systemic inflammation, host reserve, and recovery processes in supratentorial ICH.

Severe eosinophilic asthma represents a relatively small proportion of the overall asthma population but accounts for a disproportionate burden of exacerbations, oral corticosteroid (OCS) exposure and healthcare use. The advent of biologic therapies targeting type 2 (T2) inflammation has made clinical remission a realistic goal and raised new questions about how and when to de-escalate inhaled corticosteroids (ICS) and biologics in patients achieving stable disease. This narrative review summarizes current evidence and expert recommendations on: definitions and levels of clinical remission in severe eosinophilic asthma; the role of different biologics in inducing remission; safety and feasibility of ICS and biologic de-escalation after remission; and clinical and biological predictors of sustained remission and successful step-down. Biologics such as anti-IgE, anti-IL-5/5Rα, anti-IL-4Rα and anti-thymic stromal lymphopoietin (TSLP) markedly reduce exacerbations, OCS use and, in a substantial minority of patients, induce clinical or "deep" remission on-treatment. Prospective randomized controlled trials and real-world data (e.g. SHAMAL and registry studies) indicate that structured, physician-guided ICS reduction is feasible for many patients without loss of control, whereas abrupt or unsupervised reduction is associated with worse outcomes. Evidence on biologic withdrawal is more heterogeneous: discontinuation of mepolizumab, tezepelumab or omalizumab frequently leads to loss of control, although a subset maintains remission off-treatment. Favorable predictors of remission and tolerability of de-escalation include fewer prior exacerbations, lower chronic OCS exposure, shorter disease duration, better preserved FEV₁ and effective suppression of T2 biomarkers. Within the context of severe eosinophilic asthma remission, de-escalation of therapy may follow a cautious, hierarchical, clinician-led strategy prioritizing OCS, then ICS, and only subsequently biologics, with predefined failure criteria and shared decision-making. This proposed pathway is presented as a pragmatic synthesis of the available evidence and should be interpreted as expert opinion rather than formal guideline recommendations. Robust, standardized definitions and validated predictors are still needed to safely expand off-treatment remission to a larger proportion of patients.

Background: Colitis impairs life quality, and treatments are limited. Acupuncture may engage vagal anti-inflammatory pathways, but the precise circuits are unclear.

Objective: This study aimed to examine the effects of electroacupuncture (EA) at "Shangjuxu" (ST37) on murine colitis and the involvement of the cholinergic vagus system.

Methods: Mice were divided into control, model, EA (electro-acupuncture), and MLA (EA with α7nAChR antagonist) groups. A colitis model was induced in mice by freely drinking a 2.5% dextran sodium sulfate (DSS) solution for 7 days. Colitis severity was assessed via body weight, colon length, and H&E staining. Proximal colon cytokines were measured by MSD assay. Immunofluorescence evaluated activation of ChAT-positive neurons in the dorsal motor nucleus of the vagus (DMV) and local colon cholinergic markers. Anatomical interactions between ChAT-positive fibers and α7nAChR-positive cells were observed. Vagal efferent fiber activity was recorded electrophysiologically.

Results: EA at ST37 significantly reduced body weight loss and proximal colon tissue damage in colitis mice (P < 0.05). These beneficial effects were blocked by the α7nAChR antagonist MLA. Levels of five pro-inflammatory cytokines (TNF-α, IL-6, CXCL1, IL-1β, IL-5) were elevated in the model group but decreased following EA treatment (P < 0.05). Colitis increased activation of ChAT-positive neurons in the DMV, and EA further enhanced this activation (P < 0.05). The reduced α7nAChR content in the proximal colon of model mice was restored to near-normal levels by EA (P < 0.05). EA also significantly increased the activation of cervical vagal efferent fibers (P < 0.05). Anatomical associations between ChAT-positive fibers and α7nAChR-positive cells were observed in the EA group.

Conclusion: EA at ST37 alleviates inflammation in colitis mice likely by activating ChAT-positive neurons in the DMV. This stimulates vagal efferent nerves, modulates α7nAChR-positive cells in the proximal colon, and engages the vagal cholinergic anti-inflammatory pathway.

Purpose: Previous clinical studies have suggested potential differences in the response of different subtypes to febuxostat treatment. However, research on elderly gout patients, particularly those with chronic kidney disease (CKD) stage 3, remains lacking. This study aims to compare febuxostat response across subtypes in elderly gout patients.

Methods: A prospective cohort study was conducted to compare the efficacy and safety of febuxostat (20 or 40 mg daily) in 490 gout patients with the clinical subtypes for 12 weeks. Hyperuricemia was defined as the renal underexcretion subtype when UUE ≤ 600 mg/d/1.73m² and FE_UA < 5.5%, the renal overload subtype when UUE > 600 mg/d/1.73m² and FE_UA ≥ 5.5%, the combined subtype when UUE > 600 mg/d/1.73m² and FE_UA < 5.5%, or the normal subtype when UUE ≤ 600 mg/d/1.73m² and FE_UA ≥ 5.5%, assessed from 24-h urine samples. The primary endpoint was the rate of achieving serum urate (SU) < 6 mg/dL at week 12.

Results: Fewer participants with combined subtype achieved the SU target, 45.57% compared with 69.69% with renal overload subtype, 63.40% with renal underexcretion subtype and 64.06% with normal subtype. Participants with the normal subtype had the lowest baseline eGFR but showed the greatest improvement after treatment (an increase of 5.67 mL/min/1.73 m² at week 12, P < 0.001).

Conclusion: Elderly gout patients with the combined subtype exhibit poorer response to febuxostat compared to other subtypes. Urate-lowering therapy improved renal function, particularly in patients with normal subtypes.

Introduction: Dengue severity is influenced by viral load and the host's immune response. Aedes aegypti saliva increases cellularity at the bite site, which may promote viral replication. Atopic dermatitis (AD) is associated with hypersensitivity to Aedes saliva and Th2-skewed immune response, potentially increasing viral target cells in the skin and impairing the immune response to dengue. This study investigated the association between exposure to Aedes saliva, T-cell function, and dengue severity among dengue patients with AD, particularly in children, in whom the incidence of AD and the severity of dengue are higher.

Methods: This observational cross-sectional study was conducted on 62 secondary dengue patients aged 1-12 years. The ISAAC questionnaire was used to assess the history of AD. T-cell functions were evaluated by measuring the levels of IFNγ, IL10, IL13, and CCL2 cytokines in the PHA-stimulated whole blood cultures exposed to Aedes aegypti salivary gland extract (SGE) using the ELISA.

Results: The incidence of dengue hemorrhagic fever (DHF) was higher among dengue patients with AD than in those without AD (p=0.010). In the PHA-stimulated whole blood cultures exposed to SGE, higher CCL2 levels were observed in DHF patients than in dengue fever (DF) patients (p=0.044), and higher IL13 levels were found in dengue patients with AD compared to those without AD (p=0.026). In PHA-stimulated whole blood cultures without SGE, lower IFNγ levels were found in DHF patients than in DF patients (p=0.035).

Conclusion: AD may be associated with a higher incidence of DHF and increased T-cell IL-13 production in response to SGE. DHF may be associated with increased T-cell CCL2 production in response to SGE, which may reflect greater cell infiltration at the bite site, and reduced T-cell IFN-γ production in response to dengue infection.