Journal of Inflammation Research最新文献

Objective: This study aimed to elucidate the molecular mechanisms of berberine (BBR) in ameliorating diabetic kidney disease (DKD), focusing on its regulatory effects on the renal immune microenvironment and macrophage polarization.

Methods: We first employed a network pharmacology approach, integrating public transcriptomic data with drug target databases, to predict the core pathways and immune regulatory mechanisms of BBR in DKD. To experimentally validate these in silico predictions, we assessed the effects of BBR on apoptosis, fibrosis, and inflammation in a high-glucose-induced renal tubular epithelial cell (NRK-52E) model. Finally, a DKD rat model was established to confirm the therapeutic efficacy in vivo and to mechanistically investigate BBR's impact on renal macrophage polarization and the key signaling proteins of the predicted pathway.

Results: Network pharmacology and transcriptomic analysis identified 55 core genes of BBR in DKD, enriched in apoptosis, metabolism, oxidative stress, and inflammation, with immune infiltration implicating T cells, B cells, and macrophage subsets. In vitro, BBR enhanced viability of high-glucose-injured NRK-52E cells, suppressed apoptosis and fibrosis markers, and reduced IL-6, IL-17A, and TNF-α levels. In vivo, BBR reduced hyperglycemia, preserved renal function, attenuated fibrosis, and rebalanced macrophage polarization by inhibiting M1 while promoting M2 phenotypes. Mechanistically, these effects were associated with downregulation of the IL17A/TRAF6/MAPK14 pathway.

Conclusion: Berberine alleviates diabetic kidney disease by regulating macrophage polarization via inhibition of the IL17A/TRAF6/MAPK14 signaling pathway, underscoring its therapeutic potential as an anti-inflammatory and anti-fibrotic agent.

Objective: Obacunone (OB) possesses anti-inflammatory, antioxidant, and anticancer properties. This study aimed to investigate the neuroprotective effects of OB in ischemic stroke, and to elucidate the underlying mechanisms.

Methods: Primary microglia were preincubated with OB for 2 h, followed by lipopolysaccharide (LPS) stimulation for either 3 or 24 h. The levels of inflammatory cytokines in primary microglia were assessed via real-time PCR, enzyme-linked immunosorbent assay (ELISA), and Western blot. The activation of the mitogen-activated protein kinase/nuclear factor kappa B (MAPK/NF-κB) signaling pathway was evaluated via immunofluorescence staining and Western blot. For in vivo experiments, 8-week-old male C57BL/6J mice were randomly assigned to 4 groups: the sham-operated group, the middle cerebral artery occlusion (MCAO) model group and the MCAO group treated with OB (5 mg/kg/day and 10 mg/kg/day), and the sham-operated and MCAO model groups received an equivalent volume of vehicle. The neurological deficits and memory functions were evaluated by a cassette of behavior tests. 2,3,5-Triphenyl tetrazolium chloride (TTC) staining and Evans blue staining were performed to evaluate infarct size and blood-brain barrier permeability. Additionally, network pharmacology and molecular docking predicted mitogen-activated protein kinase 1 (MAPK1) as a potential target of OB, and this interaction was validated via surface plasmon resonance (SPR), cellulase thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) experiments.

Results: OB effectively inhibited the activation of the MAPK/NF-κB pathway and reduced microglia-mediated inflammatory cytokine production both in vitro and in vivo. In addition, OB attenuated ischemic brain injury in MCAO mice and improved memory function 30 days after MCAO. Moreover, OB directly bound to MAPK1, with ARG-146 as the critical binding site.

Conclusion: Our findings suggest that OB binds to MAPK1 and alleviates neuroinflammation and ischemic injury, making it a potential therapeutic agent for ischemic stroke.

Chronic spontaneous urticaria (CSU) is a common and often debilitating inflammatory skin disease characterized by recurrent pruritic wheals, angioedema, or both, persisting for ≥6 weeks. Symptoms are unpredictable, with sudden onset and resolution, fluctuating severity, variable duration, and inconsistent responses to treatment, which may substantially impair patients' quality of life. This underscores the complexity of clinical management and the need for effective therapies to achieve disease control. According to international guidelines, first-line therapy consists of second-generation H₁-antihistamines, which may be up-dosed to fourfold in patients with inadequate response. Less than half of patients on standard doses achieve disease control, increasing to 63% with up-dosing. Patients who remain uncontrolled after 2-4 weeks may escalate to add-on therapy with omalizumab, which provides complete disease control in approximately 70% of antihistamine-refractory cases. Omalizumab has transformed CSU management and is well-established as safe and effective. However, up to one third of patients, particularly those with autoimmune (type IIb) CSU, do not achieve adequate disease control. For patients refractory to antihistamines and omalizumab, recently approved add-on therapies, including remibrutinib and dupilumab, provide additional options. Cyclosporine may be considered for severe, refractory cases, particularly in type IIb CSU, though its use is limited by potential serious adverse effects. Off-label therapies, such as leukotriene receptor antagonists and short courses of systemic corticosteroids, may also be used when guideline-recommended treatments are insufficient. Additional therapeutic targets are continuously under development. Emerging treatments include Tyrosine kinase (KIT) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, TSLP inhibitors, Janus kinase (JAK) inhibitors, Mas-related G protein-coupled receptor X2 (MRGPRX2) antagonists, and interleukin 2 (IL-2), which may provide effective options for refractory patients while enhancing understanding of CSU pathophysiology. Collectively, these therapies support a shift toward more personalized and targeted management strategies, aiming to achieve faster and more efficient disease control.

Sjögren's disease (SjD) is a chronic autoimmune disease that is characterised by dryness symptoms, arthralgias, systemic disease and B-cell hyperactivity. Serum autoantibodies are key pathological features of this disease. Anti-Ro52, anti-Ro60 and anti-La immunoglobulin G autoantibodies (sometimes known as antinuclear antibodies) are perhaps the most well-known autoantibodies, are important in the formal classification criteria for SjD and exist in up to 70% of patients. Rheumatoid factors, which are present in approximately 50% of patients, can reveal important prognostic information regarding the development of B-cell lymphomas. Beyond these autoantibodies, there are several emerging and novel autoantibodies associated with SjD that hold promise in identifying clinical features of SjD and facilitating the diagnosis of patients who lack the classic SjD-associated autoantibodies. These include anti-fodrin antibodies, anti-muscarinic acetylcholine receptor 3 antibodies and those autoantibodies traditionally associated with systemic lupus erythematosus. This narrative review article provides an updated review of these autoantibodies, discussing their potential clinical utility and the current limitations. Although many clinical associations have been identified, the routine clinical use of these autoantibodies is hampered by issues such as poor diagnostic sensitivity, contradictory associations, heterogeneous studies and small single-cohort studies. Further research using harmonised testing and large, multicentre cohorts is required to explore and validate the utility of these autoantibodies.

Purpose: This study aims to explore the relationship between RMPP biomarkers and the dose of glucocorticoids.

Patients and methods: A retrospective analysis was conducted on 432 children with refractory Mycoplasma pneumoniae pneumonia (RMPP) who visited the Children's Hospital from January 2023 to December 2024. According to the dose of methylprednisolone, it was divided into three groups: low-dose, medium-dose and high-dose. We evaluated the basic characteristics, laboratory results and imaging manifestations of the patients.

Results: The median age and body mass index (BMI) of patients in the high-dose group were the lowest, which were 6.5 years (5, 8.25) and 14.25 years (13.28, 15.23), respectively. The imaging manifestations were more obvious in the high-dose group. The hospitalization time was the longest and the hospitalization cost was the highest (P<0.05). Furthermore, in the high-dose RMPP cohort, White blood cell count (WBC), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), alanine aminotransferase (ALT), creatine kinase MB (CKMB), lactate dehydrogenase (LDH), fibrinogen, The levels of D-dimer, ferritin, procalcitonin (PCT) and erythrocyte sedimentation rate (ESR) were all significantly increased (P<0.05). The dose of glucocorticoids was positively correlated with the length of hospital stay, BMI, WBC, CRP, PCT, LDH, ALT, NLR, ESR, D-dimer and ferritin levels. But there was no significant correlation with age. The correlation coefficients of NLR, ferritin and the dose of methylprednisolone were the highest, with Spearman ρ values of 0.451 and 0.592 respectively (P<0.001).

Conclusion: NLR and ferritin levels may be useful biomarkers for determining the appropriate dose of corticosteroids in children with RMPP.

Background: Serum lipocalin 2 (LCN2) and human interleukin 13 (IL-13) polymorphism are important biomarkers in neurodegeneration, neuroinflammation and the development of multiple sclerosis (MS). This study aimed to evaluate IL-13 polymorphism and serum LCN2 in MS patients and assess their role as predictors of risk and disability in MS.

Methodology: This case-control study included 48 patients and 48 controls. Blood samples were obtained to measure LCN2 and to find the IL-13 (rs20541) gene polymorphism by restriction fragment length polymorphism. Individuals with the GG genotype, which is wild normal, produced two fluorescent bands at 210 and 26 bp. Three fluorescent bands were seen at 178, 32 and 26 bp in individuals with the homozygous mutant type AA genotype. Individuals with heterozygous mutant type GA gave four fluorescent bands at 210 bp, 178 bp, 32 bp and 26 bp.

Results: The IL-13 (rs20541) polymorphism revealed a statistically significant difference between the MS group and the healthy control group. The AG genotype raises the risk of MS by 9 times, whereas the risk of MS is approximately 3.58 times higher with the A allele. There was no statistically significant difference between the severity of disability in MS regarding IL-13 (rs20541) polymorphism. Also, there was a significant direct correlation between LCN2 and Expanded Disability Status Scale. The best cutoff values of LCN2 for diagnosis and detecting disability in MS were ≥5.4 ng/mL, with an area under the curve is 0.90 with sensitivity 85.7% and specificity 82.4%.

Conclusion: The research makes a substantial contribution to the literature on the perceived significance of value of IL-13 polymorphism to the risk of MS, while LCN2 is linked to both risk and disability of MS.

Purpose: Preterm premature rupture of membranes (PROM) is a major cause of extremely preterm birth. Intrauterine infection and inflammation markedly increase the risk of neonatal acute respiratory distress syndrome (NARDS), particularly moderate or severe cases associated with poor outcomes. This study developed and validated a prediction model for moderate or severe NARDS in this population using inflammatory biomarkers.

Patients and methods: This single center retrospective cohort study included 243 extremely preterm infants with PROM from 2015 to 2024. The primary outcome was moderate or severe NARDS occurring within 72 hours after delivery, diagnosed according to Montreux criteria. Patients were grouped by NARDS severity. Predictive variables were screened using LASSO regression and incorporated into a multivariable logistic model to build a nomogram. Model performance was assessed through receiver operating characteristic curves (ROC), calibration plots and decision curve analysis (DCA).

Results: The primary outcome incidence was 20.2% (49/243). Multivariable analysis identified elevated C-reactive protein (CRP) (OR=1.04, 95% CI:1.01-1.07), decreased platelet count (OR=0.99, 95% CI:0.988-0.998), decreased albumin (OR=0.87, 95% CI:0.80-0.95), and decreased arterial pH (OR=0.01, 95% CI:0.001-0.041) as independent predictors. The nomogram integrating these four parameters demonstrated excellent discrimination with an area under the curve (AUC) of 0.824. Internal validation demonstrated good robustness (C-index=0.795). To enhance clinical translation, we developed an interactive web calculator for real time risk assessment to guide pediatricians' clinical decision making. DCA established a 30% risk threshold to inform early interventions.

Conclusion: The validated model containing CRP, platelets, albumin and pH effectively identifies high risk PROM infants. The web based interface enables practical bedside application for early detection of critical cases. Patients with predicted probabilities reaching 30% should be considered for preventive lung protection measures. Additional multicenter studies are needed to verify wider applicability and enhance clinical implementation protocols.

Purpose: Postoperative ileus (POI) commonly impedes recovery after surgical procedures. While the Yi-Qi-Dao-Zhi Formula (YQDZ) has proven its worth in treating premature ovarian insufficiency in clinical settings, the exact therapeutic mechanisms that make it tick continue to fly under the radar.

Methods: This investigation employed ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) to pinpoint the key bioactive compounds in YQDZ. For in vivo experiments, a POI mouse model was created through surgical intervention, and gastrointestinal transport function was assessed via charcoal ink experiments. Intestinal histopathology was examined using HE staining. The therapeutic impact of YQDZ on POI was thoroughly assessed using a battery of advanced laboratory techniques, including immunofluorescence staining, immunohistochemical analysis, Western blot procedures, real-time quantitative PCR assays, and ELISA testing. In vitro experiments involved the establishment of an M1-type inflammatory model by inducing mouse mononuclear macrophage RAW264.7 cells with LPS. Additional evaluations encompassed CCK-8 assays, flow cytometry, transcriptomic profiling, real-time PCR, and protein level examinations, all aimed at delving into the mode of action of YQDZ.

Results: YQDZ steers M1 macrophage differentiation through the TLR4/NF-κB/MAPK signaling pathway. This action effectively curtails the levels of key inflammatory mediators including TNF-α, IL-1β, and IL-6. Consequently, it acts as a therapeutic agent for inflamed bowels in postoperative ileus mice, helping to restore their gastrointestinal functionality.

Conclusion: The therapeutic approach of YQDZ for POI might be connected to the adjustment of the TLR4/NF-κB/MAPK signaling pathway, alongside the inhibition of macrophage polarization.

Background: Endothelial damage and NLRP3 inflammasome activation are key mechanisms underlying cerebral ischemia-reperfusion (I/R) injury. Neuregulin-1 (NRG1) alleviates endothelial damage, blood-brain barrier (BBB) disruption, and neurological deficits following acute ischemic stroke (AIS). This study investigates whether NRG1 attenuates endothelial-mesenchymal transition (EndMT) during endothelial injury by suppressing NLRP3 inflammasome activation, potentially through the AKT/NF-κB pathway, in cerebral I/R injury.

Methods: Middle cerebral artery occlusion/reperfusion (MCAO/R) mouse models and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated immortalized human cerebral microvascular endothelial cells (hCMEC/D3) were established and treated with NRG1. Neurological deficits were assessed using the modified Neurological Severity Score (mNSS), while cerebral infarct volume and caspase-1 activity were quantified. Cell viability and death were evaluated by the Cell Counting Kit-8 (CCK-8), lactate dehydrogenase (LDH) assays, and TUNEL staining. Protein expression was analyzed using Western blotting and immunofluorescence staining.

Results: NRG1 intervention significantly improved mNSS, reduced cerebral infarct volume, and decreased caspase-1 activity in MCAO/R mice. In OGD/R-treated hCMEC/D3, NRG1 enhanced cell viability while reducing cell death, as indicated by decreased LDH release and TUNEL-positive cells. Western blotting and immunofluorescence staining revealed that NRG1 enhanced AKT phosphorylation, inhibited NF-κB p65 phosphorylation, and downregulated NLRP3 and IL-1β expression. These effects were associated with the amelioration of occludin reduction and suppression of α-smooth muscle actin (α-SMA) increase during EndMT progression.

Conclusion: The results demonstrate that NRG1 reduces cerebral infarct volume, alleviates neurological deficits, and suppresses NLRP3 inflammasome activation in association with modulation of the AKT/NF-κB pathway, thereby attenuating EndMT-associated proteins following cerebral I/R injury.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease marked by chronic inflammation and frequent metabolic disturbances. Understanding the influence of body weight and hydroxychloroquine on adipokines and inflammatory markers may clarify their role in SLE progression.

Purpose: This study examined metabolic health, adipose tissue gene expression, and serum adipokine and inflammatory profiles in normal-weight (NW) and excess body weight (EBW) female patients with SLE and explored associations with disease activity and hydroxychloroquine (HCQ) use.

Patients and methods: Fifty women with SLE were classified as NW or EBW. Laboratory analyses included antibodies against double-stranded DNA, complement components (C3, C4), fasting glucose, triglycerides, total and fractionated cholesterol, and C-reactive protein (CRP). Subcutaneous adipose tissue gene expression was assessed by real-time PCR.

Results: Mean age, disease duration, and SLEDAI-2K scores were similar between groups (p > 0.05). HCQ dose adjusted by body weight was lower in EBW patients (p < 0.05). EBW patients had higher total cholesterol, LDL-c, CRP, and leptin, with lower adiponectin and reduced adiponectin/leptin ratio (p < 0.05). Adipose tissue expression of TNF-α, LEP, IL-6, and ADIPOQ was elevated in EBW (p < 0.05). Stratifying by adipo/lep ratio (≤5 vs >5) showed similar disease activity (p > 0.05), though patients with preserved adipose function (ratio >5) had higher serum C4 (p = 0.004) and a trend for increased C3 (p = 0.055). Multiple regression indicated HCQ dose (mg/kg/day) was inversely associated with abdominal circumference (β = -0.43; p = 0.003) and fat mass(β = -0.38; p = 0.009) and positively associated with adiponectin (β = 0.45; p = 0.002) and adipo/lep ratio (β = 0.39; p = 0.009). Higher HCQ doses tended to increase HDL-C (p = 0.059) and reduce leptin (p = 0.058).

Conclusion: Excess body weight in SLE is linked to an adverse adipokine profile and increased inflammation, raising metabolic and cardiovascular risk. Weight-adjusted HCQ shows protective effects on adipose metabolism, HDL-c, and adiponectin. These findings emphasize individualized, weight-based HCQ therapy and early adipose biomarker assessment to guide precision medicine in SLE management.