Mediators Of Inflammation[JOURNAL]
Sun
200 papers
Correction to "Progesterone Administration Modulates Cortical TLR4/NF-κB Signaling Pathway after Subarachnoid Hemorrhage in Male Rats".
Mediators Inflamm · 2026 · PMID 41800108 · Full text
[This corrects the article DOI: 10.1155/2011/848309.].
[This corrects the article DOI: 10.1155/2011/848309.].
Association of BRI With Psoriasis and Mediator Effect of SII: A Study Based on NHANES (2003-2006, 2009-2014).
Zhang N, Li J, Song P
Mediators Inflamm · 2026 · PMID 41800107 · Full text
BACKGROUND AND AIMS: The prevalence of psoriasis (Pso), a chronic immune-mediated inflammatory skin disease, is high in patients with obesity. This study investigates the mediating role of the systemic immune-inflammatio...
BACKGROUND AND AIMS: The prevalence of psoriasis (Pso), a chronic immune-mediated inflammatory skin disease, is high in patients with obesity. This study investigates the mediating role of the systemic immune-inflammation index (SII) in the association between body roundness index (BRI) and Pso prevalence. METHODS AND RESULTS: This study included 14,669 participants from the National Health and Nutrition Examination Survey (NHANES) (2003-2006, 2009-2014). The presence or absence of obesity was identified using the BRI, and Pso was assessed using the Pso questionnaire. The association of BRI with Pso was explored by weighted multivariate logistic regression analyses and restricted cubic spline (RCS) analyses, and the threshold effect was further examined using two-stage linear regression models. Mediation analyses assessed SII's role in the BRI-Pso association. The Pso group included 445 out of 14,669 participants. Logistic regression analyses indicated a positive association between BRI and Pso after adjusting for potential confounders. RCS analyses showed a nonlinear relation between BRI and Pso ( = 0.018), with a point of inflection at 5.103 (odds ratio [OR] = 1.09, 95% CI: 1.04, 1.14). BRI and Pso were positively correlated on the left side of the point of inflection (OR = 1.25, 95% CI: 1.09, 1.45), whereas such an association was not detected on the right side (OR = 1.04, 95% CI: 0.97, 1.11). Mediation analysis showed SII partially mediated this association, accounting for 9.48% of the effect ( < 0.001). CONCLUSION: BRI is positively associated with Pso, with SII playing a mediating role. These findings highlight the importance of visceral fat management and SII monitoring in addressing Pso and its metabolic comorbidities.
Wenyang Decoction Ameliorates DSS-Induced Ulcerative Colitis by Regulating Macrophage Polarization and the PI3K/AKT/mTOR/HIF-1α Signaling Pathway.
Li S, Yuan G, Chen C … +2 more , Lu J, Zhang X
Mediators Inflamm · 2026 · PMID 41800106 · Full text
AIM: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by intestinal inflammation and epithelial damage. This study aims to investigate the therapeutic effects of Wenyang decoction (WYD) in a...
AIM: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by intestinal inflammation and epithelial damage. This study aims to investigate the therapeutic effects of Wenyang decoction (WYD) in a dextran sulfate sodium (DSS)-induced UC model and its underlying mechanisms, with a focus on macrophage polarization and the regulation of the PI3K/AKT/mTOR/HIF-1α signaling pathway. METHODS: A DSS-induced UC model was established in C57BL/6 mice. Treatment groups received WYD at low (8.25 g/kg/day), medium (16.50 g/kg/day), or high (33.00 g/kg/day) doses, with 5-aminosalicylic acid (5-ASA, 200 mg/kg) as a positive control. Assessments included disease activity index (DAI), colon length, histopathology, and levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and oxidative stress markers (SOD, CAT, and MDA). Mechanisms were probed using western blot, qPCR, immunofluorescence, and flow cytometry to analyze macrophage phenotypes (M1/M2) and key signaling pathway proteins. RESULTS: WYD administration dose-dependently alleviated UC symptoms, significantly mitigating body weight loss, reducing DAI scores, and restoring colon length. Histological analysis revealed improved mucosal integrity and reduced inflammatory infiltration. Quantitatively, WYD significantly suppressed pro-inflammatory cytokines (e.g, IL-1β, IL-6, and TNF-α) and attenuated oxidative stress by enhancing antioxidant enzyme activities (SOD and CAT) and decreasing MDA content. Mechanistically, WYD inhibited M1 macrophage polarization (evidenced by downregulation of inducible nitric oxide synthase [iNOS] and CD16/32) and promoted M2 polarization (upregulation of Arg-1 and CD206). Furthermore, WYD treatment significantly inhibited the activation of the PI3K/AKT/mTOR pathway and its downstream target, HIF-1α, both in vivo and in LPS-stimulated RAW264.7 cells. CONCLUSION: In summary, our findings indicate that WYD exerts significant therapeutic effects in DSS-induced UC. WYD alleviates intestinal inflammation and injury by reshaping macrophage polarization, attenuating oxidative stress, and modulating the PI3K/AKT/mTOR/HIF-1α signaling pathway. This study provides a potential therapeutic strategy for UC in the future.
Circ-Eif3c Carried by M2 Macrophage-Derived Exosomes Mitigates Asthma Progression via miR-15a-5p/GSS/SOCS6 Axis Inhibition.
Yuan J, Zhao J, Ge X … +7 more , Zhu X, Li L, Ni H, Fan J, Zhang Y, Sun Y, Shang Y
Mediators Inflamm · 2026 · PMID 41783090 · Full text
BACKGROUND: In the study, we aimed to uncover potential therapeutic mechanisms concerning M2 macrophage-derived exosomes in asthma. METHODS: Exosomes were isolated from M0Φ-Exos and M2Φ-Exos. An ovalbumin (OVA)-induced a...
BACKGROUND: In the study, we aimed to uncover potential therapeutic mechanisms concerning M2 macrophage-derived exosomes in asthma. METHODS: Exosomes were isolated from M0Φ-Exos and M2Φ-Exos. An ovalbumin (OVA)-induced asthma mouse model or lipopolysaccharide (LPS)-induced alveolar epithelial cells (AECs) were created to unravel the therapeutic mechanisms. High-throughput sequencing was used to search for differentially expressed circRNA. Bioinformation analysis and luciferase report analysis were used to reveal the regulationship among circ-Eif3c, miR-15a-5p, glutathione synthetase (GSS), and suppressor of cytokine signaling 6 (SOCS6). RESULTS: The results showed that M2Φ-Exos suppressed OVA-induced inflammatory cytokine secretion and lung injury in mice. Next-generation sequencing (NGS) showed that circ-Eif3c was upregulated in M2Φ-Exos. Circ-Eif3c downregulation inhibited the therapeutic effect of M2Φ-Exos. Bioinformation analysis confirmed that miR-15a-5p, GSS, and SOCS6 were the downstream targets of circ-Eif3c, which were confirmed by luciferase report analysis. The overexpression of miR-15a-5p or the downregulation of GSS/SOCS6 reversed circ-Eif3c's protective effects on LPS-induced AEC damage. The overexpression of circ-Eif3c increased the therapeutic effect of M2Φ-Exos. CONCLUSION: In conclusion, circ-Eif3c-enriched M2Φ-Exos attenuated airway remodeling by restoring the function of AECs.
The TWEAK-HOIP-HuR Axis: A Novel Mechanism of AMPK Inactivation and Metabolic Reprogramming in Lupus Nephritis Mesangial Cells Hyperproliferation.
Ding Z, Liu E, Li X … +5 more , Zhang Y, Li L, Weng C, Liu Z, Liu Z
Mediators Inflamm · 2026 · PMID 41778053 · Full text
Cellular proliferation is intrinsically coupled to metabolic reprogramming, a conserved biological association that modulates the progression of diverse proliferative pathologies. In the present study, we unveil a novel...
Cellular proliferation is intrinsically coupled to metabolic reprogramming, a conserved biological association that modulates the progression of diverse proliferative pathologies. In the present study, we unveil a novel mechanistic link between tumor necrosis factor-like weak inducer of apoptosis (TWEAK) signaling and Human antigen R (HuR)-driven metabolic alterations in lupus nephritis (LN), a progressive renal disorder characterized by mesangial cells (MCs) hyperproliferation and glomerular dysfunction. We demonstrate that TWEAK stimulation elicits linear ubiquitination of AMP-activated protein kinase (AMPK)-a master regulator of cellular energy metabolism-mediated by the E3 ubiquitin ligase HOIL-1-interacting protein (HOIP). This posttranslational modification directly results in the functional inactivation of AMPK. Notably, suppressed AMPK activity drives the nuclear export of HuR, a ubiquitously expressed RNA-binding protein, leading to its subsequent accumulation in the cytoplasmic compartment. In the cytosol, HuR selectively binds to and stabilizes the mRNAs of key cell cycle regulators, with Cyclin D1 being a primary target. This stabilization of Cyclin D1 mRNA ultimately promotes aberrant MCs proliferation, a pathological hallmark of LN. To validate the functional relevance of the pathogenesis, we performed HOIP knockdown experiments in MCs. Consistent with our mechanistic model, HOIP depletion significantly restored AMPK phosphorylation (a well-established surrogate marker of AMPK activation), suppressed HuR cytoplasmic shuttling, reduced Cyclin D1 expression at both the transcriptional and translational levels, and ultimately inhibited aberrant MCs proliferation in vitro. Collectively, our results establish the TWEAK-HOIP-AMPK-HuR axis as a critical signaling axis that couples metabolic dysfunction to dysregulated cell cycle progression in LN. This work not only provides critical new mechanistic insights into the pathogenesis of mesangial hyperproliferation in LN but also highlights potential therapeutic targets, including HOIP and cytoplasmic HuR, for the development of targeted treatments for LN and other renal diseases characterized by abnormal MCs proliferation.
The Potential Value of Blood Inflammatory Parameters in Diagnosing the Inflammatory Microenvironment and Predicting Fetal Outcomes in Patients With Intrahepatic Cholestasis of Pregnancy.
Gao J, Li L, Huang H … +10 more , Chen J, Dong R, Wang J, Wang G, Wang R, Shi Y, Shuang L, Yang X, Zhang T, Luo L
Mediators Inflamm · 2026 · PMID 41778052 · Full text
Previous studies have indicated that the inflammatory microenvironment in pregnant women may contribute significantly to the development of intrahepatic cholestasis of pregnancy (ICP). However, the exact relationship bet...
Previous studies have indicated that the inflammatory microenvironment in pregnant women may contribute significantly to the development of intrahepatic cholestasis of pregnancy (ICP). However, the exact relationship between inflammatory blood parameters and ICP remains uncertain. This study aims to explore the relationship between serum inflammatory factors, inflammatory scoring indicators, and adverse pregnancy outcomes in ICP. Serum samples were collected after 25 weeks of gestation from women clinically diagnosed with ICP, as well as from gestational age-matched healthy pregnant controls. Cytokine levels were subsequently measured using flow cytometry. Correlation analysis was conducted to explore potential relationships between blood inflammatory parameters and other ICP-related markers. Receiver operating characteristic (ROC) curves were generated to evaluate their predictive performance for adverse pregnancy outcomes. Mendelian randomization (MR) analysis was performed to examine potential causal links between inflammation and ICP development. The results revealed significant differences in serum levels of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) between ICP patients and healthy controls. Additionally, inflammatory scoring indicators were significantly elevated in ICP patients. Most inflammatory parameters correlated with liver function indices and showed positive associations with total bile acids (TBAs). ROC analysis demonstrated that combining inflammatory markers with TBA improved the predictive accuracy for preterm birth (area under the ROC curve [AUC]: 0.865) and low fetal weight (AUC: 0.916). MR analysis identified interleukin-2 (IL-2) and TNF-α as potential risk factors for ICP. Based on these findings, blood inflammatory parameters may serve as accessible and cost-effective indicators for understanding the inflammatory microenvironment in ICP and predicting fetal outcomes.
Imbalance of the Immune Response According to Alcohol Consumption Patterns.
Martinez-Castillo M, Hernandez-Barragan A, Santana-Vargas D … +9 more , Medina-Avila Z, Hernandez-Santillan M, Flores-Sanchez A, Altamirano-Mendoza I, La Tijera FH, Torre-Delgadillo A, Cordova-Gallardo J, Pérez-Hernández JL, Gutierrez-Reyes G
Mediators Inflamm · 2025 · PMID 41777360 · Full text
BACKGROUND: Alcohol intake promotes the translocation of endotoxins, stimulating immune cell activation and the production of cellular mediators, dysregulating the inflammatory process. We simultaneously evaluated the nu...
BACKGROUND: Alcohol intake promotes the translocation of endotoxins, stimulating immune cell activation and the production of cellular mediators, dysregulating the inflammatory process. We simultaneously evaluated the number of immune cells and cytokine concentrations, in relation to the pattern of alcohol consumption. METHODS: A cross-sectional study included five groups according to alcohol intake (hazardous drinking [HD], low alcohol use disorders [AUDs] [l-AUDs], moderate-severe AUDs [ms-AUDs], no decompensated cirrhosis, and alcohol-associated hepatitis [AH]). The control (CT) group was comprised of blood bank donors with an AUD Identification Test (AUDIT) <8 and occasional alcohol consumption of ≤10 g/day. Hematological and biochemical analyses were performed. Lymphocyte subsets (CD3, CD8, CD4, natural killer [NK], and NKTcells) were determined using FACS analyses, whereas cytokine levels were determined using multiplex array technology. Multiple comparisons, Spearman correlations, calculated ratios, and receiver operating characteristic (ROC) curves were carried out. RESULTS: A total of 780 subjects were enrolled and 427 were classified according to the alcohol consumption criteria. The ms-AUD group showed the highest levels of CD8, NK, and NKT cells, whereas patients with cirrhosis had the lowest number of CD8 subsets. AH displayed the highest number of neutrophils and cytokines. Moreover, lower levels of NK and NKT cells and upregulation of IL-6, CXCL-8, and TNF-α concentrations were observed, in accordance with alcohol intake (AH >cirrhosis > ms-AUD > l-AUD > HD). CONCLUSION: The number of immune cells (CD4, CD8, NK, and NKT cells) and IL-6, CXCL-8, IL-10, and TNF-α cytokine concentrations can be used as differential diagnostic parameters for AUD and could be considered an important criterion for the treatment of alcohol-associated liver disease (AALD).
Mendelian Randomization Reveals Genetic Associations Between Immune Traits and Urethral Stricture.
Guo Q, Guo JC, Zheng ZL … +4 more , Yang K, Wang JQ, Li CY, Xi YJ
Mediators Inflamm · 2026 · PMID 41769046 · Full text
BACKGROUND: There is currently little research on the association between immune traits and urethral stricture, and the diversity of immune cell subtypes leads to an unclear association with urethral stricture. This stud...
BACKGROUND: There is currently little research on the association between immune traits and urethral stricture, and the diversity of immune cell subtypes leads to an unclear association with urethral stricture. This study investigated the relationship between immune cells and urethral stricture using the Mendelian randomization (MR) technique. METHODS: We assessed the causative relationships between urethral stricture ( = 341,285) and 731 immunological characteristics ( = 3757). The main technique was the inverse-variance weighted (IVW) approach, which was supplemented by MR-Egger and weighted median (WM). The robustness of MR results was assessed using sensitivity analyses, primarily the Egger intercept, Cochran's test, MR-PRESSO, and leave-one-out test. RESULTS: Our findings revealed that 37 immune phenotypes have suggestive causal relationships with urethral stricture, including 13 subtypes of B cells, four classical dendritic cells, three myeloid cells, five monocytes, four TBNK, five Treg cells, and three maturation stages of T cells. Sensitivity analyses revealed neither heterogeneity nor pleiotropy. CONCLUSIONS: Our findings supported a potential causal relationship between immune cells and urethral stricture. This may guide the management and treatment of urethral stricture in the future.
TUG1 and H19 lncRNAs Can Predict Anti-TNF Unresponsiveness in Patients With Ulcerative Colitis: A Machine Learning-Based Approach.
Heydari R, Tavassolifar MJ, Nazari MHD … +5 more , Roshannia R, Shahrokh S, Parvizi M, Norooz MT, Meyfour A
Mediators Inflamm · 2026 · PMID 41769045 · Full text
The present study aimed to explore the association of long noncoding RNAs (lncRNAs) with inflammation, disease activity, and predicting response to anti-tumor necrosis factor (TNF)-α therapy in patients with ulcerative c...
The present study aimed to explore the association of long noncoding RNAs (lncRNAs) with inflammation, disease activity, and predicting response to anti-tumor necrosis factor (TNF)-α therapy in patients with ulcerative colitis (UC). Whole blood samples and inflamed biopsies were collected from 42 UC patients at baseline (W0) and week 14 (W14) after receiving anti-TNF treatment as a discovery cohort. Colonoscopy images, histopathological, and clinical symptoms were used to monitor disease activity and response to treatment. LncRNA expression analysis showed increased expression of H19 in the active lesions of UC nonresponders (UCNs) compared to UC responders (UCRs) at baseline, whereas taurine upregulated gene 1 (TUG1) expression was lower. Higher expression of H19 in UCN compared to UCR was still observed at W14, whereas its expression was downregulated in UCR in the remission phase at W14 versus W0, suggesting it as a marker for monitoring disease activity. Moreover, colonic expression of H19 was positively correlated with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). In blood, both H19 and TUG1 showed increased expression in UCN versus UCR at baseline and W14. Three-fold cross-validation-based machine learning approach and receiver operating characteristic (ROC) curve analysis showed that H19 and TUG1 had strong predictive performance for anti-TNF response, with accuracies of 90% and 93% in tissue and 85% and 60% in blood, respectively. In the validation cohort (12 UCR and 10 UCN), expression patterns were reproduced, and predictive performance remained high. H19 showed better accuracy in blood (85%) than tissue (70%), while TUG1 performed best in tissue (92%) and also remained highly accurate in blood (94%). The distinct expression of lncRNAs showed that they could play an important role in the response of UC patients to treatment. They can be a potential biomarker to monitor disease activity and predict response to anti-TNF treatment in UC patients.
SNHG5 Exacerbates Sepsis-Induced Inflammatory Injury in Coronary Artery Endothelial Cells by Regulating METAP2-Mediated IL-8 Secretion.
Deng T, Li D, Liang L … +1 more , Zou Y
Mediators Inflamm · 2026 · PMID 41769044 · Full text
BACKGROUND: Long noncoding RNAs (lncRNAs) are involved in regulating inflammatory responses in sepsis. This study aimed to investigate the potential roles of lncRNA SNHG5 in the pathogenesis of sepsis-induced coronary ar...
BACKGROUND: Long noncoding RNAs (lncRNAs) are involved in regulating inflammatory responses in sepsis. This study aimed to investigate the potential roles of lncRNA SNHG5 in the pathogenesis of sepsis-induced coronary artery injury. METHODS: Cecal ligation and puncture were used to establish a sepsis mouse model. Serum and coronary artery tissues were collected to assess inflammatory markers and lncRNA expression using enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qPCR). In vitro, mouse aortic endothelial cells were exposed to septic serum. The SNHG5/miR-377-3p/methionyl aminopeptidase 2 (METAP2) axis was investigated using dual-luciferase reporter gene experiments. Loss-of-function, gain-of-function, and rescue assays were performed to elucidate the functions of these genes in sepsis. RESULTS: Septic mice exhibited elevated systemic tumor necrosis factor alpha and interleukin (IL)-6 levels, as well as dysregulated endothelial markers (eNOS downregulation and ET-1 upregulation). Among the inflammation-related lncRNAs, SNHG5 was the most significantly upregulated in septic coronary arteries and serum. Bioinformatic and experimental analyses revealed that SNHG5 acts as a competitive endogenous RNA (ceRNA) for miR-377-3p, thereby upregulating (METAP2). Silencing SNHG5 or METAP2 reduced IL-8 secretion and endothelial apoptosis; these effects were reversed by miR-377-3p inhibition. Conversely, METAP2 overexpression increased IL-8 secretion and apoptosis, which were attenuated by miR-377-3p mimics. CONCLUSION: We identified the SNHG5/miR-377-3p/METAP2 axis as a novel regulatory pathway in sepsis-induced endothelial inflammation and apoptosis. SNHG5 promotes METAP2 expression by sponging miR-377-3p, leading to increased IL-8 secretion and endothelial dysfunction. These findings provide new insights into lncRNA-mediated mechanisms in sepsis.
Imidazole Propionate Induces Kidney Damage by Activating the ROS-NLRP3 Signaling Pathway Through mTOR Inhibition of Autophagy in Renal Tubular Epithelial Cells.
Zeng C, Xiao YR, Li SQ … +7 more , Guo M, Wu Q, He YM, Zhang YF, Tan XZ, Xu Y, Teng FY
Mediators Inflamm · 2026 · PMID 41769043 · Full text
L-Histidine, a parent structure of environmental contaminants (e.g., pesticides and preservatives), may undergo bioaccumulation through the food chain and be metabolized by the gut microbiota into deleterious compounds,...
L-Histidine, a parent structure of environmental contaminants (e.g., pesticides and preservatives), may undergo bioaccumulation through the food chain and be metabolized by the gut microbiota into deleterious compounds, ultimately compromising human health. Recent studies have identified abnormally elevated levels of the histidine-derived metabolite imidazole propionate (ImP) in the serum of type 2 diabetes mellitus patients. However, the pathophysiological implications of excessive ImP on renal function and its underlying molecular mechanisms remain poorly characterized. This study is the first to elucidate the detrimental effects of ImP on renal function in mice and its molecular mechanisms. Our findings demonstrate that ImP exacerbates renal dysfunction and induces structural and functional abnormalities in renal tubules. Mechanistically, ImP significantly suppresses autophagy in renal tubular epithelial cells and activates the reactive oxygen species (ROS)-NOD-like receptor pyrin domain-containing 3 (NLRP3) signaling pathway, thereby promoting the expression of the pro-inflammatory cytokine interleukin-1β (IL-1β). Notably, the mechanistic target of rapamycin (mTOR) inhibitor rapamycin (Rap) restores autophagy, inhibits the ROS/NLRP3/IL-1β axis, and mitigates ImP-induced renal injury. Transcriptomic sequencing of mouse kidneys reveals that ImP upregulates the expression of autophagy- and inflammation-related genes, while its inhibitor suppresses these genetic alterations. This study highlights the potential nephrotoxic effects of ImP and underscores the therapeutic value of Rap, providing a theoretical foundation for understanding the role of gut microbiota metabolites in the pathogenesis, prevention, and treatment of kidney diseases.
Benzydamine Attenuates Matrix Metalloproteinase-9 Expression Through Inhibition of ERK MAPK in Activated Human Monocytic Cells Under Hyperglycemic Condition.
Do AP, Shen YC, Cheng YW … +7 more , Yang CH, Huang LC, Liu YC, Nurhan AD, Lee YM, Hsu SP, Hsiao G
Mediators Inflamm · 2026 · PMID 41756532 · Full text
Much evidence has demonstrated that the association between sepsis and diabetes can result in comorbidity effects. The endotoxin lipopolysaccharide (LPS) is a damaging factor that penetrates through the intestinal wall a...
Much evidence has demonstrated that the association between sepsis and diabetes can result in comorbidity effects. The endotoxin lipopolysaccharide (LPS) is a damaging factor that penetrates through the intestinal wall and into circulation in patients with diabetes. Benzydamine is a clinical drug widely used for pharyngitis and periodontitis with local anesthetic and analgesic properties. The purpose of this study was to investigate the anti-matrix degradative effects of benzydamine and its mechanisms on matrix metalloproteinase (MMP)-9 activation in LPS-stimulated THP-1 human monocytic cells under high-glucose condition. In this study, it was found that benzydamine could attenuate LPS-induced MMP-9-mediated gelatinolysis and protein expression in THP-1 cells under the normal-glucose condition. On the other hand, LPS induced higher MMP-9 gelatinolytic activity under the high-glucose condition than under the normal-glucose condition. Under the high-glucose condition, benzydamine also significantly inhibited LPS-induced MMP-9-mediated gelatinolysis and MMP-9 protein in THP-1 cells in a concentration-dependent manner. However, enzyme-linked immunosorbent assay (ELISA) showed that benzydamine partially affect TIMP-1 levels. Under the normal-glucose condition, benzydamine also inhibited tumor necrosis factor (TNF)-α-induced MMP-9-related gelatinolysis and its protein or mRNA expression. Among the signaling pathways, LPS-mediated phosphorylation of p38 or JNK MAPK was not affected by benzydamine. Surprisingly, it was strongly shown that benzydamine could significantly attenuate LPS-mediated phospho-ERK MAPK expression and translocation. Also, phosphorylation of p65 as NF-κB activation was markedly inhibited. Moreover, LPS-induced surface expression of TLR-4 and COVID-19 S1 protein-induced MMP-9-related gelatinolysis were abrogated by benzydamine under the high-glucose condition. In conclusion, benzydamine exerted anti-MMP-9 actions through inhibition of ERK MAPK and NF-κB activation under the high-glucose condition. This study revealed additional anti-monocytic properties of benzydamine in its potential for novel anti-inflammatory therapy.
Investigating the Relationships Among Gut Microbiota, Inflammatory Cytokines, Cerebrovascular Diseases, and the Mediation Pathways.
Li Q, Liu X, Deng X … +2 more , Huang H, Wu X
Mediators Inflamm · 2026 · PMID 41743218 · Full text
OBJECTIVES: Cerebrovascular disease (CeVD), the second leading global cause of death, has an incompletely understood pathogenesis. This study aimed to investigate causal relationships among gut microbiota, inflammatory c...
OBJECTIVES: Cerebrovascular disease (CeVD), the second leading global cause of death, has an incompletely understood pathogenesis. This study aimed to investigate causal relationships among gut microbiota, inflammatory cytokines, and CeVD, specifically examining inflammatory cytokine-mediated pathways. METHODS: Genome-wide association study (GWAS) summary statistics for 209 gut microbial taxa, 91 inflammatory cytokines, and three CeVD subtypes were obtained from publicly available datasets. Causal effects were estimated by applying four complementary two-sample Mendelian randomization (MR) methods. Reverse MR and comprehensive sensitivity analyses were performed to validate the robustness of the findings. Multivariable MR (MVMR) analyses were conducted to account for potential confounders. Mediation analysis was conducted to elucidate the pathways from gut microbiota to CeVD, mediated by inflammatory cytokines. RESULTS: Our study identified 33 gut microbiota significantly associated with CeVD, including nine with ischemic stroke (IS), 14 with intracerebral hemorrhage (ICH), and 10 with subarachnoid hemorrhage (SAH). Eighteen inflammatory cytokines showed significant associations with different CeVD subtypes. Mediation analysis revealed 10 causal pathways from gut microbiota to CeVD mediated by inflammatory cytokines; among these, three inflammatory cytokines mediated more than two pathways. CONCLUSIONS: This study demonstrated that inflammatory cytokines mediated the gut microbiota-CeVD causal pathway through genetic evidence, elucidating novel disease mechanisms, thereby providing actionable insights for developing CeVD prevention and treatment strategies.
The Role of APOL1 in Necrotizing Enterocolitis and Its Promise as a Diagnostic Biomarker.
Lu JT, Wang QH, Liu YY … +15 more , Tian S, Hou LL, Zhong X, Chen LZ, Zhang Q, Wei PF, Li L, Tian Y, He QM, Liu YF, Yin GQ, Ouyang Y, Liao L, Zhong W, Lan CT
Mediators Inflamm · 2026 · PMID 41743217 · Full text
OBJECTIVE: Necrotizing enterocolitis (NEC) is a severe inflammatory disease of the intestine. Although previous studies have demonstrated that APOL1 plays an important role in regulating macrophage polarization and immun...
OBJECTIVE: Necrotizing enterocolitis (NEC) is a severe inflammatory disease of the intestine. Although previous studies have demonstrated that APOL1 plays an important role in regulating macrophage polarization and immune-mediated inflammatory diseases, its specific function in NEC remains unclear. We aim to further explore the role of APOL1 in NEC and its efficacy as a diagnostic biomarker. METHODS: We performed tissue transcriptomic and plasma proteomic analyses based on clinical samples from preterm infants with NEC patients and conducted multilevel experimental validations. An in vitro macrophage polarization model was established to further investigate the regulatory role of APOL1 in macrophage differentiation. The diagnostic potential of APOL1 for NEC was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Multiomics analyses revealed a significant upregulation of APOL1 expression in NEC, which was further confirmed by qPCR, immunofluorescence, and ELISA. Pathway enrichment and immune infiltration analyses indicated that APOL1 is positively associated with M1 macrophage infiltration and the expression of multiple proinflammatory cytokines. Immunofluorescence staining further demonstrated that APOL1 is highly expressed in M1 macrophage-enriched regions. In vitro experiments showed elevated APOL1 expression in M1 macrophages, while its inhibition significantly reduced intracellular reactive oxygen species (ROS) accumulation and NF-κB p65 activation, thereby suppressing M1 polarization. Moreover, the combination of plasma APOL1 and lymphocyte count (LYM) demonstrated high diagnostic efficacy for NEC, with an AUC value of 0.96 (sensitivity 93.3% and specificity 93.3%). CONCLUSIONS: Our findings reveal a marked upregulation of APOL1 in preterm infants with NEC. Mechanistically, we propose that the APOL1-ROS-NF-κB axis constitutes a novel and promising therapeutic target for NEC intervention. Furthermore, the combined detection of plasma APOL1 and LYM demonstrates high efficacy.
Integrative Multi-Omics Identifies S100A4 as a Translational Hub Linking Environmental Bis(2-Ethylhexyl) Phthalate (DEHP) Exposure to Glioblastoma Risk.
Tan S, Li Z, Du Z … +7 more , You J, Qiao L, Zhao L, Yang B, Tang X, Muhammad S, Liu H
Mediators Inflamm · 2026 · PMID 41737848 · Full text
Glioblastoma (GBM) is a highly aggressive central nervous system malignancy with a dismal 5-year survival rate of less than 5%, and poorly understood environmental factors complicate its treatment. One such factor is bis...
Glioblastoma (GBM) is a highly aggressive central nervous system malignancy with a dismal 5-year survival rate of less than 5%, and poorly understood environmental factors complicate its treatment. One such factor is bis(2-ethylhexyl) phthalate (DEHP, also known as di-2-ethylhexyl phthalate), a common plasticizer with documented neurotoxicity, yet its potential role in GBM pathogenesis remains elusive. In this study, we employed an integrative computational framework that combined network toxicology, single-cell transcriptomics, proteome-wide and metabolome-wide Mendelian randomization (MR), and molecular dynamics (MD) simulations to systematically investigate the interplay between DEHP and GBM risk. Cross-dataset targets were identified by mining toxicogenomic and disease databases, followed by the construction of a protein-protein interaction (PPI) network. This approach identified 76 overlapping targets between DEHP and GBM, which were refined to 24 hub genes through topological analysis. Notably, MR analyses revealed putative causal associations between higher genetically predicted plasma levels of three hub proteins-CD63, CTSS, and S100A4-and an increased risk of GBM, with S100A4 showing the strongest effect (odds ratio [OR] = 2.03, 95% confidence interval [CI] 1.15-3.58, = 0.0149). This association was consistently validated across 11 independent cohorts, including TCGA, GTEx, and GEO datasets. Molecular docking and dynamics simulations identified S100A4 as the predominant binding target of DEHP, revealing a high-affinity interaction that may stabilize a metastasis-associated conformation. A two-step MR mediation analysis further indicated that S100A4 partially influences GBM risk by altering plasma lipid metabolites, with erucic acid mediating ~17% of the total effect. In conclusion, our analysis provides converging computational and genetic epidemiological evidence for a novel DEHP-S100A4-lipid metabolic axis that may contribute to GBM development. This pathway conceptually bridges environmental toxicology and neuro-oncology and highlights S100A4 and associated lipid disturbances as potential targets for preventive intervention. However, the proposed mechanistic links remain inferential, and definitive confirmation will require future in vitro and in vivo experiments to directly test the impact of DEHP on S100A4 expression, function, and downstream metabolic reprogramming in GBM models.
Targeting Pulmonary Hypertension: Elucidating Sophocarpine's Protective Role via Preclinical Models.
Xie F, Feng J, Li K … +3 more , Chen Y, Han L, Wu Y
Mediators Inflamm · 2026 · PMID 41737847 · Full text
BACKGROUND: Pulmonary hypertension (PH) is a serious disease that manifests itself as elevated pressure within the pulmonary arteries. The onset of PH is usually insidious, and if left untreated, it may lead to heart fai...
BACKGROUND: Pulmonary hypertension (PH) is a serious disease that manifests itself as elevated pressure within the pulmonary arteries. The onset of PH is usually insidious, and if left untreated, it may lead to heart failure and even life-threatening conditions. Recent studies have shown that sophocarpine (SOP) has significant effects on antioxidant, anti-inflammatory, antifibrotic, and hemodynamic improvement, and it may become an emerging drug for the treatment of PH. However, the specific mechanism of action of SOP still requires further experimental validation. METHODS: We established in vivo and in vitro models of PH and treated them with varying concentrations of SOP. To visualize the changes in rats and cells, we used scratch assay, flow cytometry, Western blotting, pulmonary artery pressure measurement, biochemical analysis, enzyme-linked immunosorbent assay (ELISA), ultrasound scanning, hematoxylin and eosin (HE) staining, and Masson's trichrome staining. RESULTS: Our results showed that SOP significantly alleviated the inflammatory response and apoptosis induced by PH, reduced pulmonary artery pressure, and restored the balance of pulmonary artery remodeling. These effects were found to be effective in alleviating PH. CONCLUSION: Our study provides clear evidence that SOP has a significant protective effect in the PH model and is expected to be a promising therapeutic agent for PH.
Association Between Three Systemic Inflammatory Biomarkers and Diabetic Foot Ulcer: A Cross-Sectional Study and a Clinical Retrospective Study.
Chen H, Zhou Y, Dai J
Mediators Inflamm · 2026 · PMID 41728362 · Full text
BACKGROUND: This study aimed to investigate the association between systemic inflammatory biomarkers-specifically the systemic inflammatory response index (SIRI), systemic immune inflammation index (SII), and aggregate i...
BACKGROUND: This study aimed to investigate the association between systemic inflammatory biomarkers-specifically the systemic inflammatory response index (SIRI), systemic immune inflammation index (SII), and aggregate index of systemic inflammation (AISI)-and the prevalence of diabetic foot ulcer (DFU). METHOD: We conducted a cross-sectional analysis using data from three cycles of the National Health and Nutrition Examination Survey (NHANES), supplemented by a single-center retrospective clinical study. Initially, 31,126 participants were screened from NHANES. Binary logistic regression models (both unadjusted and adjusted for covariates) were employed to evaluate the associations between ln SIRI, ln SII, and ln AISI and DFU prevalence. Restricted cubic spline (RCS) analysis was applied to assess nonlinear relationships, and subgroup analyses were performed to examine the stability of associations across strata defined by age, gender, race, body mass index (BMI), smoking status, and hypertension. Additionally, a clinical validation study was conducted from January to December 2023, comprising 34 DFU patients and 68 diabetic controls. We performed multivariable binary logistic regression analyses to assess the independent associations between systemic inflammatory indices and the presence of DFU, adjusting for age, sex, diabetes duration, BMI, and albumin levels. Receiver operating characteristic (ROC) curve analysis was used to preliminarily assess the discriminatory ability of SII, SIRI, and AISI for DFU status. RESULTS: The cross-sectional analysis included 135 participants with DFU and 1560 without DFU. Logistic regression revealed consistent positive associations between ln SIRI, ln SII, and ln AISI and DFU prevalence in both unadjusted and adjusted models. RCS analysis indicated linear dose-response relationships for all three biomarkers. Subgroup analyses confirmed that these associations remained stable across demographic and clinical subgroups. In the retrospective clinical study, ln SIRI, ln SII, and ln AISI were significantly associated with DFU prevalence, with odds ratios (ORs) as follows: ln SIRI: OR = 2.51 (95% CI: 1.39-4.54), ln SII: OR = 5.44 (95% CI: 2.48-11.91), and ln AISI: OR = 2.75 (95% CI: 1.59-4.74). After adjusting for key confounders, the associations between these biomarkers and DFU remained consistent in both direction and statistical significance. ROC analysis showed that SII was more reliable than the other two for predicting DFU. CONCLUSION: By integrating a cross-sectional NHANES-based analysis with a clinical retrospective study, this research demonstrates that elevated levels of SIRI, SII, and AISI are significantly associated with an increased prevalence of DFU. These systemic inflammatory biomarkers may serve as valuable tools for risk assessment in patients with DFU.
Association Between CBC-Derived Inflammatory Indicators and 28-Day Mortality in Patients With Coronary Heart Disease and Diabetes Mellitus: A Cohort Study From the MIMIC-IV Database.
Tu G, Cai Z, Xue S … +2 more , Zhu G, Huang M
Mediators Inflamm · 2026 · PMID 41716685 · Full text
BACKGROUND: Coronary heart disease (CHD) remains the leading global cause of death; concomitant diabetes mellitus (DM) doubles short-term mortality, largely through chronic low-grade inflammation. Inexpensive, bedside co...
BACKGROUND: Coronary heart disease (CHD) remains the leading global cause of death; concomitant diabetes mellitus (DM) doubles short-term mortality, largely through chronic low-grade inflammation. Inexpensive, bedside complete blood count (CBC)-derived inflammatory indices (NLR, MLR, PLR, SII, SIRI, and AISI) predict outcomes in CHD or DM alone, but their utility in comorbid patients is unclear. METHODS: Retrospective cohort study of CHD-DM patients from Medical Information Mart for Intensive Care-IV (MIMIC-IV; 2008-2022), split into training (2017-2022, = 1607) and validation (2008-2016, = 1145) sets. Six indices (NLR, MLR, PLR, SII, SIRI, and AISI) were calculated from initial ICU CBC (48-h mean for sensitivity analysis). Primary outcome: 28-day mortality, Cox regression, restricted cubic splines (RCSs), receiver operating characteristic (ROC) curves, calibration plots, and SHAP-based variable importance were used. RESULTS: Mortality was 10.6% (training) and 11.9% (validation). All indices showed independent, dose-dependent associations with mortality (e.g., training MLR per 1-SD: HR = 1.49, 95% CI = 1.37-1.61), discrimination was good (training AUC 0.767, C-index 0.752; validation AUC 0.755, C-index 0.746), and calibration was excellent. Spearman correlation showed moderate-to-strong interindex correlations (e.g., MLR-SIRI: = 0.84). SHAP analysis ranked PLR and MLR as top predictive indices. Sensitivity analysis confirmed robustness. CONCLUSIONS: Six CBC-derived indices independently predict 28-day mortality in critically ill CHD-DM patients, with PLR and MLR showing superior predictive weight, and can be used for rapid, cost-free bedside risk stratification.
Observational and Genetic Association of Myelodysplastic Syndromes (MDS) and Autoimmune Diseases in Adults.
Li Q, Guo Y, Xiao G … +14 more , Song X, Wei Y, Gao W, Feng G, Zuo X, Shi X, Zhao H, Hu Y, Rebetz J, Semple E, Guo L, Semple JW, Peng J, Xu S
Mediators Inflamm · 2026 · PMID 41716684 · Full text
About 25% of patients with myelodysplastic syndromes (MDS) have combined autoimmune diseases (AIDs). However, the relationships between MDS and AIDs, especially a causal relationship and the underlying shared pathophysio...
About 25% of patients with myelodysplastic syndromes (MDS) have combined autoimmune diseases (AIDs). However, the relationships between MDS and AIDs, especially a causal relationship and the underlying shared pathophysiological mechanisms, remain largely unknown. We aimed to evaluate the association between MDS and AIDs using a multicenter retrospective study, Mendelian randomization (MR), and bioinformatics analysis. About 26.6% of patients with MDS from all centers presented with AIDs. Compared to MDS patients without AIDs, MDS with AIDs was less likely to progress to acute myeloid leukemia (AML) (6.6% vs. 15.1%, = 0.037), and the pre-existing AIDs could be used as an independent protective factor of survival (HR: 0.504, = 0.048). Bidirectional MR results showed that MDS could cause the risk of systemic lupus erythematosus (SLE, OR: 1.09, = 0.015), although with no significant causal relationship in other AIDs. The effect of MDS on SLE may be partially mediated by naïve CD4+ T-cells (median proportion 6.9%) and CD45RA-CD4+ T memory cells (median proportion 9.0%). Furthermore, two hub genes (IFI27 and VSIG4) were identified by machine learning and curve analysis as potential diagnostic markers for MDS with SLE. Our study suggested that the impact and mechanisms of AIDs in MDS need to be taken seriously, which could provide more accurate treatment guidance.
The Predictive Role of Biomarkers for Leprosy Prophylaxis in Contacts of Patients Who Are Indices of the Disease: A Systematic Review of the Literature.
Figueira LRT, Silva MJA, da Silva LVM … +7 more , Marinho RL, Neves KAS, Dos Anjos TAF, da Silva LCSS, Sardinha DM, Dos Santos EC, Lima LNGC
Mediators Inflamm · 2026 · PMID 41716683 · Full text
Leprosy continues to be an important public health problem, particularly in endemic regions such as Brazil, India, and Indonesia. Household contacts of multibacillary (MB) patients represent a high-risk group for subclin...
Leprosy continues to be an important public health problem, particularly in endemic regions such as Brazil, India, and Indonesia. Household contacts of multibacillary (MB) patients represent a high-risk group for subclinical infection due to prolonged exposure and high bacillary load. Host biomarkers have emerged as promising tools for identifying early infections and guiding prophylactic interventions. This systematic review aimed to identify and synthesize evidence on inflammatory and immune biomarkers associated with susceptibility to leprosy and disease progression among contacts of index cases, evaluating their potential predictive and diagnostic value. The study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) 2020 guidelines and was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251111469). We searched CAPES, SciELO, PubMed, ScienceDirect, EMBASE, Scopus, and EBSCO databases for original studies published between 2012 and 2025, with no language restrictions. Two review authors independently selected studies using the Rayyan software, and methodological quality was assessed using the ROBIS tool. The biomarkers most frequently investigated in the studies were particularly tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-10, which play regulatory roles in the host. Elevated levels of TNF-α, interferon-γ (IFN-γ), IL-6, and IL-4 were associated with a higher risk of subclinical infection among contacts of MB patients, indicating a polyfunctional immune profile. On the other hand, paucibacillary (PB) contacts exhibited lower cytokine activation, suggesting partial protection. Additional promising markers included anti-Mce1A, PGL-I IgM, and CCL4, detected primarily by enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) methods. In summary, inflammatory and immune biomarkers-especially TNF-α, IL-10, IFN-γ, and anti-Mce1A-demonstrate potential as predictive indicators of subclinical leprosy infection. Their combined use may increase risk stratification and allow early therapeutic intervention in endemic settings. However, longitudinal validation studies are required prior to clinical application.
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