Mediators Of Inflammation[JOURNAL]
Sun
200 papers
Association Between C-Reactive Protein-Triglyceride Glucose Index and Adverse Cardiovascular Outcomes in Acute Coronary Syndrome Patients With Prior Coronary Artery Bypass Grafting.
Ma X, Chu H, Li Q … +2 more , Yang Y, Wang Z
Mediators Inflamm · 2026 · PMID 42253126 · Full text
BACKGROUND: Patients with acute coronary syndrome (ACS) who have previously undergone coronary artery bypass grafting (CABG) represent a complex, high-risk population characterized by a substantial burden of atherosclero...
BACKGROUND: Patients with acute coronary syndrome (ACS) who have previously undergone coronary artery bypass grafting (CABG) represent a complex, high-risk population characterized by a substantial burden of atherosclerosis and a marked propensity for recurrent ischemic events. The pathophysiological interplay between systemic inflammation and insulin resistance serves as a key mediator driving the progression of atherosclerosis and the destabilization of atherosclerotic plaques. However, the prognostic impact of their combined effect, quantified by a novel composite biomarker-the C-reactive protein-triglyceride glucose index (CTI)-remains uncertain in this specific high-risk population. METHODS: We enrolled 1195 ACS patients with prior CABG who underwent percutaneous coronary intervention (PCI). The CTI was calculated as 0.412 × ln (high-sensitivity C-reactive protein [mg/L]) + ln (fasting triglycerides [mg/dL] × fasting blood glucose [mg/dL]/2). Patients were divided into three groups based on their CTI tertiles. The primary endpoint was defined as the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE), which encompassed all-cause death, nonfatal stroke, nonfatal myocardial infarction (MI), and unplanned revascularization. RESULTS: Over a median follow-up of 3 years, 366 patients experienced MACCE. The incidence of MACCE progressively increased across CTI tertiles (log-rank p < 0.001). In the multivariable Cox proportional hazards model adjusted for the GRACE (Global Registry of Acute Coronary Events) risk score and a comprehensive panel of clinical, procedural, and laboratory confounders, the highest CTI tertile remained an independent predictor of MACCE (adjusted hazard ratio [HR]: 3.864, 95% confidence interval [CI]: 2.710-5.511, p < 0.001). When CTI was analyzed as a continuous variable, each unit increase was found to confer an 80.1% greater risk of MACCE (adjusted HR: 1.801, 95% CI: 1.556-2.085, p < 0.001). This association remained consistent across all predefined subgroups. Adding CTI tertiles to the baseline model-which encompassed the GRACE risk score and other confounders-yielded a modest but statistically significant improvement in predictive performance (C-statistic increased from 0.605 to 0.655, p < 0.001; continuous net reclassification improvement [cNRI]: 0.740, p = 0.032; integrated discrimination improvement [IDI]: 0.145, p = 0.020). CONCLUSIONS: The CTI-a composite biomarker that captures both systemic inflammation and insulin resistance-emerged as a significant and independent predictor of long-term MACCE in ACS patients with prior CABG who underwent PCI. Its integration into risk stratification models may improve prognostic assessment and potentially facilitate more personalized and intensive secondary prevention strategies.
Hydroxysafflor Yellow A Induces Apoptosis and Inhibits Inflammatory Cytokine Expression in Rheumatoid Arthritis Synovial Fibroblasts Through the MEK-ERK Pathway.
Li D, Yang H, Feng Y … +5 more , Liu X, Wang F, Jiang Y, Wu S, Mei X
Mediators Inflamm · 2026 · PMID 42253107 · Full text
OBJECTIVE: The objective of this study was to investigate whether hydroxysafflor yellow A (HSYA) affects the proliferation and apoptosis of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA). Synovial fibro...
OBJECTIVE: The objective of this study was to investigate whether hydroxysafflor yellow A (HSYA) affects the proliferation and apoptosis of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA). Synovial fibroblast hyperplasia is a key pathological feature of RA, and its inhibition may slow disease progression. Although HSYA has attracted significant interest, its effects on RA are not yet fully understood. Thus, we performed a series of experiments to examine the impact of HSYA on FLSs. METHODS: To investigate the effects of HSYA on FLSs, we exposed FLSs to Interleukin-1 beta (IL-1β) and assessed their proliferation via CCK8, scratch, transwell, TUNEL, and flow cytometry assays. Inflammatory cytokine levels were determined by ELISA. The involvement of the MEK-ERK signaling pathway was validated via RT-qPCR and immunofluorescence analyses. RESULTS: Treatment with HSYA significantly inhibited FLSs proliferation, while promoting their apoptosis. Moreover, HSYA altered the expression of the inflammatory cytokines IL-6, IL-10, and TNF-α in FLSs. The anti-inflammatory and anti-proliferative effects of HSYA on FLSs were mediated, at least in part, through the inhibition of the ERK signaling pathway. CONCLUSION: Our findings demonstrate that HSYA induces apoptosis, inhibits proliferation, and suppresses the production of inflammatory cytokines in FLSs via the ERK/MEK signaling pathway. These findings suggest that HSYA has potential therapeutic value in the treatment of RA and warrants further investigation.
Qingxin Lianzi Yin Improves Chronic Kidney Disease by Targeting Ferroptosis via the TLR4/HIF-1α Pathway.
Wang B, Lin B, Zheng D … +1 more , Cao L
Mediators Inflamm · 2026 · PMID 42244400 · Full text
BACKGROUND: Ferroptosis is involved in the pathogenesis of chronic kidney disease (CKD). Qingxin Lianzi Yin (QXLZY) has shown significant advantages in CKD treatment. This investigation intended to explore the impact of...
BACKGROUND: Ferroptosis is involved in the pathogenesis of chronic kidney disease (CKD). Qingxin Lianzi Yin (QXLZY) has shown significant advantages in CKD treatment. This investigation intended to explore the impact of QXLZY on ferroptosis in CKD. METHODS: The anti-CKD effects of QXLZY were evaluated using the 5/6 nephrectomy-induced rat model and TGF-β1-stimulated HK-2 cells. Oxidative stress and ferroptosis levels were assessed using commercial kits and western blot. The mechanism of QXLZY in CKD treatment was predicted through network pharmacology. TLR4 and HIF-1α levels were detected by western blot. The role of ferroptosis in CKD treatment by QXLZY was explored using the ferroptosis inducer erastin. HK-2 cells overexpressing TLR4 were treated with the HIF-1α inhibitor LW6 to investigate the underlying mechanism. QXLZY components identified through network pharmacology as potentially interacting with TLR4 were validated. RESULTS: QXLZY effectively alleviated renal injury and inhibited fibrosis and inflammation in CKD models. Moreover, QXLZY markedly suppressed oxidative stress and ferroptosis. However, the anti-CKD effects of QXLZY were partially counteracted by erastin. TLR4 and HIF-1α were identified as potential targets through which QXLZY regulates ferroptosis in CKD. Their levels were notably increased in CKD models but were decreased after QXLZY treatment. Overexpression of TLR4 reversed the anti-CKD effects of QXLZY, and this phenomenon was altered by LW6. Lauric acid (LA) and caprylic acid (CA) were bioactive components within QXLZY regulating the TLR4/HIF-1α pathway in CKD. CONCLUSION: QXLZY inhibits ferroptosis by downregulating the TLR4/HIF-1α pathway, thereby alleviating renal fibrosis and improving CKD, with LA and CA potentially playing significant roles.
Miacalcic Enhances Rotator Cuff Injury Healing in Osteoporotic Mice by Stimulating Neovascularization via the JAK Pathway.
Mao F, Zhu J, Feng X … +5 more , Peng C, Huang H, Xu F, Tong M, Wang Q
Mediators Inflamm · 2026 · PMID 42233346 · Full text
OBJECTIVE: Rotator cuff tears (RCT) are prevalent among the elderly and often lead to significant shoulder pain. While both open and arthroscopic cuff repairs are effective, the recurrence of RCT post-surgery remains hig...
OBJECTIVE: Rotator cuff tears (RCT) are prevalent among the elderly and often lead to significant shoulder pain. While both open and arthroscopic cuff repairs are effective, the recurrence of RCT post-surgery remains high, with osteoporosis being a major contributing risk factor. Local angiogenesis and tendon-bone healing are essential for optimal recovery after rotator cuff repair. This study investigates the effects of Miacalcic, an osteoporosis medication, on rotator cuff repair in osteoporotic conditions. METHODS: To explore the mechanisms underlying Miacalcic's action, we conducted RNA-sequencing and cell-based experiments on bone marrow-derived mesenchymal stem cells (BMSC) and human umbilical vein endothelial cells (HUVECs). Additionally, an osteoporotic mouse model of RCT was utilized to assess in vivo effects. RESULTS: Our findings revealed that Miacalcic had no significant effect on the proliferation of BMSCs, whereas it notably stimulated the proliferation of HUVECs. Miacalcic also significantly reduced apoptosis in HUVECs and enhanced their angiogenic potential. RNA-Seq analysis indicated that Miacalcic primarily modulates the JAK signaling pathway, which plays a key role in angiogenesis. In vivo, Miacalcic treatment in an osteoporotic mouse model enhanced vascularization and facilitated tendon-bone healing in the rotator cuff, leading to improved functional recovery following RCT. CONCLUSION: This study highlights the potential of Miacalcic as a therapeutic agent for promoting tendon-bone healing in osteoporotic patients with rotator cuff injuries. By elucidating the mechanisms through which Miacalcic enhances angiogenesis and healing, our findings offer insights into potential strategies for improving post-operative outcomes and reducing RCT recurrence. Further research is necessary to refine our understanding of the specific biological pathways involved and to explore the long-term therapeutic benefits of Miacalcic.
Urinary Polycyclic Aromatic Hydrocarbons and Advanced Cardiovascular-Kidney-Metabolic Syndrome: Inflammatory-Nutritional Pathways as Mediators.
Huang Y, Zhao Y, Man Q … +7 more , Liu S, Yang Y, Wen J, Fan L, Xie H, Zhang K, Wang J
Mediators Inflamm · 2026 · PMID 42227643 · Full text
BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants linked to adverse health outcomes. Their role in the different statuses of Cardiovascular-Kidney-Metabolic (CKM) syndrome remain...
BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants linked to adverse health outcomes. Their role in the different statuses of Cardiovascular-Kidney-Metabolic (CKM) syndrome remains poorly understood. METHODS: A cross-sectional analysis of 11,043 participants was conducted using data from NHANES. Urinary PAH levels were measured, and advanced CKM status was assessed using established diagnostic criteria. Mediation analysis was performed to evaluate the role of the red blood cell distribution width-to-albumin ratio (RAR). RESULTS: Higher urinary levels of PAHs, particularly 2-NAP and 2-FLU, were significantly associated with advanced CKM syndrome (p < 0.05). Exposure-response relationships and threshold effects were observed for these key PAHs. Mediation analysis identified RAR as a novel biomarker, explaining 6.13%-37.81% of the association depending on the specific metabolite. CONCLUSIONS: This study reveals that PAHs are independently and jointly associated with advanced CKM status, with RAR serving as a critical mediator. These findings underscore the importance of reducing environmental PAH exposure and highlight RAR as a potential biomarker for early detection and risk stratification.
Gut-Liver Axis Failure in Critical Alcohol-Associated Liver Disease: From ICU Secondary Hits to Microbiome-Targeted Therapy.
Zhang Y, Wang Y, Yang Y … +5 more , Mei H, Liu X, He Y, Qin S, Feng B
Mediators Inflamm · 2026 · PMID 42218700 · Full text
Alcohol-associated liver disease (ALD) can progress to critical illness phenotypes requiring intensive care, including severe alcohol-associated hepatitis, acute decompensation, and alcohol-associated acute-on-chronic li...
Alcohol-associated liver disease (ALD) can progress to critical illness phenotypes requiring intensive care, including severe alcohol-associated hepatitis, acute decompensation, and alcohol-associated acute-on-chronic liver failure (ACLF). In these patients, short-term outcomes are driven less by the burden of fibrosis alone than by systemic inflammation, immune dysfunction, infection, and multiorgan failure. At the core of this process is gut-liver axis failure, which links alcohol-induced dysbiosis and intestinal barrier disruption to microbial translocation, hepatic innate immune activation, and systemic inflammatory amplification. In the intensive care unit (ICU), secondary hits such as broad-spectrum antibiotics, acid suppression, parenteral nutrition, shock, sedatives or opioids, and mechanical ventilation may further exacerbate these mechanisms and disturb microbial ecology and barrier integrity. Microbiome-targeted therapies (probiotics, postbiotics, and fecal microbiota transplantation) are biologically plausible. However, current evidence is mainly derived from non-ICU or relatively stable ALD populations. Therefore, their use in critically ill patients requires strict safety boundaries, including severe barrier disruption, invasive devices, uncontrolled infections, and profound immune dysfunction. This narrative review synthesizes the pathophysiological continuum from gut barrier failure to systemic inflammation and multiorgan dysfunction in critical ALD, with particular emphasis on ICU-specific secondary hits, safety-aware microbiome modulation, and future phenotype-informed precision strategies.
Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) and Small Intestinal Submucosa (SIS) Hydrogel Composite Can Meliorate TNBS-Induced Experimental Colitis Through Regulating Inhibiting Macrophage Polarization Toward the M1 Phenotype.
Sun Z, Zhou Y, Geng X … +6 more , Gong Y, Li F, Zhuang S, Cao X, Huang J, Fu J
Mediators Inflamm · 2026 · PMID 42218603 · Full text
An imbalance of macrophage polarization exerts influence over inflammatory bowel disease (IBD) pathogenesis. To investigate how macrophage polarization influences IBD, we engineered a composite system consisting of small...
An imbalance of macrophage polarization exerts influence over inflammatory bowel disease (IBD) pathogenesis. To investigate how macrophage polarization influences IBD, we engineered a composite system consisting of small intestinal submucosa (SIS) hydrogel combined with bone marrow-derived mesenchymal stem cells (BM-MSCs). The therapeutic potential of this construct was assessed by examining its regulatory effects on macrophage polarization both in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model and in RAW264.7 macrophages in vitro. Clone formation assay was executed to identify the influence of MSC-SIS-conditioned medium on the proliferation of RAW264.7. CD206 and CD86 were measured by flow cytometric. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate cytokine gene expression. Experimental colitis was induced in mice using TNBS. Disease severity was assessed by calculating the clinical disease activity index (CDAI). Colonic tissues were subjected to histological and morphometric analyses, and serum levels of inflammatory cytokines were quantified using enzyme-linked immunosorbent assay (ELISA). Data indicated that the BM-MSCs and SIS hydrogel composite significantly promoted Raw264.7 proliferation. Compared with the lipopolysaccharide (LPS) + MSCs group, treatment with the combined MSCs and SIS hydrogel construct demonstrated a more pronounced inhibitory effect on M1 phenotype the autophagy of LPS-induced RAW264.7 in vitro; what is more, BM-MSCs and SIS hydrogel greatly inhibited cytokine mRNA levels in LPS-stimulated Raw264.7 cells compared with treatment with MSCs solely. In addition, the results implied that the mice in TNBS + MSC + SIS group had alleviated colitis compared with the TNBS + MSCs group, and the interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) levels in the serum also decreased. In conclusion, these results indicate a better wound healing effect of SIS hydrogel on BM-MSCs through promoting cell regeneration and inhibiting macrophage polarization towards the M1 phenotype in a TNBS-induced experimental mouse model.
Targeting IL-17 Presents a Promising Strategy for Treating Diseases Related to the Dysregulation of Lipid Homeostasis.
Zhang C, Xue YY, Ren DQ … +3 more , Zhu JF, Jin X, Liu J
Mediators Inflamm · 2026 · PMID 42212555 · Full text
Lipids are fundamental constituents of cell membranes and play a crucial role in signaling pathways that regulate a wide array of cellular functions. Consequently, the dysregulation of lipid homeostasis is recognized as...
Lipids are fundamental constituents of cell membranes and play a crucial role in signaling pathways that regulate a wide array of cellular functions. Consequently, the dysregulation of lipid homeostasis is recognized as a significant contributor to metabolic diseases. Given the limitations of current strategies for regulating lipid metabolism, it is essential to explore innovative approaches to modulate lipid homeostasis to effectively address diseases associated with its dysregulation. Inflammation plays a critical role in the regulation of lipid metabolism, acting through various pathways and mechanisms that influence both lipid synthesis and degradation. The involvement of Interleukin-17 (IL-17) in inflammatory responses is particularly noteworthy, as recent studies have highlighted its impact on lipid metabolism, particularly in the context of obesity and metabolic disorders. This review critically examines the IL-17 signaling pathway, elucidates the mechanisms by which IL-17 affects lipid metabolism, and explores the therapeutic potential of targeting IL-17 in the treatment of disorders related to lipid homeostasis. This review underscores the promise of targeting IL-17 signaling pathways as a therapeutic strategy for addressing the dysregulation in lipid homeostasis.
Therapeutic Potential of Bee Venom and Capsicum annum Hydroethanolic Extract in Experimental Model of Rheumatoid Arthritis in Male Rats.
Hussain A, Soliman AS, Abd-Elbaset M … +5 more , Al-Khalf AA, Ahmed EA, Khalil A, Ahmed OM, Abbas MS
Mediators Inflamm · 2026 · PMID 42206805 · Full text
BACKGROUND: Rheumatoid arthritis (RA) is a long-term inflammatory disease linked to higher mortality, joint degeneration, and long-term disability. This study evaluated the anti-inflammatory, antioxidant, and immunomodul...
BACKGROUND: Rheumatoid arthritis (RA) is a long-term inflammatory disease linked to higher mortality, joint degeneration, and long-term disability. This study evaluated the anti-inflammatory, antioxidant, and immunomodulatory effects of Capsicum annuum (CAP) hydroethanolic extract and bee venom (BV) in Freund's complete adjuvant (FCA)-induced RA in rats. METHODS: Forty-eight rats were divided into six groups: normal control (NC), RA control, and RA groups orally treated with methotrexate (MTX) (0.25 mg/kg), CAP (100 mg/kg), BV (0.25 mg/kg), and CAP (100 mg/kg) + BV (0.25 mg/kg). RA was induced by intradermal injection of FCA (100 μL/rat) into a footpad of the right hind paw at two consecutive days, and treatments were administered for 3 weeks. The study assessed serum rheumatoid factor (RF), anticyclic citrullinated peptide (ACCP) antibodies (ACPAs), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), oxidative stress markers such as lipid peroxidation, and antioxidant parameters including superoxide dismutase (SOD) and reduced glutathione (GSH). Additionally, mRNA expression of various genes (inducible nitric oxide synthase [iNOS], endothelial nitric oxide synthase [eNOS], interleukin-1β [IL-1β], TNF-α, matrix metalloproteinase-1 [MMP-1], matrix metalloproteinase-3 [MMP-3], and glutathione reductase [GR]) were analyzed, alongside histopathological evaluation. RESULTS: The data showed that CAP and/or BV significantly reduced serum inflammatory and oxidative stress biomarkers, enhanced the antioxidant defense system, and improved the histopathological changes of ankle joint. Gene expression analysis revealed downregulation of iNOS, eNOS, IL-1β, TNF-α, MMP-1, and MMP-3 gene expression, with upregulation of the GR gene expression. The combined CAP + BV treatment demonstrated the most potent antiarthritic effect. CONCLUSION: CAP and BV exhibit promising potential for alleviating RA in rats, with their combined application showing the greatest efficacy. The antiarthritic effects may be mediated via suppression of oxidative stress and inflammation and enhancement of the antioxidant defense system in addition to the modulatory effects on MMP-1 and MMP-3 gene expression. Further clinical research is essential to evaluate their safety and effectiveness in human RA management.
Inhibition of IL-17 Alleviates Blood-Brain Barrier Disruption Following Diffuse Axonal Injury Accompanied by Hyperglycemia Through the NF-κB Pathway.
Xing Z, Wei X, Zhang M … +3 more , Huang T, Zhao Y, Song J
Mediators Inflamm · 2026 · PMID 42206670 · Full text
OBJECTIVE: To clarify the effects and mechanism of interleukin-17A (IL-17) in hyperglycemia (HG)-induced blood-brain barrier (BBB) breakdown following diffuse axonal injury (DAI). METHODS: Differentially expressed protei...
OBJECTIVE: To clarify the effects and mechanism of interleukin-17A (IL-17) in hyperglycemia (HG)-induced blood-brain barrier (BBB) breakdown following diffuse axonal injury (DAI). METHODS: Differentially expressed proteins (DEPs) were identified by proteomic analysis via 4D-SmartDIA between control and high-glucose groups of BBB model established by bEnd.3 cells in vitro. A rat model of DAI was built using an instantaneous rotational damage device, and HG was mimicked by intraperitoneal (i.p.) injection of 50% glucose. The localization and expression of the IL-17 receptor (IL-17R) were tested by double-label immunofluorescence and western blotting. IL-17 levels in brain tissue and serum, as well as the concentrations of inflammatory factors, were examined. Axonal injury morphology was evaluated via transmission electron microscopy (TEM) and immunohistochemical detection of β-amyloid precursor protein (β-APP) and neurofilament light chain and heavy chain (NF-L, NF-H). Glial response and apoptosis were also assessed. The detection of BBB permeability was via levels of Evans blue (EB) leakage and tight junction protein. The IL-17 pathway was inhibited using suberoylanilide hydroxamic acid (SAHA), and western blotting was used to detect the phosphorylation (p-p65/t-p65 ratio) of the nuclear factor-κB (NF-κB) pathway. Oxidative stress levels were assessed via colorimetric assays. RESULTS: Proteomic analysis revealed 444 upregulated and 159 downregulated proteins in high-glucose-stimulated bEnd.3 cells compared with those in normal cells, with the IL-17 signaling being one of the most significantly enriched pathways according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. IL-17 and IL-17R expression was elevated in brain tissue and serum following DAI, and HG further enhanced this upregulation; IL-17R was predominantly localized to vascular endothelial cells. HG aggravated axonal injury, increased cortical apoptosis and glial response, promoted BBB disruption, elevated proinflammatory factor levels, and increased oxidative stress after DAI. The inhibition of IL-17 reversed all the damage and protected BBB integrity by maintaining tight junctions and reducing the levels of proinflammatory factors and oxidative stress in vivo. Mechanistically, HG increased NF-κB p65 phosphorylation after DAI, whereas SAHA treatment significantly suppressed this phosphorylation. CONCLUSION: IL-17 mediates HG-induced axonal injury following DAI by destroying BBB integrity via NF-κB-dependent inflammation and oxidative stress, signifying IL-17 as a target for mitigating neurovascular damage in hyperglycemic DAI.
IL-6 Exacerbates Experimental Autoimmune Prostatitis by Disrupting STAT5a-Mediated Treg Cell Function and Th17/Treg Balance.
Liu X, Bian X, Han S … +5 more , Li B, Song J, Liang C, Zhou J, Chen X
Mediators Inflamm · 2026 · PMID 42187144 · Full text
OBJECTIVE: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological condition in men. Although disruption of the Th17 (T helper 17)/Treg (regulatory T) balance has been implicated in its pathogen...
OBJECTIVE: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological condition in men. Although disruption of the Th17 (T helper 17)/Treg (regulatory T) balance has been implicated in its pathogenesis, the upstream drivers of this immune imbalance remain incompletely understood. This study investigated whether interleukin-6 (IL-6) is associated with altered Th17/Treg homeostasis and impaired Treg function in experimental autoimmune prostatitis (EAP). METHODS: An EAP model was generated in NOD mice through immunization with prostate antigen. Th17/Treg cell profiles were determined by flow cytometry, cytokine concentrations by enzyme-linked immunosorbent assay (ELISA), and signal transducer and activator of transcription 5a (STAT5a) expression by western blotting and immunohistochemistry (IHC). In vivo IL-6 inhibition was used to assess its effects on Th17/Treg balance and Treg suppressive function, whereas in vitro experiments examined the effects of IL-6 on Treg function and naïve CD4 T-cell differentiation. RESULTS: Relative to control mice, EAP mice showed higher serum IL-6 concentrations (5.28 ± 0.54 vs. 3.36 ± 0.46 pg/mL, p < 0.01), together with disturbed Th17/Treg homeostasis, as reflected by expansion of Th17 cells (1.72% ± 0.18% vs. 0.98% ± 0.08%, p < 0.001) and reduction of Treg cells (3.99% ± 0.97% vs. 5.46 % ± 0.53%, p < 0.05). Suppressive activity of Treg cells was also diminished (6.56% ± 0.80% vs. 12.41% ± 3.49%, p < 0.05). In vitro, IL-6 shifted naïve CD4 T-cell differentiation toward the Th17 phenotype while limiting Treg generation and impairing Treg suppressive activity. Mechanistically, IL-6 stimulation reduced STAT5a and p-STAT5a expression in Treg cells. Pharmacological inhibition of IL-6 partially restored Treg function and alleviated inflammatory pathology in EAP mice. CONCLUSION: IL-6 is linked to Th17/Treg imbalance and Treg dysfunction in EAP, possibly through inhibition of STAT5a signaling, and IL-6-related pathways may offer therapeutic value for CP/CPPS.
Role of BMEC-Derived Exosomal miR-144-3p in Microglial Polarization: Unveiling the NLRP3-GSDMD Pathway in Intracerebral Hemorrhage.
Ma J, Ran Z, Luo T … +3 more , Jin Z, Tan Y, Yin H
Mediators Inflamm · 2026 · PMID 42187142 · Full text
BACKGROUND: Intracerebral hemorrhage (ICH) often triggers a cascade of inflammatory responses, leading to secondary brain injury. The present work elucidated the regulatory mechanisms of NLRP3 inflammasome pathway activa...
BACKGROUND: Intracerebral hemorrhage (ICH) often triggers a cascade of inflammatory responses, leading to secondary brain injury. The present work elucidated the regulatory mechanisms of NLRP3 inflammasome pathway activation in exosomal vesicle secretion by brain microvascular endothelial cells (BMECs)-derived exosomes and its influence on the polarization and recruitment of microglial cells (GCs). METHODS: In an in vitro model, BMECs were pretreated with hemin to mimic the ICH environment and then cocultured with GCs in a replaced medium. NLRP3 inhibitor MCC950 and exosome release inhibitor GW4869 were used to observe the effects of NLRP3 inflammation and exosomes in BMECs. Gene expression was detected using western blotting (WB), immunofluorescence (IF), and real-time quantitative PCR. M1 polarization and migration of GCs were evaluated using biomarker expression, flow cytometry, and Transwell assays. The cellular mechanisms were further explored using an in vivo ICH rat model. RESULTS: Hemin pretreatment activated NLRP3 inflammasomes and upregulated gasdermin D (GSDMD-N) production in BMECs, which further contributed to enhanced migration and M1 polarization of cocultured GCs. MCC950 and GW4869 significantly inhibited the effects of BMECs on GCs migration and M1 polarization. Mechanically, the NLRP3/GSDMD pathway promoted the release of exosomes from BMECs, which were absorbed by GCs and resulted in changes in their migration ability and polarization. Furthermore, miR-144-3p was identified as an important regulator in BMEC-derived exosomes and mediated the effect of BMECs on GSDMD. Knockdown of GSDMD in BMECs weakened the enhanced migration and M1 polarization of GCs by inhibiting the release of BMEC-derived exosomes, while miR-144-3p overexpression in GCs abolished these effects. An in vivo study illustrated that MCC950 decreased pro-inflammatory cytokine and CD86 levels, which were recovered by miR-144-3p overexpressing adeno-associated virus (AAV) injection. CONCLUSIONS: This investigation revealed that the NLRP3/GSDMD pathway promotes the secretion of BMEC-derived exosomes, which transfer miR-144-3p from BMECs to GCs, further inducing the migration and M1 polarization of GCs.
Downregulation of Caveolin-2 Is a Novel Mechanism Involved in Activation of Inducible Nitric Oxide Synthase (iNOS) in Mouse Peritoneal Macrophages.
Jang S, Sowa G
Mediators Inflamm · 2026 · PMID 42183787 · Full text
Here we report that membrane protein caveolin-2 (Cav-2) is regulated during activation of primary mouse peritoneal macrophages and RAW264.7 macrophage cell line by a bacterial lipopolysaccharide (LPS) and a cytokine, int...
Here we report that membrane protein caveolin-2 (Cav-2) is regulated during activation of primary mouse peritoneal macrophages and RAW264.7 macrophage cell line by a bacterial lipopolysaccharide (LPS) and a cytokine, interferon gamma (IFN-γ). We also show that downregulation or loss of Cav-2 increases expression of inducible nitric oxide (NO) synthase (iNOS) and subsequent NO production in activated macrophages. Treatment with LPS and IFN-γ downregulated Cav-2 at the protein and mRNA level. Moreover, LPS- and IFN-γ-induced downregulation of Cav-2 inversely correlated with iNOS expression levels. Mechanistically, activation of NF-κB pathway was responsible for downregulation of Cav-2 by LPS and IFN-γ since pharmacological inhibition of NF-κB activation with pyrrolidine dithiocarbamate (PDTC) prevented Cav-2 downregulation and iNOS activation. To test if LPS- and IFN-γ-induced downregulation of Cav-2 could possibly be involved in macrophage activation, we used a combination of siRNA knockdown and genetic deletion/knockout (KO) approaches. Remarkably, reduction of Cav-2 using siRNA approach resulted in enhanced STAT1 phosphorylation, iNOS expression, and increased NO production in LPS- and LPS plus IFN-γ-stimulated macrophages. Conversely, genetic deletion of Cav-2 robustly enhanced IFN-γ-stimulated iNOS expression and subsequent NO production. Overall, our data suggest that Cav-2 is not only regulated during macrophage activation, but it also may be an important physiological regulator of macrophage activation via preventing excessive STAT1 signaling and iNOS stimulation.
Associations of Life's Essential 8 With Mortality Among Individuals With Diabetes and/or Hypertension: Statistical Mediation by Inflammation and Biological Aging.
Dong X, Zhong X, Lin Y … +5 more , Xie B, Li X, He B, Chen F, Yan L
Mediators Inflamm · 2026 · PMID 42179110 · Full text
BACKGROUND: Despite extensive evidence supporting the American Heart Association (AHA)'s life's essential 8 (LE8) framework for cardiovascular health (CVH) assessment, the underlying biological mechanisms linking LE8 to...
BACKGROUND: Despite extensive evidence supporting the American Heart Association (AHA)'s life's essential 8 (LE8) framework for cardiovascular health (CVH) assessment, the underlying biological mechanisms linking LE8 to mortality outcomes in high-risk populations remain unexplored. This study aimed to investigate the association between LE8 scores and mortality risk among individuals with diabetes, hypertension, and their coexistence, and explored whether inflammation and biological aging statistically mediate these relationships. METHODS: We conducted a large-scale longitudinal analysis using National Health and Nutrition Examination Survey (NHANES) data (2005-2018), including 4939 individuals with diabetes, 13,298 with hypertension, and 3303 with both conditions. LE8 scores were calculated from eight CVH metrics, with mortality ascertained through the National Death Index (NDI). Mediation analyses examined the roles of inflammation markers (neutrophil-to-lymphocyte ratio [NLR] and pan-immune-inflammation value [PIV]) and phenotypic age acceleration (PhenoAgeAccel). RESULTS: Higher LE8 scores were significantly associated with reduced all-cause mortality and heart disease mortality across all groups (p < 0.001). Stratified analyses showed stronger associations among younger individuals (≤60 years) and those with higher socioeconomic status. In mediation analyses, inflammatory markers and PhenoAgeAccel statistically explained a meaningful proportion of the LE8-mortality associations, with different patterns across disease groups. For all-cause mortality, in diabetes, NLR and PIV accounted for larger proportions of the association (NLR: 31.6%; PIV: 26.9%), whereas in hypertension, PhenoAgeAccel accounted for a larger proportion (56.3%). Among individuals with both conditions, PhenoAgeAccel (26.1%) and NLR (5.3%) contributed to the association. Similar patterns were observed for heart disease mortality. CONCLUSION: Higher LE8 scores are associated with reduced mortality risk in individuals with diabetes and/or hypertension, with inflammation and biological aging statistically mediating these associations in an exploratory manner. These findings suggest potential statistical mediators that may inform future mechanistic research and therapeutic targets, but causal interpretation requires further longitudinal studies.
Identifying Novel Biomarkers and Therapeutic Targets for Endometriosis: Integrative Analysis of the Plasma Proteome and Genome.
Zheng J, Yao YL, Chen XZ … +4 more , Fu LJ, Chi YG, Zhong ZH, Ding YB
Mediators Inflamm · 2026 · PMID 42175707 · Full text
BACKGROUND: There is currently no consensus on the etiology, pathogenesis, or treatment of endometriosis (EM). The discovery of disease-associated plasma proteins with causal genetic evidence provides an opportunity to i...
BACKGROUND: There is currently no consensus on the etiology, pathogenesis, or treatment of endometriosis (EM). The discovery of disease-associated plasma proteins with causal genetic evidence provides an opportunity to identify new EM biomarkers and therapeutic targets. METHODS: Protein quantitative trait loci (pQTLs) were derived from plasma proteomic associations in the UK Biobank Pharma Proteomics Project (UKB-PPP). Genetic associations with EM were obtained from the FinnGen cohort. The associations between proteins and the risk of EM were estimated by cis-Mendelian randomization (cis-MR) and validated using the GWAS catalog dataset of EM. Colocalization, protein-protein interaction (PPI) analysis, functional enrichment analysis, transcriptome differential expression gene (DEG) analysis and druggability evaluation were further performed to explore potential biomarkers and therapeutic targets for EM. RESULTS: Overall, genetically predicted levels of 23 plasma proteins were associated with EM risk, with five proteins validated via replication analysis (ALPI, KHK, HSPG2, STXBP1, and POLR2F). Lower levels of genetically predicted ALPI (odds ratio [OR]: 0.89, 95% confidence interval [CI] 0.83-0.95), HSPG2 (OR: 0.81, 95% CI 0.75-0.88), POLR2F (OR: 0.51, 95% CI 0.36-0.73), and STXBP1 (OR: 0.75, 95% CI 0.64-0.86) were associated with an increased risk of EM. Elevated levels of KHK (OR: 1.09, 95% CI 1.05-1.13) were associated with an increased risk of EM. We also identified ALPI, KHK, HSPG2, STXBP1, and POLR2F as potential drug targets and biomarkers for EM. CONCLUSION: A series of comprehensive analyses emphasized the potential role of ALPI, KHK, HSPG2, STXBP1, and POLR2F in EM and suggested that these genes could be developed into exact biomarkers and therapeutic targets for this condition in future research.
RETRACTION: Preventive but Not Curative Efficacy of Celecoxib on Bladder Carcinogenesis in a Rat Model.
Inflammation MO
Mediators Inflamm · 2026 · PMID 42163546 · Full text
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RETRACTION: Thyroxine Affects Lipopolysaccharide-Induced Macrophage Differentiation and Myocardial Cell Apoptosis via the NF-κB P65 Pathway Both In Vitro and In Vivo.
Inflammation MO
Mediators Inflamm · 2026 · PMID 42163481 · Full text
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Cytokine and Oxylipin Production in Resting and LPS-Stimulated Monocytes From Americans of African Ancestry Are Influenced by ALOX5 Promoter Tandem Repeat Polymorphisms.
Snodgrass RG, Stephensen CB, Armstrong P … +4 more , Allayee H, Snodgrass IF, Laugero KD, Newman JW
Mediators Inflamm · 2026 · PMID 42141771 · Full text
The arachidonate 5-lipoxygenase (ALOX5) specificity protein 1 (Sp1) promoter tandem repeat polymorphism is associated with enhanced cardiovascular disease (CVD) risk. However, a functional understanding of these variants...
The arachidonate 5-lipoxygenase (ALOX5) specificity protein 1 (Sp1) promoter tandem repeat polymorphism is associated with enhanced cardiovascular disease (CVD) risk. However, a functional understanding of these variants in immune cells central to disease development remains limited. We investigated oxylipin and cytokine production in resting and lipopolysaccharide (LPS)-stimulated CD14+ monocytes from individuals carrying promoter variants and common alleles of ALOX5. Compared to monocytes from subjects carrying two common five-repeat alleles (55 genotype), resting monocytes from individuals carrying one or more ALOX5 deletion (d) alleles (d5 and dd genotypes) produced increased levels of IL-1β, IL-6, TNF-ɑ, and IL-10 but lower quantities of putative trihydroxyeicosapenataenoic acid (TriHEPE) isomers detected with the same mass transition as resolvin E1 (RvE1) but slightly longer retention times. With the common 55 genotype, TriHEPEs increased as IL-6, IL-10, and TNF-ɑ production increased. This positive relationship between TriHEPEs and cytokines was diminished in monocytes with truncated ALOX5 alleles. In response to LPS, monocytes from individuals with d5 and dd genotypes produced higher levels of IL-1β, IL-6, and TNF-ɑ but not IL-10, as well as increased quantities of cyclooxygenase (COX) products 11-hydroxyeicosatetraenoic acid (11-HETE), prostaglandin E2 (PGE), thromboxane B (TxB), prostaglandin F2α (PGF), prostaglandin E1 (PGE), and prostaglandin B2 (PGB) compared to monocytes from individuals with the common 55 genotype. The observed changes in monocyte inflammatory mediator production provide a plausible link for the association of ALOX5 deletion alleles and CVD risk. Trial Registration: Clinical trial: registered on ClinicalTrials.gov (Identifier: NCT00536185).
XBP1s-Orchestrated Soluble Mediators: Participants of Oxidative Stress in Renal Ischemia-Reperfusion Injury Following Donation After Circulatory Death.
Zhang J, Zhao Y, Zhong J … +7 more , Ding H, Chen W, Li D, Chen X, Zhu D, Liao G, Gong N
Mediators Inflamm · 2026 · PMID 42138318 · Full text
Ischemia-reperfusion injury (IRI) presents an intractable challenge for kidney donors, especially in the era of donation after circulatory death (DCD). Based on in-depth studies of the renal IRI phenomenon, and the mecha...
Ischemia-reperfusion injury (IRI) presents an intractable challenge for kidney donors, especially in the era of donation after circulatory death (DCD). Based on in-depth studies of the renal IRI phenomenon, and the mechanisms involved, an increasing number of soluble mediators are being frequently associated with cellular dysfunction, cell death, and derivative rejection induced by oxidative stress, thus resulting in the failure of DCD kidney transplantation. Many of these soluble mediators are regulated by a spliced form of the X box-binding protein 1 (XBP1s), a vital effector molecule for endoplasmic reticulum stress (ERS), or exert their functionality by influencing the expression of XBP1s. Owing to the existence of multiple XBP1s-orchestrated soluble mediators, a variety of biological processes are known to be involved in the occurrence and development of IRI, thus manifesting as profound alterations in DCD kidney transplantation. In this review, we focus on the functionality of these XBP1s-associated soluble mediators and their roles in oxidative stress following renal IRI. Our goal was to contribute to the advancement of strategies to prevent and treat IRI in the context of DCD kidney transplantation.
Yiqi-Wenyang-Tiaoshen Decoction Reduces Cisplatin-Induced Acute Kidney Injury in Rats Through Autophagy and Apoptosis Signaling Pathways Based on Network Pharmacology and Experimental Validation.
Bai Y, Chang Y, Zhang L … +3 more , Zhou W, Su Y, Zhou J
Mediators Inflamm · 2026 · PMID 42112743 · Full text
CONTEXT: The mechanism of Yiqi-Wenyang-Tiaoshen decoction (YWT) in treating cisplatin-induced acute kidney injury (AKI) remains unknown. OBJECTIVE: This study identifies the key components of YWT and explores its therape...
CONTEXT: The mechanism of Yiqi-Wenyang-Tiaoshen decoction (YWT) in treating cisplatin-induced acute kidney injury (AKI) remains unknown. OBJECTIVE: This study identifies the key components of YWT and explores its therapeutic potential and mechanisms in a cisplatin-induced AKI rat model. MATERIALS AND METHODS: UPLC-ESI-MS/MS was utilized for the identification of compounds present in both the aqueous extract of YWT and serum samples. The overlapping components were recognized as active constituents, followed by a network pharmacological analysis. A rat model of cisplatin-induced AKI was established, and comprehensive pathological analyses including HE, PAS, and electron microscopy, as well as biochemical assessments of serum Cre, BUN, IL-6, and TNF-α levels, were conducted. Western blotting was utilized to evaluate the expression levels of Caspase-3, Caspase-9, BAX, Bcl-2, and LC3 Ⅱ/Ⅰ. RESULTS: Using UPLC-ESI-MS/MS, we identified 182 compounds in the aqueous extract of YWT, 34 of which are confirmed to be absorbable into the bloodstream. Network pharmacological analysis suggests that YWT primarily acts by inhibiting apoptosis and activating autophagy. In the rat model, YWT significantly ameliorated renal pathology and electron microscopic features. Additionally, YWT mitigated body weight loss and renal hypertrophy while lowering serum creatinine and blood urea nitrogen levels. YWT alleviates AKI by suppressing apoptosis-related proteins such as Caspase-3, Caspase-9, and BAX, enhancing Bcl-2 expression, increasing the LC3 Ⅱ/Ⅰ ratio, and reducing p62, a marker of autophagy. DISCUSSION AND CONCLUSION: This study confirms the therapeutic efficacy of YWT in cisplatin-induced AKI, potentially linked to its ability to inhibit apoptosis, activate autophagy, and mitigate mitochondrial damage.
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