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While typhoid fever affects both sexes at an equal rate, males are at a higher risk for intestinal perforation, which increases mortality. The mechanisms behind the increased morbidity of typhoid fever in human males remain an important but understudied question. Using a 129X1/SvJ (NRAMP Show less

Acute respiratory distress syndrome (ARDS) induced by sepsis is a clinical syndrome characterized by high morbidity and mortality rates. This study aims to clarify the effects of recombinant mouse IL-27 protein on macrophage ferritinophagy, macrophage polarization, and its interventional role in sepsis-induced ARDS. This study utilized wild-type (WT) and IL-27 receptor knockout (IL-27R This study investigates the role of IL-27 in exacerbating ferritinophagy and ferroptosis in macrophages and septic lung injury, and explores the therapeutic potential of the NCOA4 degrader CV3. We found that IL-27 synergizes with LPS to enhance NCOA4-mediated ferritinophagy, leading to increased degradation of FTH1, upregulation of LC3A/B, and promotion of ferroptosis. Ferritinophagy amplification drove M1 macrophage polarization and inflammatory cytokine release. CV3, a PROTAC-based NCOA4 degrader, effectively disrupted the NCOA4-FTH1 interaction, inhibited ferritinophagy, and mitigated ferroptosis and inflammation. In murine models of sepsis-induced ARDS, CV3 alleviated lung injury, restored antioxidant defenses, and reduced ferroptosis. Notably, IL-27R These findings reveal a potential mechanistic link between NCOA4-mediated ferritinophagy and sepsis-associated ARDS pathogenesis. Targeting this pathway with CV3 may offer a novel therapeutic strategy, which warrants further investigation. Show less

Chronic alcohol exposure disrupts blood-brain barrier (BBB) integrity and promotes neuroinflammation, with P2X7 receptor (P2X7R) signaling playing a critical role. Our prior work in male mice linked P2X7R inhibition to reduced extracellular adenosine triphosphate (eATP) release, modulated extracellular vesicle (EV) cargo, and attenuated neuroinflammation in chronic intermittent ethanol (CIE)-exposed mice. However, sex-specific roles of P2X7R signaling and EV-mediated mechanisms in alcohol-induced neuroinflammation remain unclear. Male and female mice were exposed to ethanol vapor for three weeks and treated with Brilliant Blue G (BBG), a P2X7R inhibitor. Compared to their respective CIE-unexposed controls, brain gene expression of tumor necrosis factor-α ( Show less

Respiratory bacterial infections represent a major health challenge in swine production, highlighting the need for novel immunomodulatory strategies that enhance host resistance. In this study, we investigated whether porcine intestinal lactobacilli could modulate the gut-lung axis and improve respiratory innate immunity in a mouse model of Three strains of Only strain LAFF998 significantly reduced pulmonary bacterial loads, prevented bacteremia, and attenuated lung injury. This protective effect was associated with selective modulation of respiratory immunity, characterized by reduced neutrophilic inflammation, increased lymphocyte recruitment, and enhanced activation of alveolar macrophages expressing MHC-II. LAFF998 markedly increased the production of IFN-β, IFN-γ, IL-6, IL-10, and IL-27 in the respiratory tract, without inducing excessive inflammatory damage. Ex vivo and in vitro analyses confirmed that alveolar macrophages from LAFF998-treated mice exhibited a primed phenotype with heightened cytokine responses to pneumococcal stimulation. In contrast, strains LAFF1071 and LAFF1095 failed to confer protection or significantly modulate respiratory immune responses. These findings demonstrate a strict strain-dependent effect among porcine Show less

Therapeutic interventions effective in reestablishing redox homeostasis in preterm infants require further investigation because immature lungs are extremely vulnerable to high-oxygen-induced lung injury. Flavin adenine dinucleotide (FAD) facilitates glutathione reductase (GR) activity and increases the bioavailability of the antioxidant glutathione (GSH). As such, we hypothesize that intranasal delivery of FAD can attenuate hyperoxic lung injury by restoring redox homeostasis, thereby altering pro-inflammatory signal transduction pathways. The term C57Bl6/N mouse model exposed to 0.85 fraction of inspired oxygen (85% [Formula: see text]) was used to model high oxygen-induced oxidative stress and bronchopulmonary dysplasia (BPD). Our studies show that FAD protects neonatal lungs (males and females) from high oxygen-induced oxidative stress by improving GSH/oxidized glutathione (GSSG) redox potential ( Show less

Community-acquired pneumonia (CAP) is still a leading cause of death due to infection globally, yet precise severity assessment remains a significant clinical problem. More than any other group of cytokines, interleukins are central to the regulation of inflammation and shed light on this intricate pathology. In the present review we summarize the biological and clinical characteristics of some of the principal interleukins (ILs) in CAP, classified primarily according to their physiological activity as pro-inflammatory (IL-2, IL-6, IL-8 and IL-12), anti-inflammatory (IL-7, IL-10 and IL-37), dual-action (IL-4 and IL-17), and emerging factors (IL-3, IL-27 and IL-33). Additionally, recent multimodal approaches are discussed such as combining cytokines with organ dysfunction parameters (MR-proADM) or revealing host-response patterns to inform antibiotic and corticosteroid management. We propose that the field needs to transition to immunological endotyping, multi-omics (integrating genetics and lung microbiome), and artificial intelligence (AI) models based on dynamic patient data to achieve precision medicine in CAP management. Show less

Despite a vast literature on the role of macrophages in wound healing, the role of dermal monocyte (Mo)-derived antigen presenting cells (APC) has received scant attention. Using scRNAseq and flow cytometry, we identify a population of APC that is prominent in wounds of non-diabetic mice but is reduced in wounds of diabetic mice. Using adoptive transfer experiments and Show less

Macrophages differentiated with macrophage colony-stimulating factor (M-CSF) (M-Mac) are widely used as an experimental model. Interleukin 27 (IL-27)-polarized M-Mac (27M-Mac) suppresses HIV replication; however, the effects of IL-27 polarization on granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced macrophages (GM-Mac) remain less investigation. Here, we compare multiple functional properties and gene expression profiles of 27M-Mac and IL-27-polarized GM-Mac (27GM-Mac). M-Mac and GM-Mac were generated from monocytes of healthy donors and subsequently treated with IL-27 for three days. HIV replication in 27M-Mac, GM-Mac, and 27GM-Mac was suppressed to nearly 10% of that in M-Mac; however, single-cell RNA sequencing showed that M-Mac clustered with GM-Mac, and 27M-Mac clustered with 27GM-Mac. Expression of CD38 and secretion of CXCL9 and C1q were significantly increased in 27M-Mac and 27GM-Mac compared with M-Mac and GM-Mac. Although CD16 and CD64 expression increased in 27M-Mac and 27GM-Mac relative to their respective controls, phagocytic activity in 27M-Mac and 27GM-Mac was 30% of that in M-Mac. Autophagy was promoted 3.7-fold more strongly in 27M-Mac than in M-Mac, reaching levels comparable to those in GM-Mac and 27GM-Mac. Collectively, these findings indicate that IL-27 polarizes M-Mac and GM-Mac toward transcriptionally and functionally similar subtypes, providing insight into the role of IL-27 in macrophage polarization and plasticity. Show less

Dendritic cells (DCs) encounter Leishmania differentially, and the conflict can restrict or disseminate the parasite infection, either by activating or dampening the protective T cell responses and inducing the regulatory T cells. The outcome of this conflict depends on the species of Leishmania, infection tenure, DC subtypes, and, importantly, the DC-stimulating chemical and physical mediators. The critical balance between splenic cDC1 (CD8α Show less

Probiotics such as The intestinal colonization ability of CIQ249 was assessed using cFDA-SE labeling and flow cytometry. Growth performance and intestinal morphology were evaluated in mice. Antimicrobial activity of CIQ249 cell-free supernatant was tested against various pathogens, and pathogen damage was visualized by scanning electron microscopy. Protective effects against CIQ249 demonstrated strong intestinal colonization and increased villus height and the villus-to-crypt ratio, contributing to improved growth performance. Its cell-free supernatant selectively inhibited enteropathogens and induced structural damage in CIQ249 enhances mucosal defense against enteropathogenic bacteria through a dual mechanism-strengthening the epithelial barrier and activating a coordinated DC-Tfh-IgA immune axis. These findings provide a multi-level mechanistic basis for its application as a microecological agent against intestinal infections. Show less

Diabetic nephropathy (DN) is a major complication of type 1 diabetes (T1D). Current diagnostic parameters, such as albuminuria and estimated glomerular filtration rate (eGFR), often detect the disease at advanced stages, promoting the identification of additional inflammatory markers. This study investigated the potential roles of pro-inflammatory interleukin-26 (IL-26), anti-inflammatory interleukin-35 (IL-35), and Signal Transducer and Activator of Transcription 1 (stat1) gene expression as potential biomarkers of DN in T1D. To evaluate serum levels of IL-26 and IL-35 and the gene expression of stat1 in T1D patients with and without renal dysfunction to assess their involvement in DN. This case-control study included 80 T1D patients (subgrouped to nephropathy status) and 60 healthy controls. Serum cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA), and stat1 expression in the blood was assessed using quantitative real-time PCR (qPCR). Statistical analyses included ANOVA, correlation tests, and receiver operating characteristic (ROC) curve analysis. IL-26 levels were not significantly elevated in hemodialysis T1D patients. IL-35 levels were significantly higher in T1D patients with nephropathy and in those on hemodialysis. A significant positive correlation was observed between IL-26 and IL-35 levels (r = 0.561, p = 0.0002). stat1 gene expression was significantly elevated in all T1D subgroups compared to controls, with the highest level observed in the hemodialysis group. ROC analysis indicated that stat1 had a discriminative ability for T1D, whereas IL-35 showed an acceptable diagnostic value for end-stage renal disease. This study showed that stat1 expression and IL-35 levels were linked with renal impairment in the T1D context, with stat1 expression elevated across T1D subgroups, and IL-35 expression was more accentuated in advanced renal dysfunction. Despite its limited discriminative value, IL-26 correlates with IL-35, suggesting simultaneous regulation within the inflammatory microenvironment. Show less

This study investigated the effects of high-intensity intermittent training (HIIT) Forty male Sprague-Dawley rats were randomly divided into two groups: standard diet (C, n = 10) and high-fat diet (HFD, n = 30). After 8 weeks of HFD feeding, 24 obese rats were further randomised into three subgroups: HFD (H, n = 8), HFD + moderate-intensity training (HMT, n = 8), and HFD + HIIT (HHT, n = 8). The HMT and HHT groups underwent 8 week training interventions (six sessions/week). The HMT protocol included a 10 min warm-up (treadmill speed: 10 m/min), a 40 min moderate-intensity aerobic phase (60%-70% of maximum speed), and a 10 min recovery (10 m/min). The HHT protocol featured 10 min warm-up and recovery phases (10 m/min), with 40 min of alternating treadmill training: 3 min at 50% maximum speed followed by 3 min at 90% maximum speed. No significant differences in body weight were observed between the HHT and HMT groups. HHT rats displayed significantly lower plasma triglyceride levels than H and HMT rats. Compared with HMT, HHT reduced adipose mass and adipocyte size and increased mitochondrial succinate dehydrogenase and cytochrome c oxidase (COX) activities in adipose tissue. However, HHT rats displayed lower COX activity in visceral white adipose tissue than HMT rats. Training upregulated browning-related genes and uncoupling protein 1 (UCP1) in adipose tissue, with stronger effects in HHT than in HMT. Plasma and adipose tissue IL-27 levels, as well as p38 MAPK-PGC-1α signalling pathway activation, were significantly elevated in both training groups, with greater increases in HHT. HIIT promotes adipose tissue browning by activating the IL-27 signalling pathway and ameliorates obesity-associated metabolic disorders more effectively than MAIT, supporting its potential as a therapeutic strategy for obesity. Show less

In this study, we evaluated a dual non-viable microbial therapeutic strategy combining prophylactic immune priming with heat-killed LpCFS did not directly alter cytokine or chemokine production by BAL macrophage-enriched adherent cells, indicating the absence of intrinsic immunostimulatory activity. However, therapeutic aerosol administration of LpCFS significantly reduced pulmonary and systemic PaS and PaR loads, attenuated lung damage, and modulated the inflammatory response by decreasing pro-inflammatory cytokines while increasing IL-10 during infections. Prophylactic administration of HK1505 effectively primed BAL macrophage-enriched adherent cells, enhancing their production of IL-1β, IL-6, IFN-γ, and IL-27 while reducing TNF-α and chemokine expression (CCL2, CXCL2, and CXCL10), thereby promoting efficient bacterial clearance with limited immunopathology. In this set of experiments HK1505 was compared with the live Our findings demonstrate that a non-viable probiotic-based strategy integrating prophylactic immune priming with HK1505 and therapeutic antibiofilm intervention with LpCFS effectively protects against antibiotic-resistant Show less

Persons with human immunodeficiency virus (HIV) well-treated on antiretrovirals have increased arterial inflammation, which can lead to development of atherosclerotic disease. We have previously shown that treatment with eplerenone can significantly reduce arterial inflammation, as measured by target-to-background ratio (TBR) on cardiac We performed a targeted discovery-based approach to identify a proteomics signature associated with eplerenone treatment that may provide a plausible mechanism for the reduction in arterial inflammation. In an exploratory study, we leveraged analyzable samples from participants who completed the 12-month, placebo-controlled, randomized controlled trial MIRABELLA HIV to evaluate 276 proteins (Olink Target 96 Cardiometabolic, Cardiovascular II, Cardiovascular III), with relevance to cardiovascular and cardiometabolic disease. We identified 11 proteins that differed in expression between treatment groups. Eight proteins (CDH1, CES1, ADM, IL-4RA, FGF-21, FS, FABP2, Gal-4) decreased and 2 proteins increased (CSTB, MPO) in expression with eplerenone compared to placebo. An increase in expression of IL-27 was prevented among eplerenone-treated versus placebo-treated groups. Changes in TBR of the most diseased segment of the index vessel correlated with changes in 3 of these proteins: CDH1 (ρ = 0.53, Through this proteomics approach, we discovered that 3 key proteins, CDH1, FGF-21, and Gal-4, are decreased in parallel with reductions in arterial inflammation after treatment with eplerenone. Eplerenone-induced reductions in these proteins, known to be related to inflammation, epithelial barrier disruption, vascular dysfunction, and metabolic dysregulation, provide mechanistic insight into pathways by which eplerenone may improve cardiovascular disease in HIV. NCT02740179. Show less

Multiple sclerosis (MS) is more prevalent in women, with a female-to-male ratio of 3:1. The molecular mechanisms driving this sex difference are still mostly unknown. MS results from immune dysfunction, with an imbalance in effector and regulatory T cells. Among the latter, Type I regulatory T cells (Tr1) are dysfunctional in people with MS (pwMS), secreting less IL-10, a potent anti-inflammatory cytokine, than in healthy donors. Our objectives were to explore the effect of biological sex on Tr1 cell differentiation in healthy donors and pwMS. CD4 We found that healthy female Tr1 cells produce less IL-10 than male cells (16 women and 16 men, 18-45 years old, We demonstrate that sex influences IL-10 production by Tr1 cells via the PI3K pathway, potentially contributing to the greater susceptibility of women to MS. Furthermore, our data suggest that targeting PI3Kδ may represent a novel therapeutic strategy to boost IL-10 production in female pwMS. Show less

The signaling pathways of inflammatory pain are widely explored, but practical clinical approaches to ameliorate pain remain inadequate. Quantitative PCR (qPCR) and ELISA methods were applied to measure the concentration of interleukin (IL)-27 in the inflammatory pain mouse model. Flow cytometry was conducted to identify the source of IL-27. Bone marrow-derived macrophages were stimulated by IL-27, IL-4, lipopolysaccharide, and/or interferon-gamma, followed by qPCR to assess pro-inflammatory and pro-resolving markers' dynamic expression. Then, the molecule profiling of IL-27-primed macrophages was determined using transcriptomic and proteomic sequencing. The Agilent Seahorse XF analyzer calculated energy metabolism indicators. The adoptive cell transfer method was used to verify that forkhead box class O3 (FoxO3) mediates alternatively activated macrophage differentiation induced by IL-27-Ucp2, contributing to alleviating pain sensation in mice. IL-27 is highly expressed centrally and peripherally in rodent pain models. Selective downregulation of IL-27 intensifies pain sensitivity in mice. In macrophages, IL-27 promotes the secretion of anti-inflammatory molecules, such as Arginase-1. Further, transcriptome, energy metabolic examination, and proteome analyses identified that IL-27 restructures the metabolism in macrophages, which is mediated by uncoupling protein 2 (Ucp2) and subsequently activates transcription factor FoxO3. Conditional knockdown of FoxO3 (si-FoxO3) in macrophages refrains the production of anti-inflammatory genes These findings reveal that the IL-27-Ucp2-FoxO3 axis regulates macrophage plasticity distinct from the canonical IL-4-mediated pathway through metabolic rewiring and facilitates alleviating Inflammatory pain. Show less

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by a lack of targeted therapies and poor prognosis. The tumor microenvironment (TME) plays a pivotal role in TNBC progression, with immune mediators such as cytokines, chemokines, growth factors, and immune checkpoints driving inflammation, angiogenesis, and immune evasion. We conducted a comparative analysis of 81 immune-related proteins in serum samples from 137 participants: 49 healthy controls (HC), 63 non-TNBC (NTNBC) patients, and 25 TNBC patients. Protein expression was quantified using multiplex immunoassays (ProcartaPlex and MILLIPLEX MAP® panels). Statistical analyses included principal component analysis (PCA), hierarchical clustering, receive operating curves (ROC), and pathway enrichment to identify diagnostic biomarkers and molecular networks associated with TNBC aggressiveness. Ou results revealed distinct immune dysregulation in TNBC, characterized by significant overexpression of pro-inflammatory cytokines (IFN-γ, IL-12p70, IL-8), chemokines (MIP-1α, Fractalkine), growth factors (VEGF-A, SCF), and immune checkpoints (LAG-3, PD-L1). ROC curve analyses identified LAG-3, Fractalkine, and VEGF-A as the top biomarkers distinguishing healthy controls from TNBC, while IL-5, IL-27, and TNF-β effectively discriminated TNBC from NTNBC. Cytokine network analysis highlighted TSLP, IL-12p70, and IL-17 A as central hubs coordinating Th1/Th17 inflammatory responses, stromal remodeling, and immune evasion, with strong interactions between IL-17 A-ENA-78-SCF and IL-3-IL-21 axes driving TNBC aggressiveness. Stratified analyses further demonstrated stage, grade, and metastasis revealed that IL-12p70, MIP-1α, and IL-18 were elevated in late-stage TNBC; IL-17 A, IL-5, and TWEAK were significantly overexpressed in high-grade tumors; and IFN-γ, IL-8, CTLA-4 and TSLP peaked in metastatic TNBC. Our findings identify immune mediator panels as promising diagnostic and prognostic biomarkers for TNBC. Show less

Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. The mechanisms driving this transition from acute immune activation to chronic inflammatory remodeling under viral suppression remain incompletely understood. Here, we leveraged a nonhuman primate model to characterize the longitudinal transcriptomic changes across key stages of SIV infection and ART. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-κB signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-κB, and inflammasome (NLRP3/NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-κB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART-treated macaque revealed macrophage-rich plaques with p21⁺ senescent cells with intraluminal thrombus formation, recapitulating key features of HIV-associated atherogenesis. While ART normalizes acute infection-induced immune dysregulation, chronic SIV infection sustains a chronic, macrophage- and TLR-driven inflammatory state linked to vascular injury and aging process regardless of long-term suppression of viremia. Targeting inflammasome, NF-κB, and senescence pathways may mitigate non-AIDS comorbidities in PLWH. Show less

Samples often have to be frozen and thawed prior to analysis for immunoassays. Reliable cytokine measurement from small-volume plasma and serum samples is critical for biomarker research and clinical studies. However, repeated freeze-thaw (F-T) cycles may alter analyte stability, introducing error and reducing reproducibility. Standard statistical methods often overlook donor-to-donor and matrix variability, leading to overestimation of F-T effects. We measured 80 cytokines across three donors, three matrices (EDTA-plasma (PL-EDTA), heparin-plasms (PL-heparin), serum), and four F-T cycles using an 80-plex Luminex immunoassay. Linear mixed-effects modeling was applied to partition donor, matrix, and F-T contributions, while principal component analysis (PCA) summarized global variance. Cytokines were classified as stable, decreasing, or matrix-specific based on within-matrix slopes and matrix×cycle interactions. Stability was defined as the absence of a statistically significant per-cycle change (p ≥ 0.05) within all matrices, corresponding to changes smaller than typical assay imprecision (CV%). PCA revealed that donor and matrix were the dominant sources of global variation, whereas F-T cycles contributed minimally. Most cytokines remained stable (no significant within-matrix slope across cycles; p ≥ 0.05 in all matrices) across four cycles, with only a minority showing monotonic decreases. Matrix context strongly influenced F-T effects: PL-heparin displayed both increases and decreases, PL-EDTA was largely stable, and serum showed decreases without increases. Representative analytes highlighted the three categories: IL17E/IL25 and IL27 decreased modestly across matrices, chemokines such as 6CKINE/CCL21 remained stable, and analytes like SDF1A + B/CXCL12 showed matrix-specific increases. Freeze-thaw cycling contributes far less to cytokine variability than donor or matrix effects. Most cytokines are robust across four cycles, and when F-T sensitivity occurs, it is largely matrix-dependent. These results provide evidence-based guidance for sample handling and highlight the importance of modeling donor and matrix effects in biomarker studies. Show less

Steroid-refractory (SR) disease develops in a substantial fraction of patients with grade II-IV acute graft-versus-host disease (aGvHD) and is associated with poor long-term survival. Improved mechanistic insight is needed to identify reliable predictors of steroid resistance. We retrospectively profiled peripheral blood collected prior to glucocorticoid treatment from allogeneic hematopoietic cell transplantation recipients without aGvHD, with steroid-sensitive aGvHD, and with SR-aGvHD using an integrated multi-omics approach, and validated findings in an independent multicenter cohort. Mass cytometry revealed expansion of activated CD28+ CD8+ effector-memory T (Tem) cells in SR-aGvHD. Absolute counts of these cells at neutrophil engraftment predicted subsequent steroid resistance in the multicenter cohort and performed comparably to established clinical classifiers. This phenotype was associated with a proinflammatory milieu enriched for IL-2, IL-27, and IFN-γ. Single-cell RNA sequencing and functional assays implicated a STAT1-glucocorticoid receptor (GR) regulatory axis in which inflammatory cytokines induce STAT1 phosphorylation and suppress GR expression, consistent with intrinsic glucocorticoid resistance. JAK inhibition rescued cytokine-induced steroid resistance in vitro, while in SR-aGvHD patients, clinical response to ruxolitinib was accompanied by reduced STAT1 activation, restoration of GR expression, and contraction of the expanded CD8+ Tem pool. These findings identify immune dysregulation at SR-aGvHD centered on CD8+ Tem cells with a STAT1-dependent GR deficit and support a mechanistic link to steroid refractoriness. CD28+ CD8+ Tem cell counts may serve as a biomarker of SR-aGvHD and inform development of pre-emptive, pathway-targeted strategies. Show less

Early diagnosis of pediatric sepsis is difficult because of the lack of specific clinical signs and limitations of standard biomarkers. Proteomics is a promising approach because it can identify disease-specific protein signatures. To systematically evaluate the current literature on the application of proteomics in pediatric sepsis, review and evaluate the current evidence on proteomic biomarkers for diagnosing and predicting pediatric sepsis. This is a systematic review with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-informed, structured search and transparent study-selection reporting. A structured literature search was conducted in PubMed, Scopus, and Web of Science up to January 2025. Studies involving pediatric patients (ages 0-18) with sepsis that used proteomic platforms and reported diagnostic or prognostic outcomes were included. Four studies met the inclusion criteria. Identified biomarkers included interleukin-27, signal transducer and activator of transcription 3, haptoglobin, serum amyloid A 1/2, soluble CD25, and leucine-rich alpha-2-glycoprotein 1. Sensitivities ranged from 60% to 86%, and specificities ranged from 75% to 92%. Multi-marker panels demonstrated superior diagnostic performance compared to single markers. Biomarkers were detectable within 2-6 hours of symptom onset. The analytical methods used varied and included enzyme-linked immunosorbent assays, liquid chromatography-tandem mass spectrometry, and SOMAscan. Most studies were exploratory and lacked external validation; they also used small, heterogeneous cohorts. Proteomics shows promise for earlier and more precise diagnostics of pediatric sepsis, but clinical translation is limited by small, single-center cohorts; age-dependent variability without developmental reference ranges; scarce longitudinal profiling; and minimal external validation. The priority now is multicenter, age-stratified, longitudinal studies with real-world comparators. Show less

Parental history of dementia is associated with increased dementia risk. We investigated whether having a parent with dementia is associated with increased peripheral inflammation in middle-aged adults. Participants were from the Offspring Study (n = 1204). Parental dementia status was determined by a diagnostic consensus conference. Plasma chemokine and cytokine concentrations were assayed with Luminex technology. Parental history of dementia was associated with higher levels of eotaxin and lower levels of granulocyte colony-stimulating factor, vascular endothelial growth factor A, and interleukin (IL)-27. IL-18 and epidermal growth factor levels were higher in Black individuals with a parental history of dementia compared to Hispanic individuals with the same history. Women with a parental history of dementia had higher levels of interferon-alpha 2, IL-12p70, soluble CD40 ligand, and IL-18 compared to men with the same history. Parental history of dementia is associated with elevated markers of peripheral inflammation. These associations vary across sex, race, and ethnicity. Show less

Humans and mice display elevated levels of IL-27, an immunosuppressive cytokine shown to increase during neonatal bacterial sepsis and compromise survival. This study explores two hypotheses for regulation of IL-27 expression: 1) decreased DNA methylation in newborns that contributes to increased expression of IL-27 genes; 2) neonatal hormones regulate IL-27 expression through upstream hormone response elements (HREs). Whole genome methyl-seq analysis of neonatal and adult blood-derived macrophages identified differentially methylated regions (DMRs) at steady-state. Quantitative PCR (qPCR) measured expression of IL-27 genes ( The IL-27p28 promoter contained DMRs that were increased in the neonatal cohort. The analysis did not identify DMRs within the EBI3 promoter. Dexamethasone stimulation increased These data suggest glucocorticoid (GC) signaling increases EBI3 expression. This has importance in the context of antenatal GC administration that may increase IL-27 levels. ▪ Elevated expression of IL-27 in early life impairs the host response to invasive bacterial infection in neonates.▪ Understanding the regulatory mechanisms contributing to increased IL-27 during the neonatal period is necessary to reduce susceptibility to infection in this vulnerable population.▪ The methylation status of the IL-27 genes in macrophages from neonatal and adult blood donors does not suggest regulation of differential expression with age.▪ Glucocorticoids are a signal that can induce EBI3 gene expression in a GR-dependent manner.▪ Glucocorticoid therapy for premature infants may increase IL-27 expression and promote enhanced susceptibility to infection. Show less

To assess the feasibility of intravoxel incoherent motion imaging (IVIM) for detecting renal injury in an obese rat model and monitoring renal function after weight-loss therapy. Forty-two male rats were randomly divided into high-fat diet (HF) and standard diet (St) groups ( The D, D* and IVIM is a potential tool for noninvasive and longitudinally detection of early obesity-related renal injury and renal function improvement after weight-loss therapy. The online version contains supplementary material available at 10.1186/s12880-026-02288-1. Show less

Interleukin-27 (IL-27) is an immunoregulatory cytokine, but its role in B-cell haematopoiesis and B-cell acute lymphoblastic leukaemia (B-ALL) within the bone marrow (BM) niche remains unclear. IL-27 was delivered in vivo using adeno-associated virus. B-cell reconstitution, mixed BM chimeras, and an N-myc-driven B-ALL model were analysed by flow cytometry, transcriptional profiling, and survival studies. Group comparisons were assessed using Student's t-test, and survival was evaluated by Kaplan-Meier analysis with log-rank tests. Sustained IL-27 expression selectively impaired B-cell reconstitution while preserving overall haematopoietic recovery, with marked reductions in CLPs and early B-cell subsets. IL-27 directly inhibited early B-lineage differentiation and concurrently remodelled the BM microenvironment by downregulating VCAM-1, ICAM-2, CXCL12, and IGF-1. These niche alterations were associated with reduced BM-resident B-ALL burden, enhanced chemotherapy efficacy, and improved survival in B-ALL-bearing mice. IL-27 showed no direct cytotoxicity toward B-ALL cells, supporting an indirect, niche-mediated mechanism. IL-27 constrains B-cell haematopoiesis and B-ALL progression through coordinated progenitor inhibition and BM niche remodelling, revealing a cytokine-driven strategy with the potential to enhance leukaemia therapy. This work was supported by the National Key R&D Program of China (Grant No. 2021YFA1100800 to A.-B.L.) and the National Natural Science Foundation of China (Grant No. 82100180). Show less

Neonatal regulatory T (Treg) cells in secondary lymphoid organs have greater proliferative capacity and more potent suppressive functions than adult Treg cells. However, the phenotypic and functional features of Tregs in neonatal nonlymphoid organs are not well understood. Our prior work demonstrated that thymus-derived Treg cells entering the neonatal mouse liver enhance immune tolerance and periportal liver maturation. Compared to splenic Treg cells, these hepatic Tregs have faster turnover and superior suppression of naïve T-cell proliferation. To further define this population, we conducted single-cell transcriptomic and immunophenotypic analyses of liver- and spleen-derived Tregs from neonatal and adult mice. Our analysis revealed a distinct T-box transcription factor Tbx21 (T-bet) Show less