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Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic performance and adverse side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising, safe, and noninvasive alternative intervention with demonstrated neuromodulatory efficacy. Nevertheless, its mechanisms remain unclear. This study investigated whether the antidepressant properties of taVNS are associated with the microbiota-gut-brain axis, focusing on the potential crosstalk between differentially expressed hippocampal proteins and the gut microbiota. A chronic unpredictable mild stress (CUMS) rat model of depression was established, and taVNS was administered for 14 days. Hippocampal proteomic profiling was performed using data-independent acquisition. Fecal metagenomic sequencing was conducted to characterize alterations in gut microbial communities. Key signaling pathways were validated using Western blot, qRT-PCR, HE staining, and transmission electron microscopy, all of which were employed to systematically assess behavioral, proteomic, microbial, and molecular changes. Proteomics and molecular analyses revealed that taVNS upregulated hippocampal expression of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1 (GluN1) and brain-derived neurotrophic factor (BDNF), while simultaneously restoring mitogen-activated protein kinase (MAPK) signaling activity. Metagenomic profiling demonstrated that taVNS increased the abundance of TaVNS significantly alleviated depression-like behaviors in CUMS-exposed rats. The underlying mechanism may involve the restoration of synaptic function of glutamatergic neurons by regulating the GluN1/MAPK/BDNF signaling pathway. In addition, taVNS reshaped the gut microbiota, markedly increasing the abundance of Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, accounting for an estimated 60-70% of all clinically diagnosed cases worldwide. The growing focus on microglia-neuron interactions in AD research highlights their diverse, region-specific responses, which are driven by the functional and pathological heterogeneity across different brain regions. Therefore, investigating the interactions between microglia and neurons is of crucial importance. To explore the regional heterogeneity of microglia-neuron crosstalk in AD, we integrated human single-nucleus RNA sequencing data from the prefrontal cortex (PFC), hippocampus (HPC), and occipital lobe (OL) provided by the ssREAD database. Our study delineated four microglial subtypes and uncovered a pseudotime trajectory activation trajectory leading to the disease-associated microglia (DAM) phenotype. The transition along this trajectory is driven and stabilized by a key molecular switch: the coordinated downregulation of inhibitory factors (e.g., LINGO1) and upregulation of immune-effector and antigen-presentation programs, which collectively establish the pro-inflammatory DAM state. Furthermore, we observed that each brain region displayed unique microglia-neuron communication patterns in response to AD pathology. The PFC and OL engage a THY1-ITGAX/ITGB2 signaling axis; the HPC predominantly utilizes the PTPRM pathway. Notably, THY1 dysregulation strongly correlates with pathology in the PFC, HPC, and OL, suggesting that microglia-neuron crosstalk in AD possesses both heterogeneity and commonality. The main contribution of this study is the systematic characterization of region-specific microglia-neuron interactions and the identification of THY1 as a potential mediator that may be targeted therapeutically to modulate microglial function in affected brain regions. Show less

Physical inactivity strongly predicts poor prognosis in chronic obstructive pulmonary disease (COPD) but is often underrecognized. We investigated whether combining patient-reported outcomes (PROs) with myokine profiling enhances detection of inactivity in COPD. In this multicentre cross-sectional study, 73 patients with stable COPD underwent PRO assessment (modified Medical Research Council dyspnea scale (mMRC), dyspnea-specific PROs (PROMs-D), COPD Assessment Test (CAT), Shortness of Breath Daily Activities Questionnaire (SOBDA-Q), and Kihon Checklist (KCL)), serum myokine measurement, and accelerometer-based physical activity evaluation, stratified into 1.0-1.5 METs (low-intensity/sedentary), ≥ 3.0 METs (moderate), total activity (METs·h), and step count. Correlation and logistic regression analyses were performed. mMRC and PROMs-D correlated negatively with moderate activity and step count. Among myokines, growth differentiation factor-15 (GDF-15), fatty acid binding protein 3 (FABP3), and brain-derived neurotrophic factor (BDNF) showed moderate associations with physical activity: GDF-15 and BDNF with low-intensity, GDF-15 with moderate, and FABP3 and BDNF with step count. Combined PRO-myokine models outperformed single markers, with areas under the curve of 0.77 for low-intensity activity, 0.82 for moderate activity, and 0.86 for step count. In conclusion, integrating PROs and myokines improves the specificity and accuracy of inactivity detection in COPD. This multidimensional strategy may facilitate early, personalized interventions. Show less

Movement behaviours, including moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), sedentary behaviour (SB), and sleep, influence childhood adiposity. However, their collective impact on adiposity from a sex-specific perspective remains underexplored. Our research examined the sex-specific longitudinal associations of 24-h movement behaviours with body mass index (BMI) and abdominal adiposity among children. In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study, we repeatedly measured 24-h movement behaviours using wrist-worn accelerometers (ActiGraph GT3x) and assessed adiposity (BMI, abdominal circumference, and MRI-based abdominal fat volumes) at three time points (ages 5.5-6, 7.5-8, and 10-10.5 years) within the same children in a longitudinal design. Compositional multivariable linear mixed-effect modelling and isotemporal substitution were used to estimate the associations. 531 children (49.5% girls) were included in the analysis. Significant interactions between movement behaviours and sex were observed across all outcomes. In girls, higher MVPA relative to other behaviours was linked to lower BMI [-0.8 (-1.5, -0.1) kg/m²] and total abdominal adiposity [-225.5 (-451.6, -2.5) mL], while in boys, longer sleep duration was associated with lower BMI [-1.6 (-3.2, -0.1) kg/m²] and total abdominal adiposity [-624.2 (-1225.6, -31.3) mL]. The isotemporal substitution model showed that replacing 30 min of LPA/SB with MVPA reduced BMI and abdominal circumference by 1-2% and MRI-measured abdominal adiposity by 6-9% in both sexes. However, replacing LPA/SB with sleep reduced BMI and abdominal circumference by 1% and MRI-measured adiposity by 3-6% only in boys, with no changes in girls. These associations were pronounced on visceral adiposity. This study highlights sex-specific associations of movement behaviours with adiposity in school-aged children, with stronger associations observed in MRI-derived measures compared to conventional adiposity indices. Replacing LPA/SB with MVPA reduced BMI and abdominal adiposity in both sexes, with particularly pronounced effects on visceral adiposity. However, sleep replacement benefits were observed only in boys, suggesting the need for gender-sensitive approaches in lifestyle interventions. Show less

Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice. We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI. Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD. Show less

Colorectal cancer (CRC) remains a major global health challenge, underscoring the need for reliable biomarkers to improve prognosis and therapeutic stratification. In this study, we comprehensively investigated the expression pattern, clinical significance, molecular functions, and immunological implications of LINGO1 in CRC. Integrative analyses of TCGA and GEO datasets, together with validation in 72 clinical CRC samples, demonstrated that LINGO1 is markedly overexpressed in tumors and strongly associated with advanced clinicopathological features and poor patient outcomes. Functional experiments revealed that both knockdown of LINGO1 in SW480 and LoVo cells and overexpression of LINGO1 in HCT116 cells significantly modulate malignant phenotypes, including proliferation, migration, invasion, and angiogenic capacity. Transcriptome-wide and pathway enrichment analyses further indicated that high LINGO1 expression is linked to epithelial-mesenchymal transition, angiogenesis, Wnt/β-catenin signaling, and other oncogenic pathways. Immunogenomic profiling, supported by multiplex immunofluorescence staining, showed that elevated LINGO1 is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T-cell infiltration and diminished GZMB expression, alongside upregulation of multiple immune checkpoint molecules. Collectively, our findings identify LINGO1 as a novel oncogenic driver and immune-modulatory biomarker in colorectal cancer, with potential value for prognosis and therapeutic targeting. Show less

Sepsis remains a leading cause of mortality in intensive care units (ICUs) worldwide, necessitating improved diagnostic and prognostic tools. This study aimed to estimate the novel sepsis biomarkers, including presepsin, interleukin (IL)-27, hepcidin, and plasma chitotriosidase in ICU patients with sepsis, evaluating their potential for enhancing early diagnosis and monitoring. This prospective study was conducted over 18 months at JSS Medical College and Hospital, Mysuru, India. The study included 73 ICU patients above 18 years diagnosed with bacterial sepsis based on Quick Sequential Organ Failure Assessment score and procalcitonin (PCT) levels. Blood samples were collected and analyzed using enzyme-linked immunosorbent assay with respective biomarker kits. Demographic data, clinical parameters, and laboratory values were recorded. Correlations between novel biomarkers and PCT were assessed using Pearson correlation analysis. The study population had a mean age of 55.7 years, with 60.3% male participants. Hypertension (56.16%) and type 2 diabetes mellitus (49.32%) were the most common comorbidities. Abnormal presepsin levels were observed in 53.4% of participants, showing a strong positive correlation with PCT ( r = 0.763, P < 0.001). Hepcidin levels were abnormal in 76.7% of participants, demonstrating a moderate positive correlation with PCT ( r = 0.522, P < 0.001). Only 11.0% of participants had abnormal IL-27 levels, with a weak, nonsignificant correlation with PCT ( r = 0.172, P = 0.540). All participants (100%) had abnormal chitotriosidase levels, showing a weak but significant positive correlation with PCT ( r = 0.234, P = 0.047). This study supports the potential of presepsin and hepcidin as novel biomarkers for sepsis in ICU patients. These markers showed strong correlations with PCT and high rates of abnormal levels in sepsis patients. IL-27 and chitotriosidase showed less promise in our study population. Integrating these novel biomarkers, particularly presepsin and hepcidin, into clinical practice could potentially improve early diagnosis and management of sepsis in critical care settings. Show less

Maternal immune activation (MIA) during pregnancy has been implicated as a key environmental risk factor in autism spectrum disorder (ASD). Interferon-alpha (IFN-α), a type I interferon, may disrupt fetal neurodevelopment, yet its mechanistic impact remains insufficiently understood. This study explores the effects of maternal IFN-α exposure on neurobehavioral and neurobiological outcomes in a Wistar rat model. Pregnant rats received IFN-α on gestational day 10, and offspring were evaluated through behavioral assays, neurochemical analyses, and histopathological assessments. IFN-α exposure resulted in significant reductions in GABA, 5-HIAA, and GAD-67 levels, particularly in male offspring, indicating neurotransmitter dysregulation. Histologically, neuronal loss was observed in the hippocampal CA1 and CA3 regions and cerebellar Purkinje cells. Astrocyte activation, reflected by increased GFAP immunoreactivity, was prominent, suggesting a neuroinflammatory response. Additionally, reduced brain-derived neurotrophic factor (BDNF) and elevated tumor necrosis factor-alpha (TNF-α) levels support the presence of inflammation-induced synaptic dysfunction and impaired neuroplasticity. Behaviorally, male offspring exhibited reduced sociability and impaired social novelty recognition. Both sexes demonstrated deficits in motor coordination and exploratory activity. These findings align with core ASD phenotypes and underscore a heightened male vulnerability. Overall, the study provides compelling evidence that prenatal IFN-α exposure leads to persistent neuroimmune, neurochemical, and structural alterations resembling ASD. The results highlight the need for further research into immune-mediated neurodevelopmental disruptions and sex-specific vulnerabilities, offering potential pathways for preventive and therapeutic interventions targeting MIA-related risk mechanisms. Show less

To detect the expression of Interleukin-27 (IL-27) and Interleukin-35 (IL-35) in orbital fat in patients with severe TAO (thyroid-related eye disease) exophthalmos, and to investigate its potential role and significance in the development of TAO. A study group of 30 patients (30 eyes) who underwent orbital decompression with severe TAO exophthalmos in the Department of Ophthalmology, Provincial Hospital affiliated to Shandong First Medical University from January 2022 to December 2023, the expression of IL-27 and IL-35 of the orbital adipose tissue was detected by western-blot, and which in 30 patients (30 eyes) underwent orbital fracture surgery and plastic repair as control group. The contents of IL-27 and IL-35 were higher in severe TAO patients than in normal controls, and the difference was significant ( Show less

White matter hyperintensities (WMH) on T2-weighted brain magnetic resonance imaging (MRI) are common in aging and associated with small vessel cerebrovascular disease. Standard segmentation methods treat these lesions as uniform binary entities, fundamentally reducing WMH signal by flattening a complex spectrum of tissue damage into a single label. Most WMH methods threshold voxel intensities to estimate lesion volume, missing richer characterization achievable by combining fluid-attenuated inversion recovery (FLAIR) with diffusion MRI. We introduce Voxel-wise Correlation of Neighbors (VCON), a cross-modal framework that quantifies voxel-level relationships between intensity values on T2-weighted FLAIR scans and fractional anisotropy (FA) on diffusion MRI within individuals. VCON generates hypothesis-driven WMH labels by identifying regions where increased FLAIR signal is negatively correlated with FA, suggesting underlying microstructural damage. Using MRI data from over 2,500 participants in community-based aging cohorts, we validated VCON through multi-scale analysis, age-association modeling, scanner comparisons, and intensity-based clustering of WMH into spatially coherent zones with distinct microstructural profiles. VCON revealed a gradient of WMH signal variation that tracks with age and diffusion metrics across scanners and segmentation methods. These results demonstrate that binary WMH masks may obscure clinically important variation in lesion characteristics. VCON reframes lesion segmentation as characterizing microstructural heterogeneity, offering additional structure-informed characterization beyond conventional binary methods by leveraging multimodal MRI signal variation. Show less

To investigate the genetic causality between Human blood cell (HBC) traits and sporadic lymphangioleiomyomatosis (sLAM) by mediation joint multi-omics and eQTL Mendelian randomization analysis. Quality control processes were followed to select eligible instrumental variables strongly associated with 35 kinds of HBC traits. Independent cohort of European ancestry with sLAM and lung function genome-wide association study (GWAS) summary statistics were used separately. We utilized a two-step MR approach to explore potential mediators and evaluate the proportion of effect mediated in the associations linking HBC trait candidates to sLAM. Finally MR analysis integrating single cell expression quantitative trait loci (sc-eQTL) from 14 immune cell types with GWAS of sLAM was conducted. Increased level of basophil count was positively associated with higher risk of sLAM (BASO#; OR = 3.878, 95%CI:1.137–13.221, For the first time, this study leverages mediation analysis and multi-omics MR integrated with sc-eQTL data to elucidate the roles of HBC traits, immune cells, inflammatory proteins, VEGF-related proteins and immune cell-specific genes in the pathogenesis of sLAM among the European populations. The online version contains supplementary material available at 10.1186/s13023-026-04224-6. Show less

Generation of specific antibodies against peptides by immunization requires their covalent conjugation to protein carriers to override their inherently weak immunogenicity. The vast majority of bioconjugation approaches to achieve peptide-protein constructs rely on thiol-maleimide chemistry and capitalize on a wide array of commercial maleimide-functionalized protein carriers. Disulfide-rich peptides (DRPs) possess a rigid, constrained structure that makes them ideal for designing synthetic mimics of protein regions/domains. For bioconjugation purposes, the introduction of a single spare thiol moiety into a linear peptide antigen is straightforward, while DRPs' disulfide bonds are prone to intramolecular thiophilic attack by the reactive thiolate. This unintended reactivity competes with the desired Michael addition to the maleimide moiety, ultimately disrupting the native disulfide bridging framework. As a result, DRP's tertiary structure will be altered, affording an immunogen that is a poor mimic of the native target. Although a few studies have explored the late-stage introduction of thiol-containing cross-linkers into DRP antigens for their conjugation onto protein carriers, the stability of DRPs' disulfide pattern in the presence of an extra thiol has never been examined. In this study, we systematically evaluated the influence of different spacers in "DRP-spacer-thiol" constructs under thiol-maleimide reaction conditions. Our results highlight how both linker length and flexibility are key to maintaining DRP disulfides unaltered, providing a general approach to achieve DRP bioconjugation by thiol-maleimide chemistry. We have applied our approach to a small DRP predicted to closely mimic a surface-accessible epitope of the full LINGO-1 protein and obtained a very specific antibody response upon immunization; the resulting polyclonal IgG was able to selectively bind the full-length protein in a cellular context, with stringent selectivity across its four homologs. Show less

The aim of this study was to investigate the impact of interleukin-27 (IL- 27) gene polymorphism and additional interactions with environmental factors on non-small cell lung cancer (NSCLC) risk based on a Chinese population. SNPStats online software ( http://bioinfo.iconcologia.net/SNPstats ) was used for Hardy-Weinberg equilibrium (HWE) testing. Stratified analysis was performed by logistic regression model to examine the impact of IL- 27 gene SNPs and environmental factors, and additional gene-environment interaction on NSCLC risk. Logistic regression analysis showed a significant association between rs153109, rs181206 and increased NSCLC risk. However, no significant relationship was found between NSCLC risk and rs17855750 or rs40837 genotype with minor allele. Logistic regression also indicated a significant association between smoking status or alcohol consumption and NSCLC risk in this study. We performed crossover analysis to investigate the interaction between two SNPs (rs153109 and rs181206) and two environmental factors (smoking status and alcohol consumption) using logistic regression. We found that ever or current smokers with rs153109- AG or GG genotype have the highest NSCLC risk, compared with never smokers with the AA genotype after covariate adjustment, OR (95%CI) = 3.02 (1.97-5.12), p = 0.012. However, no significant interaction effect was found between rs153109 and alcohol consumption, rs181206 and smoking, rs181206 and alcohol consumption. Our results support an important association of the IL- 27 gene rs153109, rs181206, smoking and alcohol consumption with increased NSCLC risk. We also found a significant impact of an interaction between rs153109 minor allele and ever or current smoking on NSCLC risk. 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

Pelvic radiation therapy is an essential treatment for several pelvic malignancies, but it can lead to radiation cystitis (RC), a severe progressive inflammatory bladder disorder lacking effective diagnosis and therapeutic options. RC evolves through acute, latent, and chronic phases, ultimately resulting in bladder fibrosis, vascular damage, and hematuria. Here, we characterize the molecular and immunological features associated with RC progression using a preclinical mouse model. Building on a prior analysis of the acute and chronic phases, we examined the previously unanalyzed latent phase and integrated transcriptomics, immune cell profiling, inflammatory protein measurements, and bladder function assessments across all stages. Acute radiation injury was marked by the strong activation of apoptotic pathways, whereas latent and chronic phases were dominated by inflammatory signaling with distinct cytokine and chemokine signatures. The persistent upregulation of Cdkn1a (P21) was consistent with sustained senescence-associated signaling, while reductions in IL-27 and shifts in the granulocyte-lymphocyte-enriched immune population during the latent phase were consistent with altered immune regulatory states. At chronic stages, increased SASP-associated proteins and matrix remodeling mediators coincided with bladder functional decline. Together, these findings support a model in which radiation-induced senescence, coupled with immune dysregulation during the latent phase, are coordinated features accompanying inflammation, tissue remodeling, and bladder dysfunction in RC. 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

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

Periodontitis and type 2 diabetes mellitus (T2DM) are chronic diseases with a well-established bidirectional relationship. Recent studies have focused on salivary biomarkers to better understand their shared inflammatory mechanisms. This study aimed to assess salivary levels of asprosin, interleukin (IL) -39, IL-40, and IL-1β in patients with and without periodontitis and/or diabetes. Eighty-eight participants were classified into four groups based on periodontal and diabetic status. Unstimulated saliva samples were collected and analyzed by ELISA. In addition to clinical periodontal parameters, body mass index (BMI) and glycated hemoglobin (HbA1c) levels were recorded. Salivary asprosin and IL-1β levels were elevated in periodontitis groups regardless of T2DM status and showed positive correlations with BMI. IL-39 showed no significant findings. All biomarkers, with the exception of IL-39, were positively correlated with clinical periodontal parameters. IL-40 was elevated in both diabetic and non-diabetic patients with periodontitis. Elevated salivary asprosin, IL-40, and IL-1β levels in diabetic individuals with periodontitis may indicate their involvement in the inflammatory interactions linking metabolic dysfunction and periodontal tissue breakdown. IL-39 showed limited utility. These findings enhance understanding of salivary inflammatory patterns in diabetes-associated periodontitis, although the saliva-only, cross-sectional design warrants cautious interpretation. The identification of salivary asprosin, IL-40, and IL-1β as potential indicators of periodontal and metabolic inflammation suggests that saliva-based testing could support non-invasive screening and monitoring in patients with diabetes and periodontitis. NCT06735313. 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

Microglia-mediated neuroinflammation, considered one of the most plausible pathogenic hypotheses underlying Alzheimer’s disease (AD), plays a pivotal role in the initiation and progression of this devastating condition. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated promising neuroprotective effects in both preclinical and clinical studies. Previously, we developed an orally-administered GLP-1RA peptide called OHP2, which is capable of crossing the blood-brain barrier for the treatment of AD. OHP2 has been shown to effectively reduce brain inflammation in AD mouse models. In this study, we discovered that OHP2 treatment induced IL-27 secretion from astrocytes and modulated microglial reprogramming from the neurotoxic M1 phenotype to the neuroprotective M2 phenotype through glycolysis/cGAS lactylation clock/mTOR pathway, thereby alleviating excessive neuroinflammation. These findings provide a rationale for further pharmacological investigations into OHP2 and suggest that IL-27 may hold significant implications for AD therapy as a metabolic regulator. [Image: see text] The online version contains supplementary material available at 10.1186/s12974-025-03683-1. Show less

Insulin resistance (IR), commonly associated with obesity, is linked to a range of metabolic and immune-related disorders in the contemporary human population. Nevertheless, it is evolutionary well-conserved, suggesting its potential survival advantages to our ancestors. This review aims to explore the intricate interplay between IR and the immune system as well as its implications for the development of immune-metabolic and allergic diseases in the modern era. From an evolutionary medicine perspective, the longevity of ancient humans relied on energy storage to endure food shortages and effectively activate the immune system against various diseases. Under normal conditions, insulin induces glycogen and triglyceride synthesis in the liver and adipose tissues. However, IR directs more glucose to insulin-independent tissues, such as the immune system, which are critical for survival in adverse conditions. The persistent IR in our current lifestyle promotes low-grade inflammation, accompanied by various metabolic and allergic disorders. Critically, this evolutionary mismatch not only explains disease susceptibility but also informs therapeutic design to target immune-metabolic crosstalk. Moreover, our evolutionary analysis demonstrates that the genomic regions near the PTEN, IL27, and NUPR1 genes could play an important role in this interaction across diverse populations. Show less

Few HIV-specific epitopes restricted by non-classical HLA-E have been described, and even less is known about the functional profile of responding CD8+ T cells (CD8s). This study evaluates the functional characteristics of CD8s targeting the Gag epitope KF11 (KAFSPEVIPMF) restricted by either HLA-E (E-CD8s) or HLA-B57 (B57-CD8s). CD8s from 8 people with HIV (PWH) were cocultured with KF11 peptide presented by cell lines expressing HLA-B*57:01, HLA-E*01:01, or HLA-E*01:03. CD8 responses were analyzed using single-cell RNA and TCR sequencing. Supernatants were also assessed for soluble protein profiling. HLA-I multimers were developed to identify CD8s restricted by HLA-B57 and/or HLA-E ex vivo. B57-CD8s secreted higher levels of cytotoxic cytokines such as IFN-γ, whereas E-CD8s produced more chemotactic cytokines, including RANTES, CXCL10 (IP-10), and IL-27, findings that were corroborated through single-cell RNA sequencing. TCR clonotypes stimulated by KF11 were cross-restricted by HLA-B*57 and HLA-E*01:03 as demonstrated by in vitro T cell reporter assays and ex vivo multimer screening. Ex vivo CD8s were singly restricted by HLA-B57 and HLA-E, with dual restriction only observed in PWH with lower viral load. These findings demonstrate that certain HIV-specific CD8s in PWH exhibit dual restriction by HLA-B*57 and HLA-E*01:03, leading to functionally distinct immune responses depending on the restricting allele(s). 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

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

Koolen-de Vries Syndrome (KdVS) is a neurodevelopmental disorder (NDD) caused by KANSL1 haploinsufficiency with no treatment options. To investigate neuronal network activity in KdVS, human induced pluripotent stem cell (hiPSC)-derived neurons from KdVS patients and controls were cultured on microelectrode arrays (MEAs). KdVS networks exhibited reduced burst rates and increased variability in burst rhythmicity. To bridge molecular and functional aspects of the syndrome, we applied MEA-seq, integrating electrophysiological recordings with high-throughput transcriptome profiling. This analysis revealed a negative correlation between the NDD-associated gene CLCN4 and network burst rate. Knockdown of CLCN4 in KdVS neurons restored network bursting toward control levels, highlighting how transcriptome profiling can identify mediators linking genetic defects to relevant physiological phenotypes. We also identified significant correlations between mitochondrial gene expression and network activity and consequently confirmed impaired mitochondrial function in KdVS hiPSC-derived neurons. Using the KdVS transcriptomic signature for computational screening against the LINCS drug perturbation database, we predicted compounds capable of reversing dysregulated gene expression. Ten candidates were prioritized for experimental validation, focusing on mitochondrial function. Among these, the antioxidant phloretin improved multiple aspects of the KdVS-related network activity phenotype, reduced reactive oxygen species, and rescued synaptic density across patient lines, revealing its potential as a therapeutic candidate. Together, these findings demonstrate that integrative MEA-seq profiling can connect molecular and electrophysiological alterations in KdVS, providing a robust framework for identifying novel drugs and druggable pathways for KdVS and potentially other neurodevelopmental disorders. Show less

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory disorder characterized by nasal obstruction and polyp formation. Despite its prevalence, the complex pathogenesis of CRSwNP remains not fully understood, hindering the development of effective treatments. This study aims to delineate the immunological landscape of CRSwNP by integrating single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) approaches. We conducted a systematic MR analysis using summary statistics from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data. The identified genes were further scrutinized through scRNA-seq analysis of CRSwNP tissues to assess cell-specific expression patterns. Pathway enrichment and protein-protein interaction (PPI) network analyses were performed to explore the biological mechanisms underlying CRSwNP. The MR analysis identified several genes, including HLA-DRB1, HLA-DQA1, and HLA-DQB1, as significantly associated with CRSwNP. The scRNA-seq analysis validated these findings, revealing cell-specific enrichment in basal cells. Notably, these genes were found to be involved in immune cell recruitment and the reshaping of the immune microenvironment. Furthermore, the study highlighted the role of genes like TCF7L1, KANSL1-AS1, and POLR2J3, which showed contrasting expression patterns and potential regulatory roles in CRSwNP. This integrative study provides novel insights into the molecular and cellular underpinnings of CRSwNP. The identified genes and their role in immunopathogenesis offer potential therapeutic targets and highlight the importance of cell-specific gene expression in disease mechanisms. The combination of MR with scRNA-seq represents a powerful approach to elucidate complex traits and may pave the way for precision medicine in CRSwNP management. Show less

Multiple sclerosis (MS) is a debilitating neurological disorder involving concurrent immune-mediated demyelination and progressive neurodegeneration. Although disease-modifying therapies (DMTs) effectively modulate peripheral immune responses and reduce relapse rates, they are ineffective at halting disease progression and promoting central nervous system (CNS) repair. This review outlines a new therapeutic approach that targets two important microRNAs: miR-219, which stimulates oligodendrogenesis and remyelination, and miR-146a, which regulates innate immune responses and neuroinflammation. We present compelling evidence showing that the dysregulation of these microRNAs establishes a cycle of inflammatory damage and regenerative failure in chronic MS lesions. Preclinical models show that supplementing with miR-219 drives oligodendrocyte precursor cell (OPC) differentiation and myelin restoration by repressing critical inhibitors, such as PDGFRα and LINGO-1. Concurrently, miR-146a modulates neuroinflammatory cascades by regulating the NF-κB pathway, promoting the polarization of microglia toward a protective M2 phenotype, and enhancing OPC maturation. Despite its therapeutic potential, there are significant challenges to its translation, including optimizing CNS-targeted delivery systems, navigating microRNA pleiotropy, and establishing biomarker-driven treatment paradigms. We propose that a dual-targeting approach leveraging advanced nanocarriers for spatiotemporal microRNA delivery represents a transformative frontier in MS therapeutics, potentially bridging the critical gap between immunomodulation and genuine neurorestoration. Show less