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PubMed2026

Investigating the relationship between Toll-like receptor activity, low-grade inflammation, cognitive deficits, and antipsychotic drug dose in schizophrenia patients: a moderation analysis.

BACKGROUND: Schizophrenia (SZ) is a debilitating psychiatric disorder where patients experience cognitive decline. Antipsychotic drugs alleviate positive symptoms but do not improve cognitive performance. We previously demonstrated that Toll-like receptors (TLRs), involved in cytokine production, can predict cognitive deficits in SZ patients. In this study, we aim to investigate the potential moderating effects of antipsychotic drugs on the associations between cytokines, TLRs, and cognition. METHODS: In total, 280 participants (201 controls and 79 cases of SZ) were recruited in Ireland. Venous blood from the participants was stimulated with TLR ligands. Levels of cytokines were measured from plasma and post-blood stimulation. The participants were administered a battery of cognitive tasks using the Cambridge Neuropsychological Test Automated Battery and Wechsler Adult Intelligence Scale-IIIR. Olanzapine equivalents were calculated using the defined daily dose method. RESULTS: The results indicate that antipsychotic drug dose does not predict TLR activity or cognition, indicating that antipsychotic drug dose does not have a direct effect on cognition or TLR activity. However, the relationship between TLR4 activity and visual learning and memory is moderated by the antipsychotic drug dose (B = -0.065; p < 0.001), where increasing doses have a decreasing impact on their relationship. CONCLUSIONS: Our data indicate that the dose of antipsychotic drugs alone cannot predict changes in cognitive performance and TLR4-activity. It also suggests that antipsychotic drug doses significantly affect TLR activity and its relationship with cognition. These effects are more pronounced on some domains than others. These findings open up new avenues for understanding the complex interplay between antipsychotic drugs, TLRs, and cognitive deficits in SZ.

Humans↗

PubMed2026

Comprehensive Landscape of Post-Translational Modification Alterations in Nephrolithiasis Revealing Activation of Multiple Cell Death Pathways.

Nephrolithiasis is a common urinary disorder characterized by high prevalence and recurrence, but the molecular mechanisms underlying calcium oxalate (CaOx)-crystal-induced renal injury remain incompletely understood. We applied integrated proteomic, phosphoproteomic, acetylomic, and lactylomic analyses to kidney tissues from a mouse model of CaOx nephrolithiasis followed by bioinformatic analysis and experimental validation. We identified 658 differentially expressed proteins, 735 differential phosphorylation sites, 335 differential acetylation sites, and 113 differential lactylation sites. Functional enrichment indicated immune activation, fibrotic remodeling, and alterations in PI3K-Akt, NOD-like receptor, p53, and Toll-like receptor signaling together with changes in fatty acid degradation, the tricarboxylic acid cycle, and glycolysis. Kinase activity prediction suggested the relative activation of multiple cyclin-dependent kinases. Proteins associated with ferroptosis, autophagy, necroptosis, and pyroptosis, including ACSL4, BNIP3, RIPK3, and GSDMD, showed coordinated abundance and modification changes. Several candidate sites, including MTOR_S1849, GCLM_K94, GCLM_S59, and GSS_K172, were also dysregulated. These data provide a multiomics resource for CaOx nephrolithiasis and identify candidate PTM events and regulatory pathways for future mechanistic validation.

Animals↗

PubMed2026

Rare genetic variant risks in patients with sepsis-associated acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a complex, heterogeneous, and deadly condition often resulting from pulmonary lesions due to sepsis, among other causes. There is a lack of targeted therapies to specifically treat the patients. Common genetic factors in the population (frequency > 1%) have been associated with ARDS susceptibility, but systematic genetic screens of the role of rare genetic variants are lacking. We used the network of known molecular interactions to identify ARDS risks from clusters of biologically related genes containing qualifying variants (QVs) with frequency < 1% likely affecting function. METHODS: We conducted whole-exome sequencing in sepsis patients from the GEN-SEP cohort (n = 822, of which 272 developed ARDS). A network-based heterogeneity clustering algorithm was used to discover significant gene clusters (p < 1 × 10–5). Gene-set enrichment analysis and logistic regression models aggregating QVs were used for cross-verification to confirm consistency and deepen understanding of the effect sizes of gene clusters. RESULTS: We identified 19 significant clusters (plowest = 3.29 × 10–10), each containing an average of 102 genes (11.6% mean similarity). QVs in nine gene clusters were associated with sepsis-associated ARDS (plowest = 1 × 10–5) but were not associated with 28-day survival. Clusters were enriched in several biological pathways, notably the Toll-like receptor cascades. CONCLUSIONS: These results support a marked genetic heterogeneity underlying ARDS susceptibility and the presence of rare risk variants involving multiple biological processes that are associated with sepsis outcomes. Particularly, they underscore the importance of rare variants in genes of the Toll-like receptor cascades in the risk for sepsis-associated ARDS.

Humans↗

PubMed2026

Probiotic supplementation increases fecal TLR4 agonists without improving disease activity in juvenile idiopathic arthritis: a randomized placebo-controlled trial.

Gut dysbiosis has been implicated in the pathogenesis of juvenile idiopathic arthritis (JIA), suggesting that microbiota-targeted interventions may influence immune signalling during early immune development. We conducted the PERMAJI multicentre randomized, double-blind, placebo-controlled trial to evaluate the effects of probiotic supplementation (VSL#3) on host-microbiota immune interactions and disease activity in children with oligoarticular or RF-negative polyarticular JIA. Participants were randomly assigned (1:1) to receive VSL#3 or placebo for 3 months in addition to standard therapy. Stool and serum samples collected at baseline and month 3 were used to assess gut microbiota composition, fecal innate immune agonists, intestinal permeability, and systemic cytokines. The primary clinical endpoint was the proportion achieving an ACR Pedi 30 response at 3 months. Forty-four children were enrolled between September 2017 and July 2022. Clinical responses did not differ between groups (ACR Pedi 30: 47% with VSL#3 vs 63% with placebo; p = 0.33), and conservative worst-case assumptions for missing data suggested lower response rates with VSL#3 (36% vs 68%; p = 0.03). Probiotic supplementation significantly increased fecal Toll-like receptor 4 (TLR4) agonist activity, whereas gut microbiota diversity, intestinal permeability, and systemic cytokine levels remained unchanged. These findings indicate that probiotic supplementation can modify microbial innate immune signalling without detectable changes in microbial community diversity and may increase exposure to pro-inflammatory microbial stimuli in early-life autoimmune disease. The results highlight the complexity of host-microbiota immune interactions and underscore the need for careful evaluation of microbiome-targeted therapies in paediatric autoimmune disorders.

Humans↗

PubMed2026

Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

UNLABELLED: The limited efficacy of immunotherapies in advanced prostate cancer stems from a tumor microenvironment (TME) in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. In this study, we characterized the immunometabolic properties of an ultrasmall prostate-specific membrane antigen-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in MYC-driven prostate cancer. As single agents, these particles suppressed lipid and steroid biosynthesis, disrupted lipid peroxidation control, and impaired nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reversed myeloid suppression and promoted CD8+ T-cell infiltration. When combined with CSF-1R inhibition and immune checkpoint blockade, the particles suppressed tumor growth, extended survival beyond 100 days, and achieved up to 50% complete remission in MYC-overexpressing models. These findings position TLR-ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven immunotherapies with broad translational potential in prostate cancer and other immunologically refractory malignancies. SIGNIFICANCE: Clinically validated, PSMA-targeted ultrasmall core-shell silica particles reprogram immunometabolic pathways via a TLR-ferroptosis axis, enabling tumor microenvironment remodeling and potentiating checkpoint blockade in prostate cancer, with translational implications for treatment-resistant disease.

Male↗

PubMed2026

Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant - alanine (A) to threonine (T) at residue 518 - in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Humans↗

PubMed2026

miRNA-mediated control of TLR-NLR interplay in the uterus: A hidden corner of recurrent pregnancy loss.

Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are crucial pattern recognition receptors that initiate inflammatory responses and immunological activation upon detecting pathogen- or damage-associated molecular patterns (PAMPs/DAMPS) in the female reproductive tract, thereby maintaining homeostasis and supporting pregnancy success. Their signaling pathways play a significant role in reproductive disorders by mediating the immune response to various pathogenic stimuli. Recurrent pregnancy loss (RPL), defined as the natural ending of two or more pregnancies before 24 weeks of gestation, approximately half of these patients remain idiopathic without precise prognostic, diagnostic, and therapeutic plans. Emerging data point that microRNAs are essential for immunological control in the female reproductive tract. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to mRNA and preventing translation into protein. miRNAs play a role in many biological processes, including the development and differentiation of trophoblasts, the activation and implantation of embryos, immune tolerance, and the receptivity of the endometrium during implantation. Given their capacity to regulate up to 30 % of the human genome, miRNAs offer a promising avenue for understanding the immunopathogenesis of pregnancy complications. Recent research has detected differential expression of specific miRNAs in reproductive system pathologies. This review focuses on microRNAs and their association with idiopathic recurrent miscarriage, a condition characterized by considerable heterogeneity. Future studies identifying the precise mechanisms linking miRNA-mediated immune dysregulation in RPL immunopathogenesis could open the way for novel personalized therapeutic and diagnostic strategies.

Female↗

PubMed2026

Coordinated inflammatory macrophage and vascular smooth muscle cell remodeling signatures in human atherosclerosis: An integrative single-cell and bulk transcriptomic analysis.

Atherosclerotic plaque progression is shaped by coordinated inflammatory and remodeling programs involving immune cells and vascular wall cells. Inflammatory macrophage activation and vascular smooth muscle cell (VSMC) phenotypic remodeling are central features of human atherosclerosis, but their transcriptomic relationships during plaque progression remain incompletely characterized. This study integrated single-cell and bulk transcriptomic datasets to examine highly inflammatory macrophage states, VSMC remodeling-related transcriptional programs, and candidate ligand-receptor expression patterns in human atherosclerotic plaques. Human atherosclerotic plaque single-cell RNA sequencing data from GSE260657 and bulk transcriptomic data from GSE28829 were analyzed. After quality control, 7628 cells were retained for single-cell analysis. Major cell types were annotated using canonical markers, followed by reclustering of macrophages and VSMC-related cells. Functional module scoring, differential expression analysis, Gene Ontology biological process enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to characterize macrophage transcriptional states. Slingshot was applied to infer VSMC pseudotime ordering. CellChat and NicheNet were used to prioritize candidate ligand-receptor expression patterns and ligand-associated VSMC target gene programs. External bulk transcriptomic analysis was performed to examine whether single-cell-derived inflammatory and remodeling signatures were represented at the tissue-transcriptome level during plaque progression. Macrophage reclustering identified a highly inflammatory macrophage state characterized by prominent inflammatory activation, cytokine-response, and stress-response features. Genes upregulated in this population were enriched in pathways related to tumor necrosis factor (TNF) response, nuclear factor kappa B signaling, leukocyte activation, cytokine signaling, lipid and atherosclerosis, toll-like receptor signaling, and inflammasome-associated inflammation. VSMC reclustering revealed contractile VSMCs, PTHLH+ synthetic VSMCs, KRT7+ VSMC-like cells, interferon-responsive VSMCs, pericyte-like mural cells, and osteogenic/modulated VSMCs. Pseudotime analysis showed a broad contractile-to-osteogenic/modulated transcriptional continuum accompanied by increased expression of remodeling-associated genes and selected inflammatory or remodeling-associated receptor genes. CellChat and NicheNet analyses prioritized candidate ligand-receptor and ligand-associated target gene expression patterns involving SPP1-CD44, TNF-TNFRSF1A, IL1B-IL1R1/IL1RAP, MIF-ACKR3, PDGFB-PDGFRB, and FN1-SDC1/ITGB1. In GSE28829, inflammatory macrophage-, osteogenic/modulated VSMC-, candidate ligand-receptor expression-, SPP1-CD44 candidate axis-, and NicheNet-prioritized target program-related signatures were more prominent in advanced plaques and were positively correlated with each other. This integrative transcriptomic analysis identified a highly inflammatory macrophage state and a VSMC remodeling continuum in human atherosclerotic plaques. Candidate ligand-receptor and ligand-associated target gene expression patterns linked inflammatory macrophage activation with osteogenic/modulated VSMC remodeling at the computational level. External bulk data further showed coordinated enrichment of inflammatory and remodeling signatures in advanced plaques. These findings provide a descriptive and hypothesis-generating transcriptomic framework for understanding inflammatory macrophage activation and VSMC remodeling in human atherosclerosis.

atherosclerosis↗

PubMed2026

A Cooperative Release of Mitochondrial DNA From Platelets and Neutrophils Drives an Interferon Signature in Systemic Sclerosis.

OBJECTIVE: Mitochondria are organelles with a hypomethylated circular genome. Mitochondrial DNA (mtDNA) in the systemic circulation has been implicated in inflammation. This study investigates the role of circulating DNA in systemic sclerosis (SSc) and the cellular mechanisms governing its release. METHODS: Total DNA was isolated from the plasma of healthy controls (HCs) and patients with SSc. Copy numbers were analyzed for mtDNA (ATP-6) and GAPDH abundance by quantitative real-time polymerase chain reaction. mtDNA was isolated from HCs and patients with SSc. Neutrophils and platelets were incubated with the plasma and mtDNA of patients with SSc, and neutrophil extracellular trap (NET) formation was assessed by SytoxGreen and immunostainings. Platelets were tested for mtDNA release propensity. DNA oxidation was evaluated by MitoSOX Red staining in vitro and 8-OHdG enzyme-linked immunosorbent assay (ELISA) of patient plasma. Plasma interferon (IFN) type 1 and chemokine (C-X-C motif) ligand 4 (CXCL4) were measured by ELISA. IFN signaling activation capacity was evaluated using THP-1 reporter cells and confirmed by a whole blood bulk RNA transcriptomic analysis. RESULTS: Median plasma mtDNA levels were 152-fold higher in patients with SSc compared with HCs, whereas nuclear DNA levels were similar. mtDNA from SSc plasma was highly oxidized. SSc-derived mtDNA efficiently promoted its own release by NETosis, most potently in the neutrophils of patients with SSc and by platelet activation. Oxidized mtDNA from SSc platelets in complex with CXCL4 further stimulated mtDNA release in both neutrophils and platelets. mtDNA plasma concentrations correlated with type I IFN concentrations in the blood of patients with SSc, and SSc blood exhibited elevated IFN-stimulated gene expression. SSc plasma-derived mtDNA-induced IFN signaling and NET formation via endosomal Toll-like receptors, cyclic GMP-AMP synthase/stimulator of IFN genes, and the JAK/STAT pathway. The type I IFN pathway further promoted NETosis and mtDNA release because IFN receptor and JAK inhibition antagonized the proNETotic effects of IFN. CONCLUSION: SSc plasma is characterized by highly abundant mtDNA, which drives feedback loops amplifying its own release from both neutrophils and platelets. Thus, mtDNA contributes to inflammation and tissue damage in SSc.

Humans↗

PubMed2026

Type I Interferon Signature is Associated With Lung Disease, Drug-Associated Immune Reactions, and Genetic Variation in Interferon-Linked Pathways in Still Disease.

OBJECTIVE: To evaluate the relationship across type I interferon (IFN-I)-stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to interleukin-1 (IL-1) and/or IL-6 inhibitors. METHODS: Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still or Still-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. RESULTS: Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs 0.1, P = 0.007) and DAIR (0.63 vs 0.17, P = 0.003) and lower IL-6 inhibitor use (0 vs 0.25, P = 0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in IFN-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization, and responses to stress. CONCLUSION: High IFN-I expression correlates with LD and DAIR in Still disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still disease with IFN-I signature.

Humans↗

PubMed2026

Integrative computational analysis combining network pharmacology, regulatory network modeling, and molecular dynamics reveals the mechanisms of Quanshen compound in ITP.

UNLABELLED: Immune thrombocytopenia (ITP) is a hemorrhagic disorder caused by immune dysfunction. Quanshen Compound (QSC) is an in-house preparation developed by the Uyghur Hospital in Hotan Prefecture. This study primarily investigates and validates the potential pharmacological basis and mechanism of action of QSC in modulating immune thrombopoiesis. Based on the multi-database screening of the QSC and the related targets of ITP, the intersection was obtained to construct a protein-protein interaction (PPI) network and screen the core targets; the intersection targets were analyzed for gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using R packages; a component-target-pathway network was constructed to screen the key active components and their mechanisms of action. At the same time, the TF-mRNA-miRNA regulatory network of the core targets was constructed, and chromosome localization and subcellular localization analysis were performed; further, the binding stability of key components and core targets was verified through molecular docking and molecular dynamics simulation. A total of 227 potential target sites were screened out, among which TNF, IL6, AKT1, TP53 and IL1B were the core targets. The enrichment results indicated that these intersecting target sites mainly participated in inflammatory responses, immune regulation and hemostasis-related biological processes, and were significantly enriched in the PI3K-Akt signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation and PD-1/PD-L1 signaling pathway. The core target TF-mRNA-miRNA regulatory network contained 184 nodes and 200 edges, suggesting that the core targets were subject to multi-level regulation. Molecular docking results showed that the main active components had good binding activity with the core targets, and molecular dynamics simulation further verified the stability of the complex. QSC may improve ITP through a multi-component, multi-target, and multi-pathway synergistic mechanism involving key targets such as TNF, IL6, AKT1, TP53, and IL1B, as well as the PI3K-Akt signaling pathway. These findings provide new insights into the potential therapeutic mechanisms of QSC against ITP and warrant further experimental validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00718-0.

Immune thrombocytopenia↗

PubMed2026

Liver transcriptome analysis revealed multiple immune processes and lipid metabolism pathways involved in the defense response of the turbot (Scophthalmus maximus) against Aeromonas salmonicida.

Aeromonas salmonicida is a significant pathogen causing notable economic losses in Scophthalmus maximus aquaculture. This study utilized Illumina sequencing technology to examine the transcriptional response characteristics of S. maximus liver at 24 h following A. salmonicida infection. A total of 2363 differentially expressed genes (DEGs) were identified when compared to the negative control group. The immunity-related Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, as well as metabolism-related PPAR signaling pathway and insulin signaling pathway, were notably enriched. Significant differences exist in the expression of key genes within the PPAR pathway, particularly cd36, acsl4a, pparαa, and plin2, all of which mediate the interaction between lipid metabolism and the immune response. These results offer valuable insights into the immunometabolic regulatory mechanism of S. maximus response to A. salmonicida infection.

Animals↗

PubMed2026

Transcriptomic insights into the coordinated regulation of signaling, apoptosis, immunity, and metabolism during Sinonovacula constricta larval metamorphosis.

Metamorphosis is a critical ontogenetic transition for marine bivalves, marking the shift from planktonic to benthic lifestyles, where successful transformation dictates survival. The razor clam Sinonovacula constricta is economically important; however, low larval metamorphosis rates remain a major bottleneck in seedling production. To elucidate the mechanisms governing this process, we performed a comparative transcriptome analysis of S. constricta larvae at pre- and post-metamorphosis stages using Illumina sequencing. A total of 3701 differentially expressed genes (DEGs) were identified, including 3254 up-regulated and 447 down-regulated genes. Functional annotation of the respective top 20 significantly up-regulated and down-regulated DEGs indicated their potential pivotal roles in signal transduction (e.g., up-regulated: CAV1, CHRNA2; down-regulated: APP, NOTCH1), cellular proliferation and differentiation (e.g., up-regulated: TUBA, EGF1; down-regulated: KIF23, TTC25), transcriptional and epigenetic regulation (e.g., up-regulated: NFIL3; down-regulated: OVO, HMX1), substance transport (e.g., up-regulated: LRP2, LRP1B; down-regulated: SLC51A, Slc33a1), substance metabolism (e.g., up-regulated: CPK3, CYP26A1; down-regulated: RDMT1, ADAC), immunomodulation (e.g., up-regulated: CPN2, CRISP2), and protein homeostasis (e.g., up-regulated: HSP27, NAS-27). Functional enrichment analysis further revealed that DEGs were significantly enriched in pathways related to signal transduction and developmental regulation (e.g., Ras, TNF), cell death and homeostasis (e.g., apoptosis), immune responses (e.g., Toll-like receptor), energy metabolism (e.g., lipid), cardiovascular related (e.g., Fluid shear stress), cell junction and architecture (e.g., Tight junction), and infectious disease (e.g., measles). These results suggest a synergistic interplay between signaling, apoptosis, immunity, and metabolism during S. constricta metamorphosis. This study advances our understanding of marine bivalve metamorphosis and offers candidate genes for further mechanistic studies.

Animals↗

PubMed2025

Network pharmacology combined with ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry method to explore the mechanism of Shizhi Fang in treating uric acid nephropathy mice.

OBJECTIVE: To elucidate the potential mechanisms of Shizhi Fang (SZF, ) in the treatment of uric acid nephropathy (UAN). METHODS: SZF-containing serum was prepared from six male rats and analyzed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Network pharmacology was employed was integrated with UPLC-Q-TOF-MS to predict SZF targets for the treatment of UAN, which were subsequently validated through in vivo experiments. Sixty male Bagg Albino Laboratory-Bred Mouse, substrain c mice were randomly allocated into six groups: Normal, Model, Febuxostat, and three SZF dosage groups. Except for the Normal group, all mice were administered potassium oxonate (250 mg/kg) and adenine (50 mg/kg) via gavage to induce UAN. Four hours post-administration, the Febuxostat group received Febuxostat (6 mg/kg), while the SZF groups received low (0.234 g/kg), medium (0.468 g/kg), or high (0.936 g/kg) doses of SZF. The Normal and Model groups were given an equivalent volume of saline. All treatments were conducted over a period of four weeks. Urine and blood samples were collected for biochemical analysis, and kidney tissues were subjected to histopathological examination and Western blot analysis. RESULTS: Nine prototype compounds and 30 metabolites were identified in SZF serum. Network pharmacology analysis revealed 195 drug targets and 1608 disease targets, with 76 common drug-disease targets, including signal transducer and activator of transcription 3 (STAT3), proto-oncogene tyrosine-protein kinase Src (SRC), matrix metalloproteinase-9 (MMP9), Caspase 3, and toll-like receptor 4 (TLR4) as key targets. Gene Ontology analysis identified 325 biological processes, 48 cellular components, and 72 molecular functions, while Kyoto Encyclopedia of Genes and Genomes analysis identified 113 pathways. Molecular docking demonstrated strong binding affinities between active compounds and their targets. In the animal study, SZF treatment alleviated pathological damage and improved serum and urine biochemical markers compared to the Model group (P < 0.05, P < 0.01, P < 0.001). Western blot analysis showed a significant reduction in phosphorylated-STAT3, phosphorylated-SRC, MMP9, TLR4, and Caspase3 expression in renal tissues of SZF-treated mice (P < 0.001). CONCLUSION: SZF may exert therapeutic effects on UAN through multiple targets and pathways.

Animals↗

PubMed2026

Cytokines and Inflammatory Gene Polymorphisms Associated With Nosocomial Pulmonary Infection After Spontaneous Intracerebral Hemorrhage.

Nosocomial pulmonary infection is a frequent complication after spontaneous intracerebral hemorrhage and may worsen neurological recovery, prolong hospitalization, and increase clinical burden. This retrospective clinical-laboratory study presents a reproducible workflow for evaluating inflammatory biomarker and host immune-genetic profiles associated with nosocomial pulmonary infection after primary spontaneous intracerebral hemorrhage. Patients are classified according to whether nosocomial pulmonary infection occurs after admission. Peripheral venous blood is collected in the early post-admission period under standardized pre-analytical conditions. Serum is separated, aliquoted, and stored for enzyme-linked immunosorbent assay measurement of IL-1β, IL-6, IL-10, IL-17, IFN-γ, TNF-α, TLR2, TLR4, and TLR9. In parallel, genomic DNA is extracted from anticoagulated whole blood and used for polymerase chain reaction-restriction fragment length polymorphism genotyping of selected cytokine- and Toll-like receptor-related loci. The workflow also includes quality-control procedures for sample handling, duplicate ELISA measurements, DNA purity assessment, genotype calling, and repeat genotyping. Statistical analysis includes between-group comparison of clinical characteristics and biomarker levels, Hardy-Weinberg equilibrium testing, logistic regression analysis for genotype and allele associations, adjustment for relevant clinical covariates, and false-discovery-rate correction for multiple genetic comparisons. This combined clinical, inflammatory, and immune-genetic workflow may help characterize infection-risk profiles after spontaneous intracerebral hemorrhage, although prospective multicenter validation is still required before routine clinical application.

Humans↗

PubMed2026

Exploring the proteomic landscape of THP-1 monocytes through two-challenge LPS induction.

Proteome remodelling is central to the regulation of innate immune activation, yet the temporal organisation of protein networks engaged during repeated lipopolysaccharide (LPS) stimulation remains incompletely defined. In the present study, label-free quantitative mass spectrometry-based proteomics was used to characterise protein abundance changes in THP-1 monocytes at early (30 min) and later (2 h) time points following a second LPS challenge. This analysis was complemented by an independent co-immunoprecipitation proteomics experiment designed to identify candidate proteins associated with the regulatory pseudo-kinase IRAK3 during early TLR4 signalling. At 30 min, differentially abundant proteins were enriched in pathways associated with pattern-recognition receptor signalling, NF-κB activity, RNA processing, phosphorylation, and ribonucleoprotein complex organisation. By 2 h, the proteomic response broadened to include oxidative phosphorylation, antigen processing and presentation, vesicle-mediated transport, protein folding, and cytokine-regulatory pathways. These findings indicate that repeated LPS stimulation is accompanied by progressive remodelling of inflammatory, metabolic, translational, and proteostatic programmes rather than major changes in protein identity. Co-immunoprecipitation identified established TLR/IRAK3-associated components together with candidate IRAK3-associated proteins linked to RNA regulation, kinase signalling, ubiquitin-mediated processes, redox control, cytoskeletal remodelling, and damage-associated molecular pattern responses. Collectively, these findings define a temporal framework of proteomic adaptation during repeated inflammatory stimulation and expand the range of candidate proteins potentially contributing to IRAK3-centred regulation of innate immune signalling.

Humans↗

PubMed2026

Prophylactic Inhaled Pattern Recognition Receptor Agonists Reprogram Lung Epithelial Response and Prevent Type 2 Allergic Inflammation.

Prophylactic inhalation of the synergistic agents ODN M362 and Pam2CSK4 ("Pam2ODN") protects mice against allergic lung disease, including allergic inflammation caused by house dust mite (HDM). By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects interactions among lung epithelial cells, dendritic cells, and T cells to prevent eosinophilic lung inflammation remains unclear. In the present study, we show that a single inhaled dose of Pam2ODN before HDM sensitization reduces airway Th2 polarization without affecting Th1 or Treg responses. Furthermore, Pam2ODN pretreatment inhibits the recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional Type 2 dendritic cells (DC2s), while preventing the HDM-induced decrease in conventional Type 1 dendritic cells (DC1s). Bulk RNA-seq of the whole lung reveals that Pam2ODN pretreatment restricts the expression of proinflammatory transcripts induced by HDM sensitization. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells, where proinflammatory transcripts, pathways, and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced Th2-promoting cytokines and DCs while maintaining the population of protective DC1s. These findings suggest a strategy to mitigate chronic allergic lung diseases.

Animals↗

PubMed2026

Heightened frequency of innate immunity risk alleles in south Indian diabetics with urinary tract infections.

Urinary Tract Infections are an emerging public health concern among individuals with diabetes mellitus, particularly in South Asia where high disease burden, genetic diversity and increasing drug resistance contribute to the progressive increase in burden. While metabolic and clinical risk factors are well studied, the role of host innate immune genetic variations in shaping UTI susceptibility among diabetics remains poorly understood. This case-control study evaluated functional polymorphisms in key innate immunity genes, TLR4 (rs4986790, rs4986791), MBL2 (rs1800450) and LTA (rs909253), in 70 T2D patients with UTI and 70 T2D patients without UTI. Genotyping was performed using 5'-hydrolysis probe assay. Across all the four SNPs, the risk allele consistently showed a higher frequency among T2D patients with UTI, indicating a directional trend suggestive of cumulative susceptibility. Also, a strong and significant protective association was observed for the LTA rs909253 'G' allele, which was less frequent in cases than controls. This low-inflammatory 'AA' genotype was also markedly enriched among rUTI cases compared to controls. Clinically, 34.3% of cases experienced rUTIs. This observed directional increase of risk alleles across all four innate immunity SNPs, along with the protective role of LTA rs909253 'G' allele, highlights cumulative host genetic modulation of UTI risk in T2D and supports translational use of genetic profiling in infection risk prediction.

Humans↗