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PubMed2026

Does high fructose consumption trigger microglia activation and neuroinflammation? A systematic review.

This systematic review evaluated the effects of fructose intake on neuroinflammatory markers in rodent models. The search terms Fructose AND neuroinflammation OR Neurodegeneration OR chemokines OR interleukins OR microglia OR behaviour OR memory OR cognition were used in Google Scholar, Scopus and Web of Science. Thirteen animal studies investigating fructose-induced neuroinflammation that matched the eligibility criteria were included in the study. Across the studies, 16 inflammatory markers were identified and significantly altered following exposure to fructose. The findings consistently demonstrated elevated expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-1β, following fructose administration. Fructose consumption also dysregulated MCP-1, fractalkine, and CX3CR1 levels, thereby promoting inflammatory signalling and microglial activation. Furthermore, fructose exposure significantly increased IBA-1 and CD11b, indicating sustained neuroimmune activation. Alterations in important inflammatory pathways involving TLR4, NLRP3, NF-κB, MyD88, iNOS, and cyclooxygenases (COX-1 and COX-2) were also observed. In contrast, expression of the anti-inflammatory regulator peroxisome proliferator-activated receptor gamma (PPARγ) was reduced after fructose treatment. Overall, the findings suggest that chronic fructose consumption induces neuroinflammation through multiple inflammatory and immune-related mechanisms in the brain. These effects appear to be dose- and duration-dependent and may contribute significantly to neurodegeneration and cognitive impairment.

Microglia↗

PubMed2026

Synovial short-lived plasma cells mediate adalimumab resistance in rheumatoid arthritis via MIF-CD74 axis-driven, partially TNF-α-independent inflammation.

OBJECTIVE: Synovial plasma cell infiltration predicts inadequate response to adalimumab in patients with rheumatoid arthritis (RA), yet the cellular and molecular mechanisms underlying this association remain unclear. This study aimed to dissect the functional heterogeneity of synovial plasma cells between adalimumab responders and non-responders at single-cell resolution, and to identify the molecular pathways driving treatment resistance. METHODS: This study was based on a prospective clinical cohort of 101 RA patients receiving adalimumab, from which synovial tissues of 8 patients (4 ACR20 responders and 4 non-responders) were profiled by 10x Genomics single-cell RNA sequencing (66,539 high-quality cells). A systematic ligand-receptor screening was performed to identify candidate signaling axes. Core findings were validated at four levels: an independent single-cell validation cohort (n = 4), external bulk RNA-seq cohorts (GSE15602, GSE47726), multiplex immunofluorescence on synovial tissues (n = 9 per group), and in vitro functional experiments using patient-derived peripheral blood monocyte-derived macrophages stimulated with recombinant human MIF under pharmacological intervention with adalimumab, the MIF inhibitor ISO-1, and an anti-CD74 neutralizing antibody. RESULTS: Plasma cells were significantly enriched in non-responder synovium, with a heterogeneous pattern characterized by quantitative accumulation of long-lived plasma cells (LLPCs) and functional dominance of short-lived plasma cells (SLPCs): SLPCs contributed 58.15% of total ribosomal module activity and preferentially overexpressed MIF. Systematic screening of 145 candidate ligand-receptor pairs identified MIF-CD74 as the only axis satisfying all four independent evidence layers. Tissue-level immunofluorescence confirmed that approximately 95% of synovial CD138+ plasma cells in non-responders co-expressed MIF, compared with approximately 45% in responders. In vitro, rh-MIF upregulated macrophage activation markers (CD74, CD80, CD86, HLA-DR) and induced IL-6 and TNF-α secretion. Adalimumab neutralized supernatant TNF-α but failed to suppress MIF-driven IL-6 and IL-1β activation, whereas ISO-1 and anti-CD74 effectively blocked MIF-induced effects at all levels examined. These findings were replicated in patient-derived PBMC macrophages. CONCLUSION: In adalimumab-resistant RA, a functionally active SLPC subset drives partially TNF-α-independent macrophage inflammation through the MIF-CD74 axis, representing a resistance pathway not fully addressed by anti-TNF therapy. Targeting MIF or CD74 blocked this axis in vitro, supporting MIF-CD74-directed precision intervention.

Adalimumab↗

PubMed2025

Elucidation of the immunotoxicity of PEDOT: PSS on RAW264.7 macrophages by oxidative stress, inflammatory response, and NF-κB pathway activation.

Poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT: PSS) nanoparticles, widely used conductive polymers, pose environmental and health risks due to their nanoscale dispersion. However, the characteristics of PEDOT: PSS in aquatic systems and the underlying mechanisms of its toxicity in animal and cell models remain poorly understood. This study aimed to investigate the toxicological effects of PEDOT: PSS nanoparticles on macrophages, with a focus on RAW 264.7 cells. After an acute exposure to PEDOT: PSS nanoparticles at different concentrations (5, 10, 20 μg/mL), we observed significant impairments in cell viability, proliferation, migration, adhesion, and phagocytosis, as well as morphological alterations. Concurrently, there was a marked upregulation of inflammatory markers, including reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), indicating the induction of oxidative stress and inflammation. Mechanistically, PEDOT: PSS nanoparticles activated the nuclear factor kappa B (NF-κB) signaling pathway, a key regulator of inflammatory responses, suggesting that they may mediate inflammatory responses and cell damage via activation of the NF-κB signaling pathway. These findings reveal the toxic mechanism of PEDOT: PSS nanoparticles in macrophages and provide new insights into their biological safety implications.

Animals↗

PubMed2025

Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.

Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.

Blood-Brain Barrier↗

PubMed2026

Peripheral immune markers and choroid plexus volumes as predictors of change in depressive symptoms: Insights from the EMBARC study.

Changes in choroid plexus (ChP) volume and peripheral inflammation have been associated with Major Depressive Disorder (MDD), yet their individual and combined impact on depressive symptoms is unclear. This study investigated whether baseline immune markers and ChP volumes predict changes in depressive symptoms during the 8-week treatment period among Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study participants who received either sertraline or placebo. Adults (n = 222) with MDD with peripheral blood samples were included. Circulating chemokines and cytokines were examined using a 40-plex assay. Depressive symptoms were assessed over 8 weeks using the Hamilton Depression Rating Scale (HAMD-17). Principal component analysis (PCA) was used for dimension reduction. Mixed-effects models were used to examine whether immune profiles and ChP volumes, and their interaction predicted HAMD-17, adjusting for demographic/clinical covariates and baseline depression severity. PCA identified three immune profiles. One profile, characterized by higher levels of cytokines and chemokines including IL-6, TNF-α, and IL-1β, was associated with greater depression severity, higher BMI, age, and CRP at baseline. Higher levels of these immune markers were associated with less improvement in depressive symptoms at 8 weeks (estimate = 1.211, p = 0.018) in models adjusting for right and left ChP volume (right ChP model: estimate = 1.034, p = 0.005; left ChP model: estimate = 0.993, p = 0.007). Interactions between immune markers and ChP volumes were not significant. Future investigations are warranted to examine the relationships between immune markers and ChP volume beyond structural changes in the context of depression symptoms.

Adult↗

PubMed2026

Phytolacca acinosa Roxb. induces intestinal toxicity through the histamine-MLCK-tight junction axis: Integrated evidence from proteomics, metabolomics, intestinal organoids and epithelial barrier validation.

Phytolacca acinosa Roxb. (PR) is a saponin-rich medicinal plant associated with gastrointestinal toxicity, but the mechanisms underlying PR-induced intestinal barrier injury remain unclear. In this study, raw PR extract was analytically characterized by UPLC-ZenoTOF-MS/MS, confirming triterpenoid saponins as the predominant constituents. C57BL/6 J mice were orally exposed to characterized PR extract (1.20 or 12.0 g/kg for 5 h), and Caco-2 cells and mouse intestinal organoids were used to assess epithelial toxicity and barrier disruption. Histopathology, ELISA, FITC-dextran permeability assays, immunofluorescence, CCK-8, LDH release, western blotting, DIA-based proteomics and untargeted metabolomics were integrated to define toxicological mechanisms. PR induced dose-dependent intestinal inflammation and barrier dysfunction, with the ileum as the most sensitive target. PR increased serum DAO and D-lactate and intestinal TNF-α and IL-1β, disrupted organoid morphology, enhanced epithelial permeability, and reduced ZO-1 expression. Proteomics revealed changes in inflammatory, lipid-metabolic, cytoskeletal and tight-junction pathways, including upregulation of MLCK3 and phospholipase-related proteins and downregulation of ZO-1 and ZO-2. Metabolomics identified histidine metabolism disturbance and histamine accumulation. Integrated multi-omics and pharmacological validation indicated that histamine activated the PLC/IP₃/Ca²⁺/CaM/MLCK cascade, promoting MLC phosphorylation, tight-junction disassembly and epithelial leakiness. MLCK inhibition partially restored ZO-1/ZO-2 expression and attenuated PR-induced epithelial injury. These findings identify the histamine-MLCK-tight junction axis as a key mechanism of PR-induced intestinal toxicity and support hazard identification of saponin-rich PR exposure.

Animals↗

PubMed2026

Mycobacterium tuberculosis MEM39 (Rv1977) hijacks host aldolase A (ALDOA) to subvert immunometabolism to facilitate bacterial intracellular survival.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading cause of infectious disease-related death. As a major intracellular pathogen, Mtb can escape clearance by the immune system, but the underlying molecular mechanisms remain incompletely elucidated. Specific genomic regions of deletion (RD)-encoded proteins in virulent Mtb H37Rv have been implicated in modulating pathogenicity and immunity. Here, we report a novel RD15-encoding protein, Rv1977 (a mycobacterial cell wall protein with a size of 39 kDa, named MEM39), which facilitates Mtb survival in macrophages. The survival of the Mtb H37Rv MEM39-deficient strain is reduced in both macrophage and murine infection models. Furthermore, the mycobacterial MEM39 protein binds fructose-diphosphate aldolase A (ALDOA), a key enzyme of glycolysis, thereby impairing ALDOA enzyme activity, disrupting macrophage metabolite flux, and reducing lactate production. The MEM39-ALDOA interaction also suppresses lysosomal acidification; reduces NLRP3 inflammasome activation and the production of proinflammatory cytokines (TNF-α, IL-6 and IL-1β); and thereby promotes bacterial survival within macrophages. Disruption of the interaction between MEM39-ALDOA and a cell-penetrating synthetic peptide (VLARYASICQ) significantly suppressed Mtb survival by restoring lactate production, lysosome acidification and proinflammatory cytokine production in both macrophage and mouse infection models. These findings revealed that mycobacterial MEM39 negatively regulates host immune defense through reprogramming ALDOA-mediated glycolysis in macrophages, thereby forming a "mycobacterial MEM39 virulence factor-glycolysis metabolism-immunity" regulatory axis. Targeting MEM39 or the MEM39-ALDOA interaction interface holds promise as a new therapeutic strategy against tuberculosis.

Mycobacterium tuberculosis↗

PubMed2026

Functional chimeric mRNAs encode proteins in mammalian immunity.

Individual mammalian mRNAs and proteins are typically believed to originate from single genomic loci, with isoform diversity arising through cis-splicing of pre-mRNA. Whether mRNA from distant genes can undergo trans-splicing to generate functionally relevant chimeric transcripts has remained unclear. Here we develop a pipeline combining long-read direct RNA sequencing with non-targeted and targeted validation to identify chimeric transcripts in macrophages. Chromatin conformation capture studies reveal that inflammation induces interchromosomal DNA interactions, positioning parent genes proximally to facilitate the formation of chimeric mRNA. Notably, we identify a protein-coding chimeric mRNA representing a fusion between the pore-forming protein gasdermin D (GSDMD)1,2 and a C-terminal domain translated out of frame from Tmem106a (Gsdmd-Tmem106a) in mice. We show that inflammasome priming upregulates Gsdmd-Tmem106a, with the protein localizing to the plasma membrane. After activation of the inflammasome, GSDMD-TMEM106A directly interacts with canonical GSDMD N termini to accelerate and enhance pore formation and IL-1β release. Finally, we show that GSDMD-TMEM106A balances host defence and immunopathology in vivo: its loss protects against lethal sepsis but compromises antibacterial defence, whereas overexpression enhances host protection while increasing sepsis lethality. We establish that protein-coding chimeric mRNAs formed by regulated transcript fusion events are operative during inflammation and immunity.

Journal Article↗

PubMed2025

ANXA3 hypomethylation as a prognostic biomarker in hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a poor prognosis. This research aimed to characterize the expression pattern and clinical value of Annexin A3 (ANXA3) in HBV-ACLF patients. METHODS: First of all, ACLF-related datasets were downloaded from the Gene Expression Omnibus (GEO) database to carry out bioinformatics analyses. RT-qPCR, ELISA, and Methylight were used to measure ANXA3 gene expression and promoter methylation levels. A validation cohort was leveraged to further validate the results. RESULTS: Transcriptome analysis showed that ANXA3 was among the most differentially expressed genes when comparing dead patients with HBV-ACLF to those with survivors. The mRNA and serum levels of ANXA3 were elevated, and methylation levels were decreased in HBV-ACLF patients. The PMR value of ANXA3 in patients with HBV-ACLF was negatively correlated with inflammation-related cytokines IL-6, TNF-α, and IL-1β, as well as quantitative clinical parameters AST, TBIL, PT, INR, NEUT%, and MELD score, and positively correlated with PTA (all p < 0.05). In HBV-ACLF patients, ANXA3 was considered to be an independent influence factor for the 90-day mortality. It was also found that ANXA3, especially hypomethylation, was associated with 28- and 90-day overall survival in patients with HBV-ACLF based on receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and Kaplan-Meier curves. CONCLUSIONS: ANXA3 hypomethylation has a prominent predictive value for short-term mortality in patients with HBV-ACLF and may serve as a promising biomarker of HBV-ACLF prognosis.

Humans↗

PubMed2025

Dapagliflozin reduces epicardial adipose tissue in patients with heart failure and type 2 diabetes.

BACKGROUND: Epicardial adipose tissue (EAT) has a contributory role in the progression of heart failure. We tested whether dapagliflozin reduces EAT in adults with type 2 diabetes (T2D) and heart failure and explored links with systemic inflammation and cardiac structure. METHODS: This analysis is based on pooled data from two phase 2, single-centre, double-blind, placebo-controlled randomised trials (REFORM and DAPA-LVH) conducted in Scotland. Exactly 122 participants with T2D and stage B or C heart failure were randomised to dapagliflozin 10 mg once daily or placebo for 12 months. Cardiac magnetic resonance imaging (CMR) was used to assess EAT. At baseline and follow-up, the inflammatory markers TNF, IL-1, IL-6, IL-10, and CRP were measured. RESULTS: At baseline, obesity was common (75% with BMI ≥30 kg/m2) and heart-failure phenotypes were balanced (HFpEF 51%, HFrEF 49%). After 12 months, dapagliflozin significantly reduced EAT independently of changes in BMI (-1.16 ± 0.18 vs. +0.36 ± 0.19 cm2, p < 0.001), BMI (-1.17 ± 0.16 vs. -0.18 ± 0.17 kg/m2, p < 0.001), and left ventricular mass (-3.53 ± 1.77 vs. +1.57 ± 1.83 g, p = 0.048) compared with placebo. CONCLUSION: Dapagliflozin shrinks EAT and LV mass independently of BMI in T2D patients with stage B/C heart failure, supporting EAT as a modifiable target of SGLT2 inhibition. The absence of parallel changes in systemic inflammation suggests primarily local mechanisms.

Humans↗

PubMed2026

Inflammatory Cytokines Impair Glucagon Expression and Secretion in Pancreatic α-Cells.

AIMS: Insulin resistance and obesity-associated inflammation are key drivers in the pathogenesis of Type 2 diabetes mellitus (T2DM). Whilst inflammatory cytokines are well known to impair β-cell function, their impact on pancreatic α-cells and glucagon (GCG) regulation remains poorly understood. In this study, we investigated the effects of the pro-inflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ on GCG expression and secretion. MATERIALS AND METHODS: The viability and endocrine function of α-cell line αTC1 and isolated islets were investigated by WST-1 assay, LDH assay, qRT-PCR, Western blot analysis and ELISA. The transcriptional activity of the GCG promoter was analysed by reporter gene assays. The cellular composition of isolated islets was assessed by immunohistochemistry. RESULTS: We found that exposure of the α-cell line αTC1 to a mix of these cytokines activates cellular stress responses characterised by induction of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Moreover, cytokine treatment markedly reduced GCG gene expression and secretion through repression of GCG promoter activity. Mechanistically, this was associated with a disrupted transcriptional network. These findings were confirmed in isolated mouse islets, where cytokine exposure significantly reduced GCG expression and secretion in islets of both male and female donors. CONCLUSIONS: Taken together, these findings indicate that inflammatory cytokines are potent modulators of α-cell function as well as GCG secretion and provide novel insights into inflammation-driven dysregulation of the endocrine function of pancreatic islets.

Glucagon-Secreting Cells↗

PubMed2026

Effects of aerobic exercise on inflammation and gut microbiota in obese mice: a metagenomic and metabolomic analysis.

BACKGROUND: Aerobic exercise can ameliorate insulin resistance (IR). However, the mechanism by which aerobic exercise regulates the gut microbiome to ameliorate IR and obesity remains unexplored. METHODS: Obese models were established by feeding C57BL/6 male mice a high-fat diet. A total of 26 mice were randomly divided into control group (group A, N = 8) and high-fat diet group (HFD group, N = 18). Successfully modeled mice were further assigned to model group (group B, N = 8) and exercise group (group C, N = 8). Group C underwent a 6-week treadmill exercise program (12 m/min, 60 min per day, 5 days per week). After intervention, colon tissue morphology was observed through hematoxylin-eosin staining, serum lipids and inflammatory indicators levels were detected by ELISA. The changes in the intestinal microbiota of the mice were also examined using metagenomic sequencing and UPLC-MS non-targeted metabolomics. RESULTS: Compared with the group A, the body weight, TC, TG, LDL-C, blood glucose, insulin, and IR in the group B significantly increased (P < 0.01), while the levels of pro-inflammatory cytokines TXNIP, TNF-α, NLRP3, IL-1β, and IL-18 significantly increased (P < 0.05 or P < 0.01). Compared with the group B, aerobic exercise reduced the body weight, TC, blood glucose, insulin, IR, TXNIP, TNF-α and other indicators in obese mice (P < 0.05 or P < 0.01). Moreover, aerobic exercise can regulate the imbalance of the intestinal flora in obese mice and ameliorate the disorder of metabolites. The metabolic pathways including arachidonic acid metabolism and histidine metabolism showed the most significant differences after the intervention of aerobic exercise. CONCLUSIONS: In conclusion, aerobic exercise can ameliorate glucose and lipid metabolism, IR, inflammatory response, and regulate the intestinal microecology and metabolic disorders in obese mice. The mechanism may be closely related to enhancing the diversity of intestinal flora, regulating the metabolism of arachidonic acid and histidine.

Animals↗

PubMed2026

Rumen microbiota-associated stress alleviation by creatine pyruvate in newly received cattle: a multi-omics study.

BACKGROUND: Stress experienced by newly received cattle is a significant challenge in the beef industry, frequently resulting in weakened immune responses and impaired growth. The rumen microbiota is essential to host health, and its imbalance can exacerbate stress. This study investigates the mechanisms by which creatine pyruvate (CrPyr) mitigates stress in newly received cattle through multi-omics approaches, including metagenomics, metabolomics, in vitro and in vivo experiments, and rumen microbiota transplantation (RMT) in mice. RESULTS: Our results revealed that CrPyr significantly reduces stress-related hormones (cortisol and adrenocorticotropic hormone) and inflammatory markers (IL-6, IL-1β, and TNF-α), and enhanced antioxidant capacity (SOD: 57.38 versus 46.93 U/mL, P < 0.05; GSH-Px: 305.87 versus 217.07 U/mL, P < 0.05; T-AOC: 9.62 versus 7.66 U/mL, P < 0.05). Metagenomic analysis demonstrated that CrPyr increased Prevotella abundance, a key rumen bacterium involved in volatile fatty acid (VFA) production, and enriches metabolic pathways associated with energy metabolism (ATP synthesis, and pyruvate metabolism) and antioxidant defense (glutathione metabolism, FC = 1.08, P < 0.05). In vitro and in vivo experiments, as well as RMT studies in mice, further validate these findings, demonstrating that CrPyr promote VFA synthesis and increased ATP production through the electron transport phosphorylation pathway. CONCLUSIONS: CrPyr modulates the abundance of ruminal Prevotella in transport-stressed cattle to enhance glutathione and VFA metabolism and to accelerate ATP and nucleotide synthesis, thereby alleviating stress in newly received cattle. This multimodal approach established CrPyr as an effective nutritional intervention that improves rumen function and increases livestock productivity. Video Abstract.

Animals↗

PubMed2025

Effect of acupuncture on brain microenvironment in rats with post-stroke limb spasticity based on single-cell transcriptome sequencing technology.

OBJECTIVE: To investigate the possible mechanisms by which acupuncture improves post-stroke limb spasticity using single-cell sequencing technology. METHODS: Thirty-two rats were randomly assigned to four groups: Control, Sham, Model, and Acupuncture. The middle cerebral artery occlusion (MCAO) model was established, and the acupuncture groups received acupuncture treatment. After treatment, brain morphological changes and the degree of neurological impairment were assessed. The effect of acupuncture on the proportion of brain cell types in the ischemic penumbra of MCAO rats was analyzed using single-cell transcriptomics, and the expression and enrichment of differentially expressed genes were examined. Finally, selected differential genes were validated by Western blot and quantitative real-time polymerase chain reaction. RESULTS: Triphenyltetrazolium chloride staining showed that the infarct area in MCAO rats was significantly reduced after acupuncture. Garcia scoring, hematoxylin-eosin staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling demonstrated that acupuncture reduced brain damage. Enzyme-linked immunosorbent assay results showed that acupuncture significantly decreased serum inflammatory factors, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Single-cell transcriptome analysis revealed marked changes in cell type proportions between the Acupuncture and Model groups. A total of 207 differential genes were identified, including 157 upregulated and 50 downregulated genes. Analysis of macrophage-specific differential genes in the ischemic penumbra showed enrichment in Gene Ontology terms such as Ras protein signal transduction and regulation of GTPase activity, and Kyoto Encyclopedia of Genes and Genomes pathways including lysosome, axon guidance, and mitogen-activated protein kinase signaling. S100a8 and leukocyte specific transcript 1 (LST1) were identified as key differential genes. CONCLUSION: These findings suggest that the key differential genes S100a8 and LST1 may alleviate post-stroke limb spasticity by regulating the inflammatory response in the ischemic penumbra.

Animals↗

PubMed2026

Suggestive genome-wide associations with inflammatory biomarkers in an admixed population, including a missense variant in the OR6K6 olfactory receptor gene associated with MCP-1.

BACKGROUND: Chronic low-grade inflammation drives cardiometabolic diseases and has a strong genetic basis. Most genome-wide association studies (GWAS) have focused on European populations, limiting knowledge of the genetic influences on inflammation in admixed populations such as those in Brazil. METHODS: This study is part of the cross-sectional ISA Capital Health Survey. It uses data from the 2015 ISA Nutrition cohort, which measured biochemical, genetic, anthropometric, and lifestyle factors in a probabilistic sample of São Paulo residents. Genomic DNA was extracted from 841 individuals. Genotyping was performed using the Axiom 2.0 Precision Medicine Research Array. After quality control and missing data exclusion, 244,338 SNPs from 638 individuals remained for GWAS-based association analysis with eight inflammatory biomarkers. Models were adjusted for sex, age, age2, overweight, and the first two principal components of ancestry. RESULTS: Most participants were male (53%) and not overweight (55%). The median age was 49, and 38% were older adults. In the genome-wide analysis of TNF-α, IL-10, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and adiponectin, 12 SNPs were significantly associated, most of which were intronic. Notably, one signal mapped to the missense variant rs16841009 in the olfactory receptor gene OR6K6. This variant was associated with MCP-1, suggesting a possible involvement in inflammatory responses. CONCLUSIONS: We identified new SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population, including a missense variant in an olfactory receptor gene linked to MCP-1. This association may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.

Humans↗

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

Placenta-derived Exosomes Mitigate Hypoxia-Induced Trophoblast Apoptosis and Inflammatory Progression via SASH1.

SASH1 is a signal adaptor protein involved in cell growth, apoptosis, and immune regulation, and has been increasingly studied in tumor and immune cells. Emerging evidence suggests that SASH1 plays an important role in inflammatory responses and cellular homeostasis, processes that are closely associated with the development of PE. This study aimed to determine whether SASH1 contributes to trophoblast apoptosis and inflammatory responses in PE and whether P-EXOS exerts protective effects through SASH1 regulation. In this study, three PE-related transcriptomic datasets (GSE75010, GSE10588, and GSE60438) were analyzed to identify shared differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Machine learning algorithms were further applied to screen key candidate genes, and single-cell RNA sequencing data were used to characterize cellular heterogeneity in placental tissue and to determine cell type-specific expression patterns. SASH1 was identified as a consensus candidate gene and was significantly upregulated in trophoblast cells from PE samples. In vitro, a hypoxia-treated HTR-8/SVneo trophoblast cell model was established, combined with SASH1 knockdown, SASH1 overexpression, and co-culture with P-EXOS. Functional experiments showed that knockdown of SASH1 significantly suppressed hypoxia-induced trophoblast apoptosis and reduced the secretion of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, whereas SASH1 overexpression promoted apoptosis and inflammatory responses. In addition, P-EXOS treatment markedly reduced SASH1 expression at both mRNA and protein levels and attenuated hypoxia-induced trophoblast injury, while SASH1 overexpression largely abolished these protective effects. Taken together, these findings indicate that SASH1 plays a critical role in trophoblast apoptosis and inflammatory responses in PE. P-EXOS may alleviate hypoxia-induced trophoblastic injury by suppressing SASH1 expression, providing new insights into the molecular mechanisms and potential therapeutic targets for PE.

Trophoblasts↗

PubMed2026

Polygenic risk scores associate with asthma phenotypes and proteomic analyses implicate IL1R1 in two family-based studies.

Despite its high prevalence and the discovery of hundreds of genetic associations, the genetic determinants and heterogeneous manifestations of asthma remain incompletely understood. Incorporating polygenic risk scores (PRS) into asthma research offers a powerful approach to quantify inherited susceptibility, refine risk profiles, and advance mechanistic understanding of disease development. For this study, we leveraged whole-genome sequencing (WGS) data from two family-based cohorts of childhood asthma - the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP) - to examine the transmission profiles of externally derived asthma PRS and their associations with clinical phenotypes in children with asthma. To further elucidate molecular mechanisms, we integrated large-scale external genome-wide association study (GWAS) summary statistics and genetic prediction models of protein abundance in a two-step proteome-wide association study (PWAS) of asthma. Our findings provide robust evidence supporting the validity of externally derived asthma PRS (asthma PRS association p-value p = 10-24 [GACRS and CAMP trios combined] for the Global Biobank Meta-analysis Initiative [GBMI]) and reveal consistent associations with spirometry measures and atopy markers across both studies, as 13 of 21 traits (62%) were significantly associated with the GBMI-PRS in the meta-analysis after multiple-testing correction. Moreover, the results of the integrative proteomic analysis implicate IL-1 signaling in the etiology of asthma, reinforcing the candidacy of IL1R1 antagonists for drug repurposing.

Journal Article↗