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PubMed2026

Interleukin-1α Mediates Pancreatic Fibroblast Activation, Regulates Immune Cell Recruitment and Fibrosis in Acute and Chronic Pancreatitis.

Pancreatitis is a life-threatening inflammatory disease of the pancreas. The cytokine interleukin-1α has been demonstrated to act as an alarmin released by necrotic cells. In the present study, we investigated the influence of IL-1α on the immune response during acute and chronic pancreatitis. Following tissue injury, pancreatic acinar cells released IL-1α, which activates tissue-resident fibroblasts to differentiate toward a pro-inflammatory phenotype. By secreting chemokines and cytokines such as CXCL5, CCL2, and IL-6, these fibroblasts recruit immune cells to the pancreas. The absence of IL-1α reduces disease severity in acute pancreatitis and chemokine release. Furthermore, IL-1α primes fibroblasts to enhance the production of extracellular matrix-components by the up-regulation of pro-fibrotic receptors such as Il4ra, Il13ra1, and Tgfbr3. Therefore, the deletion of IL-1α significantly reduced the development of tissue fibrosis. A therapeutic blockade of the IL1R1-signaling by i.p. administration of the IL-1-receptor antagonist Anakinra showed the same effect; the severity of acute pancreatitis and fibrogenesis during chronic pancreatitis were reduced. In conclusion, the crosstalk between necrotic acinar cells and fibroblasts mediated by IL-1α plays a crucial role in acute inflammation of the pancreas and fibrogenic signaling. Blockade of IL1R1-signaling by Anakinra is therefore a promising therapeutic intervention for both acute and chronic pancreatitis.

Anakinra↗

PubMed2026

Independent prognostic value of semaphorin-4D, interleukin-1β and complement activation in newly diagnosed multiple myeloma patients.

Multiple myeloma represents a systemic disease of the bone marrow (BM) niche, in which immune and skeletal pathways are tightly interconnected. However, the independent prognostic significance of bone and immune-related markers in newly diagnosed multiple myeloma (NDMM) remains incompletely understood. Semaphorin (Sema) 4D, activin-A, and periostin ELISA, LEGENDplex™ Human Bone Metabolism Panel and proteomic analysis for novel biomarker identification were conducted in 71 consecutive samples from NDMM patients. In 25 patients, genomic analysis was performed on sorted clonal plasma cells. NDMM patients had a median age at diagnosis of 65 years and a median follow-up of 2.5 years. Interleukin (IL)-1β and Sema4D levels predicted progression-free survival (PFS), highlighting their role in disease relapse. Proteomic profiling revealed a systemic signature associated with worse prognosis, enriched in complement activation components. Complement C5 significantly affected PFS and time to progression (TTP). IL-1β and C5 predicted PFS independently of the second revision of the International Staging System (R2-ISS) stage, and a similar trend was noted for Sema4D. Myeloma bone disease (MBD) did not significantly affect overall survival, PFS, or TTP, suggesting that contemporary treatments mitigate its impact. Genomic analyses identified variants associated with inferior PFS, including HLA-DRB5 (c.300_306delinsCGGG) and HLA-DQB1 (c.317_319delinsCGG). Sema4D and the IL-1β-complement cascade emerged as key drivers of disease progression, independent of R2-ISS stage, representing potential prognostic and therapeutic targets in NDMM.

Journal Article↗

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

IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages.

Chemical reprogramming holds transformative potential for regenerative medicine. However, the regulatory mechanisms governing cell fate transitions are not well understood. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a barrier to multi-lineage reprogramming. Pharmacological inhibition of IRAK4 enhances the reprogramming of mouse embryonic fibroblasts (MEFs) through a chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, increasing colony formation, and the expression of core XEN regulators (Sox17, Gata4, Sall4, and Foxa2). Genetic knockdown of Irak4 similarly accelerates reprogramming, whereas its overexpression blocks cell fate transitions. IRAK4 inhibition enhances chromatin accessibility and reshapes cell cycle dynamics, characterized by G0/G1 shortening and G2/M lengthening, potentially contributing to multi-lineage state establishment. Furthermore, IRAK4 suppression enhances the direct conversion of MEFs to neuron-like and hepatocyte-like cells, which exhibit enhanced functional maturity, including increased glycogen storage and improved detoxification capacity. Our findings establish IRAK4 as a regulator that constrains cellular plasticity potentially by coordinating chromatin accessibility and cell cycle dynamics.

Animals↗

PubMed2026

An endothelial RNA splicing atlas catalogs effects of IL-1β and identifies an alternative PROCR isoform with genetic links to pleiotropic vascular disease.

Alternative splicing (AS) alters the sequence and dynamics of mRNA but has not been comprehensively annotated in human endothelial cells (ECs). EC dysfunction is a hallmark of complex inflammatory diseases, including cancer and atherosclerosis. Therefore, we modeled inflammation in vitro using 53 genetically distinct human aortic EC lines exposed to interleukin-1β (IL-1β) or control media. This identified 1,224 differentially spliced transcripts (DSTs). DSTs were enriched for alternative first (AF) exon usage, including isoforms of several disease-associated and metabolic genes. To confirm that IL-1β-dependent AF exons were produced by alternative promoters, a quantitative measure of promoter activity was defined using epigenetic data. Ratios of histone 3 lysine 27 acetylation and binding of ERG and RELA between alternative promoters correlated RNA levels of AF exons, confirming our hypothesis. Finally, the effects of genetic variation on AS were investigated by mapping splicing quantitative trait loci (sQTLs). Significant sQTLs were tested for genetic colocalization with cardiovascular risk loci from genome-wide association studies. This identified 66 colocalized signals corresponding to 30 genes and 39 lead variants. The sQTLs identified here provide testable mechanisms explaining some of the genetic risk for vascular disease. For example, genetic association for a previously undescribed isoform of endothelial protein C receptor (PROCR) colocalized with genetic risk for deep vein thrombosis and coronary artery disease with opposing risk alleles. This study demonstrates the prevalence of inducible promoters upon inflammatory stimuli and shows that genetic risk for vascular disease may be in part governed through AS in ECs.

Humans↗

PubMed2024

Culture Expansion Alters Human Bone Marrow-Derived Mesenchymal Stem Cell Production of Osteoarthritis-Relevant Cytokines and Growth Factors.

PURPOSE: The purposes of this study were to characterize the human bone marrow-derived mesenchymal stem cells (BM-MSCs) production of osteoarthritis-relevant cytokines and growth factors as they are purified and multiplied, a process termed culture expansion, and to compare the immunomodulatory potential of BM-MSCs based on source and medium used for culture expansion. METHODS: BM-MSCs were obtained from iliac crest bone marrow aspirates of 4 healthy donors. These 4 BM-MSC cell lines underwent 4 rounds, or "passages," of the institutional culture expansion protocol, using institutional culture media. The secretory molecules known to play a role in osteoarthritis-related inflammatory immune response, cartilage degradation, and patient symptoms, together called the BM-MSC "secretome," were measured at each passage. Three lines of commercially available BM-MSCs from healthy donors underwent culture expansion by the same protocol, using commercial culture media. The commercial BM-MSCs secretome and the institutional BM-MSCs secretome were compared at each passage. Significance was set at P < .05. RESULTS: Institutional BM-MSCs produced less interleukin-6 at passages 3 (237 ± 113 pg/mL) and 4 (237 ± 113 pg/mL) compared with passages 1 (884 ± 97 pg/mL) and 2 (1071 ± 129 pg/mL; P < .01). Institutional BM-MSCs produced more macrophage inflammatory protein 3-alpha at passage 4 than at passage 1 (106 ± 41 vs 32 ± 7 pg/mL; P < .01). Across passages of culture expansion, institutional BM-MSCs grown on institutional medium expressed more interleukin-6 (P < .001), interleukin-10 (P < .001), interleukin-1 beta (P < .001), tumor necrosis factor alpha (P = .004), and vascular endothelial growth factor C (P = .003) than commercially available BM-MSCs grown on commercial medium. CONCLUSIONS: Culture expansion alters key molecules within the BM-MSC secretome. Additionally, differences in BM-MSC source and culture medium alter the BM-MSC secretome and its immunomodulatory potential. CLINICAL RELEVANCE: This study characterizes the in-vitro changes in BM-MSC secretome during culture expansion based on the cell source and culture medium. It suggests nonequivalence of culture-expanded BM-MSC therapies obtained from different donors using different culture media, even if delivering equivalent numbers of BM-MSCs.

Humans↗

PubMed2026

Sex-specific biomarkers predict bone mineral density loss at the contralateral hip after hip fracture.

OBJECTIVE: To identify inflammatory and hormonal biomarkers that predict bone loss at the contralateral (non-fractured) hip following hip fracture in males and females. METHODS: White participants who were not receiving pre-fracture glucocorticoids, sex-hormone therapy, or bone-active medications (100 males, 76 females) with hip fractures. Data were collected within 22 days of hip fracture and at 2, 6, and 12 months follow-up. Biomarkers were categorized into tertiles: estradiol, 25-hydroxyvitamin D3/D2, intact parathyroid hormone (iPTH), interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), soluble tumor necrosis factor-α receptor 1, sex hormone-binding globulin, and testosterone. Femoral neck bone mineral density (BMD) at the contralateral hip was assessed, and losses exceeding the mean decline were classified as greater than average. Logistic regression models, stratified by sex, were adjusted for confounders and evaluated selected biomarker associations. RESULTS: Among males, the 2nd (OR = 4.79, P = 0.012) and 3rd (OR = 6.36, P = 0.005) IGF-1 tertiles were associated with greater odds of BMD loss than the 1st tertile. The 3rd iPTH tertile (OR = 3.79, P = 0.037) was similarly associated with increased odds. Among females, the 3rd (OR = 0.20, P = 0.031) IL-1RA tertile was associated with lower odds of BMD loss compared to the 1st tertile, while the 2nd IL-6 tertile (OR = 5.99, P = 0.036) was associated with higher odds. CONCLUSION: These findings suggest that inflammatory and hormonal biomarkers may be sex-specific predictors of accelerated BMD loss following hip fracture.

Biomarkers↗

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↗

PubMed2026

Exercise-induced chronic adaptations and pro-inflammatory cytokine levels (IL-1β, IL-6, and TNF-α) in patients with depression: A systematic review and exploratory meta-analysis of randomized controlled trials.

BACKGROUND: Depression is a leading cause of disability worldwide. Although exercise has been shown to alleviate depressive symptoms, potentially by affecting the body's inflammatory response, evidence in this area remains inconsistent. This study synthesized the most recent evidence from randomized controlled trials (RCTs) on the relationship between exercise-induced chronic adaptations and pro-inflammatory cytokine levels in patients with depression. METHODS: Eligible RCTs were identified from six electronic databases. Effect sizes were pooled using mean differences (MDs) and standardized mean differences (SMDs) with 95% confidence intervals (CIs). Two independent researchers assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: The review included 21 RCTs involving 1572 participants, six of which were included in the meta-analysis. No evidence of efficacy was observed for the chronic effects of exercise on the levels of the pro-inflammatory cytokines interleukin-1-beta (IL-1β) (MD = -0.01, 95% CI [-0.06, 0.04], p = 0.79), interleukin-6 (IL-6) (SMD = -0.30, 95% CI [-0.64, 0.04], p = 0.08), and tumor necrosis factor-alpha (TNF-α) (SMD = -0.18, 95% CI [-0.50, 0.14], p = 0.27) in patients with depression. However, the pooled results for certain markers were not robust. The certainty of evidence for each outcome was very low owing to inconsistency, indirectness, and imprecision. CONCLUSIONS: Evidence for exercise improving pro-inflammatory cytokine levels in patients with depression during the chronic phase remains exploratory and uncertain. Well-designed, adequately powered studies incorporating a broader range of immune biomarkers and dynamic multi-time-point assessments are urgently needed to determine whether exercise-induced chronic adaptations can modulate inflammatory pathways in depression.

Humans↗

PubMed2026

Immune profiling in a living human recipient of a gene-edited pig kidney.

Xenotransplantation of gene-edited pig kidneys offers a promising solution to the shortage of kidneys for organ transplantation. We recently performed a gene-edited pig kidney transplantation into a living human recipient with end-stage kidney disease. Here, using transcriptomics, proteomics, metabolomics and multiplexed imaging, we conducted high-dimensional immune profiling in this individual. Despite profound depletion of circulating T cells, early T cell-mediated rejection occurred within 1 week after transplantation, likely driven by subtherapeutic immunosuppression and the presence of residual CD8+ T cells in lymph nodes. This T cell-mediated rejection event was reversed by intensified immunosuppression. After treatment, adaptive immunity remained suppressed, whereas innate immune activation, characterized by sustained monocyte and macrophage activity along with elevated levels of interleukin-1 beta and granulocyte-macrophage colony-stimulating factor, persisted. Comparative transcriptomic analysis showed that xenograft rejection profiles resembled those typically observed in human allograft rejection, while also revealing unique innate immune signatures. We did not detect antibody-mediated rejection. The levels of circulating pig donor-derived cell-free DNA rose during the initial rejection episode and declined with treatment, supporting the potential of cell-free DNA measurements as a noninvasive biomarker of xenograft rejection. These findings define the distinct immune landscape of kidney xenotransplantation and highlight the need for regimens targeting both innate and adaptive immunity to improve outcomes.

Animals↗

PubMed2026

IL1RAP Is Associated With an Inflammation-Immunity-Related State in Skin Cutaneous Melanoma: Integrative Evidence From Pan-Cancer Data and Melanoma Immunotherapy Cohorts.

BACKGROUND: The crosstalk between inflammation and immunity plays a central role in tumor progression, immune evasion, and therapeutic response. Interleukin-1 receptor accessory protein (IL1RAP) is a key adaptor in inflammatory signaling, yet its immunological relevance and clinical implications in skin cutaneous melanoma (SKCM) remain largely unexplored. METHODS: We performed an integrative analysis combining pan-cancer and melanoma-focused datasets. Bulk transcriptomic, single-cell, spatial transcriptomic, genomic alteration, pharmacogenomic, and clinical survival data were obtained from TCGA, GTEx, GEO, ENA, and other public resources. IL1RAP expression was evaluated across cancer types in relation to diagnostic performance, immune subtypes, survival outcomes, functional pathway activity, immune-genomic states, somatic alterations, and drug-response metrics. Melanoma-focused analyses examined immune infiltration, methylation-derived tumor-infiltrating lymphocyte (MeTIL) scores, and exploratory survival associations in five treatment cohorts; the survival groups were defined using cohort-specific optimal cutoffs rather than median splits. RESULTS: IL1RAP expression differed between tumor and normal tissues in multiple cancers, although the direction and magnitude varied by cancer type. Pan-cancer survival associations were likewise context dependent. Single-cell and spatial transcriptomic resources indicated cell-type and spatial heterogeneity of IL1RAP expression within tumor microenvironments. Pathway, immune-genomic, and pharmacogenomic analyses identified exploratory associations with functional states, genomic features, and drug-response metrics. In SKCM, IL1RAP expression was associated with several immune-infiltration estimates and higher MeTIL scores. Across five melanoma immunotherapy cohorts, the direction and magnitude of the overall survival associations varied substantially. CONCLUSIONS: This retrospective integrative analysis suggests that IL1RAP may mark an inflammation-immunity-related state in SKCM. The heterogeneous associations across cancers and melanoma treatment cohorts support further validation but do not establish IL1RAP as a causal regulator, a treatment-response predictor, or a therapeutic target.

IL1RAP↗

PubMed2026

[Study on mechanism of Wendan Decoction in intervening in nonalcoholic fatty liver disease based on proteomics and network pharmacology].

This study systematically explored the molecular mechanism of Wendan Decoction(WDD) in treating nonalcoholic fatty liver disease(NAFLD) by integrating network pharmacology, proteomics, and experimental validation. A mouse NAFLD model was established using a high-fat diet, and the mice were randomly divided into a blank control group, a model group, a positive drug group(simvastatin, 3.03 mg·kg~(-1)), and low-(3.035 g·kg~(-1)), medium-(6.07 g·kg~(-1)), and high-dose(12.14 g·kg~(-1)) WDD groups, with intervention lasting for 6 weeks. After the intervention, the serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglycerides(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C) were measured using an automatic biochemical analyzer. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) were detected by ELISA. Liver histopathology was observed via hematoxylin-eosin(HE) staining and oil red O staining. Network pharmacology was used to predict potential targets and pathways, and proteomics was applied to identify differentially expressed proteins and related pathways. RT-qPCR and Western blot were performed to detect mRNA and protein expression of relevant genes. Animal experiments demonstrated that WDD dose-dependently ameliorated hepatic steatosis, inflammation, and lipid deposition, significantly reducing serum levels of ALT, AST, TG, TC, LDL-C, and pro-inflammatory cytokines(IL-1β, IL-6, and TNF-α), while significantly increasing serum HDL-C levels. Network pharmacology screening identified naringenin, baicalein, and other key active components, which were involved in pathways such as the peroxisome proliferator-activated receptor(PPAR), lipid, and atherosclerosis pathways. Proteomics further revealed differentially expressed pathways including the PPAR and advanced glycation end product-receptor(AGE-RAGE) signaling pathways. Integrated analysis highlighted the PPAR signaling pathway as the core mechanism. Molecular biology validation showed that WDD significantly regulated the mRNA expression of sterol regulatory element-binding protein-1c(SREBP-1c), fatty acid synthase(FASN), carnitine palmitoyl transferase 1A(CPT1A), acyl-CoA oxidase 1(ACOX1), and PPARα, as well as protein expression of PPARα, CPT1A, and PPARγ in mouse liver tissue. These results suggested that WDD might exert a multi-component, multi-target, and multi-pathway synergistic effect to improve lipid metabolism disorders and inflammatory responses with the PPAR signaling pathway as the central hub, thereby alleviating NAFLD progression.

Animals↗

PubMed2025

Systematic acupuncture explains acupuncture at Baihui (GV20) and Fengchi (GB20) targeting the inflammatory response to regulate migraine.

OBJECTIVE: To take Baihui (GV20) and Fengchi (GB20) targeting inflammatory response to regulate migraine as an example to describe a new method for studying the mechanism of stimulating acupoints. METHODS: The target information of Baihui (GV20) and Fengchi (GB20) was retrieved, and after intersection with migraine, Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and UniProt Keywords were used for functional enrichment. After selecting the main pathway, rats were selected and nitroglycerin was used for modeling, and the behavioral scores, inflammatory factors, heme oxygenase 1 (HMOX1), protein kinase B (AKT1), signal transducer and activator of transcription 3 (STAT3), phosphorylated extracellular signal-regulated kinase 1/2 (P-ERK1/ERK2) and other states of the rats in the acupuncture, twisting, and electroacupuncture groups were compared. RESULTS: A total of 135 Baihui (GV20) targets and 27 Fengchi (GB20) targets were collected. A total of 73 target information were obtained after the intersection of these targets in migraine. These 73 targets have three main pathways: hypoxia-inducible factor 1 (HIF-1) signaling pathway, signaling by interleukins and inflammatory response. The main targets in the pathway were verified and found that interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and HMOX1, AKT1, STAT3, P-ERK1/ERK2 can be regulated by Baihui (GV20) and Fengchi (GB20). CONCLUSION: Baihui (GV20) and Fengchi (GB20) can regulate migraine by regulating inflammatory factors and HMOX1, AKT1, STAT3, P-ERK1/ERK2 and other changes in HIF-1 signaling pathway, Signaling by Interleukins and Inflammatory response pathways. Based on systems biology and network pharmacology, and with the model of "acupoint-target-disease", explore the research methods of systematic acupuncture and moxibustion. We believe this is a usable research direction for exploring the mechanism of acupuncture stimulation.

Acupuncture Points↗

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

Noise-Induced Hepatic Stress Is Associated with Transglutaminase Activation and TG7 Upregulation in Rats.

OBJECTIVE: Environmental noise is increasingly recognized as a systemic stressor capable of inducing oxidative and inflammatory responses beyond the auditory system. This study aimed to investigate the effects of chronic noise exposure on transglutaminase (TG) activation, particularly TG7, and its association with hepatic stress responses in rat liver tissue. METHODS: Thirty adult male Wistar albino rats were randomly assigned to control, short-term noise exposure (LT1), and long-term noise exposure (LT2) groups. Gene expression of TG isoforms (TG1, TG2, TG3, TG6, and TG7), inflammatory markers (IL6 and TNF-α), and apoptotic markers (CASP3 and P53) was evaluated using quantitative real-time PCR. Total TG enzymatic activity was assessed colorimetrically. TG7 protein expression and localization were examined by immunohistochemistry and immunofluorescence. DNA integrity was evaluated by agarose gel electrophoresis. Biochemical parameters, including serum malondialdehyde (MDA), interleukin-1 beta (IL1β), cortisone, aspartate aminotransferase, alanine aminotransferase, glucose, insulin, and total cholesterol, were also measured. RESULTS: Noise exposure induced selective upregulation of TG isoforms, with TG7 showing the highest increase (∼10-12-fold). Total transglutaminase enzymatic activity was significantly increased in both noise-exposed groups, with a higher increase in LT1 (*** P < 0.001) and a significant increase in LT2 (** P < 0.01) compared with control, while no significant difference was observed between LT1 and LT2. IL6 and TNF-α increased progressively, particularly in LT2, whereas CASP3 expression was elevated in LT1 but reduced in LT2. DNA analysis revealed mild alterations in genomic integrity without clear internucleosomal fragmentation. TG7 protein showed strong localization within hepatocyte cytoplasm and perisinusoidal regions. Biochemical analysis demonstrated significant increases in MDA (up to 61.28%), IL1β, cortisone, liver enzymes, glucose, insulin, and total cholesterol. CONCLUSION: Chronic noise exposure induces early TG activation, particularly TG7, accompanied by sustained oxidative stress and inflammatory responses in liver tissue. These findings identify TG7 as a potential stress-responsive mediator in noise-induced hepatic injury.

Animals↗

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

Specialized pro-resolving mediator (SPM)-enriched supplementation modulates inflammatory biomarkers in patients with symptomatic knee osteoarthritis: Blood plasma analysis from the GAUDI study.

BACKGROUND: Osteoarthritis (OA) is a leading cause of chronic pain and functional impairment, associated with persistent inflammation, potentially due to impaired resolution. Specialized pro-resolving lipid mediators (SPMs) regulate inflammation resolution and restore homeostasis. The GAUDI study previously demonstrated that SPM supplementation reduces pain and improves quality of life (QoL) in patients with knee OA. This analysis assesses the impact of SPM supplementation on inflammatory biomarkers (IB) and SPM levels and their relationship with clinical outcomes. METHODS: This is a secondary analysis of the GAUDI trial, a randomized, multicenter, double-blind, placebo-controlled study conducted in Spain in adults with symptomatic knee OA who received daily supplementation with SPMs or placebo for 12 weeks. Endpoints included changes in plasma IB and SPM levels and their correlation with clinical outcomes. RESULTS: Changes in IL-1 (15.9 vs. -1.1 pg/ml, p-value: 0.051) and IL-18 (10.3 vs. -1.4 pg/ml, p-value: 0.29) showed a tendency toward reduction in the SPM group compared to the placebo group. Changes in IL-1 and IL-8 positively correlated (r = 0.707, p-value: 0.005 and r = 0.551, p-value: 0.04; respectively) with changes in WOMAC score and negatively correlated (r = -0.797, p-value <0.001 and r = -0.804, p-value <0.001; respectively) with changes in EuroQoL-5 VAS score. Changes in IL-1 (r = 0.554, p-value: 0.048) and IL-6 (r = 0.631, p-value: 0.014 and r = 0.572, p-value: 0.031) correlated with changes in OMERACT-OARSI pain score. No significant differences in IB levels were observed between groups during the intervention. Minor changes in SPM levels point to metabolic pathways at work with SPM supplementation. In patients with a BMI ≥25 kg/m², most IB tended to decrease following SPM consumption. CONCLUSIONS: This analysis suggests a potential association between SPM supplementation, decreased inflammation, and improved pain and QoL in patients with knee OA. Subtle changes in blood plasma SPM levels were detected that indicate, through bioinformatics analysis, a pathway-specific metabolome activation induced by SPM supplementation. TRIAL REGISTRATION: NCT05633849. Registered December 1st, 2022. Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT05633849.

Humans↗

PubMed2026

The IL-1 system in inflammation and cancer.

Inflammation is a pathogenetic driver of several pathological conditions, including cancer. The tumor microenvironment, which includes cellular, molecular, and structural components, is an essential component of cancer, involved in tumor promoting or controlling processes. In particular, inflammatory players contribute to the establishment of a tumor-promoting microenvironment, which affects all stages of tumor development, from initiation to metastasis, as well as response to therapy. The IL-1 system includes two large sets of structurally related ligands and receptors, with agonist or regulatory activity, playing non-redundant roles in inflammation and immunity. Each of them has specific functions in tissue homeostasis, inflammation, innate and adaptive immune responses, and potentially contributes to processes related to carcinogenesis and metastasis, or immune-mediated control of cancer cells. Depending on the context and cellular target, IL-1 family members may play dual roles in cancer, driving both pro- or anti-tumor processes. IL-1α and IL-1β can directly promote cancer cell proliferation, survival, and plasticity, in addition to contribute to the establishment of a pro-inflammatory environment that promotes tissue remodeling, cellular stress responses, and genomic instability. On the other hand, IL-1 is a lymphoproliferative and activating molecule in innate and adaptive responses, thus contributing to anti-tumor immune mediated responses. In addition, members of the IL-1 system act as regulators of mechanisms involved in cancer, including emergency hematopoiesis, trained immunity, and metabolism. Here, we will provide an overview of the IL-1 system in cancer and discuss the functional complexity of IL-1 family cytokines, which orchestrate both protective and pro-tumorigenic responses, by directly acting on cancer cells and by driving environmental stimuli which indirectly act on cancer cells.

Humans↗