Search Results (3,537)

Background: Graft-versus-host disease (GVHD) is a common severe complication of allogeneic hematopoietic stem cell transplant. The current treatments are limited by steroid toxicity, broad immunosuppression, and the potential suppression of the graft-versus-tumor (GVT) effect. Developing less toxic therapies is an unmet need. We previously showed that systemically infused negatively charged immune-modifying microparticles (IMPs) composed of carboxylated poly-lactic-co-glycolic acid are taken up by inflammatory monocytes via the MARCO receptor, reducing symptoms and improving survival in inflammatory conditions. We hypothesized that IMPs could reduce acute GVHD manifestations. Methods: Acute GVHD was induced in an MHC-mismatched murine transplant model with radiation conditioning. IMPs were infused for five days; outcomes were compared to saline controls. We assessed organ histopathology, immune cell populations in the spleen and intestine, serum cytokine levels, and the GVT effect. Results: IMP-treated mice showed significant improvements in terms of clinical GVHD scores, histopathology, and survival. They had increased regulatory T-cells in the spleen and intestine and decreased colonic inflammatory monocytes and cytokines such as IL-6 and IFN-γ. IMPs were ineffective in MARCO knockout mice, confirming receptor dependence. Importantly, GVT activity was preserved, as evidenced by improved survival in mice with A20 lymphoma treated with IMPs. Conclusions: Systemic IMPs reduce clinical GVHD signs and improve survival, likely by decreasing inflammatory monocytes via MARCO and expanded regulatory T-cells numbers, while maintaining GVT activity. These findings support further investigation of IMPs as a targeted GVHD therapy. Full article

Malathion, a widely used organophosphate pesticide, frequently contaminates aquatic ecosystems and poses considerable toxic risks to non-target organisms, including fish. The present study provides an integrated evaluation of the protective effects of dietary probiotics against malathion-associated oxidative, metabolic, and immune-related disturbances in Nile tilapia at the biochemical and molecular levels. After determining the 96 h LC₅₀ of malathion, fish were exposed to a sublethal concentration for 7 days followed by a 14-day recovery period while receiving either a basal or probiotic-supplemented diet. Malathion exposure increased cumulative mortality, induced behavioral stress, and caused metabolic and hepatorenal disturbances characterized by elevated serum glucose and cholesterol, altered serum protein fractions, increased alanine and aspartate aminotransferase activities, and elevated creatinine and uric acid levels. Oxidative stress was evidenced by increased serum malondialdehyde and transcriptional suppression of antioxidant-related genes (sod-2 and cat) in the liver, spleen, and intestine. Malathion also triggered immune dysregulation through the upregulation of pro-inflammatory cytokine genes (il-1β and tnf-α) and suppression of regulatory cytokines (tgf-β and il-10). Probiotic supplementation during recovery significantly reduced mortality, restored metabolic and hepatorenal biomarkers, attenuated oxidative damage, and enhanced antioxidant capacity at both the biochemical and transcriptional levels. Moreover, probiotic-supplemented fish exhibited controlled pro-inflammatory signaling accompanied by the pronounced activation of regulatory cytokines, indicating balanced immune modulation. Collectively, dietary probiotics effectively mitigate malathion-induced toxicity by improving antioxidant defense, immune regulation, and physiological resilience, highlighting their potential as functional dietary additives for sustainable aquaculture in Nile tilapia. Full article

The yak (Bos grunniens), a unique bovine species that is endemic to the Qinghai–Tibet Plateau and adjacent mountainous regions, exhibits remarkable adaptations to chronic high-altitude hypoxia. However, the molecular mechanisms underlying yaks’ adaptation to this extreme environment remain poorly understood. This study aimed to elucidate the spatiotemporal expression dynamics of hypoxia-inducible factor 1α (HIF-1α) and 2α (HIF-2α) in major tissues of yaks across developmental stages (0.5, 1.5, 2.5, and 4.5 years; n = 3 per group). The tissues (heart, liver, spleen, lungs, kidneys, blood vessels and skeletal muscles) were analyzed using hematoxylin and eosin (H&E) staining and immunohistochemistry. The results revealed significant differences in the expression levels of HIF-1α and HIF-2α between tissues and at different ages. In cardiac tissue, both HIF-1α and HIF-2α are localized to the myocardial interstitium, with HIF-1α expression peaking at 1.5–2.5 years and HIF-2α expression reaching its maximum at 2.5 years. Hepatic HIF-1α showed perivenous hepatocytes enrichment and peaked at 2.5 years (p < 0.01 vs. other ages), while HIF-2α was uniformly distributed across lobules without age-related changes. Splenic HIF-1α and HIF-2α levels increased progressively with age, both peaking at 4.5 years (p < 0.01), and age was strongly correlated with expression levels (HIF-1α: r = 0.430; HIF-2α: r = 0.493). In pulmonary tissues, HIF-1α in bronchial smooth muscle peaked at 2.5 years, whereas alveolar septal HIF-2α peaked at 1.5 years (p < 0.05). In the kidney, HIF-1α was primarily localized to tubular epithelial cells and HIF-2α was diffusely distributed in the glomerular interstitium; neither factor showed significant variation across ages. In vascular tissues, HIF-1α expression remained stable across all ages and was predominantly observed in the smooth muscle layer, while HIF-2α exhibited a significant peak in endothelial cells at 2.5 years (p < 0.01). These findings suggest that HIF-1α predominates during early development stages, while HIF-2α becomes dominant as yaks approach maturity. Full article

The development of efficient and biocompatible sorbent nanomaterials for cesium removal is critical for environmental and biomedical decontamination. Here, hybrid composites based on ultra-small Prussian blue or Zn Prussian blue-type nanoparticles confined within porous chitosan beads are proposed for Cs⁺ extraction. Nanoparticle confinement ensures homogeneous dispersion and improved accessibility of ion-exchange sites, while preserving the porous polymeric network, as confirmed by physicochemical characterization. Cs⁺ adsorption was investigated under neutral and acidic conditions (pH 7.2 and 1.2), at concentrations of 0–9 mmol/L and contact times of 0–50 h, showing efficient uptake and favorable kinetics, with confirmed stability in simulated gastric fluid. In vivo performance was assessed in a mouse model of cesium contamination (70 mg Cs⁺/kg). Treatment with nanocomposites (225 mg/kg) was compared to bulk Prussian blue (75 mg/kg), revealing enhanced detoxification efficiency. Histological analysis of liver, spleen, and kidney tissues showed no detectable structural damage, consistent with unchanged systemic biomarkers. Overall, the proposed chitosan-confined Prussian blue-type nanocomposites combine high Cs⁺ removal efficiency, kinetic accessibility, and in vivo safety, highlighting their potential for decorporation applications. Full article

Oral probiotic-based therapy has emerged as a promising solution with multifaceted benefits for immunosuppression treatment. However, their widespread and clinical utility is severely limited by the poor viability of probiotics under harsh gastrointestinal conditions in the intestine. To address these challenges, a probiotic-based biohybrid (Lr@DGN) was bio-orthogonally fabricated by covalently anchoring the prebiotic β-glucan (GN) to the probiotic Limosilactobacillus reuteri (Lr). Upon oral administration, Lr@DGN colonized intestines with high survival rates, aided by gastrointestinal stress-shielding of GN, leading to immuno-enhancing effects through combining GN and live Lr. Consequently, in a Cy-induced immunosuppression mouse model, oral administration of Lr@DGN significantly mitigated body weight loss, restored the key immune organ indexes (thymus and spleen), ameliorated Cy-induced damage to the small intestine, enhanced the intestinal immune response, and elevated the serum levels of immunoglobulins IgG and IgA. By integrating the effects of a prebiotic shield and a live probiotic, this biohybrid system offers a promising and translatable approach for managing immunodeficiency and related disorders. Full article

Background: The intracellular pathogen Brucella requires biotin for survival, yet the role of its de novo synthesis intermediate enzyme, BioA, in virulence remains undefined. This study investigates the contribution of BioA to the pathogenicity of Brucella abortus. Methods: We constructed a ΔBioA mutant in Brucella abortus 104M via homologous recombination and characterized its phenotype using growth assays, electron microscopy, macrophage infection models, and murine splenic colonization. Virulence gene expression was quantified by RT-qPCR. Results: The ΔBioA mutant exhibited severe growth auxotrophy in a biotin-deficient medium and displayed damaged outer membrane integrity. Furthermore, intracellular survival in macrophages was reduced by approximately 95% compared to the wild-type strain at 48 h post-infection. Notably, mice infected with the mutant showed a significant decrease in both splenic bacterial loads and spleen weight at 3 weeks, concomitant with a marked downregulation of VirB type IV secretion system (T4SS) genes. Conclusions: This study is the first to identify BioA as a critical nexus linking biotin metabolism to Brucella virulence. We demonstrate that BioA deficiency attenuates pathogenicity by impairing both structural integrity and the transcription of key virulence-related genes (VirB operon), thereby nominating BioA as a novel and promising target for anti-brucellosis interventions. Full article

Kratom (Mitragyna speciosa) is a botanical candidate for pain management with potentially reduced opioid-related risks, partly through modulation of neuroimmune pathways involving Toll-Like Receptor 4 (TLR4). This study aimed to characterize the phytochemical profile of kratom ethanol extract and evaluate its effects on TLR4 signalling, neuroinflammatory cytokines, analgesic activity, withdrawal behaviours, and organ safety in morphine-dependent mice. Metabolite profiling was conducted using UHPLC–Q-Exactive Orbitrap HRMS, followed by molecular docking of major constituents to the TLR4 complex. In vivo assessments included flow cytometry and gene expression analyses of TLR4-mediated cytokines (NF-κB, IL-1β, IL-6), behavioural assays for antinociception, endurance, and withdrawal symptoms, and histopathological and biochemical evaluation of liver, kidney, and spleen tissues. More than 100 metabolites were identified, including mitragynine and flavonoids such as rutin and isoquercetin, which showed interactions with key TLR4 residues. Selected fractions suppressed pro-inflammatory cytokine expression, increased tail-pinch latency comparable to morphine, reduced withdrawal manifestations, and demonstrated nephroprotective and immunomodulatory effects, although mild reversible hepatic alterations were observed in specific fractions. Overall, kratom ethanol extract exhibited fraction-dependent analgesic and anti-neuroinflammatory activities associated with TLR4 modulation, supporting its potential as a botanical analgesic candidate while emphasizing the importance of safety optimization and standardized fraction development. Full article

Background: Pancreatic neuroendocrine neoplasms (PanNENs) represent a heterogeneous tumor entity with a steadily rising incidence, mainly due to advances in imaging and growing diagnostic awareness. In pancreatic ductal adenocarcinoma (PDAC), the mesopancreas (MP) has been identified as a frequent site of microscopic tumor spread and a key determinant of circumferential resection margin (CRM) status, leading to the concept of standardized mesopancreatic excision (MPE). While its oncological relevance in PDAC is increasingly recognized, the role of the mesopancreas in PanNENs remains unclear. This study aimed to systematically evaluate mesopancreatic infiltration in PanNENs and to identify associated clinicopathological predictors. Methods: Consecutive patients undergoing oncological pancreatoduodenectomy, spleen-preserving distal pancreatectomy, or distal splenopancreatectomy for PanNENs and PanNECs were included. The mesopancreas was histopathologically examined for tumor infiltration within CRM assessment. Results: MP infiltration was detected in 60% of patients. It was associated with higher Ki-67 index, larger tumor size, lymph node involvement, venous invasion, and positive CRM status. A Ki-67 index ≥ 5% and tumor size ≥ 21.5 mm were identified as predictors of MP infiltration. Higher T stage predicted reduced overall survival (OS), whereas MP infiltration, lymphatic (L1) and venous (V1) invasion, and Ki-67 ≥ 5% were associated with impaired disease-free survival (DFS). Conclusion: Mesopancreatic infiltration is frequently present in PanNENs and correlates with aggressive tumor characteristics. Given its association with CRM positivity and reduced DFS, consideration of the mesopancreas in staging and surgical strategies appears oncologically justified. Larger studies are required to validate these findings. Full article

The gut microbiota serves as a critical interface for host immunity, making it a promising target for probiotic intervention. In this study, we investigated the immunomodulatory potential of the strain Bifidobacterium breve (B. breve) MN15965 and the underlying role of gut bacterial communities in this process. We first assessed its in vitro immunomodulatory activity by measuring nitric oxide and cytokine secretion in THP-1 macrophages. Subsequently, an immunosuppressed mouse model was established by treating BALB/c mice with cyclophosphamide (CTX), a chemotherapeutic agent known to cause immune dysfunction and mucosal damage. In this model, we performed a series of analyses, including H&E staining, measurement of hematological parameters and serum cytokines/immunoglobulins, quantification of fecal short-chain fatty acids (SCFAs) by gas chromatography, and profiling of gut microbiota composition via 16S rRNA gene amplicon sequencing. The results showed that MN15965 supernatant enhanced TNF-α, IL-1β, and GM-CSF secretion in THP-1 cells, promoting M1 macrophage activation in vitro. In the in vivo model, MN15965 administration restored spleen and thymus tissue integrity and improved physiological indices, hematological parameters, and immunoglobulin levels. Furthermore, MN15965 increased fecal SCFAs, particularly butyric and valeric acid, increased gut bacterial diversity, and enriched potentially beneficial SCFA-producing taxa, including Lachnospiraceae and Eubacterium. These findings demonstrate that B. breve MN15965 alleviated CTX-induced immunosuppression by activating immune responses, regulating gut bacterial communities, and boosting SCFA production. Full article

Chikungunya virus (CHIKV) infection presents a wide spectrum of clinical outcomes, ranging from mild self-limiting disease to severe and fatal manifestations, which are influenced by both host and viral factors. Animal models are essential for elucidating CHIKV pathogenesis and for preclinical evaluation of antiviral strategies; however, a well-characterized model evaluating the effect of different viral doses in AG129 mice remains limited. In this study, we investigated the clinical, virological, and pathological outcomes of CHIKV infection in male AG129 mice inoculated intraperitoneally with different viral doses (10, 100, and 1000 PFU/mL) of a Brazilian strain belonging to the East/Central/South African (ECSA) lineage. Lower-dose inoculation (10 PFU/mL) resulted in a milder disease course, characterized by transient viremia, limited tissue viral dissemination, minimal histopathological alterations, partial survival, and viral clearance. In contrast, higher doses (≥100 PFU/mL) led to rapid systemic viral dissemination, severe histopathological damage in the spleen, liver, and kidneys, and uniform lethality. Viral RNA was detected in serum and multiple organs in a time-dependent manner, with limited differences among inoculum doses in most tissues. Notably, dose-related differences were observed in specific compartments and time points, particularly in hind-limb muscles at early time points and in serum at later stages. Full article

Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully understood. Methods: The four publicly available CRC microarray datasets—GSE41258, GSE44076, GSE81558, and GSE117606—along with TCGA-COAD and TCGA-READ datasets and their associated clinical data were obtained. MDK expression was measured at both the mRNA and protein levels using quantitative real-time PCR (qRT-PCR) and Western blotting. To investigate its oncogenic functions, a comprehensive set of assays was performed: transwell and wound healing assays for invasion and migration; CCK-8 and colony formation assays for proliferation; and tail vein/spleen injection models combined with xenograft models to study metastasis and tumor growth in vivo. To uncover underlying mechanisms, Western blotting was used to examine the involvement of epithelial–mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Results: MDK is significantly overexpressed in CRC tissues and cells compared to normal tissues and cells. Notably, patients with high MDK levels show poorer overall survival (OS). Overexpression of MDK increases CRC invasion, migration, proliferation, and metastasis both in vivo and in vitro, while its knockdown reverses these effects. Mechanistically, MDK activates the PI3K/AKT pathway, leading to increased AP2A1 expression and promotion of EMT in CRC. Conclusions: MDK promotes invasion, migration, proliferation, metastasis, and EMT in CRC cells through the PI3K/AKT pathway by inducing AP2A1 expression, which could serve as a diagnostic marker. The PI3K inhibitor LY294002 significantly reduces AP2A1 levels and inhibits MDK-induced malignant behaviors. Targeting MDK-related signaling pathways may offer new strategies for CRC treatment. Full article

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent lymphoma with extremely limited population-level evidence on social and treatment correlates of survival. Methods: We conducted a retrospective cohort study using SEER (2000 to 2022) to evaluate OS in primary SMZL (ICD O 3 9689; spleen C42.2). We summarized baseline features and treatments and used Kaplan–Meier and Cox regression. Results: The cohort included 3548 patients (mean age: 68.2 years; 53.6% female). Most were White (89.8%) and non-Hispanic (92.1%). The Ann Arbor stage was missing in 39.4%. Treatment included systemic antineoplastic therapy in 26.4%, beam radiation in 0.7%, and primary site surgery in 21.4%. At last follow-up, 56.8% were alive; non-Hodgkin lymphoma accounted for 15.8% deaths in the cohort, with substantial competing causes including heart disease (6.1%). In multivariable Cox analysis, OS was independently associated with age (HR 1.082 per year, 95% CI 1.072–1.091), male sex (HR 1.34, 95% CI 1.14–1.57), Hispanic ethnicity (HR 1.42, 95% CI 1.08–1.88), systemic antineoplastic therapy (HR 1.42, 95% CI 1.18–1.70), divorced/separated marital status vs. married (HR 1.35, 95% CI 1.03–1.77), and stage IV disease (HR 1.70, 95% CI 1.16–2.50). Race and year of diagnosis were not independently associated with OS in the adjusted model. Conclusions: In our large population-based analysis, OS in SMZL tracks with demographic and social variables and competing risks. Stage missingness and treatment selection limit causal inference for management effects. Full article

Differences in the gut microbiota are directly reflected in lung–gut axis crosstalk, which may increase susceptibility to pulmonary infections, such as those caused by the bacterium Pseudomonas aeruginosa. Deficiency of the cytokine IL-10 leads to gut inflammation, and this pro-inflammatory environment is partly due to changes in the gut microbiota. To better understand the effects of IL-10 deficiency on the gut microbiota, the intestinal microbial composition of IL-10 KO mice was assessed, and an increase in the phyla Bacteroidetes and Proteobacteria and a decrease in the phylum Firmicutes were observed in the faeces compared with the wild-type group (WT). Additionally, IL-10 KO mice had a higher pro-inflammatory immunostimulatory caecal content. Furthermore, it was found that heterologous faecal microbiota transplantation (FMT) between groups reversed this gut imbalance. IL-10 KO mice showed greater susceptibility to acute pulmonary infection by P. aeruginosa, with a higher recovery of viable bacteria in the lung and spleen, greater tissue damage and increased expression of genes encoding pro-inflammatory cytokines in the lungs. This greater susceptibility was reversed after FMT. Taken together, these results demonstrate the role of endogenous IL-10 in the gut microbiota constitution and its importance in the pulmonary immune response against P. aeruginosa infection. Full article

Atopic dermatitis (AD) is a chronic inflammatory dermatosis driven by skin barrier dysfunction, immune dysregulation, and gut–skin axis imbalance. While probiotics show promise, the therapeutic potential and mechanisms of topical postbiotics in modulating the gut–skin axis remain understudied. Here, we investigated the efficacy of Schleiferilactobacillus harbinensis JNDM-derived cell-free supernatant (CFS) and lysate (ShL) in a DNFB-induced AD mouse model. Topical application of both CFS and ShL significantly attenuated AD-like symptoms, reduced epidermal thickening, and restored the expression of the barrier protein filaggrin. Immunologically, treatment suppressed the Th2-dominant inflammatory cascade (IL-4, IL-5, IL-13, IL-33, TSLP) and reduced serum IgE and IFN-γ levels. Notably, ShL exhibited superior systemic efficacy, significantly inhibiting mast cell infiltration and reducing the spleen index. 16S rRNA sequencing revealed that topical intervention remotely remodeled the gut microbiota, specifically reversing the depletion of the beneficial genus Alistipes and suppressing the compensatory increase in Odoribacter. This microbial restructuring was accompanied by distinct metabolic changes: ShL treatment resulted in an approximately 4-fold elevation in fecal butyrate concentrations compared with the model group. Correlation analysis further validated a strong positive axis linking Alistipes abundance and butyrate levels to skin barrier integrity. Collectively, our findings demonstrate that S. harbinensis postbiotics—particularly the lysate—ameliorate AD through a dual mechanism of local barrier repair and systemic metabolic modulation via the gut–skin axis, presenting a promising non-steroidal therapeutic strategy. Full article

Attention-Deficit/Hyperactivity Disorder (ADHD), affecting 5–10% of children globally, faces treatment limitations due to adverse effects and uncertain long-term risks of current pharmacotherapies. This study investigated the therapeutic potential of sepia ink (SI), a marine-derived natural complex from cuttlefish, in a scopolamine-induced ADHD-like mouse model. The chemical constituents of SI were characterized via Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). The behavioral assessments, histopathological examinations, flow cytometry, and complete blood counts were utilized to evaluate its effects on ADHD-like phenotypes, neuroinflammation, and immune function. Integrated transcriptomic, plasma metabolomic, and 16S rRNA sequencing were used to explore the underlying mechanisms. SI significantly alleviated hyperactivity and improved spatial learning and memory deficits. It reduced hippocampal neuronal damage, attenuated neuroinflammation, and reversed scopolamine-induced immunosuppression in spleen and thymus. SI also restored the balance of immune cell subsets in both mesenteric lymph nodes and spleen, and the peripheral blood cell counts. Multi-omics analyses suggested that the beneficial effects of SI were associated with reduced neuroinflammation, rebalanced systemic immune responses, partial correction of lipid metabolic disturbances, and restoration of gut microbiota homeostasis. Collectively, our findings indicate that SI effectively mitigates the in vivo ADHD-like impairments by coordinating immune, metabolic, and gut microbiota-related processes, thereby supporting its potential as a marine-derived therapeutic candidate for further ADHD treatment. Full article