Search Results (777)

Galectins are a functionally diverse family of β-galactosyl-binding lectins that are ubiquitously present in animal species, with key roles in development and immune regulation. Recently, galectins have been found to recognize microbial glycosylated moieties, but the detailed mechanisms of their innate immune functions in mucosal epithelia have remained elusive. The zebrafish (Danio rerio) represents an ideal genetically tractable model to address these questions, as the skin, gills, and gut display mucosal surfaces exposed to the environment. In this study, we investigated the range of endogenous and microbial glycans that are recognized by zebrafish galectin Drgal1 present in epidermal mucus, which would be consistent with defense functions against a bacterial challenge. Results revealed that zebrafish galectin isoform Drgal1-L2 can recognize selected bacterial glycans, as well as zebrafish mucus glycans and cell-surface receptors for bacterial adhesins such as fibronectin (K_D = 1.593 × 10⁻⁶ M) and CD147 (K_D = 1.115 × 10⁻⁶ M). Furthermore, preliminary experiments revealed that Drgal1-L2 may hinder bacterial adhesion to epidermal mucus in about 50% at 2.5 μg/mL. Our results suggest that Drgal1-L2 present in epidermal mucus can prevent access of pathogenic bacteria to the epithelial cell surface by alternate or synergic binding to bacterial glycans and to zebrafish mucus components and epithelial receptors for bacterial adhesins. Thus, the present study provides key information for the testing of the abovementioned hypothesis by implementing gene-silencing approaches targeting both zebrafish Drgal1-L2 and its ligands. Full article

Background: Surfactant Protein D (SP-D) is a critical immunomodulatory collectin maintaining alveolar homeostasis. Obstructive sleep apnea (OSA)-related intermittent hypoxia (IH) disrupts pulmonary surfactant integrity; however, severity-dependent SP-D dynamics remain incompletely characterized. This study explores SP-D as a potential indicator of IH-induced alveolar stress and evaluates whether Galectin-3 (Gal-3) inhibition modulates surfactant homeostasis. Methods: Forty adult male Sprague-Dawley rats (8 per group) were randomized to Control (normoxia), Moderate IH (MIH; 15–30 events/hour), Severe IH (SIH; 30–60 events/hour), MIH + Gal-3 inhibitor (Modified Citrus Pectin, 800 mg/kg/day), or SIH + Gal-3 inhibitor. IH exposure lasted 8 h/day for 10 days. Outcomes included circulating SP-D, Surfactant Protein B (SP-B), inflammatory markers, physiological parameters, and histopathological lung injury scores assessed via American Thoracic Society guidelines. Results: SP-D levels showed numerical reductions with increasing IH severity (Control: 1969.07 pg/mL [IQR: 262.15]; SIH: 1404.30 pg/mL [IQR: 351.88]), representing a 28.6% decrease. However, between-group variability resulted in non-significant omnibus testing (Kruskal–Wallis p = 0.187). Gal-3 inhibition elevated SP-D levels, particularly in severe IH (2133.95 pg/mL [IQR: 1240.70]), though high inter-individual variability was observed (CV = 58.1%). SP-B showed significant suppression under moderate IH (p = 0.019) with restoration by treatment. Exploratory correlation analysis revealed moderate positive associations between SP-D and heart rate (r = 0.587) and respiratory rate (r = 0.419) in severe IH, though these did not reach statistical significance (p = 0.126 and p = 0.301, respectively). Histologically, severe IH induced diffuse alveolar damage (total lung score: 19.67 ± 0.82). Gal-3 inhibition produced context-dependent effects: protective in severe IH but paradoxically exacerbating inflammation under moderate IH (29.20 ± 4.64 vs. 20.00 ± 4.34; p < 0.05). Gal-3 inhibition significantly attenuated cardiac injury (injury score: 0.00 ± 0.00 vs. 7.17 ± 0.75 in severe IH; p < 0.001, η² = 0.859). Conclusions: SP-D demonstrates severity-associated alterations consistent with alveolar epithelial stress during IH, though high variability limits definitive biomarker validation in this sample. Gal-3 inhibition modulates surfactant homeostasis and attenuates cardiopulmonary injury in a context-dependent manner. These findings support further investigation into SP-D as a component of multimodal severity stratification in OSA and highlight Gal-3 inhibition as a context-dependent anti-inflammatory strategy, pending validation in larger cohorts with tissue-level confirmation. Full article

Galectin-3 (Gal-3) is a multifunctional molecule that exerts pleiotropic effects in inflammatory responses and contributes to the pathogenesis of numerous immune-mediated diseases. Although Gal-3 has been known for more than five decades, it remains a lectin with intriguing and not yet fully elucidated properties. The existing body of evidence underscores the importance of Gal-3 in the regulation of homeostatic and inflammatory processes. Neurotrophins are traditionally recognized as key regulators of neuronal development, survival, and synaptic plasticity; nevertheless, accumulating evidence indicates that they also play important roles in immune regulation and neuroimmune communication. Importantly, neurotrophins are also produced by immune cells, including monocytes, macrophages, lymphocytes, and basophils, which express functional neurotrophin receptors including tropomyosin receptor kinase A (TrkA), tropomyosin receptor kinase A (TrkB), and p75 neurotrophin receptor (p75NTR). In this narrative review, we synthesize current evidence on neuroinflammation, neurotrophins, and Gal-3, with a particular focus on the molecular mechanisms involved in the crosstalk between neurotrophins and Gal-3 or immune cells. We further examine how this neuroimmune–neurotrophic crosstalk contributes to the pathogenesis of psychiatric and neurodegenerative disorders, as well as other neurological conditions. Finally, we discuss the emerging therapeutic potential of targeting neurotrophins and Gal-3 as modulators of neuroinflammation. Full article

Galectin-3 (Gal3) is one of the most pro-inflammatory proteins and a biomarker of inflammatory diseases and cancer. Previous studies showed that Gal3 binds to αv and β1 integrins, but it is unclear how Gal3 binds to integrins. Here, we show that Gal3 bound to soluble αvβ3 and αIIbβ3 integrins in 1 mM Mn²⁺ in cell-free conditions in a glycan-independent manner. Docking simulation predicts that Gal3 binds to the classical RGD-binding site (site 1) of αvβ3, but the predicted Gal3-binding site does not include galactose-binding site. RGDfV or eptifibatide inhibited Gal3 binding to αvβ3 and αIIbβ3, respectively, but lactose, a pan-galectin inhibitor, did not inhibit Gal3 binding to integrins. Point mutations of the predicted site 1 binding interface of Gal3 effectively inhibited Gal3 binding to site 1. Site 2 is involved in pro-inflammatory signaling (e.g., TNF and IL-6 secretion), and we previously showed that pro-inflammatory cytokines (e.g., CCL5 and TNF) bind to site 2 and allosteric integrin activation. Docking simulation predicted that Gal3 binds to site 2 of αvβ3 and α5β1. We found that Gal3 induced allosteric activation of soluble integrins αvβ3, αIIbβ3, and α5β1 in 1 mM Ca²⁺ in cell-free conditions. Point mutations in the predicted site 2 binding interface inhibited Gal3-induced integrin activation, suggesting that Gal3 binding to site 2 is required for Gal3-induced integrin activation. Known anti-inflammatory agents, Ivermectin, NRG1, and FGF1, inhibited integrin activation induced by Gal3 in αvβ3 and αIIbβ3. These findings suggest that Gal3 binding to site 2 may be a potential mechanism of pro-inflammatory and pro-thrombotic action of Gal3. Full article

Acute coronary syndrome patients undergoing percutaneous coronary intervention remain at high risk for major adverse cardiovascular events (MACE: cardiovascular mortality, non-fatal myocardial infarction, and stroke). Inflammatory–oxidative stress biomarkers are potential prognostic tools; however, the influence of sampling timing—pre-procedural versus post-procedural—remains unclear. This meta-analysis evaluated six biomarkers: sST2, GDF-15, OPG, sLOX-1, H-FABP, and Galectin-3. Pooled Hazard Ratios (HRs) for time-to-event outcomes and Standardized Mean Differences (SMDs) between event and non-event groups were synthesized using random-effects models involving 40 studies (18,933 patients). Elevated pre-procedural levels of sST2 (HR = 3.32, p < 0.0001), GDF-15 (HR = 3.00, p < 0.0001), sLOX-1 (HR = 2.61, p = 0.0023), and OPG (HR = 1.79, p = 0.0206) significantly predicted MACE. Notably, pre-PCI sST2 strongly predicted heart failure hospitalization (HR = 6.30, p < 0.0001). Additionally, pre-PCI H-FABP demonstrated a moderate significant effect on adverse outcomes (SMD = 0.67, p < 0.0001). While pre-PCI Galectin-3 was not significant, its post-procedural levels showed a large significant effect (SMD = 1.15, p < 0.0001). In conclusion, inflammatory and oxidative stress biomarkers, particularly sST2 and GDF-15, demonstrate consistent associations with adverse outcomes in ACS patients undergoing PCI, offering more reliable baseline risk stratification than post-procedural measurements. Full article

Myxomatous mitral valve disease (MMVD) is a common cardiac disorder in older small- to medium-sized dogs. Diagnosis and staging are primarily based on echocardiography; however, circulating cardiac biomarkers have gained increasing interest because they are rapid and easily measurable. In this context, the investigators’ aim was to study the clinical value of galectin-3 (Gal-3) and trimethylamine N-oxide (TMAO), in dogs affected by MMVD, in comparison to cardiac troponin I (cTnI), a well-established biomarker of myocardial injury, and echocardiography. Twenty-two dogs were classified as healthy controls or affected by MMVD and staged according to American College of Veterinary Internal Medicine (ACVIM) guidelines. Serum concentrations of Gal-3, TMAO, and cTnI were measured and compared among groups. No significant differences in serum Gal-3 concentration were detected among groups (p = 0.955). In contrast, TMAO levels were significantly higher in both asymptomatic and symptomatic dogs compared with healthy controls (both p < 0.001). Serum cTnI showed limited sensitivity, with increased values observed only in some symptomatic dogs. Despite study limitations, including small sample size and demographic differences among groups, these preliminary findings suggest that TMAO could be a potential biomarker associated with MMVD development and progression; however, further studies are needed to confirm this association. Full article

Melanoma remains a highly aggressive malignancy, particularly in advanced metastatic stages where therapeutic options are limited. Natural compounds provide a structural basis for discovering novel anticancer agents. In this study, we employed an integrated in silico approach to evaluate the pharmacokinetic properties, toxicity profiles, and molecular targets of key alkaloids from Chelidonium majus, including berberine, sanguinarine, chelerythrine, chelidonine, protopine, umbelliferone and coptisine. ADME/T predictions (SwissADME and DeepPK) revealed favorable drug-likeness and oral bioavailability for most compounds, with berberine exhibiting the most balanced safety and absorption profile. All compounds demonstrated high intestinal absorption (>99%) and implicated key melanoma targets, including APE1/Ref-1, CXCR4, CCR2, TLR8, galectin-3, and VEGFR2. These molecules represent valuable templates for the development of melanoma therapies. Among the tested compounds, chelidonine emerged as a potential APE1 inhibitor, exhibiting the highest binding affinity and forming specific interactions within the enzyme’s catalytic site, suggesting its potential as a DNA repair-targeted agent in melanoma. These findings support the further exploration of natural alkaloids, including structural optimization or advanced formulation strategies, to enhance safety, bioavailability, and therapeutic efficacy in melanoma. Full article

Background: The progression of idiopathic pulmonary fibrosis (IPF) involves distal airway remodeling and bronchiolization; however, the mechanisms driving these changes, particularly the contributions of epithelial stem cells, are not fully understood. K13⁺ hillock cells, normally quiescent in proximal airways, were examined for their potential contribution to IPF pathogenesis. Methods: Spatial immunofluorescence was used to profile K13 expression along the airway axes in IPF and control lungs. Multiplex staining complemented by ex vivo culture assays was used to test expression stability. Single-cell RNA-sequencing (scRNA-seq) data were re-analyzed to identify cell subclusters and pathway enrichments. Meanwhile, cell–cell communication was inferred by using CellChat. Results: K13 was ectopically upregulated in IPF honeycomb cysts, triggering a proximal-like pseudostratified phenotype. This shift was marked by surges in K13⁺ regionally overlapping expression patterns (K5⁺, ~9%; CC10⁺, ~53%; ACE-TUB⁺, ~44%; MUC5AC⁺, ~23%) and a decline in SOX2 expression (~95% to ~64%), with ~70% of residual SOX2^low cells exhibiting elevated K13. Accompanying the expansion of K13⁺ subclusters (basal: 1.8% to 41.5%; club: 10.7% to 31.5%), it was observed that the profibrotic markers (K17, S100A2, LGALS7, IGFBP6) and ontologies related to RNA processing, stress response, and senescence were also enriched. These subclusters also amplified pro-fibrotic signaling (e.g., TGF-β, SEMA3, and GALECTIN-9) associated with epithelial subtypes and HAS1^high fibroblasts. Conclusions: Here, we demonstrate that K13⁺ cell activation is a pivotal event, driving the dysregulated proximalization of distal airways in IPF through fate reprogramming and epithelial-mesenchymal crosstalk. Thus, elucidating these K13-mediated fate dynamics provides a critical framework for understanding IPF pathogenesis. Full article

Programmed Death-Ligand 1 (PD-L1) promotes tumor progression through several mechanisms, including its intrinsic effect on breast cancer cell proliferation via the S-Phase Kinase-Associated Protein 2 (SKP2)–p21^Cip1/p27^Kip1 (SKP2-p21/p27) axis. However, the specific regulatory signaling through which PD-L1 influences the SKP2–p21/p27 axis to drive cell proliferation remains unclear. To investigate how PD-L1 mediates SKP2-dependent proliferation, proteomic analyses, gene-expression manipulation via knockdown or overexpression, Western blotting, quantitative immunofluorescence, colony-forming assays, real-time cell analysis, and Xenograft-derived cells were used. Proteomic data analysis identified several PD-L1 downstream targets as potential candidate regulators of the SKP2–p21/p27 axis and activators of the PI3K/AKT pathway. Candidate screening by gene knockdown, followed by analyses of SKP2, p21, and p27 protein expression, revealed Livin and Galectin-1 as upstream regulators of the SKP2–p21/p27 axis. Moreover, Western blotting and quantitative immunofluorescence in three breast cancer cell lines confirmed that PD-L1 is an upstream regulator of Livin, Galectin-1, and SKP2 protein expression. Mechanistically, Livin and Galectin-1 enhanced AKT phosphorylation (Ser473) to sustain PI3K/AKT pathway activation in a positive feedback loop to upregulate SKP2 expression. Functional assays, including colony-forming assays and real-time cell analyzer, demonstrated that Livin and Galectin-1 are critical for PD-L1-mediated, SKP2-dependent proliferation. These findings were corroborated in vivo using xenograft-derived cells. Overall, these findings delineate a tumor-intrinsic signaling axis in which PD-L1 upregulates Livin and Galectin-1 to sustain PI3K/AKT activity and drive SKP2-dependent cell proliferation. Targeting Livin and/or Galectin-1 may provide a rational strategy to disrupt PD-L1-associated proliferative signaling and improve combinatorial therapeutic approaches in breast cancer. Full article

Background/Objectives: Accurate preoperative discrimination between women with ovarian pathology and healthy controls, as well as between benign and malignant ovarian tumors, remains challenging. This study aimed to evaluate the usefulness of osteopontin and galectin-7 on the diagnosis of ovarian tumors. Methods: This prospective single-center case–control study was conducted at the Third Department of Obstetrics & Gynecology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece, between 2018 and 2024. Preoperative serum levels of osteopontin, galectin-7, and established tumor markers (CA-125, CA19-9, CA15-3, CEA, AFP) were analyzed. Biomarker distributions were compared using non-parametric tests. Associations with clinical variables were explored using correlation analyses. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess diagnostic performance. Results: The study population included 116 women: 52 healthy controls, 45 patients with benign ovarian tumors, and 19 patients with malignant ovarian tumors. Serum osteopontin and galectin-7 levels did not differ significantly between control and study group (p = 0.562 and p = 0.138, respectively), nor between benign and malignant tumors (p = 0.784 and p = 0.140, respectively). Osteopontin showed no discriminatory ability (AUC = 0.47), while galectin-7 demonstrated weak discrimination (AUC = 0.63). A combined model yielded modest improvement (AUC = 0.69), remaining below clinically meaningful thresholds. CA-125 was the only biomarker significantly associated with malignancy (OR = 1.03, p = 0.038). Galectin-7 levels were higher in premenopausal women and inversely correlated with age, suggesting demographic rather than malignant influence. Conclusions: Despite strong biological relevance, circulating osteopontin and galectin-7 did not provide meaningful diagnostic discrimination between women with ovarian pathology and healthy controls or between benign and malignant ovarian tumors. CA-125 remained the most informative serum marker in this setting. Future efforts should focus on multi-marker strategies integrated with imaging and clinical assessment. Full article

Background: Oral squamous cell carcinoma (OSCC) remains clinically challenging, particularly in advanced disease, where treatment resistance limits therapeutic outcomes. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential anticancer vulnerability. Galectin-1 (Gal-1/LGALS1), a β-galactoside–binding lectin frequently overexpressed in OSCC, is associated with tumor progression and unfavorable prognosis; however, its involvement in ferroptosis regulation remains incompletely understood. Methods: To investigate whether Triptolide (TPL) influences ferroptosis-associated responses through Gal-1 modulation, OSCC cell lines (SAS and HSC-3) were treated with TPL and analyzed for cell viability, lipid reactive oxygen species (ROS) accumulation, and glutathione peroxidase 4 (GPX4) expression. Publicly available The Cancer Genome Atlas (TCGA) datasets were examined to evaluate Gal-1 expression patterns and survival associations. An OSCC xenograft mouse model was further used to assess the antitumor effects of TPL and changes in ferroptosis-related markers in vivo. Results: TPL treatment reduced cell viability and increased lipid ROS accumulation in OSCC cells, accompanied by downregulation of GPX4 expression. Gal-1 expression was also decreased following TPL exposure in vitro and in xenograft tumors. Analysis of TCGA data revealed that elevated Gal-1 expression was significantly associated with poorer overall survival in OSCC patients. Conclusions: These findings indicate that TPL induces ferroptosis-associated responses in OSCC and suggest that this effect is partly mediated through modulation of Gal-1 expression. Gal-1 may represent a clinically relevant factor influencing ferroptosis susceptibility, and targeting this pathway warrants further investigation as a potential therapeutic strategy for OSCC. Full article

Recognition and binding to β-galactose-containing carbohydrates and lipids are crucial for several fundamental biological processes that are mediated primarily by a family of proteins known as galectins (S-type lectins). Galectins in the human placenta regulate critical processes such as maternal–fetal immune tolerance, trophoblast invasion, vascular remodeling and angiogenesis, ensuring proper fetal development and preventing pregnancy complications such as preeclampsia and miscarriage. Gestational diabetes mellitus (GDM) is a widespread complication of pregnancy, affecting approximately 1 in 7 pregnancies, and its incidence is increasing globally, indicating a particularly strong association with the obesity pandemic. Profiles of placental expression and distribution of individual galectins significantly change during the course of GDM. This is accompanied by placental dysfunction, which is especially severe with poor glycemic control. The aim of this review is to present the current state of knowledge on the involvement of abnormal galectin signaling in the pathomechanisms of GDM-associated placental dysfunction. Further research is needed to determine whether changes in placental galectins occur secondary to metabolic abnormalities in GDM or are involved as a primary cause. Galectins present in placental tissue and serum should be validated as potential biomarkers of GDM. Full article

Prostate cancer remains largely refractory to immunotherapy, implying the existence of context-specific immune landscape programs that diverge between circulation and tumor. Here, we integrate bulk RNA sequencing from three cohorts (patient peripheral mononuclear cells, primary prostate tissue, and biochemical-recurrence tumors) with multiparameter flow cytometry, unsupervised UMAP/T-REX (Tracking Responders Expanding) mapping, and de novo discovery of long non-coding RNAs (lncRNAs) to characterize context-specific immunoregulation. Patient PBMCs revealed a coherent IL-1/TNF/IL-17 inflammatory architecture with strong chemotactic programs and an unexpected neutrophil-like signal despite density-gradient isolation, consistent with low-density PMN-MDSCs. In contrast, tumors broadly repressed chemokines and innate immune mediators, yet upregulated prostate cancer-associated lncRNAs, indicating local immune quiescence coupled with non-coding regulatory programs. Recurrent tumors acquired epithelial–mesenchymal transition and metabolic remodeling, accompanied by relapse-associated lncRNA signatures, whereas long-term nonrecurrent tumors preserved epithelial and stress-response networks. High-dimensional cytometry confirmed discrete, cancer-enriched myeloid clusters expressing CD47, SIRPα, PD-L1, CD73, and Galectin-9. Network analysis highlighted inflammatory hubs (CXCL2, PTGS2) in PBMCs and loss of mechanotransduction modules in tumors. Structural modeling uncovered a three-way junction and 3′ triple helix in lncRNA. Collectively, these data suggest that circulating inflammatory rewiring is associated with checkpoint-rich suppressor expansion and tumor immune quiescence, outlining integrated myeloid- and RNA-directed strategies for cancer research. Full article

Introduction: Radioresistance in prostate cancer (PCa) poses a major therapeutic challenge. Galectin-3 (Gal-3) is overexpressed in aggressive PCa and may contribute to resistance mechanisms. This study evaluated the role of Gal-3 in radioresistance and assessed the effect of its pharmacological inhibition using GB1107. Methods: Parental (22RV1-P) and radioresistant (22RV1-RR) PCa cell lines were treated with GB1107. Western blotting assessed Gal-3 and Protein Phosphatase 1 alpha (PP1α) expression. Cell viability (PrestoBlue™), migration (wound assay), and clonogenic survival post-irradiation were evaluated. Statistical significance was set at p < 0.05. Results: Gal-3 was significantly upregulated in 22RV1-RR cells (p = 0.0237). GB1107 reduced viability and impaired migration in both cell lines. Radiosensitisation was observed in 22RV1-P cells (p < 0.0001) but was not significant in 22RV1-RR cells (p = 0.1258). A non-significant increase in PP1α expression was detected in RR cells. Conclusion: Gal-3 contributes to radioresistance. Further studies are needed to clarify the role of PP1α and optimise Gal-3-targeted strategies. Full article

Diabetes is a chronic inflammatory disease due to decreased insulin release or insulin resistance. Diabetes complications stem from high blood sugar damaging blood vessels and nerves, leading to issues like heart disease, stroke, kidney failure, nerve damage, vision loss, foot ulcers, gum disease, skin infections, and digestive/bladder issues. Galectins, especially galectin-3, are emerging as key players in diabetes complications, promoting fibrosis, inflammation, and vascular damage. This suggests that galectins may be potential therapeutic targets in diabetes and its complications, and a need to understand their role and therapeutic potential. The objective of this review is to synthesize current evidence on galectin biology in diabetes mellitus (mainly on type II diabetes) and DFUs, delineate their mechanistic roles in metabolic dysfunction and wound healing, summarize findings from human and preclinical studies, and evaluate emerging diagnostic and therapeutic strategies. Finally, this review highlights key gaps that must be addressed to advance clinical translation. The literature search suggests that galectins play a critical role in the pathogenesis of diabetes and related complications and may be potential therapeutic targets. Full article