Search Results (769)

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

Background and Hypothesis: Mortality in hemodialysis (HD) remains high and is not fully explained by traditional risk factors. Biomarkers reflecting myocardial stress and fibrosis, together with measures of vascular stiffness, may provide additional prognostic information in this population. Methods: We conducted a retrospective study evaluating 173 HD patients who were clinically stable and asymptomatic at baseline over a follow-up period of over 10 years. Patients were classified into four groups based on median baseline values of NT-proBNP and galectin-3 (4234 pg/mL and 28.1 ng/mL, respectively). Primary outcomes were all-cause mortality and major adverse cardiovascular events (MACE). Pulse wave velocity (PWV) was evaluated as an additional prognostic marker. Results: During follow-up, 76.9% of patients died. Higher NT-proBNP levels were associated with increased all-cause mortality, irrespective of galectin-3 levels, with adjusted hazard ratios of 2.58 and 1.93 compared with the reference group (p < 0.05). Age and PWV were independently associated with mortality risk, corresponding to a 4% increase in risk per year of age and a 6% increase per 1 m/s increase in PWV. MACE occurred in 26.8% of patients and did not differ significantly between biomarker-defined groups. Conclusions: In this long-term HD cohort, elevated NT-proBNP and increased arterial stiffness were independently associated with higher all-cause mortality. These findings support the complementary prognostic value of markers of cardiac stress and vascular stiffness in chronic hemodialysis patients. Full article

Introduction: The one-step membrane technique, derived from the Masquelet induced membrane technique, uses human acellular dermal matrix (hADM) that is wrapped around the bone defect to bypass membrane induction, reducing treatment time. Pre-colonization of hADM with bone marrow cells (BMC), particularly after CD8⁺ T cell depletion, enhances bone regeneration. This study examined how CD8⁺ T cell depletion alters the proteins accumulated in the hADM during early healing. Materials and Methods: Eighteen male Sprague-Dawley rats received 5 mm femoral defects filled with autologous bone chips and wrapped with hADM, hADM + BMC, or hADM + BMC-CD8. hADMs were recovered on days 3 and 7 (n = 3/group/timepoint), incubated ex vivo, and conditioned medium analyzed with a proteome profiler detecting 79 proteins. Results: The protein content of the hADM evolved dynamically. At day three, 41 proteins were detected, rising to 47 by day seven, with RGM-A, osteoprotegerin, LIF, IL-6, CCL20, and CCL17 emerging late, consistent with increased regenerative activity. CD8⁺ T cell depletion suppressed early inflammatory and pro-osteogenic mediators (e.g., CCL2, IGF-I, IL-1RA) while upregulating LIX. By day seven, regenerative mediators (CCL20, GDF-15, RGM-A) were enriched, whereas inflammatory factors (CCL21, IL-1a, WISP-1) declined. MMP-9, Galectin-1, and GDF-15 increased exclusively in the CD8-depleted group. Conclusions: The hADM protein content transitions from pro-inflammatory to pro-regenerative within one week after surgery. CD8⁺ T cell depletion accelerates this shift, highlighting hADM as a dynamic scaffold that contributes to the immune–regenerative crosstalk in bone healing. Full article

The oncogene KRAS drives tumor growth by activating pathways such as MAPK and PI3K-AKT in a constitutive manner. Although direct KRAS inhibitors exist, they are often limited in clinical use due to therapeutic resistance and toxicity. Therefore, alternative combinatorial therapeutic strategies are urgently needed. This study examined the knockout of five KRAS-related proteins—galectin-3 (GAL3), phosphodiesterase delta (PDEδ), nucleophosmin (NPM1), IQ motif-containing GTPase-activating protein 1 (IQGAP1), and SHOC2—using CRISPR-Cas9 in adenocarcinoma cell lines harboring the KRAS(G12V) oncogenic mutation, as well as in the noncancerous HEK-293 cell line. These proteins act as critical modulators that regulate KRAS activity, cellular localization, and that of its downstream signaling components. We analyzed the downstream activation of ERK and AKT kinases and evaluated subsequent cancer cell proliferation. Knockout of GAL3 and PDEδ was highly effective, significantly reducing MAPK and PI3K-AKT pathway activity and substantially impairing cell proliferation. SHOC2 knockout selectively and potently disrupted MAPK activation, while NPM1 knockout resulted in the complex, reciprocal modulation of the two major pathways. Notably, knocking out IQGAP1 enhanced PI3K–AKT and mTORC2–AKT signaling without affecting the MAPK pathway. These distinct modulatory roles highlight the non-redundant functions of the accessory proteins. In conclusion, our findings establish GAL3 and PDEδ, two KRAS-associated proteins, as promising combinatorial drug targets. Targeting these modulators provides an effective alternative strategy to overcome resistance mechanisms and enhance the clinical utility of existing KRAS inhibitors. Full article

Background: Device-detected subclinical atrial fibrillation (SCAF) and atrial high-rate episodes (AHRE) are increasingly recognized in patients with cardiac implantable electronic devices and through long-term rhythm monitoring. Although often asymptomatic, these episodes are associated with a higher risk of clinical atrial fibrillation (AF), stroke, and heart failure. Aims: This narrative review summarizes clinical, electrocardiographic, echocardiographic, and circulating biomarkers associated with the development and progression of device-detected SCAF/AHRE. Methods: We performed a comprehensive search of PubMed, Embase, and Scopus using combinations of the terms “subclinical atrial fibrillation”, “atrial high-rate episodes”, “device-detected AF”, “predictive factors”, “P-wave morphology”, “echocardiographic parameters”, “left atrial strain”, and “biological markers”. We included English-language-only studies of patients with cardiac implantable electronic devices or long-term monitoring and reporting incident SCAF/AHRE or AF as outcomes, published in the last 10 years. Results: Older age, high body mass index, heart failure, obstructive sleep apnea, and C₂HEST score are consistently associated with SCAF. On-surface electrocardiogram (ECG) and device electrograms, prolonged and dispersed P-wave indices, low atrial sensing amplitude, and specific pacing configurations, particularly right ventricular apical pacing with wide QRS, predict incident and longer-lasting AHRE. Echocardiographic markers of atrial cardiomyopathy, including increased left atrial volume and impaired atrial strain, together with indices of left ventricular diastolic dysfunction, further refine risk. Among circulating biomarkers, galectin-3 and high-sensitivity C-reactive protein show the most reproducible associations with incident AHRE. Conclusions: A multiparametric approach combining clinical profile, ECG features, advanced echocardiography, and selected biomarkers may improve identification of patients at risk for device-detected SCAF. Further prospective studies are needed to define risk thresholds that justify intensified rhythm surveillance and early initiation of anticoagulation or rhythm control strategies, especially in AHRE shorter than 24 h. Full article

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia worldwide and is now increasingly regarded as a disease of chronic inflammation and progressive atrial fibrosis. Understanding of molecular mechanisms that mediate the linkage between systemic metabolic dysregulation, inflammation, and structural atrial changes is crucial for informing risk stratification and targeting of prevention strategies. This review provides evidence from 105 studies focusing on the contributions of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-a (TNF-α), interleukin-6 (IL-6), galectin-3, and galectin-1 to cardiac fibrogenesis, atrial fibrosis, and AF pathogenesis. We also link metabolic syndrome to these biomarkers and to atrial remodeling, as well as echocardiographic correlates of fibrosis. TGF-β1 is established as the central profibrotic cytokine and promotes Smad-based fibroblast activation, collagen accumulation, and structural atrial remodeling. Its role is highly potentiated by thrombospondin-1 by turning latent TGF-β1 into its potent form. TNF-α and IL-6 also play an integral role in the inflammatory fibrotic continuum by activating NF-κB and STAT3 signaling, promoting fibroblast proliferation, electrical uncoupling, and extracellular matrix accumulation. Galectin-3 is a potent profibrotic mediator that promotes TGF-β signaling and is a risk factor for negative outcomes, whereas Gal-1 seems to regulate inflammation resolution and may exert context-dependent protective or maladaptive roles. Metabolic syndrome is strongly associated with excessive levels of these biomarkers, chronic low-grade inflammation, oxidative stress, and ventricular and atrial fibrosis. Chronic clinical findings show that metabolic syndrome (MetS) increases AF risk, exacerbates atrial dilatation, and is associated with worse postoperative outcomes. Echocardiographic data are connected to circulating biomarkers and are non-invasive for evaluating atrial remodeling. The evidence to date supports that atrial fibrosis should be considered an end point of systemic inflammation, metabolic dysfunction, and activation of profibrotic molecular pathways. Metabolic syndrome, due to its chronic low-grade inflammatory environment and prolonged levels of metabolic stress, manifests as an important upstream factor of fibrotic remodeling, which continuously promotes the release of cytokines, oxidative stress, and fibroblast activation. Circulating fibrotic biomarkers, in comparison with metabolic syndrome, serve separate yet interdependent pathways that help orchestrate atrial structural remodeling through the simultaneous process but can also provide a long-term indirect measure of ongoing profibrotic activity. The integration of these biomarkers with superior atrial imaging enables a broader understanding of the fibrotic substrate of atrial fibrillation. This combined molecular imaging approach can facilitate risk stratification, refine therapeutic decisions, and facilitate early identification of higher-risk metabolic phenotypes, thus potentially facilitating directed antifibrotic and anti-inflammatory therapy in atrial fibrillation. Full article

Background: Psoriasis is a chronic, immune-mediated skin disorder characterized by accelerated epidermal turnover. Galectins are a family of carbohydrate-binding proteins that play crucial roles in various biological processes. Methods: This study aimed to assess the plasma concentrations of galectin 7 and 8 (gal-7 and 8) in 60 psoriatic patients compared to the control group of 30 individuals without dermatoses. Results: The median gal-7 plasma concentration in patients was 188.8 (11.43–1406) pg/mL, and it was significantly higher than in controls (p < 0.001). There was a positive correlation between gal-7 concentration and psoriasis area and severity index (PASI; R = 0.3, p = 0.0199), and a negative with RBC (R = −0.41, p < 0.001), hemoglobin concentration (R = −0.34, p < 0.01), total cholesterol (R = −0.38, p < 0.01) and LDL concentration (R = −0.36, p < 0.05). In contrast, gal-7 was not correlated with psoriasis duration or patients’ age or sex (p > 0.05). The median gal-8 plasma concentration in patients was 0.07 (0.02–0.5) ng/mL, and was significantly higher in patients than controls (p < 0.05). There was a positive correlation between gal-8 concentration and glucose concentration (R = 0.26, p < 0.05). Gal-8 concentration was not correlated with PASI, BMI, age or sex of patients (p > 0.05). We also analyzed the receiver operating characteristic (ROC) curve to evaluate the predictive power of gal-7 and 8 for psoriasis. Gal-7 achieved statistical significance in predicting psoriasis and had an area under the curve (AUC) value of 0.842 (p < 0.001), a sensitivity of 80%, and a specificity of 86.7%, whereas gal-8 had an AUC value of 0.644 (p = 0.025), a sensitivity of 81%, and a specificity of 47%. Conclusions: Gal-7 and gal-8 could potentially serve as psoriasis biomarkers, whereby gal-7 could also serve as a marker of its severity. Future studies are needed to clarify their actual role or potential as therapeutic targets in psoriasis. Understanding their precise functions may open new perspectives for personalized treatment strategies in psoriatic patients. Full article

Background: Galectin-10 (Gal-10), the main constituent of Charcot–Leyden crystals, is a recognized marker of eosinophilic inflammation, yet its role in nasal mucosal remodeling in Seasonal Allergic Rhinitis (SAR) remains poorly defined. Methods: Gal-10, IL-5, MUC5AC, and IFN-γ were analyzed in Nasal lavage (NL) samples from children with SAR by ELISA. Unsupervised clustering and discriminant analyses were applied. The functional effects of Gal-10 were investigated ex vivo using a 3D epithelial–mesenchymal trophic unit (EMTU) model stimulated with NL containing high, low, or depleted Gal-10 levels. EMT (epithelial–mesenchymal transition) markers (vimentin, E-cadherin, SNAIL1) and MUC5AC secretion were assessed by immunohistochemistry, Western blot, and ELISA. Results: Gal-10 levels in NL positively correlated with IL-5 and MUC5AC and inversely with IFN-γ. Clustering analysis identified distinct SAR endotypes, with Gal-10 showing the highest discriminative power. In the 3D EMTU model, high Gal-10 NL induced increased vimentin and SNAIL1 expression and enhanced MUC5AC secretion, effects attenuated after Gal-10 depletion. Conclusions: Gal-10 is associated with Th2-type inflammation, mucus hypersecretion, and early epithelial–mesenchymal transition in pediatric SAR, supporting its role as a mediator of nasal mucosal remodeling and a potential therapeutic target Full article

Beyond their traditional role as short-lived antimicrobial cells, neutrophils are increasingly recognized as key regulators of adaptive immunity and tumor progression. This AI-assisted integrative review investigated the neutrophil–T-cell axis, particularly the role of Galectin-9 (Gal-9), across adult T-cell leukemia/lymphoma (ATL), Sézary syndrome (SS), coronavirus disease 2019 (COVID-19), and psoriasis. Leveraging AI tools (GPT-5 and Adobe Acrobat AI Assistant) for literature synthesis (2000–2025) and expert validation, we aimed to identify common immunological mechanisms. Across all conditions, neutrophils displayed persistent activation, elevated Gal-9 expression, and modulated T-cell interactions. In ATL and SS, neutrophilia correlated with poor survival and TCR signaling dysregulation, suggesting Gal-9-mediated immune modulation. In COVID-19 and psoriasis, neutrophil-derived Gal-9-linked innate hyperactivation to T-cell exhaustion and IL-17-driven inflammation. These findings define a recurring neutrophil–Gal-9 regulatory module connecting innate and adaptive immune responses. This study underscores the feasibility of combining AI-driven literature synthesis with expert review to identify unifying immunological mechanisms and therapeutic targets across malignancy and inflammation. Full article