Search Results (91)

Background: Osteoporosis (OP) is a chronic disease characterized by decreased bone mass and altered microarchitecture, leading to bone fragility and fracture risk. To date, although carbohydrate-binding proteins Galectins 1 and 3 (Gal-1/Gal-3) have been implicated in bone metabolism, inflammation and aging, their levels and potential regulation by microRNAs (miRNAs) have not yet been investigated in OP. Methods: In this pilot study, 13 osteoporotic (OP) and 10 non-osteoporotic (NOP) patients, all undergoing hip or knee arthroplasty, were enrolled. Due to the unavailability of DXA measurements, OP classification was based on cortical bone ratio and distal femoral cortical index. Clinical parameters and blood samples were collected preoperatively, while bone biopsies were obtained intraoperatively. ELISA and qRT-PCR were used to quantify Gal-1, Gal-3, miR-22 and miR-21 in bones and sera. Correlations with clinical parameters were assessed. Results: Several OP biopsies exhibited a reduction in Gal-1 levels, whereas miR-22, Gal-3 and miR-21 were increased. Serum analysis revealed similar dysregulation patterns, with increased miR-21 and decreased Gal-1 and miR-22 levels in several OP patients. Conclusions: This pilot study suggests a putative association of Gal-1, Gal-3, and their previously reported related miRNAs with osteoporotic bone status, indicating their potential involvement in OP-related bone metabolism. Full article

Histiocytic sarcoma (HS) is an aggressive hematological malignancy whose transformed cells exhibit morphological and immunophenotypic characteristics similar to macrophages, and arises de novo or as part of a clonal ‘evolution’ of other pre-existing hematological neoplasms. This study investigates the potential use of the J774A.1 cell line (a cell line derived from murine tumor cells, commonly used in macrophage research) as a research model to study the role of polydisperse extracellular vesicles (PEVs) secreted by the HS cells, considering that bacterial infections are common in patients with cancer, including HS. The influences of bacterial components on tumor progression are still not fully understood. We stimulated the J774A.1 cell line in vitro with a fraction of E. coli, and our results show that the bacterial stimulation increases the secretion of PEVs by these cells. Comparative results of J774A.1 cells with PEVs using confocal and scanning electron microscopy with micrographic reports of HS histological slides (from several cited mammal species, including humans) suggest a possible relationship of large PEVs with marks, footprints, or traces of possible large PEVs disrupted in the HS of these reports. A subsequent proteomic analysis of these PEVs revealed a diverse subcellular origin of their components, such as proteins including: Triosephosphate isomerase (TPI), Heat shock cognate 71 kDa, Apolipoprotein A-1, Rho GDP-dissociation inhibitor 1, GAPDH, Galectin, Moesin, globular Actin, and Annexin. These results highlight the importance of studying the interplay between HS, other hematological cancers, and bacterial infections to better understand the progression of this cancer, identify new therapeutic targets, and emphasize the importance of preventing bacterial infections in cancer patients. Furthermore, the results demonstrate the potential use of the stimulated J774A.1 cell line for research on HS-related PEVs. 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

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

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

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

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

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

Chronic lymphocytic leukemia (CLL) is a heterogenous disease, with varied clinical outcomes. Multiplex assays used to measure soluble immune checkpoints offer a less laborious method of monitoring patients with CLL, but none of these panels have been validated. The aim of the study was to assess soluble immune checkpoint profiles in patients with CLL and to correlate these with independent prognostic markers such as β2-microglobulin (B2M), Rai stage, fluorescence in situ hybridization (FISH) status, and the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI). We measured plasma levels of soluble interleukin-2 receptor alpha (sCD25), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), galectin-9, programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) using cytometric bead array-based assays. We further measured plasma levels of B2M using an enzyme-linked immunosorbent assay (ELISA) kit. Soluble immune checkpoints were correlated with prognostic markers. The plasma levels of sCD25, TIM-3, galectin-9, PD-1, and PD-L1 were significantly increased in patients with CLL compared to the control group, p < 0.0001. Galectin-9 plasma levels were directly associated with B2M levels (β = 0.65, p = 0.012). Our findings suggest that galectin-9 may provide valuable prognostic significance for patients with CLL. Full article

Heart failure (HF) is a major cardiovascular complication in people with type 2 diabetes (T2D), where heart failure with preserved ejection fraction (HFpEF) is the most common presentation. Despite its high prevalence, HF in T2D often remains undiagnosed during its early stages due to nonspecific symptoms and the limitations of conventional diagnostic tools. Epicardial adipose tissue (EAT), a visceral fat depot surrounding the myocardium, has emerged as a mechanistic and clinically relevant contributor to myocardial dysfunction. In T2D, EAT expansion fosters a pro-inflammatory, fibrotic, and metabolically adverse milieu that may directly promote the onset and progression of HF. This perspective synthesizes current translational evidence on the role of EAT in the pathogenesis of HF among individuals with T2D. We highlight diagnostic challenges related to imaging-based quantification and the limited sensitivity of natriuretic peptide-based screening, while emphasizing the potential relevance of emerging biomarkers such as GDF-15, Galectin-3, sST2, LDL particle size, GGT, and soluble low-density lipoprotein receptor-related protein 1 (sLRP1) to enhance early detection and risk stratification. Additionally, therapeutic approaches—including lifestyle modification, SGLT2 inhibitors, and GLP-1 receptor agonists—are considered for their potential to modulate EAT volume and reduce cardiovascular risk. Advancing knowledge on EAT biology and its circulating biomarkers holds promise to refine HF risk stratification and support translational efforts toward precision cardiometabolic care. Full article

CaMK4, a calcium/calmodulin-dependent protein kinase, is an important mediator of cellular signal transduction, yet its role in the regulation of skeletal muscle satellite cells (MuSCs) in goats has remained unclear. In this study, CaMK4 overexpression and knockdown models were established, and integrated transcriptomic and proteomic analyses were performed to systematically elucidate its regulatory network. CaMK4 overexpression altered key pathways associated with cell proliferation and muscle development, including cAMP, PI3K-Akt, and actin cytoskeleton regulation, while proteomic data highlighted calcium signaling and JAK-STAT pathways. Conversely, CaMK4 knockdown enhanced MuSC proliferation by upregulating cell cycle-related genes and proteins. Integrated analyses further identified that Galectin-9 (LGALS9), Collagen triple helix repeat containing-1 (CTHRC1), Hyaluronan Synthase 1 (HAS1), and L-Threonine Dehydrogenase (TDH) may serve as potential key nodes regulating cell cycle, apoptosis, and metabolic control. This suggests a regulatory role for CaMK4. Collectively, these findings provide a mechanistic framework for understanding CaMK4 function in ruminant muscle development and may offer insights for improving goat muscle growth, meat quality traits, and production efficiency. Full article

Lichen sclerosus (LS) is a chronic, relapsing skin disease that predominantly affects the perineal and genital regions, although extragenital manifestations can occur. Despite its significant impact on patients’ quality of life, particularly affecting sexual and urinary function, LS remains underdiagnosed. Multiple factors, including genetic predisposition, hormonal changes, immunological abnormalities, trauma, and urine irritation, contribute to its development and persistence. This review aims to clarify the complex pathophysiology of LS by exploring three main mechanisms: autoimmune dysregulation, sclerotic tissue formation, and oxidative stress. Autoimmune dysregulation involves T-cell infiltration and the roles of miR-155 and extracellular matrix protein 1 dysfunction, leading to chronic inflammation. miR-155 contributes to sclerotic tissue formation alongside galectin-7, promoting fibroblast proliferation and collagen synthesis. Oxidative stress results in tissue damage, autoimmunity, chronic inflammation, and an increased risk of carcinogenesis. Understanding these mechanisms is crucial for developing targeted therapies and improving LS management. Further research is needed to unravel the genetic basis, immune responses, and interactions between key mediators, ultimately advancing innovative therapeutic strategies and precision medicine in LS. Full article

Galectin-9 (Gal-9, LGALS9) is a member of the family of carbohydrate-binding lectins known as galectins. Galectins bind a diverse repertoire of galactose-bearing glycoprotein receptors expressed across multiple cell types. These interactions elicit a broad spectrum of pleiotropic effects important in both normal physiology and disease pathogenesis. Gal-9 contains two separate carbohydrate recognition domains with overlapping yet also divergent binding affinities for distinct glycostructures. This tandem repeat motif enables fine-tuning of its various biological functions. Additional control of Gal-9 activity is provided via multiple gene variants, protein isoforms, tissue distribution, and cell type-associated glycoprotein binding profiles. Within the tumor microenvironment, Gal-9 interacts with immune, non-immune, and cancer cells to influence malignant progression. Its binding of the premier immune checkpoint glycoreceptors, T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3) and programmed cell death protein 1 (PD-1), places Gal-9 apart as a burgeoning target for immunotherapy. In this review, we delve into important aspects of Gal-9 immunobiology in tumorigenesis, including glycobiological and lineage-dependent functions. We further examine Gal-9 as a promising new glyco-immune checkpoint target for cancer therapy. Full article

Background and Objectives: Galectin-3 (Gal-3), a pro-inflammatory cytokine, has been implicated in atherosclerosis and adverse cardiovascular outcomes. While its role in coronary artery disease (CAD) is increasingly recognized, its association with systemic atherosclerosis remains underexplored. Objective: To investigate serum Gal-3 levels in patients with CAD and evaluate correlations between CAD severity and extra-coronary atherosclerotic involvement (carotid, femoral, and radial territories). Materials and Methods: We prospectively enrolled 56 patients with CAD undergoing coronary angiography (42.8% with acute-ACS; 57.2% with chronic coronary syndromes-CCS). Gal-3 levels were measured within 24 h of admission. Atherosclerosis severity was assessed angiographically and through vascular ultrasound of the carotid, femoral, and radial arteries. Patients were stratified by median Gal-3 levels, and clinical follow-up was performed at 1 and 3 months. Results: Gal-3 levels were significantly higher in CAD vs. controls (20.7 vs. 10.1 ng/mL; p < 0.00001) and in ACS vs. CCS (22.18. vs. 17.93 ng/mL; p = 0.019). Gal-3 correlated positively with culprit lesion diameter stenosis (DS) (R = 0.30; p = 0.023) and maximum severity of additional treated lesions (R = 0.62; p = 0.006). Gal-3 also correlated positively with carotid plaque thickness (R = 0.32; p = 0.016), while patients with Gal-3 levels above the median showed increased median values for femoral plaque thickness (32.4 vs. 26.45 mm, p = 0.046). No correlation was found with radial artery calcification. Gal-3 showed moderate discrimination for ACS (AUC = 0.685; cut-off 20.18 ng/mL). On multivariate analysis age, DS, and ACS presentation were independent predictors of Gal-3 above 19.07 ng/mL. Conclusions: Gal-3 levels are elevated in ACS and correlate with atherosclerotic burden, particularly in coronary, carotid, and femoral territories. These findings support Gal-3 as a potential marker of lesion severity and systemic vascular involvement, highlighting its possible role in risk stratification and the monitoring of atherosclerotic disease progression. This study provides integrated insights into the impact of Gal-3 across multiple vascular beds by assessing them concurrently within the same patient cohort. Full article

T lymphocytes infiltrate the CNS in response to murine cytomegalovirus (MCMV) infection and form a pool of long-lived brain tissue-resident memory T-cells (bT_RMs), which display markers of residency (i.e., CD103, CD69, CD49a). However, the functional role of these bT_RMs is still unknown. By 30 days postinfection, a latent viral brain infection was established, as indicated by absence of viral transcripts (IE1, E1, and gB) produced during productive infection. Following intracerebroventricular injection of either depleting α-CD8 Ab (clone YTS169.4) or α-CD103-sap (clone IT50) into the brain, 90–95% T-cell depletion was achieved. Using luciferase-expressing mice, we observed recommenced imaging signals indicative of de novo MCMV IE promoter activity in depleted animals. Surprisingly, using an explant assay, we efficiently recovered reactivatable, infectious virus from untreated, latent animals, but not from those depleted of bT_RMs (viral recovery in explants was reduced from 100% to 50% by day 21). We identified Lgals3 (galectin 3), Gpnmb (glycoprotein nonmetastatic melanoma protein B) and Hmox1 (heme oxygenase 1) as genes that were most upregulated in bT_RM-depleted groups. When bT_RMs were depleted, there was transient expression of viral IE genes which resulted in antiviral microglia with a phagocytic, disease-associated (DAM) or neurodegenerative (MGnD) phenotype. These data provide new insights into the role of bT_RMs in controlling both CNS reactivation and driving microglial phenotypes. Full article