Search Results (141)

Tumor-associated glycosylation is a defining hallmark of cancer, exerting profound effects on multiple aspects of tumor biology. This phenomenon arises from the central role of glycosylation in a wide range of cellular processes and its inherently diverse structural complexity. In cancer cells, aberrant glycosylation often results in the modification of glycoconjugate structures, leading to alterations in cell surface architecture that disrupt cellular homeostasis and signaling pathways. These changes can enhance tumor cell proliferation, invasion, and metastasis by modulating cell adhesion, receptor activation, and intracellular communication. Beyond its direct impact on cancer cells, tumor-associated glycosylation plays a pivotal role in shaping the tumor microenvironment. Aberrant glycan structures influence immune cell infiltration by altering antigen presentation and immune checkpoint interactions, contributing to immune evasion. Additionally, these modifications regulate angiogenesis by affecting endothelial cell function and promoting the formation of aberrant vasculature, which supports tumor growth and metastasis. Glycosylation also mediates tumor–stroma interactions, influencing extracellular matrix remodeling and fibroblast activation, further enhancing cancer progression. This interplay between cancer-associated glycan modifications and their functional roles in tumorigenesis presents a promising therapeutic approach. Unlike conventional treatments, glycan-targeting therapies confer high tumor specificity, operate independently of canonical immune checkpoint targets, and help mitigate immune cell exhaustion. This review explores commonly dysregulated glycan motifs implicated in tumorigenesis and delves into their mechanistic contributions to cancer pathogenesis. We then highlight emerging opportunities for therapeutic intervention, including the development of glycan-targeted therapies and biomarker-driven strategies for cancer diagnosis and treatment. We also outline where glycan-targeted agents (e.g., desialylating biologics, glycomimetics, and anti-glycan mAbs) can complement checkpoint blockade and potentially overcome immune escape. Full article

In mammals, CD22 is a member of the Siglec family and plays essential roles in B-cell activation, signal transduction, and immune regulation. However, its functions in teleost fish remain largely unclear. In this study, a CD22 homolog designated On-CD22 was identified and cloned from Nile tilapia (Oreochromis niloticus). On-CD22 transcripts were highly expressed in the head kidney and peripheral blood of healthy fish and showed significant expression changes following infection with Streptococcus agalactiae, Aeromonas hydrophila, or stimulation with poly(I:C). Subcellular localization analysis indicated that On-CD22 is predominantly localized to the plasma membrane. Luciferase reporter assays performed in heterologous cell systems showed that overexpression of On-CD22 was associated with changes in the basal transcriptional activities of NF-κB, IFN1, IFN3, and STAT1 responsive promoters under unstimulated conditions. Furthermore, single-cell transcriptomic analysis revealed that On-CD22 expression was mainly confined to the B-cell population within head-kidney leukocytes. Collectively, these findings suggest that On-CD22 may be involved in immune regulatory processes in Nile tilapia. Full article

Background/Objectives: Psoriasis is a chronic, inflammatory, systemic skin disease. Although topical and systemic drugs with proven effectiveness are used in the treatment, ozone therapy is also applied as a treatment option based on clinical personal experience and with limited published knowledge. In this project, the aim was to evaluate the effectiveness of major ozone therapy in psoriasis patients together with biomarkers in serum. Methods: A total of 26 psoriasis patients and 19 healthy controls were included in the study. The disease severity was evaluated by the psoriasis area severity index score and grouped as mild, moderate/severe. Serum tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL-1β), high-sensitivity C-reactive protein (Hs-CRP), sialic acid, and Sialic acid binding Ig-like Lectin-14 (Siglec-14) levels were investigated in controls and psoriasis patients. Results: Psoriasis area severity index (PASI) score decreased significantly in psoriasis patients after ozone autohemotherapy application (p < 0.005). The values of IL-1β, sialic acid, and Siglec-14 after treatment in healthy subjects were statistically significantly higher than in psoriasis patients. It was found that Hs-CRP and Siglec-14 decreased in all patients after treatment, Hs-CRP decreased more significantly in mild psoriasis patients, and Siglec-14 decreased in both mild and moderate-severe groups (p < 0.05). Conclusions: Our research results suggest that ozone autohemotherapy has clinical efficacy in psoriasis patients, inflammation also has a role in the mechanism of action, and its effectiveness in treatment can be evaluated with inflammation markers. Full article

Background and Objectives: Type I interferon (IFN-I) transcriptional signatures are widely utilised as readouts of innate immunity. We evaluated whether age and sex affect single interferon-stimulated genes (ISGs) and the composite IFN-I score, with implications for control selection and assay calibration. Materials and Methods: Ninety-five healthy individuals (53 males, 42 females; 18 days to 89 years) were studied. Whole-blood expressions of IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1 was quantified by RT-qPCR, normalised to GAPDH and calibrated to a paediatric reference. Age associations used Spearman’s rho; sex differences, two-sided Mann–Whitney U tests. Results: Age effects were modest and gene-specific: IFI44L declined and IFI27 increased with age (significant overall and in females), whereas in males only IFI44L decreased; other ISGs were null (|r| ≤ 0.36). The composite IFN-I score showed no association with age or sex, indicating that aggregation mitigates small gene-level variation and that demographic influences on baseline IFN-I readouts appear minimal within this six-gene whole-blood qPCR panel in our cohort. Conclusions: Methodologically, a single primary cut-off within homogeneous pipelines is appropriate. Although best practice favours age-, sex- and matrix-matched healthy controls, our data show no significant age- or sex-related differences in the composite IFN-I score; matching therefore primarily supports comparability and clinical governance rather than correction of demographic shifts. Full article

Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K⁺ efflux; (iii) a self-amplifying astrocyte–microglia–neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle–mediated propagation of β-amyloid (Aβ) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)/vimentin, connexins, and janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1/Mitochondrial fission protein 1 (Drp1/Fis1) fission imbalance and dysregulation of the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1/PGC-1α) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2–STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase–protein kinase B (PI3K–AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)/spleen tyrosine kinase (SYK)/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1/ CX3C motif chemokine receptor 1 (CX3CL1/CX3CR1), Cluster of Differentiation 200/ Cluster of Differentiation 200 receptor 1 (CD200/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer’s disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective—integrating diverse glial processes to enable comparison across interconnected pathological conditions. Full article

Pleomorphic rhabdomyosarcoma is a rare soft-tissue tumor that occupies an uncertain middle ground between rhabdomyosarcoma and undifferentiated pleomorphic sarcoma. With its relative rarity, aggressiveness, and lack of detailed characterization, it presents a challenging task for therapeutic treatment. In this case study, we use single-cell transcriptomics to investigate the heterogeneous landscape of pRMS and the tumor microenvironment. We demonstrate that the tumor populations in pRMS have a clear division into myogenic and non-myogenic clusters, with the non-myogenic clusters having more numerous communication links with the immune populations. All pRMS tumor clusters use the MIF-CD74 pathway to suppress the immune response, while APP, PTN, and CXCL12 signaling are employed predominantly by the non-myogenic tumor clusters. The cytotoxic T cells in pRMS bear markers of exhaustion (LAG3, HAVCR2, EOMES), and the macrophages express myeloid checkpoint-related genes (SIGLEC1, SIRPA, CSF1R, HAVCR2). This transcriptomic data suggests that targeting MIF and APP signaling in pRMS may have therapeutic potential; however, studies on multiple-patient cohorts, protein verification, and in vitro and in vivo validation are still needed for clinical actionability. Full article

Siglec-10 is a cell-surface lectin that belongs to the sialic acid-binding immunoglobulin-like lectins (Siglecs) receptor involved in immune tolerance, but its role in reproduction remains unknown. Because immune regulation is essential for sperm survival and fertilization, Siglec-10 may represent an unexplored factor in camel fertility. Here, we investigated its expression and localization in the male reproductive tract and spermatozoa of dromedary camels during the rutting season. Testis, epididymis, and vas deferens were analyzed by immunohistochemistry and quantitative PCR, while spermatozoa from fresh ejaculates, frozen–thawed semen, and epididymal samples were examined using chromogenic and fluorescent immunostaining. Siglec-10 was strongly expressed in the testis and epididymis but absent in the vas deferens. In spermatozoa, the signal was localized mainly to the head and midpiece, with consistent patterns in fresh and frozen–thawed semen but absent in epididymal sperm. These findings provide the first descriptive evidence of Siglec-10 in camel reproductive tissues and ejaculated spermatozoa, suggesting a possible involvement in mechanisms that support sperm integrity under stress conditions; however, further studies are needed to clarify its functional role in semen preservation, and highlighting its relevance as a fertility biomarker in seasonal breeders. Full article

The adaptor molecule DNAX-activating protein of 12 kDa (DAP12) is broadly expressed in innate immune cells, but its role in autoimmunity remains unclear due to its dual regulatory functions. We investigated the contribution of the DAP12 pathway to bullous pemphigoid (BP), the most common autoimmune blistering disease, using a mouse model induced by transfer of anti-type XVII collagen (Col17) IgG. Repeated anti-Col17 IgG injections over 12 days produced comparable disease activity in DAP12-deficient and wildtype mice (n = 17/group), indicating that disease induction occurs independently of DAP12 signaling. Flow cytometry and immunofluorescence analysis of lesional skin further revealed a strong upregulation of the DAP12-associated triggering receptors expressed on myeloid cells (TREM) 1 in wildtype BP lesions, whereas TREM2⁺ cell frequencies in anti-Col17 IgG-treated wildtype and DAP12 knock-out animals were significantly lower than in healthy controls. Additional flow cytometry analysis demonstrated altered inflammatory infiltrates with notably reduced frequencies of Siglec-f⁺ eosinophils in DAP12-deficient vs. wildtype lesional skin. In addition, pharmacological inhibition of PI3Kδ, a downstream kinase of the DAP12/TREM pathway, did not affect disease progression in anti-Col17 IgG-induced BP. Collectively, these findings indicate that while DAP12 signaling modulates local immune cell composition, the DAP12/TREM1/2-axis does not influence overall disease activity in experimental BP. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits marked resistance to immunotherapy. Beyond its characteristically low tumor mutational burden, post-translational modifications (PTMs) remodel the immunopeptidome and promote immune escape through reversible, enzyme-driven programs. Subject Matter: We synthesize evidence that aberrant glycosylation, O-GlcNAcylation, phosphorylation, and citrullination constitute core determinants of antigen visibility operating within spatially discrete tumor niches and a desmoplastic stroma. In hypoxic regions, HIF-linked hexosamine metabolism and OGT activity stabilize immune checkpoints and attenuate antigen processing; at tumor margins, sialylated mucins engage inhibitory Siglec receptors on innate and adaptive lymphocytes; within the stroma, PAD4-dependent NET formation enforces T cell exclusion. We also delineate technical barriers to discovering PTM antigens labile chemistry, low stoichiometry, and method-embedded biases and outline practical solutions: ETD/EThcD/AI-ETD fragmentation, PTM-aware database searching and machine-learning models, and autologous validation in patient-derived organoid–T cell co-cultures. Finally, we highlight therapeutic strategies that either immunize against PTM neoepitopes or inhibit PTM machinery (e.g., PAD4, OGT, ST6GAL1), with stromal remodeling as an enabling adjunct. Conclusions: PTM biology, spatial omics, and patient sample models can uncover targetable niches and speed up PDAC vaccination, TCR, and enzyme-directed treatment development. Full article

Sialic acids are terminal monosaccharides that cap glycans on glycoconjugates. Accumulating clinical and experimental evidence shows that obesity, insulin resistance, and diabetes are accompanied by changes in sialic-acid levels. In these conditions, the sialic-acid axis is also broadly remodeled: writers (sialyltransferases), erasers (neuraminidases), and readers (Siglecs) are dysregulated across adipose tissue, liver, pancreas, endothelium, and blood, shifting insulin signaling and inflammatory tone. This review summarizes relevant studies from the perspectives of disease clinical indicators, molecular mechanisms, and interventions targeting sialic acid. Taken together, these results confirm that sialic acids and related molecules play important roles in multiple metabolic diseases; however, controversies remain due to differences in glycan structure, isoforms, and tissue specificity, particularly regarding the precise roles of neuraminidases. Future studies should build on advanced, standardized glycomic and glycoproteomic measures to define molecule- and tissue-specific roles of sialic acids in metabolic disease, enabling reliable biomarkers and guiding targeted therapy. Full article

Recent studies in murine disease models have identified Siglec-F⁺ neutrophils, which express a marker traditionally associated with eosinophils, as a functionally distinct population characterized by extended lifespans and context-dependent roles. While conventional neutrophils typically return to the bone marrow or undergo apoptosis at the site of inflammation, these cells remain in tissues for extended periods. These cells demonstrate remarkable functional plasticity, promote bacterial clearance and immune activation during infections, foster immunosuppression and tumor progression in cancer, and contribute to tissue remodeling in fibrotic diseases. In this review, we examine the key features governing Siglec-F⁺ neutrophil differentiation and function—including Siglec-F signaling, metabolic programming, and upstream cytokine cues—and explore how targeting these pathways may offer promising avenues for precision immunomodulation. Full article

Background and Objectives: Siglec-XII, encoded by SIGLEC12, is a unique sialic acid-binding immunoglobulin-like lectin. It lacks a highly conserved R122 residue for sialic acid recognition in humans. Although it is upregulated in bladder cancer (BCa), its role in tumorigenesis remains largely unexplored. This study aims to investigate the expression patterns of SIGLEC12 in BCa and its correlation with disease features. Materials and Methods: An integrated analysis of transcriptomic data and clinical profiles was conducted using various databases and tools, including UALCAN, GEPIA, TIMER, CAMOIP, and CPADs. The analyses encompassed SIGLEC12 expression, survival rates, immune infiltration levels, promoter methylation, and correlation with drug response. Results: SIGLEC12 expression was higher in both low-grade papillary and high-grade invasive non-papillary BCa. Higher SIGLEC12 expression resulting from low promoter hypomethylation was detected at the stage II-IV of BCa, and was unrelated to disease stages and metastatic stages. Elevated SIGLEC12 expression correlated with increased immune cell infiltration, higher expression of oncogenic and immune checkpoint blockade-related genes, and drug resistance signatures. Mutation analysis confirmed the absence of the canonical R122 missense mutation, indicating that the structural integrity and potential functionality of Siglec-XII are preserved in BCa. Conclusions: SIGLEC12 may have sialic acid recognition functions and serve as a potential early biomarker of BCa. Full article

Sialic acid, typically positioned at the terminal ends of glycoprotein or glycolipid chains via glycosyltransferase activity, is indispensable for intercellular recognition and signal transduction. Aberrant sialylation has been implicated in disrupted cell communication and oncogenic signaling, contributing to carcinogenesis. Consequently, targeting sialic acid metabolism has emerged as a promising strategy for cancer diagnosis and therapy. This review first delineates the physiological biosynthesis of sialic acid and molecular mechanisms underlying its pathological dysregulation. We then examine the sialic acid–Siglec axis as an immune checkpoint in cancer immunotherapy, highlighting its functional convergence and divergence from the PD-1/PD-L1 pathway. Furthermore, we elucidate how aberrant sialylation drives malignant transformation. Finally, we synthesize current therapeutic strategies targeting the sialic acid–Siglec axis, with particular emphasis on implementing nanomaterial-based platforms in clinical translation. These advances may yield novel diagnostic tools and therapeutic targets for glycobiology-guided precision medicine. Full article

Aims: Myocardial inflammation in cardiac amyloidosis is associated with poor clinical outcomes. This study aimed to (a) investigate the relationship between peripheral blood cytokine levels and the presence of inflammatory cells within the myocardium, and to (b) evaluate the potential of cytokines as predictors of major adverse cardiovascular events (MACE) in transthyretin (ATTR) and immunoglobulin light chain (AL) cardiac amyloidosis. Methods: Peripheral blood samples were collected from 50 patients with cardiac ATTR or AL amyloidosis between 2018 and 2023 at baseline and every three months during follow-up visits. Cytokine analysis was performed using Olink’s Proximity Extension Assay. For MACE prediction analysis, only patients with MACE occurring within ±14 days of a study visit were included (n = 16). Associations were evaluated using linear models. Results: No significant associations were identified between the EMB-confirmed myocardial presence of inflammatory cells and cytokine levels. There was a trend of weak-to-moderate associations between serial blood cytokine levels and MACE, albeit this was non-significant after adjustment for multiple testing (FDR): r² = 0.28 for PON3 (p = 0.00075, FDR = 0.28), SIGLEC1 (p = 0.00077, FDR = 0.28), and IL-6 (p = 0.00086, FDR = 0.31). Conclusions: Peripheral blood cytokine levels were not reliable biomarkers for the myocardial presence of inflammatory cells. PON3, SIGLEC1, and IL-6 demonstrated a statistically non-significant trend of a weak-to-moderate association with MACE in cardiac amyloidosis. Since we recently demonstrated that amyloidosis with an inflammatory component is associated with poor outcomes, these additional findings underscore the need for alternative approaches to identify and manage inflammation in this patient population. Full article

Neonatal pneumonia, a leading cause of morbidity and mortality, is frequently caused by Group B Streptococcus (GBS). The mechanisms underlying protective immunity to this pathogen in the neonatal lung remain incompletely understood. Using a clinically relevant neonatal mouse model of GBS pneumonia, we investigated the immune mechanisms influencing disease severity. We demonstrate that neutrophils are effectively recruited to the lungs of infected neonates, but their phenotype differs with disease severity. In pups with moderate disease, we observe significant infiltration of SiglecF^hi neutrophils, a phenotype associated with enhanced phagocytic capacity and bacterial clearance. In contrast, pups with severe disease failed to develop SiglecF^hi neutrophils, resulting in reduced bacterial clearance and worsened pathology. We further show that severity is associated with increased expression of calcitonin gene-related peptide (CGRP) in the lungs. CGRP suppressed neutrophil activation into the SiglecF^hi phenotype, thereby limiting their antibacterial function. Our findings show that GBS exploits the neuroimmune axis to evade host immunity through CGRP-mediated suppression of neutrophil activation. Full article