Search Results (523)

Celiac disease (CD) is an autoimmune enteropathy of the small intestine affecting genetically susceptible individuals, characterized by an aberrant immune response to gliadin and sustained IgA-driven inflammation. IgA exists in two main subclasses, IgA1 and IgA2, which differ in distribution and function, but their profile in CD remains poorly characterized. Circulating free light chains (FLCs) are markers of B-cell activation and immune dysregulation, yet their role in CD has not been fully explored. The aim of this study was to characterize IgA subclasses and FLC profiles in newly diagnosed celiac patients. We analyzed sera from 108 CD patients and 29 healthy controls, assessing conventional serological markers (anti-tissue transglutaminase and anti-endomysial antibodies), together with total IgA, IgA1, IgA2, and FLC levels using a turbidimetric method. CD patients exhibited higher total IgA levels and an increased IgA1/IgA2 ratio, alongside a decreased k/λ ratio; these differences remained significant after adjustment for age and sex. When combined in a multivariable logistic model, these biomarkers yielded an AUC of 0.827, suggesting that the parameters identified in the univariate analyses provide complementary, non-redundant information that jointly highlights a reorganization of the humoral immune response. Due to the limited sample size, our results need confirmation in larger cohorts. However, our findings suggest a reorganization of the IgA compartment in CD, with selective expansion of IgA1 and preferential λ light chain usage, highlighting coordinated alterations in the humoral immune response. The integration of such markers, potentially in combination with -omics approaches, may contribute to a more refined and less invasive characterization of celiac disease. Full article

Celiac disease (CD) is an immune-mediated enteropathy triggered by dietary gluten in genetically predisposed individuals. Although HLA-DQ2 and HLA-DQ8 are the primary genetic determinants of susceptibility, they are not sufficient to explain disease onset and progression. A key molecular event in CD pathogenesis is the post-translational modification of gluten peptides by transglutaminase 2 (TG2), which enhances their binding to HLA-DQ molecules and promotes CD4⁺ T cell activation. TG2 also acts as the principal autoantigen, driving the production of anti-TG2 autoantibodies through linked recognition mechanisms. Beyond its enzymatic activity, TG2 is tightly regulated by gene regulatory mechanisms, including cytokine-driven transcription, epigenetic modulation, and stress-responsive signaling pathways. These processes determine TG2 expression and activity in the intestinal mucosa, thereby influencing the efficiency of gluten peptide modification and antigen presentation. Here, we propose that TG2 operates at the interface between gene regulation and antigen processing, linking transcriptional control of TGM2 to HLA-restricted immune activation. In this framework, disease susceptibility arises from the coordinated interaction between HLA-dependent peptide presentation, TG2-mediated modification of gluten epitopes, and regulation of TG2 expression within the intestinal mucosa. This integrated model provides a mechanistic basis for disease heterogeneity and identifies TG2 as a central regulatory node and potential therapeutic target in CD. Full article

Background/Objectives: Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by gluten ingestion in genetically predisposed individuals, with a highly heterogeneous clinical presentation encompassing both intestinal and extraintestinal manifestations. Despite growing clinical awareness, diagnostic delay remains a significant challenge, and the evolution of clinical and histopathological features following gluten-free diet (GFD) initiation remains incompletely characterized. This study aimed to compare the clinical, serological, and histopathological profile of adults with newly diagnosed CD and those maintained on a long-term GFD. Methods: This prospective observational study enrolled 50 adult patients with biopsy-confirmed CD: 16 at the time of diagnosis (gluten-consuming) and 34 on a GFD for at least one year. All participants underwent standardized clinical assessment, serological testing (IgA anti-tissue transglutaminase [tTG] and/or IgA anti-endomysial antibodies [EMAs]), upper digestive endoscopy with duodenal biopsies graded according to the Marsh–Oberhuber classification, and evaluation for Helicobacter pylori co-infection. Between-group comparisons were performed using the Mann–Whitney U test, Fisher’s exact test, and chi-square test, as appropriate. Results: Newly diagnosed patients exhibited a significantly longer median duration from symptom onset to diagnosis compared to the GFD group (p = 0.03). Histopathological severity was greater in the newly diagnosed group, with more advanced Marsh–Oberhuber grades (p = 0.03). Among individual symptoms, bloating was significantly more frequent in newly diagnosed patients (p = 0.02). Notably, thrombocytosis was identified significantly more often in the newly diagnosed group compared to GFD patients (p = 0.02), representing a potentially underrecognized extraintestinal marker of active CD. Overall rates of intestinal and extraintestinal manifestations and CD-specific seropositivity did not differ significantly between groups. Conclusions: The clinical and histopathological profile of adults with celiac disease differs meaningfully between the time of diagnosis and during GFD adherence. Bloating and thrombocytosis were significantly more prevalent at diagnosis, with thrombocytosis emerging as a potentially underrecognized marker of active disease. Conversely, several manifestations persisted despite dietary treatment, underscoring the heterogeneous nature of CD across its clinical course. These findings may support earlier disease recognition and more individualized follow-up strategies in routine clinical practice. Full article

Celiac disease (CD) is an autoimmune inflammatory enteropathy triggered by consuming gluten-containing cereals. A key role in its pathogenesis is played by type 2 transglutaminase, an enzyme that causes an increase in gluten immunogenicity. Celiac cells seem to present constitutive characteristics, even recognizable under a gluten-free diet, such as defects in vesicular trafficking and autophagy, protein hyperphosphorylation, and cytoskeleton rearrangement. In this work, by using an omics approach, we attempted to identify those proteins differentially expressed or differentially phosphorylated in a cell model suitable to study cell behavior in the absence of inflammation, i.e., primary cultures of dermal fibroblasts from control or CD subjects. By performing mass spectrometry analyses, we found several up- and-down expressed or phosphorylated proteins in CD samples, mainly involved in signaling, homeostatic responses, cytoskeleton organization, vesicular trafficking, and extracellular vesiculation. These proteins may represent a molecular signature of the celiac cellular phenotype and may contribute to adding new insight into the comprehension of the complex mechanisms of CD pathogenesis. Full article

Background and Objectives: The pathogenesis of liver steatosis is associated with obesity and systemic inflammation, particularly in subjects with body mass index (BMI) above 40 kg/m² and altered serum levels of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10). Recent evidence suggests that disruption of the blood–brain barrier (BBB) may be associated with the development of steatosis, although limited data are available in humans. Thus, we assessed serum levels of neuron-specific enolase (NSE), transglutaminase 2 (TGM2), and glial fibrillary acidic protein (GFAP) as indirect markers of BBB dysfunction and examined their associations with steatosis severity, TNF-α and IL-10 in patients with morbid obesity. Materials and Methods: We biopsied the liver during bariatric surgery to assess steatosis by histology and serum markers by ELISA. Results: Most study subjects were women aged 38.7 ± 9.9 years with an average BMI of 42.3 ± 7.9 kg/m² and a steatosis prevalence of 78.9%. After grading steatosis as none (n = 8), mild (n = 17), moderate (n = 8), or severe (n = 5), we found no differences in sex, age, BMI, comorbidities, or laboratory variables, including liver enzymes. One-way ANOVA showed that serum IL-10 was 4-fold less in severe steatosis than in mild steatosis (p = 0.038), whereas TNF-α levels increased twice in severe steatosis compared to no steatosis (p = 0.029). NSE and GFAP serum levels, but not TGM2, increased proportionally to steatosis stage, showing differences between severe steatosis and no steatosis (p = 0.012 and p = 0.0002, respectively). Pearson correlation coefficients showed that NSE and GFAP were significantly associated with TNF-α (r = 0.600 and r = 0.402, respectively), but not with IL-10. Conclusions: Steatosis severity is significantly associated with markers of BBB disruption and systemic inflammation in patients with morbid obesity, suggesting a link between the BBB and liver steatosis. Full article

Background/Objectives: The prerequisite for diagnosing celiac disease (CD) in children without duodenal biopsy is a tissue transglutaminase antibody (TGA) level exceeding 10 times the upper limit of normal levels, along with a positive confirmatory anti-endomysial antibody (EMA) test in a secondary blood sample. The aim of our study was to determine whether determination of TGA in a second blood sample could be as reliable as determination of EMA as the confirmatory test in children eligible for the no-biopsy approach. Methods: A retrospective analysis of medical data was conducted, including children under 19 years old who were diagnosed with coeliac disease at our department from January 2013 to June 2025. We examined the diagnostic process, focusing on TGA levels at the time of diagnosis. Results: Data from 185 CD patients (59.5% female, median age 8 years) were available for the analysis. 49 (26.5%) patients were diagnosed using no-biopsy approach and 46 (93.9%) of those had TGA > 10 × ULN in second blood sample as well. In the group of children diagnosed using duodenal biopsy (N = 136; 96.3% 3 Marsh), 78 (57.4%) children had initial TGA > 10 × ULN. In 34 (43.6%) of those children, secondary serology performed before introducing a diet showed that 30 (88.2%) of them had TGA > 10 × ULN. Conclusions: Our study suggests that TGA levels > 10 × ULN could serve as a reliable test for confirming the diagnosis of CD in children, eligible for the no-biopsy approach, thus making the diagnostic process more cost-effective and efficient, while maintaining accuracy. Full article

Lysine carboxymethyl cysteinate (LCC) has been identified as a glutathione (GSH) precursor for the use of cosmetic products, providing a defense against oxidative stress by elevating GSH levels, and mitigating UVB-induced pigmentation and barrier disruption. In this study, the protective efficacy of LCC on epidermal barrier integrity under UVB irradiation was systematically evaluated and its underlying mechanisms were investigated. Results from the UVB-exposed 3D living skin equivalent model (LSE) indicated that LCC effectively restored UVB-induced reductions in epidermal living cell thickness by 9.67%. In addition, LCC markedly increased the expression of key biomarkers related to cornified envelope (CE) formation and skin hydration, including transglutaminase 1, involucrin, loricrin and aquaporin 3 by 104.80%, 121.67%, 218.63% and 388.39%, respectively, compared with the UVB group. Transcriptomics analysis in human primary keratinocytes further revealed that LCC regulated multiple biological functions, including glutathione synthesis pathway, oxidation response, inflammatory process, and notably autophagy. After confirming LCC’s potential in boosting autophagy-associated gene expression (p-value < 0.05) and autophagy activity (p-value < 0.01) in keratinocytes, functional validation in the same model confirmed that LCC counteracted UVB-induced suppression of genes involved in barrier formation, particularly those associated with CE development and autophagy, while these protective effects were abolished by chloroquine, an autophagy inhibitor. Findings from the UVB-exposed LSE model further substantiated this mechanism. Collectively, these results demonstrate that LCC safeguards the epidermis from UVB-induced cornification abnormalities through the activation of autophagy. Full article

Serotonin is a critical morphogen in early development, yet the mechanisms regulating its homeostasis in the preimplantation embryo remain unclear, particularly under conditions of maternal antidepressant exposure. Here, we investigated embryonic serotonergic autonomy using mouse models of pharmacological transport blockade (maternal fluoxetine treatment) and in vitro treatment with the monoamine oxidase inhibitor pargyline. We employed immunofluorescence, RT-qPCR, and live-cell imaging to assess metabolic flux, gene expression, and physiological health. We demonstrate that monoamine oxidase functions as a metabolic firewall, progressively maturing from zygote to blastocyst to degrade excess amines. Paradoxically, maternal serotonin transporter blockade triggered significant intracellular serotonin hyper-accumulation in blastocysts, associated with a trend toward a compensatory upregulation of the biosynthetic gene Ddc. While this serotonin overload did not compromise morphology, mitochondrial function, or pluripotency marker expression, it induced a robust epigenetic response. Excess serotonin promoted elevated H3Q5ser immunoreactivity in both nuclear and cytoplasmic compartments via a transglutaminase-dependent mechanism. These findings reveal that the preimplantation embryo possesses a resilient, autonomous serotonergic system capable of compensatory synthesis. However, environmental fluctuations are chemically recorded via transglutaminase-mediated serotonylation, representing an epigenetic mark that warrants further long-term study within the Developmental Origins of Health and Disease (DOHaD) framework. Full article

Corneal alkali burns represent one of the most severe forms of ocular surface injury and frequently result in persistent inflammation, corneal neovascularization, stromal remodeling, and permanent visual impairment. Current therapeutic approaches incompletely control the inflammatory mechanisms that sustain pathological angiogenesis and tissue disorganization. In this study, we evaluated the effects of a transglutaminase-binding fusion protein (FP) in a rat model of alkali-induced corneal injury. Following standardized alkali burns, animals were treated topically with FP, secretory leukocyte protease inhibitor (SLPI), or Buffer. Corneal epithelial healing, opacity, and neovascularization were assessed clinically and by digital image-based quantification, while histological and immunofluorescence analyses were used to evaluate stromal organization and vascular invasion. Molecular mechanisms were investigated by RT-qPCR and Western blot analysis of key inflammatory, angiogenic, and signaling mediators. FP treatment significantly accelerated corneal re-epithelialization, reduced corneal opacity, and markedly attenuated corneal neovascularization compared to SLPI and Buffer controls. These effects were associated with coordinated downregulation of pro-inflammatory cytokines and angiogenic mediators, including TNF-α, IL-17, VEGF, and cPLA₂. Notably, FP suppressed transglutaminase 2 expression and induced early and sustained downregulation of NF-κB pathway components, identifying modulation of an upstream inflammatory pathway central to corneal angiogenesis and stromal remodeling. Collectively, these findings demonstrate that FP effectively limits inflammation-driven corneal neovascularization and tissue remodeling following alkali injury, supporting its potential as a disease-modifying therapeutic strategy for inflammatory ocular surface disorders. Full article

Human transglutaminases (hTGs) are Ca²⁺-dependent enzymes that catalyze protein crosslinking, deamidation and other post-translational modifications, thus acting as key stabilizers of tissue architecture and modulators of protein function across diverse physiological contexts. This family comprises eight catalytically active members, TG1-7, the blood coagulation factor FXIII, and the inactive structural protein Band 4.2 of the erythrocyte membrane. Recent structural and biochemical advances have refined our understanding of the molecular principles governing transglutaminase function. Thus, current evidence reveals how domain organization and catalytic architecture integrate calcium binding, nucleotide-dependent regulation in TG2 and proteolytic activation in selected isoforms to control enzymatic activity. In this review, we provide an updated and comprehensive overview of the active hTGs, combining structural, biochemical and functional data to explain how closely related enzymes achieve isoform-specific regulation and distinct biological roles. We further examine how disruption of these mechanisms contributes to human pathology, highlighting representative examples in autoimmunity, inherited disorders and complex diseases. By integrating recent biochemical and structural findings with disease-associated evidence, we aim to offer a coherent framework for understanding how TG regulation underlies their diverse biological functions and clinical relevance. Full article

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer diagnosed worldwide after basal cell carcinoma. CSCC represents a growing global public health challenge due to its higher potential of local invasion, recurrence, and metastasis. Incidence rates of cSCC are projected to increase due to rising exposures to risks factors. Ultraviolet light exposure is the primary cause, and lighter skin pigmentation, immunosuppressive conditions and skin phototype are the primary risk factors. CSCC typically presents as a red, scaly, flat lesion (in situ tumors) or a red, firm, raised lesion with scale or erosion (invasive tumors). Surgical excision remains the standard-of-care for localized cSCC and is often curative. Although, most patients achieve favorable outcomes, a subset of cSCC exhibits a highly aggressive and metastatic phenotype (postoperative recurrence rates are approximately 5%). Addressing the clinical challenge posed by these high-risk cases requires a more comprehensive understanding of the underlying molecular drivers. This review examines the interaction between transglutaminase 2 (TG2) and the G-protein-coupled receptor 56 (GPR56) as a pivotal driver of the aggressive cSCC phenotype. This molecular axis is particularly significant for its role in the maintenance of epidermal cancer stem (ECS) cells, which contribute to tumor progression and therapy resistance. While the definitive link between the TG2-GPR56 complex and systemic metastasis in cSCC is currently being elucidated, significant evidence from analogous malignancies and in vitro keratinocyte models provides a clear mechanistic roadmap for its involvement in tumor invasion. Full article

To enhance the gelling functionality of plant proteins, this study developed hybrid gels by blending casein with soy protein isolate (SPI) at various ratios using microbial transglutaminase (MTG) as a cross-linking catalyst. The gels were systematically characterized in terms of microstructure, water distribution, rheological and textural properties, secondary structure, and intermolecular interactions. Incorporation of casein significantly improved gel strength, water-holding capacity, and network uniformity. Notably, the 1:1 casein-to-SPI ratio yielded the highest performance, featuring extensive inter-protein cross-linking, an increased proportion of ordered secondary structures, and a finely porous matrix that effectively immobilized water. Mechanistically, MTG-catalyzed covalent bonding established the primary network scaffold, while hydrophobic interactions and disulfide bonds further stabilized the gel matrix. These findings demonstrate that MTG-induced Casein–SPI hybrid gels can enhance the functional properties of plant proteins and offer a viable strategy for designing sustainable protein-based food structures with tailored performance. Full article

Growing demand for low-sodium surimi products has driven the search for safe salt alternatives. Anionic peptides (APPs) and cationic peptides (CPPs) were isolated from sheepskin collagen via Diethylaminoethyl (DEAE) chromatography. CPPs contained higher arginine (46.11%) and lysine (4.64%) than APPs (40.57% and 3.99%, respectively), while APPs were enriched in acidic amino acids like glutamic acid (3.88%). Comprehensive evaluations of low-salt silver carp surimi gels showed both peptides significantly improved gel strength and water-holding capacity (WHC). The water-holding capacity increased from 60.68% in the blank control group to 74.31% in the CPP-treated group, while that in the APP-treated group was 66.86%. Cooking loss was significantly reduced, decreasing from 40.64% in the blank control group to 28.57% in the CPP-treated group and 34.52% in the APP-treated group. The samples achieved a quality comparable to that of the NaCl-supplemented group, with CPP outperforming APP in terms of hardness and gel network density. The LF-NMR confirmed enhanced water retention by reducing free water (T₂₂) and increasing bound water (T₂b). The FTIR indicated a conformational shift from α-helix to β-sheet, and the SEM revealed denser networks with fewer large voids. The SDS-PAGE demonstrated enhanced myosin heavy chain (MHC) cross-linking, more pronounced in the CPP-treated samples. CPPs exerted stronger electrostatic attraction with negatively charged surimi proteins (isoelectric point 5.5), while APPs chelated Ca²⁺ to activate transglutaminase. These findings validate APPs and CPPs as promising salt substitutes, enabling low-sodium surimi production and high-value utilization of sheepskin by-products. Full article

N-acetyl-amino acids were additives for improving kokumi of soy sauce, which was obtained by Transglutaminase (TG) and protease A2SD using amino acid and acetic acid in aqueous solution. In this study, we studied sensory characters and physical–cheimcal properties of soy sauce treated with TG, TG and acetic acid, protease A2SD, protease A2SD and acetic acid (T, TA, P and PA). T and P had higher umami, sweetness, saltiness, kokumi, amino acid nitrogen and colour, and lower bitterness than control. Addition of acetic acid could increase this effect which increased by 103%, 17%, 18%, 18%, 5%, 21%, respectively, and decreased by 30% in TA. Chemical compound analysis indicated soy sauce treated with TG and protease A2SD had lower molecular weight distribution and higher free amino acids, N-acetyl-amino acids and N-acetyl-dipeptides content, which might resulted in taste difference of different soy sauces. This study offered an alternative method for improving kokumi of soy sauce by N-acetyl-amino acids. Full article

Collagen sponges are widely used for oral tissue regeneration, due to their extracellular matrix-mimetic architecture and excellent biocompatibility. However, in practical biomedical applications, collagen sponges may exhibit hydration-induced structural instability, and there can be associated inflammatory responses under physiological conditions, potentially compromising their regenerative performance. In this study, we investigated how two cross-linking strategies—transglutaminase (TG) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS)—modulate the structural stability and inflammatory profiles of collagen sponges. TG-cross-linked sponges exhibited microstructural collapse, associated with macrophage activation and engagement of the Itgαvβ3/5–Src–RhoC–NF-κB signaling axis. In contrast, EDC/NHS-cross-linked sponges preserved a stable porous architecture, effectively suppressing this signaling cascade and establishing a low-inflammatory microenvironment. These findings elucidate a key mechanism by which cross-linking regulates the microstructural integrity of collagen scaffolds and provides in vitro-derived preliminary design principles for developing next-generation collagen biomaterials with low-inflammatory properties. Full article