Search Results (76,124)

Hyaluronic acid (HA) is widely used in medical, cosmetic, and nutraceutical applications, yet the systemic fate of orally administered HA, particularly non-animal forms, remains poorly characterised. This study investigates the stability, absorption, metabolism, and biological effects of a novel fungal-derived HA extracted from Tremella fuciformis using a sequential in vitro multi-barrier model simulating human physiological compartments, including gastric, intestinal, hepatic, renal, chondrocyte, and keratinocyte environments. Across the gastrointestinal stages, fungal-derived HA demonstrated high structural stability, maintained molecular weight, and exerted superior antioxidant and anti-inflammatory activity compared with sodium hyaluronate. It efficiently crossed the intestinal barrier without increasing hyaluronidase activity, indicating protection from premature enzymatic degradation. In hepatic cells, fungal-derived HA exhibited reduced intracellular uptake and greater extracellular persistence, suggesting lower first-pass metabolism and suggesting improved persistence under in vitro conditions. At peripheral targets, it increased the cluster of differentiation 44 (CD44) expression and HA internalisation in chondrocytes and keratinocytes, supporting anti-inflammatory and pro-regenerative effects. Renal assessments revealed minimal excretion and no cytotoxicity, supporting potential systemic availability. Overall, these results provide the first integrated in vitro evidence describing the absorption, distribution, metabolism, and excretion process of fungal-derived HA. This supports the conclusion that this form of HA is stable, biocompatible, and bioactive with therapeutic potential for joint and skin health, as suggested by the in vitro models. Full article

Mitophagy serves as an essential quality control mechanism that maintains mitochondrial homeostasis through selective autophagic clearance of damaged organelles. Vascular dementia (VD) has been increasingly associated with mitophagy dysregulation in recent studies. However, the precise molecular mechanisms underlying mitophagy’s involvement in VD pathogenesis remain poorly characterized. To elucidate the role of mitophagy in VD, we systematically examined the expression of key mitophagy pathways in hippocampal neurons of bilateral common carotid artery occlusion (BCCAO) rats and in oxygen–glucose deprivation (OGD)-treated HT22 cells. Intriguingly, under autophagy-deficient conditions, both BNIP3 and BNIP3L were markedly downregulated, whereas FUNDC1 expression increased; PINK1/Parkin levels remained unaltered. To further dissect the functional contributions of BNIP3 and BNIP3L, we administered the mitochondrial fission inhibitor Mdivi-1 to BCCAO model rats. Histopathological analysis revealed pronounced neuronal damage and apoptosis in the hippocampal region, which was further exacerbated upon Mdivi-1 treatment. In vitro, BNIP3 silencing significantly compromised cell viability, elevated reactive oxygen species (ROS) accumulation, disrupted mitochondrial membrane potential (ΔΨm), suppressed mitophagy, and increased apoptotic rates. Conversely, BNIP3 overexpression reversed these detrimental effects. Notably, treatment with the autophagy inhibitor 3-methyladenine (3-MA) diminished LC3B-Tomm20 colocalization and intensified apoptosis, reinforcing the critical role of BNIP3-mediated mitophagy in neuronal survival. Similarly, BNIP3L overexpression enhanced cell viability, attenuated ROS production, restored ΔΨm, and mitigated apoptosis, while 3-MA treatment again impaired mitophagic flux and worsened cell death. Collectively, these findings underscore the critical and distinct roles of BNIP3 and BNIP3L in maintaining mitochondrial homeostasis and neuronal survival under ischemic conditions. Full article

Background: Protein phosphatase 2Cs (PP2Cs) constitutes the largest phosphatase family in plants, playing a pivotal role in signal transduction. Within this family, the PP2C.D subfamily exerts significant influence on cell elongation and stress adaptation by mediating the ‘SAUR-PP2C.D-H+-ATPase’ regulatory module in the auxin signaling pathway. In rice, OsPP2C61 is a PP2C member whose molecular features and potential regulatory context remain unclear. Methods: Our study conducted a preliminary characterization of OsPP2C61 through integrated bioinformatics analysis, spatiotemporal expression profiling, and subcellular localization experiments in tobacco leaf cell. Results: OsPP2C61 encodes a 377-amino-acid protein predicted to be hydrophilic, basic, and structurally unstable. Secondary-structure prediction identified three major elements with random coils as the predominant component, whereas 3D modeling indicated alternating α-helices and β-sheets consistent with a canonical PP2C fold. Phylogenetic inference placed OsPP2C61 within the PP2C.D clade and revealed conserved motifs shared with OsPP2C25, OsPP2C28, and OsPP2C39. Promoter analysis showed enrichment of abscisic acid (ABA)- and methyl jasmonate (MeJA)-responsive elements along with multiple stress-related cis-regulatory motifs. Spatiotemporal expression analysis showed that OsPP2C61 is highly expressed in roots. Subcellular localization assays further demonstrated that the OsPP2C61-GFP fusion protein localizes to the nucleus and the plasma membrane when transiently expressed in epidermal cells of Nicotiana benthamiana. Conclusions: This work delivers the first comprehensive characterization of OsPP2C61, establishing a foundation for mechanistic studies and positioning OsPP2C61 as a candidate gene for rice improvement. Full article

Pluripotent stem cell (PSC) differentiation is orchestrated by intricate autocrine and paracrine signaling networks. Among these, exosomes, key components of the cellular secretome, are implicated as crucial mediators of intercellular communication via delivery of bioactive molecules, including microRNAs (miRNAs). This study investigated the role of exosomal miRNAs in stem cell differentiation using Dgcr8-deficient mouse embryonic stem cells (mESCs), which are incapable of producing mature miRNAs. Although the differentiation capacity was markedly impaired in these cells, partial restoration was observed following treatment with exosomes derived from differentiating wild-type mESCs. Exosomal miRNA uptake was confirmed, and gene ontology analysis revealed significant enrichment of pathways associated with cell fate determination, morphogenesis, and apoptosis regulation. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that exosomal miRNAs modulated multiple osteoinductive signaling cascades, notably the MAPK and TGF-β pathways, in Dgcr8-deficient cells. Apoptotic markers were also downregulated, suggesting a protective effect conferred by the exosomal cargo. Collectively, our results suggest that exosome-mediated delivery of miRNAs may represent a fundamental mechanism by which pluripotent stem cells coordinate stress responses and differentiation trajectories, providing novel insights into the regulation of embryogenesis. Full article

The objective of this paper is to propose a sociological and interdisciplinary framework for analyzing the digitization of emotions in adolescence. This contribution aims to promote theoretical reflection and inform educational and political interventions in the digital age, framing adolescents’ digital experiences as emotionally embodied and socially integrated processes. These aspects are of paramount importance due to the rapid proliferation of digital technologies and artificial intelligence, which have precipitated a profound transformation in the emotional, relational, and educational experiences of adolescents. The role of digital and AI-based environments in mediating communication is expanding beyond the scope of simple facilitation. These environments are increasingly implicated in the production, modulation, and regulation of emotions, thereby influencing developmental trajectories and identity formation processes. This phenomenon is theorized as a socio-technical process, wherein emotions are embodied, narrated, and governed within digital environments. The article introduces the concept of digital emotional embodiment, drawing on the sociology of emotions, theories of embodiment, and critical perspectives on artificial intelligence. Specifically, the concept refers to the manner in which adolescents experience and express emotions through avatars, images, emojis, algorithmic feedback, and AI-mediated interactions. Therefore, it is imperative to underscore the evolution of empathy, which is progressively configured as a virtualized and datafied process, diverging from the tradition established by Hume and characterized by sympathy. In contemporary processes, shaped by the logic of platforms, recommendation systems, and emotionally reactive technologies, conventional emotional concepts have undergone deconstruction, and digital constructs are undergoing a gradual restructuring. In this context, AI systems do not merely reflect adolescents’ emotions but rather actively contribute to the construction of emotional narratives, influencing emotional regulation, social connection, and future orientation. Digital environments have been shown to encourage emotional expressiveness, experimentation, and inclusivity. Conversely, they have the capacity to encourage emotional standardization, dependency, and forms of affective vulnerability, particularly during a sensitive developmental stage such as adolescence. Full article

Atherosclerosis (AS) is the leading cause of cardiovascular disease worldwide, yet its clinical heterogeneity and close association with metabolic disorders are not fully explained by the classical “endothelial injury–lipid deposition–inflammatory amplification” paradigm. In this review, we introduce the PVAT–MAMs axis as a hypothesis-driven, cross-scale conceptual framework linking extravascular metabolic dysfunction to intracellular stress signaling in vascular cells. We propose that, under metabolic stress, dysfunctional perivascular adipose tissue (PVAT) may influence mitochondria-associated endoplasmic reticulum membranes (MAMs) via the release of inflammatory, lipotoxic, and oxidative mediators. Accumulating experimental and associative evidence suggests that perturbation of MAMs is associated with dysregulated calcium handling, lipid metabolism, inflammatory signaling, and redox imbalance, processes implicated in AS progression. Although direct causal relationships remain to be fully established. By synthesizing current findings, this framework provides an integrative perspective on disease heterogeneity and highlights testable pathogenic nodes spanning from PVAT to subcellular MAMs. Finally, we discuss how this conceptual axis may inform hypothesis-driven therapeutic strategies. Importantly, the PVAT–MAMs axis is presented as a hypothesis-driven conceptual model rather than an established signaling pathway, and its mechanistic architecture requires rigorous experimental and translational validation. Full article

Background: Tumor cells can reprogram their metabolism, constituting a hallmark of cancer that plays a crucial role in tumor progression. As tumor cells exhibit an increased demand for nutrients, e.g., amino acids, they rely on extracellular sources and show deregulation of transport proteins. Among these, SNAT1 (SLC38A1) is described as the loader for glutamine that is responsible for the main influx of this amino acid. The aim of this study was to assess the molecular function of SNAT1 in melanoma regarding its role in amino acid transport and regulation of cellular metabolism. Methods: siPool-mediated downregulation of SNAT1 expression in melanoma cell lines was used to investigate the molecular function of this protein. Glutamine transport was assessed by measuring the intracellular and extracellular concentrations of glutamine. Regulation of downstream effectors was evaluated with qRT-PCR and Western Blot. Metabolism was investigated by performing Seahorse flux analysis. Mitochondrial staining was examined via flow cytometry. Protein interaction was assessed with Co-IP, and in silico modeling of protein interaction was performed with AlphaFold3. Results: In this study, we uncovered the new finding that SNAT1 is not primarily implicated in glutamine influx into melanoma cells but in signaling in response to extracellular glutamine. We identified P62 and cMYC as downstream effectors of SNAT1. By activating the P62/cMYC-axis and target genes of cMYC, SNAT1 modulates the metabolism of melanoma cells depending on the glutamine level. SNAT1 and P62 are interaction partners. Conclusions: This finding newly suggests that SNAT1 may function as a sensor or receptor (“transceptor”) for glutamine rather than being a direct and primary glutamine transporter, and could open up new therapeutic options targeting melanoma cells. Full article

Background and Objectives: Pro-inflammatory diet and high-fat diet (HFD) often coexist in real-world, but their combined impact on the gut–liver axis and potential nutritional countermeasures remain insufficiently studied. This study aimed to evaluate a pro-inflammatory–high-fat composite dietary pattern on the intestine and liver in the population, and to further evaluate the protective potential of astaxanthin (ATX) in complementary experimental systems. Methods: Data from the NHANES 2005–2010 were used to construct four composite exposure groups based on the dietary inflammation index (DII) and energy from fat. Survey-weighted regression analyses were performed to examine associations with systemic inflammation and liver injury. Interaction and C-reactive protein (CRP)-mediated effect analyses were conducted. Fifty SD rats were randomly divided into control group, model group induced by HFD combined with inflammatory factors, and low-, medium-, and high-dose Haematococcus pluvialis (HP) intervention groups. Serum lipids, liver enzymes, liver and colon pathology, and inflammatory and oxidative markers were measured in rats. In an in vitro organ-on-chip barrier model, the effect of ATX was observed when colonic barrier damage was induced using palmitic acid and lipopolysaccharides. Results: The high DII combined with HFD showed the largest increases in CRP, liver enzymes, and fatty liver index. A synergistic interaction was observed between DII and HFD, with CRP mediating approximately 20% of the effect. In rat model, HP-derived ATX improved the lipid profile, attenuated hepatic steatosis and oxidative damage, and reduced colonic pro-inflammatory cytokines, while restoration of tight junction proteins was limited. In colon organoid model, ATX showed limited efficacy in improving inflammation and barrier function. Conclusions: The pro-inflammatory–high-fat dietary pattern synergistically exacerbates gut–liver dysfunction. HP-derived ATX alleviates metabolic and inflammation-induced enterohepatic comorbidity, but its effect on repairing barrier structure is limited. Full article

Digital technologies are widely recognized for their potential to support active learning and foster higher-order cognitive skills, including critical thinking. However, limited research has examined the extent to which students are directly involved in selecting digital tools that shape their learning. This study investigates teachers’ ability to engage students in the selection and pedagogical use of digital technologies, with attention to practices supporting active, personalized learning and critical thinking. Data were collected from 156 educators across diverse disciplines in five teacher-training colleges in Israel using an online questionnaire assessing levels of digital tool use, from non-use to active student involvement. Item Response Theory (IRT) was applied to model teachers’ proficiency and examine differences across tools and background characteristics. Results indicate substantial variability in teachers’ ability to involve students, with particularly low involvement in tools related to problem-solving, differentiation, and personalized learning. Gender and institutional role were significant predictors, with female educators and those holding additional roles demonstrating higher proficiency. These findings highlight the importance of teachers’ techno-pedagogical competence in enabling student participation in digital decision-making and suggest that involving students in tool selection can support the development of critical thinking and learner agency in digitally mediated learning environments. Full article

Background: Epstein-Barr virus-related acute pharyngotonsillitis is common in children and adolescents and is generally managed successfully with positive outcomes by both ENT specialists and pediatricians. However, a variety of acute, life-threatening complications can occur, including upper airway obstruction and infectious or immune-mediated sequelae. Methods: This paper describes our recent experience with four pediatric patients presenting with severe ENT manifestations of infectious mononucleosis (IM) that led to life-threatening complications, all of whom were hospitalized and managed at our tertiary pediatric hospital between January 2022 and April 2025. Results: We report four cases (two boys and two girls) aged 5 to 16 years, hospitalized with complicated EBV-related pharyngotonsillitis. Presentations included respiratory distress (cases 1 and 2), hemophagocytic lymphohistiocytosis resulting in death (case 3), and a retropharyngeal abscess (case 4). Conclusions: The prognosis of IM in the pediatric population is generally favourable. However, acute, life-threatening complications may arise. In such cases, timely and coordinated multidisciplinary management involving ENT specialists, pediatricians, and anesthesiologists is crucial. Full article

Background: Non-invasive approaches to brain tumour detection and diagnosis are limited by the absence of clinically validated circulating biomarkers. This study utilised a miniaturised tissue perfusion model to maintain human brain tumour tissue ex vivo with the aim of identifying tissue-derived proteins with potential biomarker utility. Methods: 55 tumour samples from 11 different brain tumours (glioblastoma n = 4, low-grade glioma n = 4, brain metastases n = 3) were micro-dissected and maintained ex vivo on a continuous-flow perfusion device for 168 h. Proteomic analysis of tumour effluent was performed by reversed-phase capillary liquid chromatography-mass spectrometry. Two candidate proteins—extracellular matrix protein 1 (ECM1) and cathepsin D—were quantified using ELISA. Results: All tumour subtypes retained tissue viability over 168 h of perfusion. Proteomic profiling identified 90 tissue-derived proteins in the tumour effluent. Many proteins corresponded to previously described cancer biomarkers such as glial fibrillary acidic protein (GFAP) while others, including Serpin A12 and collapsin response mediator protein-2 (CRMP2), had not yet been described in a brain tumour context. ELISA confirmed significantly higher ECM1 levels in high-grade glioma effluent compared with low-grade glioma (p = 0.0407), whereas cathepsin D levels did not differ significantly between tumour types. Conclusions: The ex vivo perfusion model effectively preserved primary and metastatic human brain tumour tissue and enabled direct characterisation of tumour-secreted proteins. The proteins identified here warrant further validation as tumour biomarkers in patient serum or cerebrospinal fluid. Full article

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a systemic disorder with clinically significant extrapulmonary manifestations. Among these, renal dysfunction—manifesting as chronic kidney disease (CKD) and acute kidney injury (AKI)—is highly prevalent, frequently underdiagnosed, and strongly associated with adverse clinical outcomes. Meta-analytic data indicate that COPD is associated with more than a twofold increase in CKD prevalence, independent of shared risk factors such as age, smoking, hypertension, and diabetes. CKD in COPD is associated with increased mortality, exacerbation burden, and healthcare utilization. AKI represents a particularly severe expression of renal involvement, occurring most commonly during acute exacerbations of COPD (AECOPD). Although the reported incidence of AKI during AECOPD varies widely by clinical setting—from approximately 2% in population-based studies to over 20% in hospitalized cohorts—its presence is consistently associated with marked increases in mortality, respiratory failure, need for mechanical ventilation, and hospital length of stay. This review synthesizes current evidence supporting a lung–kidney interorgan crosstalk framework in COPD, whereby chronic and acute pulmonary pathophysiology generates systemic disturbances that progressively impair renal structure and function. The heart is incorporated as a physiological intermediary, modulating hemodynamic transmission and venous congestion, without constituting the primary disease axis. Recognizing the role of kidney complications in COPD is crucial, as it influences how we diagnose, predict outcomes, and treat patients—especially when there are sudden flare-ups. Full article

The programmed death-ligand 1 (PD-L1) plays a critical role for promoting cancer immune evasion. However, the resistance to PD-L1-targeted immunotherapy greatly limits its application. α-lipoic acid (ALA) is an endogenous antioxidant, while whether ALA affects PD-L1 expression remains unknown. In IFN-γ-stimulated castration-resistant prostate cancer (CRPC)-mimicking PC3 and DU145 cells, the expression of PD-L1 and its regulatory genes was determined by Western blotting, RT-PCR, and immunofluorescence. The T-cell-mediated tumor-killing activity was evaluated in a co-culture system of cancer cells and Jurkat T cells. ALA significantly inhibits IFN-γ-induced PD-L1 protein and mRNA expression without affecting its degradation. The upstream genes accounting for PD-L1 induction, including JAK1/STAT1/IRF-1 cascade, c-Myc, HIF-1α, and GSK3β activity, were markedly suppressed by ALA. The decreased expression of PD-L1 and these regulators by ALA is also modulated by attenuation of mTOR/p70S6K/4EBP1-dependent protein translation and ROS production. In the co-culture system, ALA markedly increased T-cell-mediated tumor-killing activity compared to that of ALA treatment alone, suggesting that ALA may augment the antitumor immunity. Collectively, we demonstrated that ALA-mediated inhibition of PD-L1 expression is regulated by multiple mechanisms, which indicates that ALA may be a potential agent to enhance cancer immunotherapy, particularly in CRPC. Full article

Malaria, caused by Plasmodium parasites, remains a global health crisis, necessitating novel therapeutic strategies targeting host–parasite interactions. During liver-stage infection, parasites exploit host vesicular trafficking machinery, particularly SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins that mediate membrane fusion. Using a CRISPR/Cas9 knockout system in HeLa cells combined with advanced microscopy of Plasmodium berghei-infected HeLa cells, we identified specific endolysosomal SNAREs including Vesicle-Associated Membrane Protein 7 (VAMP7), Vesicle-Associated Membrane Protein 8 (VAMP8), Vesicle Transport Through Interaction With T-SNAREs 1B (Vti1B), and Syntaxin 7 (Stx7) to be recruited to the parasitophorous vacuole membrane (PVM) with distinct temporal profiles. This demonstrates the parasite’s precise manipulation of host endolysosomal trafficking pathways. VAMP7 and Vti1B were localized to the PVM within 30 min post-infection, suggesting potential roles during invasion, while VAMP8 and Stx7 appeared later around 24 h post infection (hpi), coinciding with increased nutrient acquisition. Single gene deletions showed minimal impact, but combinatorial knockouts (KO) revealed critical redundancy. VAMP7-VAMP8 as well as VAMP7–Vti1B double KO significantly reduced parasite infection and growth, with Vti1B playing a dominant role. Triple KO phenotypes mirrored VAMP7-Vti1B disruption, underscoring Vti1B’s dominant role. SNARE depletion also impaired the lysosome–PVM association and LAMP1 positive vesicle recruitment. Our findings indicate Plasmodium hijacks a coordinated host SNARE network to fuse lysosomes with the PVM for nutrient uptake. Targeting Vti1B-containing complexes disrupts this pathway without host cell toxicity, offering a promising host-directed antimalarial approach. Full article

Background/Objectives: Schools, as structured social environments, are important settings for shaping lifelong eating habits, and teachers play a mediating role in nutrition education. This study aimed to assess nutrition knowledge among public school teachers, examine their perceptions of the school food environment, and identify factors associated with knowledge scores. Methods: A stratified cross-sectional survey was conducted among 736 teachers from 12 public schools during the fall of 2025. A structured questionnaire based on the Knowledge–Attitudes–Practice model was used to evaluate nutrition knowledge, teaching practices, perceived school food environment, and teachers’ observations of student food-related behaviors. Group differences were examined using t-tests and ANOVA, and multivariable logistic regression was applied to identify factors associated with low nutrition knowledge. Results: The mean knowledge score was 6.26 ± 2.64 out of 12, with 23.6% of teachers classified as having low knowledge, 59.9% satisfactory, and 16.4% good. Primary school teachers scored significantly higher than subject teachers (7.27 vs. 5.64; p < 0.001). Regular conduct of nutrition classes was associated with lower odds of low knowledge (adjusted OR 0.10, 95% CI 0.05–0.23, p < 0.001). A sensitivity analysis using continuous knowledge scores confirmed this pattern, with the absence of nutrition teaching predicting a 1.40-point reduction in scores (95% CI −1.86 to −0.94, p < 0.001). Teachers rated school meal quality moderately high, and frequently observed student refusal of canteen food and purchase of sweets or fast food outside school. Conclusions: This study found that public school teachers in Karaganda, Kazakhstan showed satisfactory overall nutrition knowledge, with gaps in applied understanding and common dietary myths. Primary teachers and those actively teaching nutrition had higher knowledge scores, indicating an association between pedagogical engagement and content knowledge. To help optimize the school food environment, educational policies would benefit from the development of cross-curricular instructional materials fitted specifically for secondary school subject teachers. Full article