Search Results (27,701)

Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Methods: Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. Results: CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Conclusions: Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers. Full article

The redox mechanisms of RAW 264.7 macrophages exposed to 2.45 GHz RF-EMF at subthermal specific absorption rates and to lipopolysaccharide (LPS) and/or the SARS-CoV-2 spike protein (CSP) were investigated. To this end, cellular responses (lysosomal and mitochondrial activity, nitric oxide (NO) production, and cell survival/death) were measured after 6, 24, and 48 h. Selective loss of viability in cells exposed to RF and LPS was observed at 6 h, consistent with early defects in membrane permeability. Lysosomal activity was significantly enhanced in cells treated with RF + LPS. Mitochondrial activity decreased in cells exposed to RF + LPS at 6 h and increased in cells treated with RF + CPS/LPS. Cell viability decreased greatly in cells treated with LPS and CSP + LPS after 24, particularly after 48 h. Nitrite levels peaked in non-irradiated cells treated with RF + LPS and in CSP + LPS at 24 h and decreased in irradiated cells after 48 h. Irradiation affected selection of the death mode: apoptosis decreased or remained unchanged in cells subjected to any of the treatments, while necrosis increased in cells treated with CPS, LPS, or both for 48 h. The combination of RF-EMF and infectious agents reprogrammed the interaction between mitochondria/lysosomes/nitric oxide (NO)/cell death in macrophages in a time- and stimulus-dependent manner. Full article

Background: Intervertebral disc degeneration (IVDD) is driven by the interplay between inflammatory signaling, extracellular matrix (ECM) degradation, and impaired cellular adaptation. Although several nutraceutical compounds have been reported to exert protective effects in IVDD-related models, their multitarget mechanisms within integrated molecular networks remain incompletely characterized. Methods: An in silico framework integrating molecular docking with network-based analyses was employed to evaluate resveratrol, quercetin, melatonin, curcumin, and baicalein against a predefined panel of IVDD-associated targets, within an exploratory in silico framework. Binding affinities and interaction profiles were assessed using molecular docking, followed by protein–protein interaction (PPI) network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and hub gene identification. Results: Docking analyses revealed binding energies ranging from −4.59 to −13.25 kcal/mol, with curcumin and quercetin showing plausible docking poses across a subset of selected targets under the applied protocol. Network analysis showed a highly interconnected structure centered on key inflammatory regulators, including NFKB1, IL6, TNF, IL1B, STAT3, and NLRP3, together with ECM-associated components such as ACAN, COL2A1, SOX9, MMP13, and ADAMTS5. Enrichment analyses further suggested significant associations with inflammatory signaling pathways, cytokine regulation, and ECM organization. Conclusions: These findings are compatible with a distributed, multitarget interaction pattern of nutraceutical compounds within IVDD-associated molecular networks. By integrating molecular docking with network-based analyses, this study offers a system-level framework for interpreting previously reported effects within a disease-specific context. Docking-derived interaction patterns should be interpreted as qualitative and exploratory observations, as docking scores represent model-dependent estimates and do not establish comparable pharmacological effects across heterogeneous targets. The results should be considered hypothesis-generating and require experimental validation. Full article

We performed a protein-docking study for eight DNA aptamers (SEQ1–SEQ8) against chicken Cluster of Differentiation 40 (chCD40), which were experimentally identified via SELEX in our previous study. In silico and molecular docking analyses were performed to predict and obtain the secondary and tertiary structures of the aptamers. Aptamers SEQ3 and SEQ4, which showed the best inhibitory effects, were selected and utilized to produce a DNA-based vaccine adjuvant using rolling circle amplification (RCA). These aptamers had been previously characterized via mass spectroscopy to determine their molecular weight and regions that could potentially interact with chCD40. In the present study, these results were corroborated and expanded. A series of free software methods, including Mfold v.1.0, 3dADN v.2.0, ClusPro v.2.0, Hdock v.1.0, and PLIP v.1.0, were used to determine the aptamers’ secondary and tertiary structures and docking interactions, as well as the specific residues involved in the interactions and their distances. The structures were used to explain and thus understand their effect on the binding, selectivity, and stability of the aptamers. The main objective of the study was to determine whether these aptamers could be used as vaccine adjuvants against viral and bacterial pathogens, specifically chicken avian influenza. The docking results were in good agreement with the experimental and biological results. The procedure employed in this study could be an easy and effective tool for exploring the potential of the new technology of systematic evolution of ligands by exponential enrichment (SELEX) in the preparation of aptamers to control viral and bacterial infections as well as diseases, such as cancer and Alzheimer’s. Full article

This study evaluated the effects of Nypa fruticans fruit pellet supplementation combined with different CP levels on rumen fermentation characteristics and CH₄ production using an in vitro gas production technique. A 3 × 4 factorial arrangement was used, consisting of three CP levels (12, 14, and 16%) and four levels of Nypa fruticans fruit pellet supplementation (0, 0.5, 1.0, and 1.5% of substrate dry matter), with incubation run included as a random effect in the statistical model. Rumen fluid from Thai native beef cattle was incubated under anaerobic conditions. Gas production kinetics, ruminal pH, ammonia–nitrogen (NH₃–N), protozoal populations, digestibility, volatile fatty acids (VFA), and CH₄ production were determined. Significant interactions between CP level and Nypa fruticans fruit pellet supplementation were observed for gas production kinetics. Ruminal pH was influenced by CP level at 24 h, while NH₃–N increased with higher CP levels but decreased with increasing supplementation. Protozoal populations were reduced by Nypa fruticans fruit pellets. Methane production was affected by CP level, Nypa fruticans fruit pellet supplementation, and their interaction. A clearer reduction was observed at 24 h, particularly at higher supplementation levels. At 24 h of incubation, total VFA, propionate, and butyrate concentrations increased with supplementation, whereas no clear effects were observed at 12 h. In vitro dry matter digestibility was affected at 24 h (p < 0.05), but no effect was observed at 48 h, while organic matter digestibility remained unchanged. In conclusion, Nypa fruticans fruit pellets, in combination with CP level, modified rumen fermentation patterns and were associated with lower CH₄ production under in vitro conditions, without negatively affecting digestibility. These findings suggest potential for further in vivo evaluation. Full article

Background/Objectives: Due to the widespread problem of antimicrobial resistance (AMR), there is an urgent need to identify new antibacterial targets that act through mechanisms distinct from those of existing antibiotics. One of these targets is the essential cell division protein FtsQ, which is a central hub of the Gram-negative divisome, but the druggability of its extensive protein–protein interaction (PPI) interfaces remains poorly defined. Here, we present a comprehensive structure-based in silico characterization of Escherichia coli FtsQ aimed at identifying and prioritizing druggable regions for PPI modulation. Methods: We analyzed E. coli FtsQ in both apo and complexed states (FtsQB, FtsQL, and FtsQBL) using a combination of pocket-mapping tools (FTMap and SiteMap), evolutionary conservation analysis (ConSurf), and structure property assessment (BLAST, ProBiS) to map and evaluate potential binding pockets of FtsQ protein. Results: Eight potential binding sites were predicted across the β and POTRA domains of FtsQ. One previously unreported site within the POTRA domain was prioritized as a candidate site, characterized by favorable druggability scores, strong evolutionary conservation, and a putative role in the FtsQ–FtsW/FtsN/FtsI interaction network. In contrast, two highly conserved sites at the FtsQ–FtsB/FtsL interaction interface were structurally flat, indicating limited suitability for classical small-molecule binding and greater compatibility with alternative modalities such as macrocycles or peptidomimetics. Conclusions: Although FtsQ lacks deep canonical binding pockets, this study proposes several conserved and potentially tractable regions as candidate sites, supporting its potential as a non-classical but promising antibacterial target for disrupting bacterial cytokinesis. Full article

The gut microbiota takes charge in a pivotal role in metabolic equilibrium, immune response, and modulating gut lining stability and has become the main focus of nutrition and functional food research. In this regard, the definition of prebiotics has progressed past the traditional approach limited to indigestible dietary fibers, embracing more targeted, biologically active, and functional delivery systems. In recent years, plant-derived exosomes (PDEs), a subclass of exosomes defined as extracellular vesicles (EVs) in the 30–150 nm size range, have emerged as an innovative class of nanostructures supporting this transformation. Plant-derived exosome-like nanoparticles (PELNs) have been taken into account as natural nanocarriers which are suitable for the gastrointestinal system with the help of their high biocompatibility, low immunogenicity profiles and rich bioactive cargo contents. This review discusses structural features of PELNs, molecular cargo content, and biological roles comprehensively and focuses especially on gut microbiota interactions. MicroRNAs, proteins, lipids, polyphenols, and glycans which PELNs contain are discussed with regard to shaping the microbial composition, regulating microbial metabolic activity, and modulating host-microbe communication. Findings derived from in vitro, in vivo, and limited translational studies indicate that PELNs can modulate specific microbial taxa, increase short-chain fatty acid (SCFA) yield, strengthen mucosal immune homeostasis, and induce source-dependent responses in the gut microbiota. In their traditional definition, prebiotics are taken into account as food components which selectively support proliferation and metabolism of helpful microbes, especially Bifidobacteria and Lactobacilli. Within this framework, PELNs are not only passive carriers of functional components but also evaluated as active systems which can directly affect microbiota composition and metabolic functions. Thus, they are repositioned as “prebiotic nanocarriers.” Also this review evaluates the potential of functional food and integration of major edible PELNs into synbiotic formulations by discussing their isolation and characterization methods and stabilities in the gastrointestinal environment. Limitations of clinical applications and lack of research from a prebiotic nanocarrier perspective of PELNs show that this field still contains important research gaps. The novelty of the study lies in its integration of PELN research with nutrition-based approaches to microbiota modulation and innovative functional food strategies under a single multidisciplinary conceptual framework. Full article

Disease-specific alpha-synuclein (αsyn) strains have been linked to different synucleinopathies. Current αsyn biomarkers are limited to binary detection of pathogenic αsyn in peripheral tissue biopsies or fluids, limiting differential diagnosis. Hence, there is an urgent need for methods that allow strain-specific detection and characterization of αsyn strain architecture. Notably, luminescent conjugated oligothiophenes (LCOs) have been successfully used to detect distinct protein strain conformers in prion diseases and Alzheimer’s disease, highlighting their utility in differentiating disease-specific amyloid structures. Species-dependent differences in αsyn structure are increasingly recognized as one of the critical aspects that shape how fibrils form, propagate and interact with molecular LCO probes. Here, we evaluate the potential of the LCO h-FTAA to differentiate species-specific αsyn strains and conduct a translational investigation using peripheral cardiac tissue of a gut-first synucleinopathy rodent model. Our in vitro data demonstrate strain-specific probe–fibril interactions, reflecting a differential strain architecture and cellular micro-environment. While h-FTAA binds with comparable efficiency to mouse (mo-) and human (hu-) pre-formed fibrils (PFFs), h-FTAA exhibits markedly lower quantum yield when bound to moPFFs versus huPFFs. Spectral imaging revealed h-FTAA-moPFF binding produces blue-shifted maxima (505–550 nm), contrasting with the red-shifted maxima (545–580 nm) of huPFFs. Fluorescence lifetime imaging microscopy confirmed h-FTAA’s intrinsic sensitivity to species-dependent variations through distinct temporal fluorescence signatures (moPFFs: ~0.60–1.5 ns vs. huPFFs: ~0.65–1.0 ns). Our translational investigation showed h-FTAA binding to peripheral cardiac pathology exhibits comparable red-shifted emission, but distinct fluorescence lifetimes of h-FTAA-bound aggregates in moPFF-injected (~1.0–1.4 ns) versus huPFF-injected (~0.69–0.8 ns) rats. Interestingly, we observed distinct blue-shifted emission profiles in a few selected regions of the heart of moPFF-injected rodents, further characterized by extra-long fluorescence decay shifts (~1.5–1.9 ns), reflecting differences in both aggregate conformation and maturity in moPFF-induced compared with huPFF-induced rats. Taken together, our findings underscore the potential of LCO ligands, like h-FTAA, to enable more precise disease staging and diagnosis through peripheral biopsies, complementing existing αsyn biomarker methods. Full article

To address the environmental sensitivity and low bioavailability of riboflavin, this study constructed a soybean protein isolate fibril (SPF)/κ-carrageenan (κC) composite gel delivery system. This study systematically investigated the effects of two independent variables (protein type: SPI/SPF; κC concentration: 2, 4, 6, 8 mg/mL) on the gel structural stability, riboflavin encapsulation performance, and in vitro digestive delivery characteristics of the system. Thioflavin T (ThT) fluorescence and ultraviolet (UV) absorption spectroscopy confirmed the successful preparation of SPF and verified specific intermolecular interactions between SPF and κC. Intermolecular forces, protein leaching rates, and differential scanning calorimetry (DSC) results indicated that compared with SPI-κC composite gels, κC regulates SPF molecular conformation via hydrogen bonding and hydrophobic interactions to exert a synergistic effect. This conformational regulation significantly reduced the protein leaching rates in SPF-κC composite gels, elevated the thermal denaturation temperatures (up to 79.82 °C), and enhanced the gel structural stability. As the κC concentration increased, the environmental stability of SPF-κC riboflavin-loaded composite gels were markedly enhanced, which effectively delayed the gel degradation during simulated gastrointestinal digestion. This was manifested as a reduced protein loss rate (reduced to 22.23%). At a κC concentration of 8 mg/mL, the in vitro release mechanism of riboflavin shifted from Fickian to non-Fickian diffusion. Full article

Fibroin-based films represent a promising platform for sustainable and bio-derived materials. Existing literature has mainly focused on isolated molecules, plasticizers, or chemical cross-linkers, and the function of complex, multi-component natural extracts as structure-modulating agents in fibroin films remains poorly understood. In this study, edible films containing mulberry leaf extract (MLE; 2–8 wt%) and fibroin (8 wt%) were prepared by solution casting, and their structures were investigated using spectroscopic, morphological, thermal, mechanical, and barrier property analyses. The results reveal that MLE induces concentration-dependent changes in film performance through multicomponent, non-covalent interactions with the fibroin. An approximately 187% increase in tensile strength was achieved at high MLE concentration, confirming effective physical reinforcement. The water vapor transmission rate decreased markedly from 0.888 to 0.170 g·h⁻¹·m⁻², indicating an enhanced moisture barrier, whereas oxygen permeability increased at higher extract loadings, suggesting localized chain rearrangements. High optical transparency in the visible region was maintained (79.95–83.77%), while UV response was selectively altered with extract concentration. Overall, the 8MLE formulation exhibited the most balanced performance. This study demonstrates that plant-derived extracts can serve as effective natural modifiers for tailoring fibroin film properties without inducing crystallization, offering a sustainable strategy for designing bio-based and edible protein film systems. Full article

Cardiac surgery represents a cornerstone of modern cardiovascular medicine, yet it is intrinsically linked to significant systemic stress responses that can compromise remote organ function. Among postoperative complications, cardiac surgery-associated acute kidney injury (CSA-AKI) remains a significant clinical challenge characterized by high morbidity and complex pathophysiology. While hemodynamic instability and ischemia–reperfusion injury are established risk factors, renal dysfunction frequently persists despite optimal perfusion. This observation suggests the involvement of potent circulating mediators in cellular injury. Extracellular vesicles (EVs) are essential for intercellular communication and serve as central hubs for transporting bioactive lipids, proteins, and genetic material. Accumulating evidence indicates that the mechanical and oxidative stress inherent to cardiopulmonary bypass triggers substantial release of EVs from platelets, erythrocytes, and injured vascular tissues. These vesicles may function as vectors that traffic oxidized mitochondrial components and pro-inflammatory cargo to the renal parenchyma. This signaling cascade appears to disrupt renal homeostasis through a proposed “dual-hit” mechanism involving the induction of endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT), followed by tubular epithelial injury via mitochondrial fragmentation, redox imbalance, and downregulation of anti-aging factors. The complexity of these EV-mediated interactions may contribute to an incomplete understanding of why specific patient phenotypes fail to recover. This narrative review examines the mechanisms of surgery-induced EV biogenesis, the molecular pathogenesis of endothelial and tubular damage, and the role of intercellular crosstalk. Additionally, we discuss future perspectives on targeting the “EV vector” through therapeutic apheresis and mitochondrial pharmacotherapy to potentially improve clinical outcomes in high-risk surgical patients. Full article

Mango leaves (Mangifera indica), an underutilized residue, represent a promising source of functional proteins with potential applications in emulsion-based delivery systems. Leaf protein concentrate (LPC) was extracted and modified by high-intensity ultrasound (HIU) to enhance its techno-functional properties. The modified protein was subsequently used as a natural emulsifier to develop oil-in-water (O/W) emulsions enriched with Curatella americana leaf extract, a phenolic-rich source of antioxidant bioactive compounds. Ultrasound-assisted emulsification (UAEm) conditions were optimized using a Box–Behnken experimental design, evaluating the effects of protein concentration (0.5, 1, and 1.5%), oil-to-water ratio (1:4, 1:4.5, and 1:5, mL:mL), and sonication time (2.5, 5, and 7.5 min) on droplet size (D_[4,3], µm). The optimized formulation consisted of 1.5% protein, an O/W ratio of 1:4 mL, and a time of 7.5 min, producing an emulsion with a droplet diameter of 7.23 µm. The emulsions exhibited high resistance to storage, pH variation (2–10), ionic strength (100–500 mM NaCl), and thermal treatments up to 50 °C. Additionally, incorporating C. americana extract enhanced thermal stability, photostability, and antioxidant retention under UV exposure, suggesting the formation of reinforcing protein–polyphenol interactions. These findings demonstrate the potential of mango leaf protein as a sustainable emulsifier and protective carrier for sensitive bioactive compounds, supporting its application in functional food and nutraceutical formulations. Full article

Delayed cerebral ischemia (DCI) is a major complication of aneurysmal subarachnoid hemorrhage (aSAH), strongly associated with neurological deterioration and poor outcomes. Its pathophysiology remains incompletely understood and involves multiple interacting processes. Increasing evidence highlights the role of redox imbalance triggered by hemoglobin breakdown and the subsequent generation of reactive species, leading to vascular dysfunction, impaired nitric oxide signaling, and inflammatory activation This review aims to summarize current knowledge on redox-related mechanisms involved in DCI and to explore the potential role of the peroxiredoxin (PRDX) family in this setting. A narrative review of experimental and preclinical studies was performed, focusing on molecular pathways associated with vascular regulation, cellular injury, and antioxidant defense. Particular attention was given to the distribution and biological functions of PRDX isoforms within the central nervous system. This work addresses a topic not previously systematically discussed, the potential involvement of PRDX proteins in aSAH-related complications. By integrating available data, it provides a conceptual framework linking PRDX to mechanisms relevant for DCI. The manuscript serves as a starting point for future research, particularly translational and clinical studies in humans, which are necessary to verify the relevance of these findings and to better understand their potential clinical implications. Full article

Lentils (Lens culinaris; family: Fabaceae) are increasingly recognized as functional legumes with potential benefits for gut health because they provide bioactive peptides, resistant starch, and polyphenol-rich fractions within a shared food matrix. However, most existing studies have focused on individual lentil-derived compounds, and their matrix-dependent complementary interactions during digestion and fermentation remain insufficiently resolved. This review synthesizes current evidence on lentil-derived peptides, resistant starch, and polyphenols, with particular emphasis on their matrix-dependent complementary relationships, digestion-dependent transformation, microbial co-metabolism, and implications for intestinal barrier function. During gastrointestinal digestion and colonic fermentation, lentil proteins, resistant starch, and phenolic compounds undergo sequential transformation, yielding bioactive peptides, fermentable substrates, short-chain fatty acids (SCFAs), and phenolic metabolites that may collectively influence microbial composition and metabolic activity. Emerging evidence suggests that these interconnected processes may support gut health through microbiota–host crosstalk by modulating tight junction-related markers, reducing intestinal permeability, and maintaining epithelial homeostasis. Mechanistically, these effects have been associated with SCFA-mediated G protein-coupled receptor (GPCR) signaling, suppression of TLR4–NF-κB/MAPK inflammatory cascades, and activation of Keap1–Nrf2 antioxidant defenses, thereby attenuating oxidative stress and pro-inflammatory responses. Current evidence is more consistent with matrix-dependent complementary or convergent actions than with demonstrated synergy. At present, phenolic-rich fractions provide clear pathway-level evidence, whereas fermentation-linked carbohydrate effects are more strongly supported by microbiota- and in vivo-associated outcomes, and protein- or peptide-related mechanisms remain comparatively underdefined. Nevertheless, the evidence base remains limited by the scarcity of integrated studies, well-controlled human intervention trials, and factorial experimental designs capable of distinguishing complementary, additive, and truly synergistic effects among lentil bioactives. This review therefore highlights the need to move from describing coexisting beneficial effects toward formally testing interaction effects within physiologically relevant lentil matrices. Full article

Second-generation anticoagulant rodenticides (SGARs) were developed to overcome warfarin resistance in rodent populations; however, their prolonged hepatic retention has raised concerns regarding secondary poisoning of non-target wildlife. All major SGARs exist as cis–trans isomeric pairs, and differences in biological half-life between isomers have been reported, yet the molecular basis for such isomer-dependent pharmacokinetic behavior remains poorly understood. In this study, we conducted an integrated evaluation of cis and trans isomers of SGARs using in vivo, in vitro, and in silico approaches, with vitamin K epoxide reductase (VKOR) serving as the molecular target. The individual compounds exhibited distinct isomer-dependent profiles in hepatic retention, inhibitory potency (IC₅₀), and VKOR interaction-related properties. Molecular dynamics simulations further revealed isomer-dependent differences in torsional flexibility around specific rotatable bonds and in ligand–VKOR interaction fractions. For flocoumafen and bromadiolone, the presence of an ether oxygen was associated with increased torsional and orientational flexibility and enhanced hydrogen-bonding potential, which may facilitate metabolic processing and contribute to the relatively faster elimination of cis isomers. Collectively, these results suggest that isomer-specific VKOR interaction patterns may contribute, in a compound-dependent manner, to isomer-dependent pharmacokinetic behavior, offering structural perspectives for the design of rodenticides with reduced ecological risk. Full article