Search Results (4,443)

Advanced Glycation End Products (AGEs) are reactive compounds formed through the non-enzymatic glycation of proteins, lipids, or nucleic acids due to exposure to reducing sugars. They accumulate through endogenous metabolic dysregulation and exogenous dietary intake, particularly high-fat and high-sugar foods prepared at high temperatures. The interaction between AGEs and their receptor, RAGE (receptor for Advanced Glycation End Products), has been implicated in a range of pathological conditions, including diabetes and metabolic syndrome. However, the impact of AGEs accumulation on neurodevelopment remains poorly understood. In this study, we investigated the effects of AGEs on human-induced pluripotent stem cell (iPSC)-derived cerebral organoids comprising neurons, astrocytes, and microglia. Our findings reveal that AGEs induce RAGE expression, leading to microglial activation, increased deposition of amyloid-beta (Aβ) aggregates, and impaired neurodevelopment. Additionally, elevated levels of AGE-modified proteins, along with altered microglial polarization, were observed in cerebral organoids modeling Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism–Dementia Complex (ALS-PDC). These findings demonstrate AGEs as active drivers of neurodevelopmental disruption and establish a mechanistic link between metabolic stress and increased susceptibility to neurodegenerative disease. Full article

Background/Objectives: Population-specific genomic data are essential for understanding hepatocellular carcinoma (HCC) biology, particularly in underrepresented regions. This study aimed to perform exploratory single-nucleotide polymorphism (SNP)-array-based profiling of HCC tumor samples from Indonesian patients and to prioritize candidate functional variants using a systematic in silico framework. Methods: This retrospective cross-sectional study included 15 resected HCC cases with available formalin-fixed paraffin-embedded (FFPE) tumor tissue. Genome-wide SNP genotyping was performed using the Illumina Asian Screening Array. Following quality control and filtering, variants were annotated using the Ensembl Variant Effect Predictor. A case-only functional prioritization approach incorporating multiple in silico prediction tools was applied, followed by gene-level burden aggregation. Results: After multistep filtering, 11 samples and 104 prioritized variants were retained for analysis. Variants consisted predominantly of splice-region, missense, and regulatory changes. Gene-level burden analysis identified Nuclear Autoantigenic Sperm Protein (NASP, rs775916096) as the highest-ranked candidate gene, while G protein-coupled receptor 78 (GPR78, rs558447540) emerged as a secondary candidate with predicted functional annotations but currently limited biological evidence in HCC. Given the tumor-only design without matched normal tissue, the prioritized variants cannot be distinguished from rare germline variants. Conclusions: This exploratory SNP-array study provides a hypothesis-generating framework for functional variant prioritization in Indonesian HCC. NASP and GPR78 represent preliminary candidates that require validation in larger cohorts with matched normal tissue and sequencing-based confirmation. Full article

Modification of PLA with functional nanoparticles is a promising approach for imparting new properties to the material. In this work, titanium nanoparticles (Ti NPs) and titanium dioxide nanoparticles (TiO₂ NPs) were synthesized by laser ablation and characterized by dynamic light scattering, spectrophotometry, and transmission electron microscopy. The average hydrodynamic diameter of Ti NPs was 12 nm, while that of TiO₂ NPs was 24 nm; both dispersions possessed a positive zeta potential (23–27 mV) and spherical morphology. L-PLA composite films containing 0.1 wt.% Ti NPs or TiO₂ NPs were obtained by solution casting. Atomic force and modulation-interference microscopy confirmed the uniform distribution of nanoparticles within the polymer matrix, although partial aggregation was observed. The introduction of TiO₂ NPs increased the water contact angle. Mechanical testing revealed a significant reinforcing effect: the addition of 0.1 wt.% NPs increased the Young’s modulus by 62–68% and the ultimate tensile strength by 16–18% while maintaining a ductile fracture pattern with elongation at break up to ~8%. Both types of composites generated reactive oxygen species (ROS) in aqueous solutions: Ti NPs increased H₂O₂ production by 5.5 times and TiO₂ NPs by 4.9 times, and they also induced the formation of hydroxyl radicals. The accumulation of 8-oxoguanine in DNA and long-lived oxidized protein species confirmed the materials’ ability to cause oxidative damage to biomacromolecules. For E. coli, growth inhibition reached 40.5% (for composites with Ti NPs) and 71% (for composites with TiO₂ NPs). The effect was even more pronounced for S. aureus, where inhibition levels were approximately 70% and 80%, respectively; flow cytometry confirmed the strong bactericidal effect, showing that materials containing TiO₂ NPs increased the proportion of dead cells to 25% for E. coli and ~68% for S. aureus. Cytotoxicity assessment on human fibroblasts (HSF) demonstrated the high biocompatibility of neat L-PLA and composites with Ti NPs (viability > 95%) and with TiO₂ NPs (viability ~93%). The obtained results indicate that L-PLA-based composites with Ti NPs and TiO₂ NPs exhibit pronounced ROS-mediated antibacterial activity without additional UV irradiation. These findings position these materials as highly promising candidates for active biodegradable food packaging to extend shelf-life and for biomedical devices, such as wound dressings and implants, where reducing the risk of bacterial colonization is critical. Full article

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. Full article

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain. Full article

Soy protein concentrate (SPC) undergoes continuous thermal and structural changes during passage through a cooling die, yet these changes are often interpreted using viscosity-based descriptions that do not explicitly account for structural development rate (SDR). This study developed a rheology-guided framework to analyze SPC behavior in a three-stage cooling die by integrating isothermal and non-isothermal rheological characterization with computational fluid dynamics (CFD). SPC samples containing 76, 78, and 80% moisture were evaluated using strain sweep, frequency sweep, viscosity, time sweep, and temperature sweep tests. Lower moisture promoted stronger structure development, higher viscosity, and faster gelation. For the 76% moisture sample, peak SDR increased from 6.66 Pa/s at 50 °C to 22.46 Pa/s at 100 °C, while the time to peak decreased from 937 to 360 s. During non-isothermal cooling, the major structure development occurred in the 80–50 °C interval, where ΔG′ reached 4902.54 Pa at 76% moisture. CFD analysis showed that the gelation-kinetics-based model predicted both pressure and extrudate temperature more accurately than the viscosity-based model. Pressure RMSE ranged from 8.57 to 14.43 kPa for the kinetic model, compared with 11.31 to 22.39 kPa for the viscosity model. These results demonstrate that the three-stage cooling die should be interpreted as a coupled thermal, flow, and structure-development domain. Full article

Background: Unhealthy expansion of adipose tissue (AT) due to excessive dietary intake of omega-6 or overnutrition stimulates the overaccumulation of the extracellular matrix (ECM), resulting in AT metabolic dysregulation. Hypertrophic conditions, excessive adipose depots, and hypoxia stimulate the overproduction of collagenous and non-collagenous proteins, which pathophysiologically initiate the pro-fibrotic signaling pathway associated with fibrosis progression, resulting in atherosclerosis and cardiovascular diseases. Methods: We aimed to investigate adipocyte plasticity in response to a varying ratio of omega-3 (ω3) to omega-6 (ω6) supplementation during the chemically induced adipogenic differentiation of human mesenchymal stem cells. Additionally, changes in lipid accumulation, adipocyte hypertrophy and hyperplasia, active lipid metabolites, and inflammatory cytokine profiles were evaluated. Furthermore, conditioned media from adipocytes treated with different ω3/ω6 ratios were applied to platelets to assess inflammatory responses through prostaglandin and thromboxane measurements. Results: A 1:3 ratio of ω3/ω6 (20:60 µM) significantly reduced lipid accumulation, promoted brown-like adipocyte morphology, and decreased apoptosis and reactive oxygen species (ROS) generation, as confirmed via FACS analysis. Transcriptional control of adipose tissue expansion was confirmed by the downregulation of LIPIN1 and COL1A1 mRNA expression and p-prostaglandin12-R protein levels in a 1:3 ratio when compared with 1:1, 1:2, 1:4, or 2:6 ratios of ω3/ω6. Notably, a 1:3 ratio of fatty-acid-treated adipocyte-conditioned media-treated platelets significantly reduced platelet activation and aggregation, as evidenced by lower p-thromboxane A2 protein levels. Conclusions: Supplementation with a 1:3 (20:60 µM) ω3/ω6 ratio favored the development of lean adipocytes, evidenced by the decreased lipid storage achieved by mitochondrial thermogenesis, which attenuated minimal adipocyte expansion and metabolic inflammation. Full article

Alzheimer’s disease (AD) is the leading cause of dementia, responsible for approximately 60–70% of cases globally. AD is a gradually progressive neurodegenerative disorder that is characterized by widespread deposition of β-amyloid (Aβ) plaques, followed by aggregation of tau protein in the neocortex, neurodegeneration, and cognitive decline. Within these complex pathological interactions, Aβ and tau proteins, together with astrogliosis, neuroinflammation, and other factors, play a key role in the development of clinical AD. Accumulating evidence indicates that the formation of protein oligomers, followed by their aggregation into pathological fibrils, constitutes an early and critical step in the pathogenesis of the disease. Specific pathological proteins are often treated as biomarkers of particular diseases because their presence, concentration, or altered structure reflects an underlying disease process. It is well established that the Aβ and tau proteins are the key hallmarks of AD, and their mutual interaction may significantly influence the pathology of the disease. Early diagnosis is crucial for maximizing the therapeutic benefits of currently available symptomatic treatments, which can alleviate symptoms and modestly delay clinical deterioration in patients with AD. This review highlights the mechanisms involved in protein-dependent neurodegeneration and describes both traditional and novel approaches for the cure of AD. The most important aspect of this publication is the integration of the two key proteins: Aβ and tau, and the resulting shift toward a new therapeutic approach. Full article

Myofibrillar protein microgel particles (MMP) are promising Pickering stabilisers due to their structure and delivery potential. However, their fibrous, irregular shape promotes aggregation, limiting practical use. This study investigated the effect of xanthan gum (XG) concentration (0.025–0.4%) on MMP dispersion in water and its role in stabilising Pickering emulsions. FTIR and interaction analysis revealed that hydrophobic interactions dominate between XG and MMP, followed by hydrogen bonding and electrostatic forces. At higher XG concentrations (0.2–0.4%), complex particle size decreased from 5.21 μm to 4.49 μm, the contact angle increased from 57.67° to 77.33°, and a uniform dispersed state was achieved. Although increasing XG gradually reduced the emulsifying activity of MMP, it significantly improved the emulsion stability. Microstructure analysis showed that at low XG concentrations, emulsions exhibited phase separation. Rheological measurements indicated that XG-MMP complexes increased continuous-phase viscosity and shear resistance, enhancing macroscopic stability. In summary, at a critical XG concentration of 0.2%, the emulsion undergoes a transition from aggregation-driven instability to network-mediated stabilisation, achieved through the interfacial layer with spatial confinement by a weak aqueous-phase network. This work provides a theoretical foundation and a practical design strategy for fabricating highly stable, tuneable Pickering emulsions based on protein microgel particles. Full article

This review aggregates the latest reports on the role of environmental factors in the male reproductive system and cancer development. We analyzed environmental pollution-related studies and disorders of mechanisms responsible for defense against the impact of xenobiotics on prostate cancer. We focused on polymorphisms that, when exposed to environmental stressors, might exacerbate an organism’s defense mechanisms against the effects of xenobiotics. It is well known that environmental factors, such as toxic heavy metal pollution, xenobiotic exposure, and undue and differentiated stressors, affect the human reproductive system. There were many studies suggesting an association between these factors and prostate cancer development, but there are still no unambiguous or conclusive results. Investigations of specific marker changes that occur in response to varied environmental stressors are also critical to mutual relations. They focus on the influence of chemical element destabilization and heavy metal pollution on organisms and the environment. Simultaneously, antioxidant enzymatic mechanisms in conditions of anthropogenic impact and the influence of polymorphisms in genes involved in genetic material damage under stress conditions were also studied. This review aims to provide essential data suggesting the role of environmental factors in the initiation and development of carcinogenic processes in the male reproductive system based on prostate cancer cases. It further clarifies this field’s current needs and research directions. It is possible to conclude that there is a relationship between the studied polymorphisms and antioxidant mechanisms, lipoperoxidation, and trace element concentrations in the blood of men with prostate cancer. The results indicate the need to consider environmental factors as necessary in assessing the risks resulting from exposure to oxidative stress in prostate cancer patients. Available data suggest the existence of interactions between exposure to environmental stressors and increased susceptibility to cancers, including male reproductive system cancers. Differentiated chemical elements introduced into the body may play a significant role. Individuals with cancer have a disturbed antioxidant enzyme status, which could be a basis for decreased defense against carcinogenic factors or the effect of disturbed body balance caused by the carcinogenic process. In turn, studies of repair gene polymorphism may indicate disorders of proteins needed for the organism’s defense against xenobiotics. The analysis presented provides data for conclusive population-based studies of the impact of environmental factors on the carcinogenic process in the male reproductive system. This review provides a basis for constructing current needs and the research direction in the discussed field of knowledge. This will allow for a precise study of the explanation of possible multilateral interactions between exposure to varied environmental stressors and the increased incidence of male reproductive system cancer at present. Full article

Neuropsychiatric diseases are characterized by complex molecular underpinnings that remain challenging to fully elucidate. Molecular dynamics (MD) simulations have emerged as a powerful computational tool, providing a crucial bridge between static genetic data and the dynamic functional consequences of molecular alterations. This review offers a comprehensive overview of the application of MD simulations in studying the molecular basis of neuropsychiatric disorders. We highlight key applications, including the assessment of mutation pathogenicity in disease-associated proteins, the influence of post-translational modifications on protein function, folding, misfolding, and aggregation, and the characterization of psychopharmacological drug–target interactions at atomic resolution. Through relevant examples from research on psychiatric and neurodegenerative diseases, we illustrate how these computational methods are implemented to gain mechanistic insights. Importantly, this review traces the historical development of MD simulations in biological applications, critically examines the method’s limitations, and outlines future perspectives for simulating long-timescale physiological processes, large molecular ensembles, and even whole-cell environments. Ultimately, this work highlights MD simulations as a useful and complementary tool for modern neuropsychiatry research, capable of revealing disease mechanisms and guiding the development of novel therapeutic strategies. Full article

DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids 16 and 17, with similar or even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies. Full article

Cuproptosis represents a novel form of programmed cell death that relies on copper ions and targets the mitochondrial tricarboxylic acid cycle, offering fresh avenues for tumor therapy. Elesclomol, as a highly efficient small-molecule copper ion carrier, transports copper ions into mitochondria. Under the action of ferredoxin-1 (FDX1), it induces abnormal aggregation of lipoylated proteins and loss of iron–sulphur clusters, thereby generating protein toxicity stress and killing tumor cells. Furthermore, elesclomol effectively remodels the tumor immune microenvironment by promoting dendritic cell maturation and CD8⁺ T cell infiltration, demonstrating synergistic effects with immune checkpoint blockade therapies. However, tumor cells can develop resistance mechanisms through metabolic reprogramming via hypoxia-inducible factor-1α (HIF-1α) and the nuclear factor E2-related factor 2 (Nrf2)-driven reductive pathway, which partially limits the drug’s clinical efficacy. Addressing this limitation, combination therapies integrating elesclomol with targeted agents such as ferroptosis inducers or chemotherapeutic drugs have demonstrated significant antitumor advantages. Future research must urgently leverage the selection of precise biomarkers and the development of novel intelligent nanodelivery systems to further advance the safe and efficient clinical translation of elesclomol. Full article

The central role of YB-1 in messenger ribonucleoprotein particle (mRNP) metabolism and stress-granule biology highlights the importance of defining the determinants of its self-assembly. YB-1 fibrillogenesis has been attributed primarily to the cold shock domain (CSD). Here, we show that the YB-1 fragment spanning residues 1–129 (AP–CSD) form amyloid fibrils under near-physiological ionic strength (0.12–0.15 M KCl). Fibrillization proceeds without a pronounced exponential growth phase and increases approximately linearly over 45–50 h. Far-UV circular dichroism (CD) and attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) indicate no substantial change in overall secondary-structure content during aggregation. In parallel, ¹H nuclear magnetic resonance (NMR) spectroscopy reveals the depletion of soluble species, and oriented fiber X-ray diffraction displays the hallmark cross-β reflections at approximately 4.7 Å and 10 Å. The prolonged formation time implies an activation barrier that is unlikely to require global refolding. Instead, it may reflect early association events such as dimerization or other local rearrangements required for primary nucleation, followed by consolidation into stable intermolecular contacts. Aggregation that preserves a largely native-like fold while establishing cross-β order may reduce recognition by cellular quality-control systems that preferentially target globally unfolded or strongly destabilized states. This provides a plausible framework for how YB-1 derived assemblies could persist under stress and during age-associated proteostasis decline. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β aggregation, mitochondrial stress, and aberrant kinase activity. Carotenoids, naturally occurring pigments with antioxidant and neuroprotective properties, have emerged as promising candidates for AD intervention. In this study, we performed a systematic stepwise computational screening of a large carotenoid library (n = 1191) to identify multitarget candidates against AD–related proteins. The workflow consisted of predefined ADMET filtering (oral absorption > 90%, Caco-2 > 0.9, logBB > −1, and absence of major CYP inhibition and toxicity alerts), reducing the dataset to 61 compounds, followed by multi-target molecular docking against AChE, BChE, BACE-1, MAO-B, and GSK3-β. Compounds were ranked using an aggregated mean docking score across all five targets, and the top-performing candidate was subjected to detailed mechanistic analyses. Hopkinsiaxanthin emerged as the highest-ranked multitarget carotenoid and was further evaluated using frontier molecular orbital (FMO) analysis, pharmacophore modeling, 100 ns molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and per-residue decomposition. Docking predicted favorable estimated binding affinities toward all targets. MD simulations confirmed stable receptor–ligand complexes with low RMSD values (0.278–0.285 nm). MM/PBSA analysis indicated favorable binding free energies, particularly for GSK3-β (−22.73 kcal/mol) and AChE (−21.50 kcal/mol). Per-residue decomposition identified key hotspot residues driving stabilization. Overall, this structured computational framework identifies Hopkinsiaxanthin as a promising multitarget scaffold and supports its prioritization for experimental validation in AD models. Full article