Search Results (13,959)

Background/Objectives: SARS-CoV-2 pandemic led to the identification of peptide-based main protease (M^pro) inhibitors. The overwhelming majority of them carry an electrophilic warhead and a γ-lactam at the P1 position. During the selectivity assessment of an in-house Michael acceptors targeting SARS-CoV-2 M^pro, we unexpectedly observed a significant inhibition of human cathepsin S (hCatS). Methods: The biological investigation of three compounds (i.e., SPR38, SPR39, and SPR41) against hCatS was performed. The binding mode of SPRs was investigated by docking and molecular dynamics simulations. Results: Biological investigation has corroborated that hCatS is sensitive to peptide-based analogues harbouring γ-lactam at the P1 position and a vinyl methyl ketone warhead. In silico studies revealed that despite being solvent exposed, the γ-lactam at P1 might be involved in water-mediated H-bonds that could be optimized to gain inhibition potency and selectivity. Conclusions: The molecules repurposing of peptide-based SARS-CoV-2 M^pro inhibitors carrying the γ-lactam at the P1 site could pave the way for the identification of novel potent and selective hCatS ligands. Full article

In this study, the oxidation of industrial hemp staple fibers by the TEMPO/NaBr/NaClO system was explored by the real-time monitoring of the changes in reaction rate, selective oxidative conversion, and reaction time under different operating conditions such as TEMPO usage, NaBr usage, NaClO usage, reaction time, and reaction temperature. We propose a variable-speed competition mechanism between NaClO and TEMPO, which provides experimental support for the long-standing hypothesis that hypochlorite delays acid formation through modulation of the HOCl/OCl⁻ and HOBr/OBr⁻ equilibrium dynamics. The innovative use of combined analysis for several consecutive first-order reactions to investigate the rate-limiting reactions of TEMPO, TEMPO⁺, and TEMPOH over a range of concentrations revealed that the reaction that generates TEMPOH is the key rate-limiting reaction. We characterize the apparent oxidation kinetics of industrial hemp staple fiber in the TEMPO/NaBr/NaClO system using a pseudo-first-order kinetic model, revealing distinct apparent reaction rates across both primary and secondary bast fiber regions. This paper explained the difference in reaction rate between the two aspects of microfibril spatial structure and cellulose crystal structure. The single-factor analysis indicates that reaction time and temperature exert the most significant influence on the conversion rate of selective oxidation within this system Full article

The rising global prevalence of inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, is paralleled by an increased risk of colitis-associated colorectal cancer. Persistent intestinal inflammation promotes genetic instability and epigenetic reprogramming within epithelial and immune cells, driving the multistep transition from inflammation to neoplasia. This review integrates human and preclinical model evidence with literature mining and bioinformatic analyses of genetic, epigenetic, and ncRNA data to dissect molecular mechanisms driving colitis-associated colorectal cancer from chronic inflammation. We highlight how pro-inflammatory cytokines (e.g., TNF-α, IL-6), oxidative stress, and microbial dysbiosis converge on key transcriptional regulators such as NF-κB and STAT3, inducing DNA methylation and histone modifications (e.g., H3K27me3); altering chromatin dynamics, gene expression, and non-coding RNA networks (e.g., miR-21, MALAT1, CRNDE); ultimately reshaping pathways involved in proliferation, apoptosis, and immune evasion. This review updates new potential associations of entities with these diseases, in their networks of interaction, summarizing major aspects of genetic and chromatin-level regulatory mechanisms in inflammatory bowel disease and colorectal cancer, and emphasizing how these interactions drive the inflammatory-to-neoplastic transition. By underscoring the reversibility of epigenetic changes, we explore their translational potential in early detection, surveillance, and precision epigenetic therapy. Understanding the interplay between genetic mutations and chromatin remodeling provides a roadmap for improving diagnostics and personalized treatments in inflammatory bowel disease-associated colorectal carcinogenesis. Full article

Poly(carboxybetaine methacrylate)s (PCBMA) belongs to a class of zwitterionic polymers that offer promising alternatives to polyethylene glycol (PEG) in biomedical applications. This review highlights how the unique zwitterionic structure of PCBMA dictates its strong antifouling behavior, low immunogenicity, and sensitivity to environmental stimuli such as pH and ionic strength. These features make PCBMA promising for designing advanced systems suited for complex biological environments. This review describes PCBMA-based materials—ranging from hydrogels, nanogels, and surface coatings to drug carriers and protein conjugates—and critically evaluates their performance in drug delivery, tissue engineering, diagnostics, and implantable devices. Comparative studies demonstrated that PCBMA consistently outperformed other zwitterionic polymers and PEG in resisting protein adsorption, maintaining bioactivity of conjugated molecules, and ensuring long circulation times in vivo. Molecular dynamics simulations provide additional information into the hydration shells and conformational behaviors of PCBMA in aqueous dispersions. These insights underscore PCBMA’s broad potential as a promising high-performance material for next generation healthcare technologies. Full article

Silicon-doped C₆₀ fullerenes represent a distinctive class of heterofullerenes with tunable structural, electronic, and chemical properties arising from substitutional incorporation of Si atoms into the carbon cage. This review provides a comprehensive analysis of substitutional Si–C₆₀ systems and their endohedral and exohedral complexes, with emphasis on synthesis strategies, structural features, and theoretical investigations. Experimental methods, including laser vaporization and arc discharge of Si-containing graphite targets, have enabled the preparation of Si-doped fullerenes, although challenges remain in controlling the dopant number, position, and distribution. Computational studies, dominated by density functional theory and molecular dynamics simulations, elucidate the effects of Si substitution on cage geometry, HOMO–LUMO modulation, charge localization, aromaticity, and finite-temperature stability. Exohedral functionalization and endohedral encapsulation of Si-doped cages significantly enhance their potential for applications in sensing, catalysis, energy storage, and nanomedicine. Si incorporation consistently strengthens adsorption of small molecules, pharmaceuticals, biomolecules, and environmental pollutants, often transforming weak physisorption into strong chemisorption with pronounced electronic and spectroscopic changes. The synergistic insights from experimental and theoretical work establish Si-doped fullerenes as versatile, electronically responsive nanoplatforms, offering a balance between stability, tunability, and reactivity, and highlighting future opportunities for targeted synthesis and application-specific design. Full article

Prostate stem cell antigen (PSCA) is a Ly6/uPAR protein that targets neuronal nicotinic acetylcholine receptors (nAChRs). It exists in membrane-tethered and soluble forms, with the latter upregulated in Alzheimer’s disease. We hypothesize that PSCA may be linked to a wider spectrum of neurological diseases and could induce neuroinflammation. Indeed, PSCA expression is significantly upregulated in the brain of patients with multiple sclerosis, Huntington’s disease, Down syndrome, bipolar disorder, and HIV-associated dementia. To investigate PSCA’s structure, pharmacology, and inflammatory function, we produced a correctly folded water-soluble recombinant analog (ws-PSCA). In primary hippocampal neurons and astrocytes, ws-PSCA differently regulates secretion of inflammatory factors and adhesion molecules and induces pro-inflammatory responses by increasing TNFβ secretion. Heteronuclear NMR and ¹⁵N relaxation measurements reveal a classical β-structural three-finger fold with conformationally disordered loops II and III. Positive charge clustering on the molecular surface suggests the functional importance of ionic interactions by these loops. Electrophysiological studies in Xenopus oocytes point on ws-PSCA inhibition of α3β2-, high-, and low-sensitive variants of α4β2- (IC₅₀ ~50, 27, and 15 μM, respectively) but not α4β4-nAChRs, suggesting targeting of the β2 subunit. Ensemble docking and molecular dynamics simulations predict PSCA binding to high-sensitive α4β2-nAChR at α4/β2 and β2/β2 interfaces. Complexes are stabilized by ionic and hydrogen bonds between PSCA’s loops II and III and the primary and complementary receptor subunits, including glycosyl groups. This study gives new structural and functional insights into PSCA’s interaction with molecular targets and provides clues to understand its role in the brain function and mental disorders. Full article

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms—insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features. Full article

The curing of silicone networks from dimethylsilanediol and methylsilanetriol chainbuilder–crosslinker precursor mixtures is investigated from combined quantum/molecular mechanics simulations. Upon screening different crosslinker content from 5 to 15%, we provide a series of atomic-resolution bulk models all featuring 98–99% curing degree, albeit at rather different arrangement of the chains and nodes, respectively. To elucidate the nm scale alignment of the polymer networks, we bridge scales from atomic simulation cells to graph theory and demonstrate the analyses of 3-dimensional percolation of -O-Si-O- bonds, polydimethylsiloxane branching characteristics and the interpenetration of loops. Our findings are discussed in the context of the available experimental data to relate heat of formation, curing degree and elastic properties to the molecular scale structural details—thus promoting the in-depth understanding of silicone resins. Full article

Cellular plasticity enables cells to dynamically adapt their phenotype in response to environmental cues, a process central to development, tissue repair, and disease. Among the most studied plasticity programs is epithelial–mesenchymal transition (EMT), a transcriptionally controlled process by which epithelial cells acquire mesenchymal traits. Originally described in embryogenesis, EMT is now recognized as a key driver in both tumor progression and fibrotic remodeling. In cancer, EMT and hybrid epithelial/mesenchymal (E/M) states promote invasion, metastasis, stemness, therapy resistance, and immune evasion. In fibrotic diseases, partial EMT (pEMT) contributes to fibroblast activation and excessive extracellular matrix deposition, sustaining organ dysfunction mainly in the kidney, liver, lung, and heart. This review integrates recent findings on the molecular regulation of EMT, including signaling pathways (TGF-β, WNT, NOTCH, HIPPO), transcription factors (SNAIL, ZEB, TWIST), and regulatory layers involving microRNAs and epigenetic modifications. Moreover, we discuss the emergence of pEMT states as drivers of phenotypic plasticity, functional heterogeneity, and poor prognosis. By comparing EMT in cancer and fibrosis, we reveal shared mechanisms and disease-specific features, emphasizing the translational relevance of targeting EMT plasticity. Finally, we explore how cutting-edge technologies, such as single-cell transcriptomics and lineage tracing, are reshaping our understanding of EMT across pathological contexts. Full article

Transketolase-like protein 1 (TKTL-1) has been implicated in altered cancer metabolism, yet its structure and molecular function remain poorly understood. In this study, we established a homology model of TKTL-1 using multiple templates and validated it through sequence alignment and structural comparison with the canonical transketolase (TKT). Binding-site identification was performed using CASTp, receptor cavity mapping, and blind docking, all of which consistently pointed to a conserved region involving interactive residues shared between TKT and TKTL-1. Comparative docking revealed the reduced affinity of TKTL-1 for TDP, supporting functional divergence between TKTL-1 and TKT. We further analyzed conserved residues and receptor surfaces, which enabled us to propose predictive scaffolds as potential modulators of TKTL-1. While these scaffolds remain theoretical, they provide a computational framework to guide future pharmacophore modeling, molecular dynamics simulations, and experimental validation. Together, our study highlights the structural features of TKTL-1, establishes its key differences from TKT, and lays the groundwork for future drug discovery efforts targeting cancer metabolism. Full article

This study aims to elucidate the neurodevelopmental toxicity and molecular mechanisms of endocrine-disrupting chemicals (EDCs) in neurodevelopmental disorders (NDDs) through a network toxicology approach, using triclosan exposure as a case example. Potential targets of triclosan were identified via comparative analysis of toxicogenomics databases such as the Comparative Toxicogenomics Database (CTD), Similarity Ensemble Approach (SEA), SwissTargetPrediction, and TargetNet. NDD-related targets were retrieved from GeneCards, Disease Gene Network (DisGeNET), and Online Mendelian Inheritance in Man (OMIM), resulting in 633 overlapping genes associated with disease pathology and triclosan effectors. Protein–protein interaction networks were constructed using STRING and Cytoscape, applying median-based algorithms to identify six core genes: AKT1, TP53, EGFR, FN1, SRC, and ESR1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses via Metascape revealed that triclosan-induced NDDs are primarily associated with endocrine signaling disruption and activation of the PI3K-Akt pathway. Molecular docking with CB-Dock2 demonstrated strong binding affinities between triclosan and the core targets, while YASARA molecular dynamics simulations confirmed stable interactions, notably with EGFR, exhibiting high binding stability. Collectively, these findings delineate the potential molecular mechanisms underlying triclosan-induced NDDs and underscore the utility of network toxicology, molecular docking, and molecular dynamics simulations in assessing neurotoxicity and related molecular pathways. This research provides novel insights for future investigations, enhances understanding of the potential impact of neurodevelopmental disorders on health, and lays a scientific foundation for the development of preventive and therapeutic strategies. Full article

The growth plate is a specialized cartilage structure near the ends of long bones that orchestrates longitudinal bone growth during fetal and postnatal stages. Within this region reside a dynamic population of growth plate skeletal stem cells (gpSSCs), primarily located in the resting zone, which possess self-renewal and multilineage differentiation capacity. Recent advances in cell-lineage tracing, single-cell transcriptomics, and in vivo functional studies have revealed distinct subpopulations of gpSSCs, which are defined by markers such as parathyroid hormone-related protein (PTHrP), CD73, axis inhibition protein 2 (Axin2), forkhead box protein A2 (FoxA2), and apolipoprotein E (ApoE). These stem cells interact intricately with their niche, particularly after the formation of the secondary ossification center, through stage-specific regulatory mechanisms involving several key signaling pathways. This review summarizes the current understanding of gpSSC identity, behavior, and regulation, focusing on how these cells sustain growth plate function through adapting to biomechanical and molecular cues. Full article

The activation and dissociation of O₂ molecules play a key role in the oxidation of toxic gas molecules and the oxygen reduction reaction (ORR) in hydrogen–oxygen fuel cells. The interactions between O₂ molecules and the surfaces of Fe-doped γ-graphyne were systematically explored, mainly adopting the combined method of the density functional theory with dispersion correction (DFT-D3) and the climbing image nudged elastic band (CI-NEB) method. The order of the formation energy values of these defective systems is E_f(Fe_C2) < E_f(Fe_C1) < E_f(Fe_D1) < E_f(V_C1) < E_f(V_D1) < E_f(V_C2) < E_f(Fe_D2) < E_f(V_D2), which indicates that the process of Fe dopant atoms substituting single-carbon atoms/double-carbon atoms is relatively easier than the formation of vacancy-like defects. The results of ab initio molecular dynamics (AIMD) simulations confirm that the doped systems can maintain structural stability at room temperature conditions. Fe-doped atoms transfer a certain amount of electrons to the adsorbed O₂ molecules, thereby causing an increase in the O-O bond length of the adsorbed O₂ molecules. The electrons obtained by the anti-bonding 2π* orbitals of the adsorbed O₂ molecules are mainly derived from the 3d orbitals of Fe atoms. There is a competitive relationship between the substrate’s carbon atoms and the adsorbed O₂ molecules for the charges transferred from Fe atoms. In the C1 and C2 systems, O₂ molecules have a greater advantage in electron accepting ability compared to the substrate’s carbon atoms. The elongation of O-O bonds and the amount of charge transfer exhibit a positive relationship. More electrons are transferred from Fe-3d orbitals to adsorbed O₂ molecules, occupying the 2π* orbitals of adsorbed O₂ molecules, further elongating the O-O chemical bond until it breaks. The dissociation process of adsorbed O₂ molecules on the surfaces of GY-Fe systems (C2 and D2 sites) involves very low energy barriers (0.016 eV for C2 and 0.12 eV for D2). Thus, our studies may provide useful insights for designing catalyst materials for oxidation reactions and the oxygen reduction reaction. Full article

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior. Full article