Search Results (15,806)

HIV-1 protease (PR) is an essential enzyme in the viral life cycle and a primary target of antiretroviral therapies, particularly protease inhibitors (PIs). Understanding the dynamics of viral evolution and the factors governing the emergence or loss of resistance-associated mutations is critical for improving PI efficacy and managing drug resistance in HIV/AIDS treatment. In this study, we investigated the impact of three natural HIV-1 polymorphisms (T12A, L63Q, and H69N), whose prevalence varies depending on treatment status and viral subtype, on the structural stability and conformational dynamics of PR using molecular dynamics (MD) simulations. Three independent 500 ns MD simulations were performed for the native protease and each mutant system. Although none of the mutations disrupts the overall structural integrity of HIV-1 PR, they induce mutation-specific alterations in flexibility and residue interactions. In particular, T12A and H69N exhibit increased structural deviations, especially in the flap regions, along with enhanced conformational fluctuations. In contrast, the L63Q mutation shows a slight reduction in flap flexibility compared to both the native protease and the other mutants. Consistently, the fraction of time spent in open-flap conformations is higher for T12A and H69N and lower for L63Q relative to the native system. Moreover, mutations in the Fulcrum (T12A) and Cantilever (L63Q and H69N) regions do not disrupt the long-range network of correlated motions observed in the native protease, both inter- and intra-monomer, but instead increase the extent of correlated and anti-correlated motions in other regions of PR. Full article

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation, epithelial barrier disruption and immune dysfunction. Alleviating and curing these pathological manifestations is the goal of IBD treatment. Despite substantial advances in targeted immunotherapies and anti-inflammatory strategies, achieving sustained intestinal mucosal healing remains a major clinical challenge. Dynamin-related protein 1 (Drp1) is a GTPase that mediates mitochondrial fission and plays a crucial role in maintaining the dynamic balance of mitochondrial morphology and function. In IBD, Drp1 expression is frequently upregulated and continuously activated, resulting in excessive fission and fragmentation of mitochondria. This mitochondrial dysregulation contributes to ATP depletion and excessive reactive oxygen species (ROS) production, thereby exacerbating disease progression and amplifying inflammatory signaling. This review highlights the distinctive role of Drp1 as an integrative node in IBD. Specifically, we connect mitochondrial dynamics with epithelial barrier failure, immune dysregulation, inflammatory cell death, and intestinal microenvironment remodeling. We further emphasize the potential relevance of Drp1 for biomarker-based patient stratification and mechanism-informed therapeutic targeting, thereby distinguishing this review from more descriptive accounts of mitochondrial dysfunction in intestinal inflammation. Full article

Background/Objectives: Neuroinflammation is characterized by the sustained activation of neuroglial cells, resulting in the production of cytokines and chemokines. It is associated with neurodegenerative processes. This study aims to assess the potential mitigating effect of a novel coumarin–quinoline hybrid by evaluating oxidative stress, apoptosis, and pyroptosis in an experimentally induced model of neuroinflammation. Methods: The study was conducted on 60 mice, allocated into six groups of ten: Group I served as the control; Group II received the new coumarin–quinoline hybrid; Group III received lipopolysaccharide (LPS); Group IV received LPS followed by the coumarin–quinoline hybrid; Group V received LPS followed by dexamethasone (DEX); and Group VI received LPS followed by the coumarin–quinoline hybrid and DEX. The model was validated by behavioral assessments, while oxidative stress was quantified via nitric oxide (NO), malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity, apoptosis by caspase-3, and pyroptosis by NLRP3. Results: An anti-inflammatory effect of a new coumarin–quinoline hybrid, evidenced by decreased NLRP3 and NF-κB expression, reduced NO and MDA production, elevated SOD activity, and brought about suppression of caspase-3. Additionally, the newly formulated coumarin–quinoline hybrid demonstrated favorable ADMET characteristics, with in silico molecular studies indicating a stable energetic profile and dynamic equilibrium. Conclusions: Findings suggest that the new coumarin–quinoline hybrid holds significant potential as an adjuvant therapeutic option for neuroinflammation. Full article

Background/Objectives: KRAS G12C mutations define a clinically actionable subset of solid tumors, particularly non–small cell lung cancer. Clinical responses to approved covalent inhibitors remain limited by intrinsic and acquired resistance, highlighting the need for structurally distinct inhibitor scaffolds to expand therapeutic options. The objective of this study was to identify novel covalent binders targeting the KRAS G12C switch-II pocket through large-scale in silico screening and experimental validation. Methods: More than 1.9 million small molecules from diverse commercial libraries were screened using covalent docking, followed by multi-stage refinement incorporating molecular dynamics simulations, MM/GBSA free-energy estimation, and cancer-focused QSAR modeling. Results: This integrated workflow yielded 50 prioritized compounds spanning several chemically distinct scaffold classes. These candidates displayed favorable predicted binding energetics, stable ligand-protein interactions over extended simulation timescales, and low structural similarity to clinically approved KRAS G12C inhibitors sotorasib and adagrasib. Benchmarking against these clinical agents, using identical computational parameters, yielded comparable predicted binding energies for several candidate molecules. In cellular NanoBRET target-engagement assays, selected scaffolds, including K788-7251 and AN-989/14669131, exhibited sub-micromolar engagement of KRAS G12C with minimal endothelial cytotoxicity. Conclusions: Collectively, these findings identify structurally distinct, KRAS G12C inhibitor chemotypes and provide tractable starting points for the development of next-generation targeted therapies. Full article

Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has garnered attention for its cardiovascular benefits beyond glycemic control. Ferroptosis, a novel form of regulated cell death, contributes to the pathogenesis of diabetic cardiomyopathy (DCM). However, whether EMPA mitigates DCM by suppressing ferroptosis remains unclear. Here, Type 2 diabetic db/db mice were used to establish a DCM model and treated with EMPA (10 mg/kg/day) for 12 weeks. EMPA significantly improved cardiac function, reduced myocardial fibrosis, and attenuated ferroptosis, concomitant with upregulated silent information regulator 3 (SIRT3) expression. In the rat cardiomyocytes (H9c2 cells) exposed to high glucose and palmitic acid, EMPA treatment or SIRT3 overexpression alleviated oxidative stress, mitochondrial dysfunction, and ferroptosis. Mechanistically, molecular docking, molecular dynamics simulation, cellular thermal shift assay and drug affinity responsive target stability assay confirmed that SIRT3 is the drug target of EMPA, stabilizing its protein levels and reducing acetylated p53 expression. Notably, SIRT3 silencing abolished EMPA’s beneficial effects on oxidative stress and ferroptosis. Our findings demonstrate that EMPA exerts cardioprotective effects by inhibiting oxidative stress and ferroptosis in cardiomyocytes, which is mediated by SIRT3. This study provides novel insights into the mechanisms underlying EMPA’s therapeutic effects in DCM. Full article

Background/Objectives: Zebrafish fin regeneration serves as a classic model for investigating vertebrate tissue regeneration, yet the core regulatory networks and their crosstalk with the immune microenvironment remain incompletely characterized. This study aimed to identify hub genes, and elucidate the underlying molecular mechanisms and immune microenvironment dynamics during zebrafish fin regeneration. Methods: We integrated multiple bulk RNA-seq datasets of zebrafish fin regeneration from the GEO database, followed by data standardization with batch effect removal. Hub genes were screened via differential expression analysis, weighted gene co-expression network analysis (WGCNA), and predictive models constructed with 13 classic machine learning algorithms. Functional enrichment, time-ordered gene co-expression network (TO-GCN) method, immune infiltration analyses and RT-qPCR validation were further performed. Results: We identified upregulated differentially expressed genes, regeneration-correlated gene modules and their overlapping genes, including 82 candidate genes and 10 hub genes enriched in cytoskeleton remodeling, extracellular matrix organization, and focal adhesion. Temporal analysis uncovered hierarchical gene regulation and functional switching during regeneration. Hub gene expression was significantly correlated with the infiltration of B cells, M1/M2 macrophages and CD8+ T cells, revealing a stage-specific immune microenvironment. RT-qPCR validation showed high consistency with the multi-omics data. Conclusions: This study provides potential gene targets for understanding zebrafish fin regeneration, and offers a valuable reference for investigating the crosstalk between regulatory networks and the immune microenvironment in vertebrate tissue regeneration. Full article

Molten salt chlorination is a key industrial route for producing titanium tetrachloride (TiCl₄), yet the atomistic catalytic role of iron (Fe) in the carbothermic chlorination of titanium oxides remains unclear. Here, the chlorination behavior of the NaCl–C–Cl₂–FeTiO₃ system was investigated by combining thermodynamic calculations with Ab Initio Molecular Dynamics (AIMD) and Deep Potential Molecular Dynamics (DPMD) simulations. AIMD results show that carbon adjacent to Fe exhibits enhanced reactivity, and that Fe-C synergistic electron transfer promotes both titanium oxide reduction and subsequent titanium chlorination. DPMD results further reveal that Fe not only accelerates these transformations, but also improves interfacial contact among carbon, titanium oxides, and molten salt, thereby enhancing mass transfer and shortening the formation time of TiCl₄. Temperature-dependent analysis indicates that Fe-C and C-O coordination numbers remain high near 1073 K, where TiCl₄ formation is efficient and relatively stable. Although increasing temperature can further enhance diffusion, its effect on reaction acceleration is limited, while excessively high temperatures weaken Fe-C interactions and reduce catalytic efficiency. These findings clarify the catalytic mechanism of Fe in molten salt chlorination at the atomic scale and provide theoretical support for process optimization. Full article

Two-dimensional (2D) materials are promising candidates for nanoscale wear-protective coatings. The mechanisms governing their tribological behaviour (i.e., friction and wear) are material-dependent. In this work, we use atomistic molecular dynamics simulations to investigate nanoscale sliding, friction, and lithographic tracks in two 2D materials, graphene and MoS${}_2$, both placed on a SiO${}_2$ substrate. Our results reveal fundamentally different deformation mechanisms in the two materials, where deformation comes as a consequence of applied normal load. MoS${}_2$ deforms via the formation of a stable out-of-plane pucker beneath the contact, enabling efficient absorption and elastic redistribution of mechanical energy within the coating as well as simultaneous reduction of plastic deformation of the underlying material. Wear prevention in the substrate comes at the cost of localised damage to the MoS${}_2$ layer along the sliding path once it reaches the rupture point. On the contrary, graphene exhibits strongly localised deformation due to its high in-plane stiffness and atomic thickness, leading to plastic deformation of the underlying material and mitigating layer damage. These findings provide clear design guidelines for 2D coatings in nanotribological applications, and highlight layered materials, such as MoS${}_2$, as particularly effective for wear protection. Full article

Chlorine (Cl) and sulfur (S) are two crucial mineralizing agents in silicate melts, and are closely related to the genesis of metallic mineral deposits. Magmatic ore deposits usually form in mafic–ultramafic silicate melts by the separation (liquation) of a cooling, sulfur-rich magma into two immiscible liquids. It is not easy to identify the complexation between gold (Au), cooper (Cu) and Cl, S using the current experiment methods, and the coordination of Au and Cu with Cl and S is still unclear in mafic–ultramafic silicate melts. In this study, by using first-principles molecular dynamics technique, we investigated the structure of Au, Cu, Cl and S in the (a) anhydrous and (b) hydrous peridotite melt to reveal their coordination geochemistry. Our results show that Si⁴⁺–Cl⁻, Cu⁺–O²⁻, Au⁺–O²⁻, Cu⁺–Cl⁻, Au⁺–Cl⁻, Au⁺–S²⁻, and Cu⁺–S²⁻ cannot form stable ion pairs in silicate melts; therefore, Au⁺ and Cu⁺ cannot form stable complexes with S²⁻, O²⁻ or Cl⁻ in the melts. But the diffusion coefficients of Au⁺, Cu⁺, S²⁻ and Cl⁻, their RDF values and the bonding time ratio of the silicate melt systems show that, although they cannot form stable complexes, within the range of effective chemical bond lengths, they have a high probability of approaching and interacting with each other, which enables them to form crystal embryos or liquid-phase molecules during magma evolution. Full article

Background: Spasmolytic polypeptide-expressing metaplasia (SPEM) is an injury-induced gastric epithelial reprogramming state with limited therapeutic options. Although mitochondrial dysfunction has been implicated in epithelial stress responses, its contribution to SPEM development remains incompletely understood. Traditional herbal decoctions have shown potential in alleviating gastric epithelial injury, yet their underlying mechanisms remain largely unclear. Purpose: This study aimed to investigate whether refined Jianpi Huayu Jiedu Decoction attenuates tamoxifen (TAM)-induced SPEM, with a focus on LCN2-associated mitochondrial dysfunction. Methods: TAM-induced SPEM models were established in mice and gastric epithelial cells. Histological, molecular, and mitochondrial analyses were performed to evaluate SPEM features and epithelial stress responses. UPLC–MS/MS-based chemical profiling, network pharmacology, transcriptomic analysis, and LCN2 knockdown experiments were integrated to explore the underlying regulatory mechanisms. Results: Refined Jianpi Huayu Jiedu Decoction significantly alleviated TAM-induced gastric mucosal injury and suppressed the expression of SPEM-associated markers in vivo and in vitro. JHJD treatment improved mitochondrial function, reduced oxidative stress, and normalized mitochondrial dynamics, accompanied by downregulation of LCN2 expression. Chemical profiling identified multiple bioactive components of JHJD, and integrative analyses combining transcriptomics, network pharmacology, and molecular docking suggested that these components are associated with LCN2-related epithelial stress and mitochondrial regulatory networks. Functional validation further demonstrated that LCN2 knockdown partially recapitulated the protective effects of JHJD on mitochondrial homeostasis and epithelial reprogramming. Conclusions: These findings indicate that refined Jianpi Huayu Jiedu Decoction attenuates TAM-induced SPEM in association with restoration of mitochondrial homeostasis and suppression of LCN2-related stress signaling, providing mechanistic insight into early gastric epithelial reprogramming. 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

Eucommia ulmoides gum (EUG), a sustainable plant-derived natural polymer, was functionalized via three distinct routes, including vulcanization, epoxidation, and hydroxylation to yield vulcanized (VEUG), epoxidized (EEUG), and hydroxylated EUG (HEUG), respectively. We systematically characterized the effects of modification route and degree on the chemical structure, crystallization behavior, thermal stability, hydrophilicity, and mechanical properties of functionalized EUG and further evaluated the high/low-temperature performance, microstructure, and mechanical properties of the corresponding modified asphalt binders (VEMA, EEMA, HEMA) as a function of modifier type and loading. For VEUG, C-S cross-linking networks formed during vulcanization suppress EUG crystallization, enabling a rigid-plastic to elastic transition, while high-temperature cleavage of C-S bonds reduces its initial thermal stability. For EEUG, epoxidation breaks C=C double bonds and introduces epoxy groups to strengthen intermolecular interactions; subsequent ring-opening grafting of hydroxyl groups onto EEUG yields HEUG, which forms additional cross-links via dynamic hydrogen bonds. Increasing modification degree for both EEUG and HEUG reduces their number- and weight-average molecular weights with narrower distribution, diminishes crystallinity, enhances thermal stability and hydrophilicity, and drives a rigid-plastic to elastic transition, characterized by decreased strength (0.65 MPa < σ_HEUG < σ_EEUG < 10.18 MPa) and markedly improved ductility (143.6% < ε_EEUG < 262.0%, 679.9% < ε_HEUG < 1360.3%). In asphalt binders, VEUG’s cross-linked network endows VEMA with refined more abundant bee-like microstructures, drastically boosting high- and low-temperature performance: relative to pristine EUG-modified asphalt (EUGMA), VEMA’s DMT modulus decreases by 94%, and adhesion increases by 87%. EEMA forms covalent bonds with polar asphalt components via epoxy groups, while HEMA constructs a hydrogen-bonded cross-linked network; both effectively inhibit asphaltene aggregation. With increasing modifier loading, EEMA and HEMA exhibit increased modulus, reduced adhesion, and gradually improved high- and low-temperature performance, except for the non-significant high-temperature enhancement of HEMA at higher loadings. Full article

This study addressed the issue of insufficient activity in CALB lipase during the catalytic synthesis of key chiral intermediates for moxifloxacin. A structure-guided protein engineering strategy was employed to systematically modify its functional domains. Through molecular dynamics simulations of CALB-I189K, multiple regions exhibiting high conformational flexibility were preliminarily identified. Subsequently, by integrating 3D structural alignment with active site pocket distance analysis, the functionally most critical region (143–146) was selected. A site-directed saturation mutation library was constructed specifically targeting this region. Building upon the previously reported CALB-I189K, a mutant I189K/L144R/A146K was ultimately obtained through high-throughput screening combined with chiral HPLC validation. This mutant maintains excellent stereoselectivity (E = 206.52) while enhancing catalytic efficiency (k_cat/Κ_m) to 273.73 min⁻¹·mM⁻¹, approximately 4.5-fold that of I189K. At a substrate concentration of 1 M, it achieves 50% conversion within 2.6 h, demonstrating kinetic resolution capabilities approaching industrial standards. Molecular simulation analysis indicates that the L144R and A146K mutations synergistically enhance catalytic performance primarily by optimizing spatial distances between catalytic residues. This study not only provides a high-performance catalyst for the efficient biosynthesis of moxifloxacin chiral intermediates but also offers new insights for enzyme rational design based on dynamic structural information. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited therapeutic options, in part due to frequent activation of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Gain-of-function mutations in NRF2 disrupt its negative regulation by Kelch-like ECH-associated protein 1 (KEAP1), resulting in sustained NRF2 signaling that promotes tumor growth and resistance to chemotherapy and radiation. We previously identified the FDA-approved drug pyrimethamine (PYR) as an NRF2 inhibitor and demonstrated that inhibition of dihydrofolate reductase (DHFR) represents the primary mechanism underlying its NRF2-suppressive activity, supporting its advancement into a Phase I window-of-opportunity clinical trial (NCT 05678348). Meanwhile, in NRF2^W24C-KYSE70 and NRF2^D77V-KYSE180 cells, PYR promoted NRF2^Mut ubiquitination and proteasomal degradation and shortened its half-life. This study aims to explore additional modes of action by which PYR inhibits NRF2. Methods: Cell cycle analysis was performed by flow cytometry. Cell proliferation, apoptosis and chemosensitivity were assessed by Live-Cell Analysis System, while radiosensitivity was evaluated using X-ray irradiation and the CellTiter-Glo assay. Molecular interactions between NRF2 and KEAP1 were examined through Co-IP and PLA, and the direct binding of PYR to KEAP1 was quantified using ITC and SPR. Molecular docking and dynamic simulations were employed to predict potential PYR-binding pockets within the Kelch domain. Results: Using genetically defined isogenic ESCC cell models, we show that activation of mutant NRF2 (NRF2^Mut) or wild-type NRF2 (NRF2^WT) produces distinct, context-dependent effects on squamous differentiation, proliferation, and therapeutic response. We further demonstrate that PYR restores sensitivity to chemotherapy and ionizing radiation in NRF2^Mut ESCC cells. Mechanistically, short-term PYR treatment promotes KEAP1-dependent proteasome-mediated degradation of NRF2^W24C. Biochemical and biophysical assays indicate that PYR enhances the interaction between KEAP1 and NRF2^W24C in a manner associated with KEAP1-dependent proteasomal degradation. Computational modeling further suggests that PYR may engage a pocket within the Kelch domain to facilitate the NRF2^W24C-KEAP1 interaction. Conclusions: These findings show that PYR functionally restores KEAP1-mediated NRF2 degradation of select NRF2^Mut through a glue-like effect and overcomes therapy resistance in ESCC. Although the proposed glue-like mechanism remains hypothetical, this work supports further investigation into the NRF2–KEAP1 interaction and may inform the development of KEAP1-targeted strategies for NRF2^Mut cancers, including ESCC. Full article

Cancer cell dormancy is a clinically consequential yet computationally under-defined phenomenon characterised by reversible growth arrest and delayed disease recurrence. Although advances in single-cell and multi-omic profiling have improved detection of dormant and persister populations, their molecular identity and dynamical behaviour remain difficult to resolve. In this review, we examine how computational methods have been applied to infer dormant cell identity, heterogeneity, microenvironmental regulation, state transitions, and reactivation dynamics. We highlight how single-cell transcriptomics, lineage tracing, spatial profiling, and integrative multi-omic analyses reveal substantial context-dependent variability, undermining the notion of a universal dormancy signature. We further discuss emerging mathematical and statistical frameworks to model the awakening from dormancy, alongside approaches linking dormancy-associated features to clinical outcomes. Recurring challenges include fragmented operational definitions, rare-state detection, cross-study incompatibility, and the use of snapshot data to interrogate inherently temporal processes. We argue that progress will depend on computational frameworks that treat dormancy as a dynamic, multi-scale systems problem rather than a static cell-type classification task. Full article