Search Results (11,451)

Background/Objectives: Alzheimer’s disease (AD) involves amyloid and tau pathology with neuroimmune dysregulation, and Yixin Yangshen Granules (YXYS) shows neuroprotective promise, though mechanisms remain unclear. This study aimed to elucidate the multi-target mechanisms of YXYS in AD. Methods: The study began by analyzing a public human AD hippocampal snRNA-seq dataset to identify cell-type-specific pathological pathways and profiled YXYS constituents by UPLC-QTOF-MS. In vitro, YXYS cytoprotection against mitochondrial dysfunction and oxidative stress was tested in Aβ_25–35-challenged HT22 cells; in vivo efficacy was assessed in Aβ_1–42-induced mice via behavioral and histopathological analyses. Integrated transcriptomic and proteomic profiling of brain tissue, with ELISA, qRT-PCR, and Western blot validation, confirmed pathway targets. Using the intersection of transcriptomic and proteomic targets as biological input, the DTIAM deep learning framework was employed to prioritize active YXYS constituents. Finally, molecular docking and 100-ns dynamics simulations demonstrated direct binding of Ganosporelactone A to HIF−1α. Results: AD snRNA-seq analysis highlighted HIF−1 and AGE-RAGE signaling as prominent pathways in the AD hippocampus, particularly enriched in brain microvascular endothelial cells, implicating neurovascular hypoxic and inflammatory stress. In Aβ-induced mice, YXYS improved cognition, reduced Aβ pathology, suppressed neuroinflammation, and promoted neuronal survival, consistent with in vitro evidence of restored mitochondrial function. Multi-omics confirmed convergence on HIF−1 and AGE-RAGE pathways, with YXYS rebalancing the neuroimmune microenvironment by reducing pro-inflammatory M0 macrophages. Screening against these consensus signaling hubs, deep learning analysis prioritized Ganosporelactone A as the top-ranked modulator, and molecular further demonstrated the stable binding of Ganosporelactone A to HIF−1α, linking YXYS to mitigation of hypoxic stress. Conclusions: Guided by multi-omics and deep learning, our findings suggest that YXYS may alleviate AD-related phenotypes through multi-target modulation of the HIF−1 and AGE-RAGE pathways, with associated improvements in neuro-immune homeostasis and reductions in oxidative stress, neuroinflammation, and hypoxia. Full article

Traumatic brain injury (TBI) initiates a cascade of molecular and cellular reactions leading to long-term disturbances of neuronal and glial homeostasis. One of the key mechanisms of secondary injury is a pathological increase in intracellular Ca²⁺ concentration. Parvalbumin (PV) plays an important role in the regulation of Ca²⁺ homeostasis in neurons. In turn, connexin 43 (Cx43) is the principal protein of astrocytic gap junctions (GJs), which ensure neuroglial communication. The spatiotemporal changes in these proteins and the mechanisms of their interaction after TBI remain insufficiently studied. In the present study, a comprehensive analysis of the expression, localization, and spatial organization of PV and Cx43 in the cerebral cortex following TBI was performed. In intact tissue, PV was localized predominantly in neurons, whereas Cx43 formed typical punctate structures of astrocytic GJs. Twenty-four hours after TBI, a sharp activation of PV with pronounced nuclear translocation was observed against the background of a catastrophic decrease in Cx43 expression, accompanied by a reduction in the number of NeuN⁺ neurons and signs of apoptosis. However, after 7 days, a mirror-opposite effect was detected, characterized by decreased PV expression and increased Cx43 levels with its aggregation into cluster-like structures, as well as partial restoration of NeuN immunoreactivity. In addition, molecular dynamics simulations demonstrated that the stability of the PV–Cx43 complex is determined by the presence of Ca²⁺ and physiological pH, whereas acidosis and Ca²⁺ overload destabilize their interaction. Taken together, these results reveal a phase-dependent mirror-opposite pattern of PV and Cx43 expression and localization and emphasize the key role of Ca²⁺- and pH-dependent neuroglial interactions in TBI. Full article

The limited selectivity of most catalytic-site ADAMTS-5 inhibitors and the necessity to preserve aggrecan integrity in early-grade knee osteoarthritis require the development of selective aggrecanase inhibitors. The present study conducted rational in silico screening of flavonoids as potential ADAMTS-5 inhibitors by integrating high-throughput virtual screening, molecular docking, and molecular dynamic simulations targeting the exosite domains of ADAMTS-5 (the Disintegrin-like and spacer domain). The objective was to identify plant-derived flavonoids with favorable drug-like properties and specific interactions towards the ADAMTS-5 exosite as a more targeted alternative to catalytic-site inhibition. In this study, 847 flavonoids were screened using drug-likeness and ADME criteria to identify promising leads. The top 16 selected flavonoids were further subjected to molecular docking and SAR analysis. Of these compounds, Homoeriodictyol satisfied key drug-likeness criteria and exhibited the highest binding affinity to the Disintegrin-like domain, with a binding energy of −23.1 kcal/mol and favorable interactions. Molecular dynamics simulations of the Homoeriodictyol–ADAMTS-5 complex over 100 ns demonstrated stable binding throughout the trajectory. DCCM analysis and PCA further supported the proposed exosite-mediated modulation. To extend exosite mapping beyond the Disintegrin-like domain, this study also examined the spacer domain using a machine-learning-predicted structural model and identified key residues that contribute to ligand binding. Full article

Myocardial ischemia/reperfusion (MI/R) injury affects heart attack outcomes. Endothelial cells dysfunction immediately after MI/R, but the key molecules and how to block them remain unclear. We combined single-cell atlas analysis, AI simulation, and experimental single-cell RNA sequencing data from mouse MI/R; we did quality control, cell annotation, hdWGCNA, and differential gene screening to identify endothelial genes. We constructed a protein network with STRING, predicted structure with AlphaFold3, and used AutoDock for molecular docking to find potential drugs. Virtual knockout simulations were used to check gene deletion effects. The compound andrographolide (AG) was tested in in vitro and in vivo MI/R models by measuring cell viability, inflammation, pathway activity, infarct size, and cardiac function. Single-cell analysis showed that S100 calcium binding protein A8 (S100A8) is an important element in vascular inflammation. It promotes inflammation by interacting indirectly with Cluster of differentiation 14 (CD14). Molecular docking showed that AG binds stably to S100A8. In vitro, AG reduced endothelial injury and blocked the IL-17 pathway. In vivo, AG reduced infarct size, improved cardiac function, and lowered S100A8 and IL-17 pathway proteins. Using single-cell analysis, AI, and experiments, we showed that S100A8 is related to MI/R injury. Andrographolide protects microvasculature via the S100A8 pathway, offering a promising treatment approach and new insights into heart injury mechanisms. Full article

In this study, a combined approach of molecular dynamics (MD) simulations and experimental bottle tests was employed to systematically investigate the demulsification performance and underlying mechanisms of two distinct demulsifiers—Demulsifier X (SP/BP series and alcohol-initiated polyethers) and Demulsifier Y (AP/AE series and amine-initiated polyethers)—targeting polymer-containing oil-in-water (O/W) emulsions derived from heavy oil polymer flooding. Molecular models for heavy oil, saline water, partially hydrolyzed polyacrylamide (HPAM), and demulsifiers were constructed using BIOVIA Materials Studio software. Their dynamic behaviors at the oil–water interface were simulated within three distinct saline systems containing NaCl, CaCl₂, and MgCl₂, respectively. Simulation results indicated that the demulsifiers effectively displaced interfacial HPAM molecules, increased interfacial tension, and reduced interfacial interaction energy. Experimental bottle tests, evaluating the effects of settling time, temperature, and concentration on dehydration rates and oil content, confirmed that Demulsifier Y outperformed Demulsifier X. Specifically, Demulsifier Y achieved superior dehydration rates with lower dosages, shorter settling times, and reduced temperature requirements under optimal conditions. This work provides both microscopic mechanistic insights and macroscopic experimental validation for the screening and application of high-efficiency demulsifiers. Full article

Antibiotic resistance among several bacteria is a warning sign that reinforces the need for research to identify new compounds that are effective against resistant strains. In this sense, bioinformatics stands out as an excellent tool for identifying drug candidates by using computational methodologies to detect compounds with potential biological activity. Two pivot compounds (QNZ and 0Y5) with biological activity against Staphylococcus aureus were selected. A virtual screening was performed in the MolPort database with a Tanimoto index of 0.5, resulting in 20,000 compounds, 10,000 compounds for each template. Then, methodologies were applied to calculate pharmacokinetic and toxicological parameters using Discovery Studio software; molecular docking via DockThor; lethal dose via ProTOX; lipophilicity, solubility, and Lipinski parameters via SwissADME; in silico prediction of bacterial activity via Way2Drug; theoretical synthetic accessibility via SwissADME and AMBIT-SA; and, finally, molecular dynamics simulations via AMBER 18. After the entire methodological process, 10 compounds were identified with potential results according to the criteria adopted in this study and with possible antimicrobial activity against resistant bacterial strains of S. aureus. Our theoretical findings suggest 10 potential candidates with possible antimicrobial activity against S. aureus and other genera and species of bacteria as these compounds presented excellent results using the proposed methodology. Certainly, more in vitro and in vivo study steps are necessary. Full article

The essential reaction of CO₂ hydration, fundamental to all living organisms, is facilitated by the enzyme carbonic anhydrase (CA, EC 4.2.1.1). This enzyme plays a crucial role in regulating various physiological and pathological processes. A series of heterocyclic benzenesulfonamide derivatives (19 compounds) were evaluated as possible inhibitors of human CAs. Their inhibitory properties were tested against several isoforms such as the cytosolic hCA I and hCA II, as well as the transmembrane isoforms hCA IV, hCA IX and hCA XII. The tested molecules demonstrated notable inhibitory potential, particularly toward hCA II and hCA IV, where five and four compounds, respectively, exhibited greater potency than the reference inhibitor, acetazolamide. Molecular docking simulations were further performed to elucidate the binding interactions of the most active compounds with the human CA II, IV IX and XII isoforms Full article

Background/Objectives: Cholestasis is a clinically intractable liver disorder. Da-Huang-Xiao-Shi Decoction (DHXSD), a classic traditional Chinese medicine formula, demonstrates notable efficacy, yet the mechanistic basis for its multi-herb synergy remains unclear. The purpose of this study was to decipher the pharmacokinetic interaction underlying the synergy of DHXSD. Methods: A cholestatic rat model was established in male Sprague Dawley rats. Hepatoprotective efficacy was evaluated, and the pharmacokinetics of anthraquinones were profiled. Key interaction mechanisms were investigated using the everted intestinal sac model, the breast cancer resistance protein (BCRP)-overexpressing MDCKII cells, and molecular docking simulations. Results: DHXSD provided significantly stronger hepatoprotection than its principal herb Rheum palmatum L. (DaHuang, DH) alone. This enhanced efficacy correlated with an approximate 2-fold increase in the systemic exposure of rhein compared to DH monotherapy. We identified berberine from Phellodendron amurense Rupr. (Huang Bo, HB) as the key synergist, which potently inhibited the BCRP efflux transporter, thereby enhancing rhein absorption. In contrast, geniposide from Gardenia jasminoides Ellis (Zhi Zi, ZZ) showed minimal effects. Conclusions: This work elucidates a concrete, transporter-mediated pharmacokinetic interaction as the core mechanism underlying herbal synergy in DHXSD. Our findings offer a rational strategy—targeted efflux transporter modulation—for improving the oral bioavailability of challenging drug molecules. Full article

A miniaturized variant of the artificial luciferase (ALuc), named picALuc, has been generated through the deletion of N- and C-terminal residues in ALuc. Although picALuc is small and active, questions remain regarding its the structural organization and inter-residue interactions in the protein. Here, combining computational analysis and mutational studies, we show that the E50A mutation in picALuc results in an increased bioluminescence activity of the protein. Specifically, we generated a structural model of picALuc using the available structure of the Gaussia luciferase (GLuc) that revealed a ‘hole’ in the structure due to the deletion of N-terminal α-helices. Gaussian-accelerated molecular dynamics (GaMD) simulation revealed a rapid ‘compaction’ of the picALuc structure during the initial phase of the simulation and a number of residues such as E10, E50, and D94 showed salt bridge interactions. Mutation of the residues E10, E50, and D94 individually to an A revealed increased bioluminescence activity of the E50A mutant, while E10A and D94A mutants showed activities similar to the WT protein in living cells. In vitro assays revealed an increase in the V_max of the E50A mutant, while K_half and thermal stability of the mutant remained unchanged. Further, dynamic cross-correlation and principal component analyses of the GaMD simulation trajectories of the WT and the E50A mutant picALuc revealed altered collective dynamics in the protein. Finally, we developed a protein fragment complementation assay using picALuc that allows for the monitoring protein–protein interactions (PPIs) in live cells. We envisage that the brighter picALuc reported here will find broad applicability in developing bioluminescence-based assays. Full article

Background/Objectives: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant whose adverse biological effects are primarily mediated through activation of the aryl hydrocarbon receptor (AhR). Upon ligand binding, AhR undergoes conformational changes that initiate nuclear translocation and transcriptional activation of xenobiotic-responsive genes, contributing to toxicity, carcinogenesis, and dysregulated immune and metabolic responses. Understanding the molecular basis of AhR activation by TCDD is therefore critical for the rational development of targeted therapeutic strategies. Methods: In this study, molecular docking simulations were employed to characterize the interaction of TCDD and selected AhR antagonists (CH223191, BAY 2416964, GNF-351) with the ligand-binding domain of AhR, with particular emphasis on the canonical PAS-B domain. Results: Docking analyses identified the PAS-B cavity (pocket C1) as the most biologically relevant binding site for high-affinity ligands, consistent with experimental evidence. Comparative docking of known AhR antagonists revealed stable binding poses characterized by hydrophobic packing, π–π interactions, and hydrogen-bonding networks that competitively block agonist access and prevent receptor activation. These findings support a competitive antagonism mechanism as a viable approach to counteract TCDD-induced AhR signaling. Conclusions: Collectively, this in silico study provides mechanistic insight into TCDD toxicity at the molecular level and highlights AhR antagonism as a promising strategy for the development of targeted therapies against dioxin-related pathologies. Full article

The appearance of antibiotic-resistant strains of Helicobacter pylori (H. pylori) is leading to a decreased eradication rate of H. pylori infection. There is an urgent need to find new agents with antimicrobial mechanisms different from those of antibiotics, with therapeutic potential to clear colonization of H. pylori in the stomach. Some antimicrobial peptides (AMPs) possess bactericidal activity by enhancing the permeability of the outer membrane and damaging the integrity of the cell membrane. Bacteria are not susceptible to drug resistance through this antimicrobial mechanism. In this study, 28 short peptides containing 12 amino acid residues were designed based on nine amino acid fragments (KRIVQRIKD) from human cathelicidin LL-37, which is stable in gastric juice, and 3 amino acids were added at the C-terminus of the peptide. These designed peptides were not digested and degraded by pepsin at low pH values. The peptides were predicted using the online tool platform. Then, the strongest antimicrobial peptide, named SAMP-12aa (KRIVQRIKDVIR), was screened from 28 short peptides. Further studies found that SAMP-12aa retained anti-H. pylori activity after incubation in simulated gastric juice. The MIC and MBC of SAMP-12aa were 8 μg/mL and 32 μg/mL, respectively. SAMP-12aa showed good bactericidal kinetics. SAMP-12aa was found to have cell selectivity, penetrating and damaging bacterial cell membranes and exhibiting almost no toxicity to human cells at a relatively high concentration (128 μg/mL). Regulatory T (Treg) cells express CD25^High with immunosuppressive activity that induces immune tolerance in response to H. pylori. Molecular docking prediction revealed that SAMP-12aa could target the active center of Foxp3. Flow cytometry analysis revealed that SAMP-12aa can inhibit Foxp3 activity and downregulate CD25 protein expression on CD4⁺ T cells, thereby reducing the development and differentiation of CD4⁺Foxp3⁺CD25^High Treg cells with immunosuppressive effects. Further research revealed that the levels of the cytokine interferon-γ (IFN-γ), which activates CD8⁺ T-cell activity, were significantly elevated, and the levels of transforming growth factor-β (TGF-β), which inhibits CD8⁺ T-cell activity, were significantly reduced. The results of this study reveal that SAMP-12aa not only possesses antibacterial activity but also has immunomodulatory effects. Full article

Dual-phase layered microstructures containing alternating regions of soft and hard phases can produce alloys with a unique combination of strength and ductility. In this study, the molecular dynamics (MD) method was utilized to simulate nanoindentation of a Ni/NiTi/Ni nanostructured film (NSF). This film features a unique alternating FCC/B2/FCC microstructure, in which the B2-phase NiTi acts as a superelastic shape memory alloy (SMA). The results indicate that Ni/NiTi/Ni NSF significantly reduces its hardness due to the superelasticity of the B2 phase. The presence of the NiTi interlayer effectively blocks the propagation path of dislocations and stacking faults by transforming the local dislocations transferred from the upper layer into a large-scale coordinated phase transition, significantly reducing local deformation misalignment. As the thickness of the surface film λ increases, the dislocation slip plane propagating horizontally appears in the upper pure Ni layer. The thicker the surface film, the more horizontal slip planes are formed. This study provides new insights into the contact mechanical behavior of nanostructured films based on NiTi shape memory alloys from the perspective of atomic scale. Full article

In this study, the continuous strengthening behavior of CoCrNi medium-entropy alloy at 1.2–4.2 nm twin spacings was revealed by molecular dynamics simulation. It was found that the yield strength increased linearly with the decrease in twin spacing, up to 12.526 GPa, and there was no softening inflection point. The strengthening mechanism is mainly due to the effective obstruction of coherent twin boundaries (TBs) to the dislocation slip, especially the stair-rod and Lomer–Cottrell lock structures generated by ISF and ESF stacking faults when crossing the interface. These structures significantly enhance the work-hardening capacity of the alloy by inducing dislocation stacking, although the very dense twin boundary will reduce the dislocation growth rate by limiting dislocation propagation. This precise interface control provides an important atomic-scale basis for the design of novel high-strength and high-work-hardening alloys. Full article

Bubble nucleation in flowing liquid films is a common interfacial phenomenon affecting the heat and mass transfer at the solid–liquid interfaces in many thermal and functional material production processes, yet realizing its molecular-scale mechanisms under coupled flow, pressure, and heating conditions is important. In this study, molecular dynamics simulations are performed to investigate the bubble nucleation and growth in a liquid argon film on a heated platinum substrate under controlled pressure, with liquid flow driven by an applied body force. Bubble evolution is analyzed by the nucleation time, critical nucleation volume, bubble volume variation, and migration of the bubble’s center of mass. The results show that system pressure and substrate temperature dominantly regulate the nucleation: increasing pressure delays nucleation, whereas increasing substrate temperature accelerates it. Under a fixed system pressure and substrate temperature, liquid flow exhibits a non-monotonic influence. The applied forces from $4.0\times {10}^{-7}\mathrm{e}\mathrm{V}/\mathrm{Å}$ to $1.0\times {10}^{-6}\mathrm{e}\mathrm{V}/\mathrm{Å}$ gradually promote the nucleation and enhance the bubble growth by facilitating near-substrate heat transfer and density fluctuations, while the forces from $1.0\times {10}^{-6}\mathrm{e}\mathrm{V}/\mathrm{Å}$ to $1.4\times {10}^{-6}\mathrm{e}\mathrm{V}/\mathrm{Å}$ suppress nucleation and do not further promote the growth due to the intensified shear and interfacial instability. These findings provide molecular-level insight into the coupled thermodynamic and kinetic effects of pressure, temperature, and flow on bubble nucleation and growth at material interfaces, offering guidance for the design and operation of heat-transfer and functional materials processes. Full article

Solid-phase peptide synthesis (SPPS) allows for the sequential assembly of diverse peptide sequences. Alongside its scalability and capacity for automation, this makes it the method of choice for the synthesis of peptide-based pharmaceuticals. SPPS reaction pathways, however, suffer from a negative environmental footprint due to the super-stoichiometric quantities of reagents and high solvent use required to ensure reaction completion. In this paper, we propose the use of charge-based measurements as a complement to optical methods for measuring reaction completion. We extend the capabilities of our hybrid modeling framework to a representative four-step SPPS pathway on SiO₂, showing each reaction intermediate, its molecular encoding, and the resulting modeled surface potential (${\psi }_0$). We show that the simulated ${\psi }_0\left(\mathrm{pH}\right)$ plots are separable for three of the four key reaction steps in the representative pathway, indicating that charge-based measurements may help verify protection/deprotection steps. Full article