Search Results (2,657)

Background/Objectives: L1 cell adhesion molecule (L1CAM) has been implicated in colorectal cancer progression, but its cellular source and immune microenvironmental context remain incompletely defined. This study aimed to characterize the expression pattern, cellular localization and immune-associated features of L1CAM in colorectal cancer using public bulk and single-cell datasets. Methods: TCGA, GTEx and CPTAC/UALCAN datasets were used to assess L1CAM expression, protein abundance and clinical associations across cancers, with a focus on colorectal cancer. Single-cell RNA sequencing data from GSE178341 were analyzed to identify L1CAM-expressing cell populations, characterize transcriptional programs and evaluate sample-level associations with immune-cell composition and T/NK cytotoxicity signatures. Candidate ligand-receptor interactions and conceptual mod el-based sensitivity analyses were used to explore stromal-immune communication axes. Supplementary external single-cell datasets were analyzed exploratorily. Results: In colorectal cancer, L1CAM showed tumor-normal expression differences and was associated with progression-free interval, but not overall survival. Single-cell analysis detected L1CAM mainly in rare fibroblast and epithelial subsets rather than T/NK cells. L1CAM-positive fibroblasts showed neural-like, wound-response and matrix-remodeling transcriptional features. In the main cohort, L1CAM-Fib+ samples showed lower T/NK cytotoxicity transcriptional signatures, whereas supplementary external datasets did not reproduce the same direction of association. Candidate communication analyses nominated Galectin, HLA-E, TGFB and extracellular matrix-related axes. Conclusions: These findings suggest that L1CAM-positive fibroblast-associated stromal states provide a dataset-specific exploratory context for interpreting L1CAM-associated immune features in colorectal cancer. The results should be considered hypothesis-generating and require spatial and functional validation. Full article

Cannabidiol (CBD), the principal non-psychoactive phytocannabinoid of Cannabis sativa, exhibits diverse pharmacological activities through interactions with multiple molecular targets. Thus, breast, colorectal, and lung cancers arise from distinct molecular mechanisms. This study investigated the potential multi-target pharmacological mechanisms of CBD using an integrated approach combining network pharmacology and molecular docking. CBD-associated targets from three prediction platforms were intersected with disease-associated genes for each cancer type, yielding 143 overlapping targets that formed a significantly enriched protein–protein interaction network. Maximal Clique Centrality (MCC) analysis identified 10 hub proteins, including SRC, SIRT1, PTGS2 (COX-2), PPARG, NFKB1, MMP2, IGF1R, ESR2, ESR1, and EGFR, which represent key regulators of hormone signaling, inflammation, cell proliferation, and tumor progression. Molecular docking against these targets, benchmarked using each protein’s authentic co-crystallized ligand, predicted predominantly moderate binding affinities for CBD. Compared with the corresponding reference ligands, CBD generally exhibited lower predicted binding affinity, although comparable or slightly stronger scores were observed for PTGS2, ESR2, and EGFR. Independent validation using AutoDock Vina demonstrated overall agreement with the MOE docking results, supporting the robustness of the predicted binding profiles. Collectively, these findings suggest that CBD may exert its biological activity through coordinated modulation of multiple cancer-related signaling pathways rather than a single molecular target. By integrating pooled cancer-associated network pharmacology with co-crystallized ligand benchmarking, this study provides a computational framework for prioritizing biologically relevant CBD targets for future experimental validation. These findings should be regarded as hypothesis-generating rather than evidence of clinical efficacy. Full article

Colorectal cancer therapy requires drug delivery systems that improve treatment efficacy and minimize systemic toxicity. In this study, chitosan-based nanoparticles were fabricated and functionalized with folic acid (FA), phenylalanine (PA), and butyric acid (BA) to enhance the delivery of curcumin to Caco-2 cancer cells. The nanoparticles were prepared using an ionic gelation method, and their physicochemical properties, cellular uptake efficiency, and cytotoxicity—including safety evaluation against normal HIEC-6 cells—were investigated. Results showed that ligand conjugation significantly influenced the physicochemical properties of the nanoparticles. CRFANP (FA-modified) exhibited the largest particle size (263.5 nm) due to its rigid aromatic structure, while CRPANP (PA-modified) showed an intermediate size (138.0 nm) and the lowest surface charge (15.59 mV). In contrast, CRBANP (BA-modified) presented the smallest particle size (128.2 nm) and the highest positive surface charge (23.27 mV). These distinct physicochemical properties directly influenced their cellular interactions; CRBANP and CRFANP showed higher uptake than CRPANP, with CRBANP yielding the maximum accumulation of curcumin in Caco-2 (21.92 nM/mg protein) and HT-29 cells (22.09 nM/mg protein). Correlating with the uptake data, cytotoxicity assays revealed that CRBANP was the most potent formulation, exhibiting the lowest IC₅₀ of 1.30 µM in Caco-2 cells, which was significantly lower than that of CRFANP (3.49 µM) and CRPANP (7.40 µM), while demonstrating high selectivity against Caco-2 cells with an SI of 46.5 and no apparent toxicity toward normal HIEC-6 cells. This enhanced efficacy is attributed to the synergistic action of butyric acid as a histone deacetylase inhibitor (HDACi), which complements curcumin’s anticancer activity. These findings indicate that integrating butyric acid into chitosan nanoparticles provides an effective and selective strategy for targeted colorectal cancer therapy. Full article

Background/Objectives: Infection with Bordetella pertussis causes whooping cough. CD4⁺ T cell responses depend on bacterial peptides displayed by HLA class II, yet allele- and strain-resolved maps of naturally processed B. pertussis HLA-DR ligands remain limited. We sought to define which antigens yield HLA-DR ligands in a human macrophage model and whether presentation is skewed by HLA-DR molecule and bacterial strain. Methods: THP-1–derived macrophages were pulsed with whole-cell lysates of B. pertussis vaccine/reference strain Tohama I or clinical isolate D420. HLA-DR was immunoaffinity purified; eluted peptides were identified by LC-MS/MS and assigned to HLA-DR molecules encoded by HLA-DRB1*01:01, HLA-DRB1*15:01, and HLA-DRB5*01:01. Results: We identified 63 B. pertussis peptide ligands from 29 source proteins. Presentation was skewed by HLA-DR molecule: DRB1*01:01 accounted for 37 ligands from 21 antigens, DRB1*15:01 for 22 from 7, and DRB5*01:01 for 4 from 4. Most source proteins contributed ligands primarily to one HLA-DR molecule, so an antigen that supplies peptides to one DR product need not supply peptides to another. Strain further partitioned the ligandome: 32 ligands unique to Tohama I, 12 to D420, and only 19 from 8 proteins with both lysates. Only three antigens contributed ligands to both DRB1*01:01 and DRB1*15:01; two of these, pertactin and filamentous hemagglutinin, are components of current acellular pertussis vaccines. Conclusions: B. pertussis HLA-DR ligandomes are jointly shaped by bacterial strain and HLA-DR molecule. Antigens can interact selectively with individual HLA-DR products, and peptides from a given antigen may be recovered after pulse with one strain but not another. These findings support HLA-DR and strain-aware interpretation of class II presentation and nominate BrkA autotransporter (Bordetella resistance to killing A), outer membrane protein A (OmpA), tracheal colonization factor (TcfA), and a divalent metal transporter (DMT) family transporter for follow-up. Full article

Background/Objectives: Ephedrae Herba (EH) is widely used in traditional East Asian medicine, but safety concerns regarding its adverse events remain. This study aimed to investigate EH-associated adverse events using clinical pharmacovigilance data and to perform exploratory in silico analyses to propose potential molecular mechanisms underlying these adverse events. Methods: A disproportionality analysis was performed using individual case safety reports from the Korea Adverse Event Reporting System database. EH-containing products were compared with other herbal medicine products using reporting odds ratios (RORs), proportional reporting ratios, and information components. Network pharmacology identified adverse event-related genes and pathways, and protein–protein interaction networks were constructed. Molecular docking predicted direct adverse event-associated targets of ephedrine and compared mechanisms with control compounds (aconitine and spinosin). Results: Four adverse-event signals were detected in the primary analysis: sleep disorder, dry mouth, insomnia, and palpitations. Sensitivity analysis identified four signals, with three (dry mouth, insomnia, and palpitations) consistent across both analyses; constipation emerged only in the sensitivity analysis. Conclusions: Adverse event-associated network analysis predicted key pathways: Neuroactive ligand–receptor interaction, Pathways of neurodegeneration, and Dopaminergic synapse. Molecular docking predicted that ephedrine may act on downstream signaling mechanisms shared by neurotransmitter systems, including the dopaminergic system, distinct from control compounds. Full article

Protein–ligand interactions are fundamental to physiological processes and drug discovery. Based on the types of information on protein–ligand interactions provided by nuclear magnetic resonance (NMR) experiments, these NMR experiments can be categorized into three distinct classes: (i) molecular-level qualitative binding detection, (ii) residue-level mapping of binding interfaces, and (iii) atomic-level structure determination and conformational dynamics of protein–ligand complexes. This hierarchy enables a workflow that accelerates the progression from initial binding identification to structural and dynamic characterization. In this review, we discuss how these experiments characterize molecular recognition. Notably, the term “ligand” in this article refers exclusively to small molecules. Full article

Background: Paclitaxel is a cornerstone chemotherapeutic agent widely used in breast cancer treatment, primarily through the stabilization of microtubule dynamics. Beyond its canonical tubulin-targeting activity, increasing evidence suggests that paclitaxel may engage additional molecular targets, contributing to its complex pharmacological profile. In this study, an integrated computational workflow was applied to evaluate the structural compatibility between paclitaxel and the neurokinin-2 receptor (NK2R), a G protein-coupled receptor involved in tumor-associated inflammatory and proliferative signaling pathways. Physicochemical profiling and target prediction were performed using SwissADME and SwissTargetPrediction, followed by molecular docking and molecular dynamics simulations using AutoDock Vina and GROMACS 2024.1. Paclitaxel exhibited physicochemical properties consistent with transient interactions in hydrophobic transmembrane environments. Docking analysis identified a plausible binding mode within the NK2R transmembrane cavity, primarily stabilized by hydrophobic contacts. Molecular dynamics simulations over 100 ns revealed stable ligand occupancy and overall complex stability, while MM-PBSA calculations indicated a favorable transient association. The predicted interaction is consistent with secondary or non-canonical receptor engagement. While NK2R is not established as a pharmacological target of paclitaxel, the results support the structural feasibility of a previously uncharacterized receptor interaction and provide a reproducible computational framework for exploring GPCR-associated effects of cytotoxic agents. Full article

Background/Objectives: The molecular mechanisms underlying susceptibility to severe COVID-19 remain incompletely understood. We aimed to identify the signaling pathways associated with disease severity by integrating transcriptomic data and characterizing ligand–receptor interactions involved in the host response to SARS-CoV-2 infection. Methods: We integrated publicly available bulk RNA-sequencing data from nasopharyngeal (NP) swabs (GSE152075) and single-cell RNA-sequencing data from bronchoalveolar lavage fluid samples (GSE145926). Analyses focused on secreted ligands and their cognate receptors and were performed in relation to demographic and clinical characteristics associated with susceptibility to severe COVID-19, including sex, age, and viral load. Results: Patients with characteristics associated with increased susceptibility to severe disease, including male sex, advanced age, and high viral load, exhibited transcriptional programs enriched for inflammatory and immune-response pathways. In contrast, individuals with lower susceptibility displayed reduced expression of 43 ligand genes compared with matched negative controls, suggesting distinct secretory programs associated with the host response to infection. We identified an association between the expression of lactoferrin (LTF) and its receptor, LDL receptor-related protein 11 (LRP11), and susceptibility to severe COVID-19. LRP11 was predominantly expressed in human pulmonary epithelial cells, and its expression increased during SARS-CoV-2 infection in monkeys. Conclusions: Our findings provide insight into the molecular mechanisms associated with susceptibility to severe COVID-19 through the analysis of ligand and receptor expression in nasopharyngeal swabs and bronchoalveolar lavage fluid samples. The association between LTF and LRP11 highlights a potentially relevant signaling axis in disease pathogenesis and provides a rationale for future functional studies aimed at clarifying its role in COVID-19 severity. Full article

In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered “foreign”. For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, may render normally functional deoxyribonucleic acid (DNA) and RNA persistently available and aberrantly structured ligands for innate immunity. Z-DNA-binding protein 1 (ZBP1), recently identified as an important component of this innate immune system, recognizes both left-handed DNA (Z-DNA) and left-handed RNA (Z-RNA) using its tandem Z-alpha (Zα) domains and couples recognition of these conformational states to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-, receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-, and mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent inflammatory and cell-death pathways. More recent studies have also shown that ZBP1 plays a role in recognizing damaged self-nucleic acids associated with tauopathies, Alzheimer’s disease (AD), traumatic brain injury (TBI), and amyloid-associated neuroinflammation. The nucleic-acid forms associated with these conditions include transposable-element activation, extended repeat-containing transcripts, RNA–RNA duplexes or RNA:DNA hybrids, oxidized mitochondrial DNA (mtDNA), and intercellularly transferred nucleic acids, all of which may exhibit substrate structures compatible with Z-form formation. Signaling by ZBP1 does not occur simply based upon nucleic-acid abundance; rather, signaling occurs after prolonged exposure to a nucleic acid when it persists in a structurally competent state, sufficient receptors are present to bind its exposed regions, the receptor proteoforms are competent to participate in signaling, receptor-interacting protein homotypic interaction motif (RHIM)-dependent assembly occurs, and the appropriate adaptor molecules are present. Furthermore, the identity of the cell type expressing ZBP1 determines whether the response produces RIPK3–MLKL-dependent neuronal injury, microglia-mediated inflammation, apoptosis, or mixed cell death. Finally, competition with adenosine deaminase acting on RNA 1 (ADAR1), melanoma differentiation-associated protein 5 (MDA5), double-stranded RNA-dependent protein kinase (PKR), the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway, and other nucleic-acid-sensing proteins divides the available pool of endogenous nucleic acids among the outcomes of immune tolerance, type I interferon (IFN-I) signaling, translational inhibition, neuroinflammation, and necroptosis. Full article

Background: Cordyceps militaris (C. militaris) is a medicinal mushroom recognized for its diverse pharmacological activities, largely attributed to its principal bioactive nucleosides, cordycepin and adenosine. Although accumulating evidence supports their neuroprotective potential, the molecular mechanisms underlying their effects against Alzheimer’s disease (AD) remain incompletely understood. This study investigated the neuroprotective effects of cordycepin and adenosine against amyloid-β (Aβ₄₂)-induced neurotoxicity and explored their potential molecular mechanisms using integrated experimental and computational approaches. Methods: SH-SY5Y neuroblastoma cells were pretreated with cordycepin (COR), adenosine (ADE), or donepezil (DNPZ) prior to Aβ₄₂ exposure, and cell viability was assessed using the MTT assay. Drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were evaluated in silico, followed by network pharmacology to identify potential therapeutic targets and enriched biological pathways. Molecular docking and molecular dynamics simulations were performed to elucidate the interactions of the compounds with selected Alzheimer’s disease-related proteins. Results: COR and ADE significantly attenuated Aβ₄₂-induced cytotoxicity and improved SH-SY5Y cell viability. Network pharmacology identified 84 shared molecular targets, including 9 AD-associated genes. Protein–protein interaction analysis revealed hub genes involved in signal transduction, epigenetic regulation, and purine metabolism, while Gene Ontology and KEGG enrichment analyses highlighted pathways associated with neuroactive ligand–receptor interaction, calcium signaling, and inflammatory regulation. ADMET analysis predicted favorable pharmacokinetic properties for both compounds, although cordycepin was predicted to be AMES-positive. Molecular docking and molecular dynamics simulations demonstrated stable interactions of COR and ADE with liver X receptors (LXRα and LXRβ), whereas donepezil exhibited stronger binding affinity toward β-secretase (BACE1). Conclusions: COR and ADE exert neuroprotective effects through coordinated modulation of multiple AD-related signaling pathways rather than a single molecular target. These findings provide mechanistic insights into the neuroprotective activities of C. militaris-derived nucleosides and support further investigation of their potential as multi-target therapeutic candidates for AD and other neurodegenerative disorders. Full article

Background: Mitogen-activated protein kinase 3 (MAPK3/ERK1) plays a central role in cellular proliferation, inflammation, apoptosis, and survival signalling and has been implicated in oral squamous cell carcinoma (OSCC), periodontitis, oral lichen planus, and other chronic oral inflammatory diseases. The present study employed an integrated computational workflow combining machine learning (ML)-based quantitative structure–activity relationship (QSAR) modelling, molecular docking, density functional theory (DFT), molecular dynamics (MD) simulation, and MM-GBSA analysis to identify and characterise potent MAPK3 inhibitors. Methods: A curated dataset of 907 experimentally validated MAPK3 inhibitors was retrieved from the ChEMBL database and processed using molecular descriptors and Morgan fingerprints. Multiple ML algorithms were evaluated under scaffold-based validation, with Light Gradient Boosting Machine (LightGBM) demonstrating the best predictive performance. Results: The final model achieved strong classification capability with ROC-AUC values of 0.898 and 0.926. Feature importance analysis revealed that local structural motifs captured by fingerprint descriptors played dominant roles in MAPK3 inhibitory activity. The top-ranked compounds were subjected to molecular docking, where compounds 58324148 and 137531515 exhibited strong binding affinities of −11.9 and −11.0 kcal/mol, respectively. DFT calculations demonstrated favourable electronic properties with low HOMO–LUMO energy gaps, while MD simulations confirmed stable receptor–ligand interactions throughout 200 ns trajectories. MM-GBSA analysis further supported strong binding stability dominated by van der Waals interactions. Conclusions: Overall, the integrated computational framework successfully identified promising MAPK3 inhibitor candidates with potential therapeutic relevance for oral inflammatory and proliferative diseases. Full article

GPIV (CD36) is a multifunctional membrane protein expressed on various cells, including platelets, where it plays a role in adhesion and activation through the interaction with its ligands, including collagen types I and III and thrombospondin 1. Inherited GPIV deficiency, historically recognized in anti-Naka alloimmunized East Asian donors, is considered asymptomatic and associated with normal platelet aggregation, although impaired adhesion under high-flow conditions has been reported. Here, we reconsider the molecular basis, epidemiology and functional consequences of GPIV deficiency and report four unrelated patients in whom heterozygous CD36 variants are associated with markedly reduced platelet GPIV expression and a clinically relevant mucocutaneous bleeding diathesis. Patients suffered lifelong bleeding symptoms despite normal light-transmission aggregometry and platelet granule content and release and displayed decreased GPIV expression. Three of them showed slightly decreased VWF. Platelet adhesion to Type I collagen was reduced at high shear. These cases suggest for the first time an association between CD36 gene variants and bleeding and underscore the importance of including GPIV in the diagnostic workup of inherited platelet disorders, particularly when conventional assays do not reveal abnormalities. Full article

This study investigated the effects of terpene compounds from Schinus molle fruit essential oil (EO) against osteoarthritis (OA) using integrated network pharmacology, molecular docking, and molecular dynamics. The EO, obtained by steam distillation (yield: 6.95%), was characterized by GC-MS, detecting 55 peaks (98.61% of the total), of which 49 were identified and dominated mainly by monoterpene hydrocarbons (73.93%), with α-phellandrene (20.35%), camphene (11.36%), and Z-β-ocimene (8.69%) as the major constituents. Additionally, seven compounds with favorable ADME profiles and low predicted toxicity were selected for the target prediction. Overlap analysis between compound targets and osteoarthritis-related genes (Os-teoDIP) revealed 171 common genes that triggered inflammatory pathways, including PI3K-Akt, HIF-1, and NOD-like receptor signaling. Protein–protein interaction network analysis identified 11 hub genes, including TLR4, HSP90AA1, PTGS2, and MAPK1. Molecular docking revealed that γ-cadinene exhibited the best binding affinities, particularly against HSP90AA1 (−6.38 kcal/mol) and TLR4 (−5.87 kcal/mol). A 200 ns molecular dynamics simulation confirmed the stability of the γ-cadinene–TLR4 complex through persistent hydrophobic contacts with residues F379, C391, F409, I310, and F377, with contact occupancy of up to 0.95. The receptor backbone RMSD plateaued between 2.5 and 3.5 Å after equilibration, and the ligand remained in the binding pocket throughout the trajectory. These findings suggest that the terpenes of S. molle EO, particularly γ-cadinene, may modulate the inflammatory pathways related to OA. However, it is necessary to complement experimental validation in vitro and in vivo. Full article

The c-Myc oncoprotein is a central regulator of oncogenic transcriptional programs that remains challenging to inhibit directly, necessitating strategies that target c-Myc–associated protein complexes rather than the protein alone. This study conducted an in silico evaluation of the natural biphenolic lignan pinoresinol as a potential modulator of the c-Myc–TBP–TAF1 (TATA-binding protein (TBP)- Multiple direct interactions of TBP with the MYC oncoprotein) transcriptional complex (PDB ID: 6E16). Prior to molecular docking, the protein structure was subjected to energy minimization using the AMBER ff14SB force field to optimize conformational stability and structural reliability; ligand preparation and docking were performed with standard, widely used tools (e.g., AutoDock Vina v1.1.2; visualization and interface analyses in UCSF Chimera/ChimeraX and SeamDock). Molecular docking and binding-interface analyses identified reproducible interactions within defined pockets P₀, P₁, and P₂, with pocket P₀ exhibiting the highest Drug Score of 0.82. Binding affinities ranged from −5.0 to −7.1 kcal/mol, which are consistent with moderate docking scores typical for small natural ligands. Across multiple ligand poses, LYS327, LYS310, and ASP209 emerged as consistent interaction hotspots, with LYS327 showing the most frequent contacts. Furthermore, in silico ADMET analysis predicted a high probability of cytotoxic inactivity (0.98), suggesting a favorable safety profile compared to traditional agents like vincristine. These results support a protein–protein interface-oriented approach and position pinoresinol as a promising lead scaffold for disrupting c-Myc–associated transcriptional regulation. Full article

With the growing interest in pandan-based products, bitterness and astringency associated with flavonoids may limit their sensory acceptance. This study investigated the interactions and taste-modulating effects of two milk proteins, β-casein (β-CN) and β-lactoglobulin (β-LG), with two representative bitter flavonoids, catechin (C) and naringin (NAR), in aqueous model systems. Fluorescence spectroscopy showed that both flavonoids produced concentration-dependent quenching of the milk proteins. β-CN exhibited more pronounced interaction-related spectroscopic responses than β-LG, which may be associated with its flexible and intrinsically disordered structure. Molecular docking predicted hydrogen-bonding and hydrophobic interactions in all four protein–flavonoid systems, with catechin and naringin interacting mainly with the internal hydrophobic cavity of β-LG and surface-exposed regions of the β-CN model. Circular dichroism and Fourier-transform infrared spectroscopy indicated ligand-dependent structural changes. For β-LG, catechin slightly decreased the estimated antiparallel and total β-sheet fractions, whereas naringin produced a modest increase. For β-CN, catechin produced a more apparent redistribution between the estimated α-helix and β-sheet fractions, while naringin caused comparatively smaller changes. Electronic tongue measurements showed that the addition of the milk proteins reduced the bitterness- and astringency-related sensor responses of catechin and naringin. Under the tested conditions, β-CN produced greater attenuation of these responses than β-LG, while the umami-related response remained comparatively high. These findings support the potential application of milk proteins as taste-modulating components in flavonoid-containing dairy formulations, although validation in real food matrices is required. Full article