Adolescent idiopathic scoliosis (AIS) involves systemic bone-metabolic dysregulation and paraspinal microenvironment remodeling, but whether nutrition-related micronutrient-associated molecular programs overlap with these alterations remains unclear. Vitamin E (VE), comprising lipid-soluble tocopherols and tocotrienols, is linked to membrane protection, lipid peroxidation control, inflammatory mediator regulation, and endothelial responses. This study examined whether VE-related molecular signatures converge on AIS-associated redox, lipid-inflammatory, vascular, and multicellular remodeling programs. Peripheral blood miRNA data (GSE235203) and bone marrow transcriptomic data (GSE110359) were integrated using HERB-based compound mapping, VE-AIS shared-target enrichment, feature prioritization, intradisease GSEA, single-cell localization, CellChat analysis, and NHANES contextualization. HERB mapping generated a VE/tocopherol-related prioritization signal, not direct evidence of VE involvement in AIS. Forty-two shared VE-AIS targets were enriched mainly in oxidative stress, glutathione/peroxidase activity, and glutathione metabolism, with additional lipid-inflammatory and vascular signals. Five prioritized genes (SOD1, GCLC, PTGS1, PTGS2, and KDR) defined redox-buffering, lipid-inflammatory, and vascular-response axes. Single-cell and CellChat analyses localized these signatures mainly to endothelial, dendritic/APC-like, MSC-like, and stromal/osteogenic populations, suggesting a predicted concave-side enrichment of inflammatory-endothelial-stromal communication. Structural analyses supported the computational plausibility of α-tocopherol compatibility with selected proteins, particularly PTGS2. No AIS cohort with measured VE exposure or status was analyzed. NHANES provided external clinical nutrition context rather than AIS-specific validation. Overall, VE-related signatures overlapped with redox, lipid-inflammatory, vascular-response, and multicellular remodeling programs in AIS. These findings generate testable molecular hypotheses but do not show that VE intake, tocopherol status, or supplementation modifies AIS risk, severity, or progression.
As a non-canonical secondary structure of nucleic acids, G-quadruplexes (G4) play pivotal roles in key physiological processes, including cell replication, transcription, and translation. The specific recognition and monitoring of G4 have emerged as a prominent research focus. In this study, a water-soluble pyrene-based diimidazolium molecular probe (1·2Cl-) is rationally designed and synthesized efficiently via a one-step SN2 reaction. This probe employs two covalently linked pyrene moieties as the core signal-generating module, with an anthracene moiety and two imidazolium moieties as the linker. Owing to the distinctive dimerization of 1·2Cl- in aqueous media, the probe enables selective recognition of dinucleotides through an intercalation binding mode and identifies G4 structures via a surface contact mode. As a chirality and fluorescence dual-response probe, 1·2Cl- recognizes G4 structures with high specificity and low background signal via dimerization and chiral stacking of pyrene moieties, with corresponding circular dichroism (CD) and fluorescence detection limits of 0.38 µM and 4.65 nM, respectively. These results overcome the core limitations of conventional G4 probes and establish a new strategy for designing selective multi-responsive probes for functional nucleic acids, thereby expanding the application of supramolecular probes in bioanalysis.
Serum albumin (SA), the most abundant protein carrier in blood plasma, is a major allergen source. Chicken serum albumin (CHSA) is associated with chicken meat allergy due to its cross-reactivity with human serum albumin (HSA). To elucidate the structural basis underlying this immunological cross-recognition, Molecular Dynamics (MD) simulations combined with data-driven artificial intelligence (AI) analyses were employed to compare the structural and dynamic characteristics of CHSA and HSA. Despite moderate sequence identity (∼46.6%), CHSA displays comparable protein compactness and backbone flexibility to HSA, with slightly greater compactness. Domains I and III of CHSA govern a conserved scissor-like motion like HSA. This dynamic similarity may facilitate structural mimicry, enabling antibody cross-recognition. Moreover, CHSA exhibits larger drug sites (Sudlow sites I and II) than HSA, affecting ligand-binding affinity and specificity. The reactive C34 in CHSA demonstrates a similar hydrogen bond network to that in HSA, suggesting comparable redox reactivity. C34 of CHSA can hydrogen bond with L31, Y84, and S35. Deep learning models distinguished HSA and CHSA based on their MD-derived features. To gain insight into the learned representations, an explainable AI approachTesting with Concept Activation Vectorswas employed. AI-based analysis identifies nuanced differences in spatial organization and dynamics patterns, particularly in flexibility, solvent exposure, and internal stabilization. These differences, not captured by averaged measures, may influence epitope presentation. This study provides molecular-level insights into CHSA-HSA similarities and differences, informing their potential biomedical applications and highlighting the need for further experimental validation.
The present agricultural scenario with soil infertility, low productivity, climate change, environmental pollution and local economic instability challenges calls for coordinated efforts towards global sustainable development. The role of crop-friendly microbes, thus, becomes indispensable. Standard global regulations to devise and implement sustainable cropping and yield improvement measures seem emergent in such context. Microbes that are actively involved in soil physiology and crop growth could increase crop yield and reduce the dependency on agrochemicals, while promoting sustainable agriculture. To advance the sustainable development goals, it was essential to understand molecular mechanisms of microbial activities like N2-fixation (nif genes), phosphate solubilisation (phoD, appA and phnX), phytohormone production (ipdC for indole-3-acetic acid synthesis), ACC (1-aminocyclopropane-1-carboxylate) deamination (acdS), thermotolerance (hsp) and reactive oxygen species (ROS) detoxification (katE and sodA) that underlie. Formulated crop-associated microbial consortia as synthetic microbial community (SynCom) could extend such benefits. In line with green (sustainable) farming, SynCom approach enhances the stability of a formulated allochthonous microbial community through the synergistic ecological interactions between the participating members and would promote crop productivity with lesser use of agrochemicals. Omics approach, either stand-alone or combined with advanced bioinformatics, is another strategy that employs non-culture techniques to identify microbial genome in an ecological niche and their functional traits. Such insights on the plant-microbe associations and the underlying molecular mechanisms could be useful in enhancing agricultural productivity and crop wellbeing on sustainable bases. This article is an attempt to dissect the recently reported literature, understand the underlying aspects in greater details, and present the current knowledge in a lucid and interlinked manner for a better and insightful understanding of the readers, with the future research directions. Plant-microbe interaction supports sustainability in agriculture through biofertilisation and biocontrol activity of PGPR by inducing nitrogen fixation, phosphorus solubilisation, ROS neutralisation, phytostimulation and provides protection from biotic/abiotic stress. This approach helps achieve sustainable development goals, promotes sustainable agriculture, enhances climatic resilience and supports resource efficient farming.
Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death driven by lethal lipid peroxidation and has emerged as a pivotal regulator of skeletal muscle physiology and pathology. This review systematically delineates the core molecular machinery of ferroptosis, including the system Xc--glutathione-GPX4 axis, dysregulated iron metabolism, and lipid peroxidation, together with key regulatory networks involving p53, Nrf2, and AMPK. We further highlight the context-dependent roles of ferroptosis in skeletal muscle: during development and regeneration, transient and moderate ferroptotic signaling may facilitate myogenesis and tissue remodeling, whereas sustained or excessive ferroptosis drives satellite cell depletion and impaired regenerative capacity. Pathologically, ferroptosis is implicated in a spectrum of muscle disorders-including sarcopenia, muscular dystrophy, sports-related injuries, and inflammatory myopathies-through mechanisms such as iron overload, oxidative stress, and mitochondrial dysfunction. Finally, we summarize emerging therapeutic strategies targeting ferroptosis, including iron chelators, GPX4 activators, natural compounds, gene-based interventions, and physical exercise, and discuss future directions toward precision medicine and combinatorial approaches. By integrating current evidence, this work provides a comprehensive framework for understanding ferroptosis in skeletal muscle homeostasis and disease and offers insights for the development of novel therapeutic interventions. This review establishes ferroptosis as a convergent pathogenic mechanism across muscle disorders, offering a framework for patient stratification by ferrototic signatures. It synthesizes preclinical evidence for pharmacologic inhibitors, natural products, and gene-based interventions, while critically evaluating clinical feasibility, safety, and dosing. A tiered translational roadmap from biomarker validation to early-phase trials is proposed to accelerate bench-to-bedside development.
Aurora kinase A (AURKA) is a pivotal driver of malignant progression and poor prognosis in triple-negative breast cancer (TNBC). In this study, we developed a cascaded AI-driven virtual screening pipeline, integrating sequence-based affinity prediction (PSICHIC), equivariant deep learning docking (KarmaDock), and geometric rescoring (DeepDock) to identify novel AURKA inhibitor candidates. From an in-house 160,000-compound screening library assembled from commercially available collections, three leads (compounds 3, 5, and 8) were selected and subsequently validated via HTRF biochemical assays, exhibiting potent enzymatic inhibition with IC50 values of 157 nM, 21.64 nM, and 46.03 nM, respectively. Cell-based assays demonstrated that compound 3 produced stronger short-term cell-growth inhibition in MDA-MB-231 (TNBC) cells compared to clinical benchmarks MLN8237 and CCT241736, whereas compounds 3 and 5 showed cell-growth inhibition in NIH/3T3 cells within the same concentration range as the reference inhibitors. Triplicate 500 ns molecular dynamics simulations supported stable binding modes of the identified leads in the AURKA binding pocket. Additional computational analyses further provided supportive information for subsequent lead optimization. This study provides a transparent and open-source workflow for AI-assisted identification of AURKA-active chemotypes.
Breast cancer heterogeneity is crucial for treatment decision-making and prognosis prediction. Magnetic resonance imaging (MRI) is a key tool in breast imaging, providing a non-invasive assessment of morphological characteristics, cell density, hemodynamics, and vascular proliferation. Integrating MRI with advanced techniques such as radiomics, habitat imaging, and artificial intelligence enables a deeper understanding of tumor morphology and biological behavior through analysis of imaging features, thereby characterizing the heterogeneity inherent in breast cancer. This review explores MRI's role as an imaging biomarker for evaluating breast cancer molecular subtypes, aiming to support personalized treatment strategies and improve therapeutic outcomes.
Juvenile myelomonocytic leukemia (JMML) rarely manifests with extramedullary involvement beyond spleen, liver, or skin; testicular infiltration at diagnosis is unreported. We describe a Novel Case of bilateral testicular leukemic infiltration as the initial presentation of NRAS-mutant JMML in a toddler, with rapid remission following azacitidine bridging and haploidentical HSCT. A 2-year-old boy presented with pallor, abdominal distension, and bilateral scrotal swelling. Labs: leukocytosis (58 × 10⁹/L, monocytes 12.8 × 10⁹/L), anemia (Hb 8.2 g/dL), HbF 22%. BM confirmed JMML with NRAS p.G12D (VAF 42%). No pathogenic variants were detected in KRAS, PTPN11, CBL, or NF1. Conventional cytogenetic analysis demonstrated a normal male karyotype (46,XY). US: testes enlarged (18.8/18.2 mL) with hypoechoic infiltration. Azacitidine (75 mg/m²/d × 5, 2 cycles) reduced counts and size. Paternal haplo-HSCT (Flu-Treo-TT conditioning, PTCy) engrafted D + 18; testes normal at 6 weeks, molecular remission (NRAS-) at 3 months. This novel case underscores the efficacy of azacitidine and haploidentical HSCT for NRAS-mutant JMML with testicular involvement. Routine genital examination and ultrasound are recommended for male patients.
[This retracts the article DOI: 10.1021/acsomega.3c08077.].
[This retracts the article DOI: 10.1021/acsomega.3c09890.].
[This retracts the article DOI: 10.1021/acsomega.3c05938.].
Stress fractures are overuse injuries that develops in response to repetitive loads applied to bone with normal structural integrity and is highly prevalent among physically active populations, but their underlying mechanisms remain incompletely understood. This article reviews the complex pathogenesis and healing mechanisms of stress fractures. Stress fractures develop when repetitive mechanical loading on the bone exceeds its threshold for adaptive repair, leading to the progressive accumulation of microdamage and ultimately disrupting the physiological equilibrium between bone resorption and formation. The healing of stress fractures is characterized by intramembranous ossification, a process that begins with periosteal woven bone formation to stabilize the fracture and proceeds through subsequent bone remodeling to repair the cracks. The development and repair processes of stress fractures involve dynamic alterations in cell types and tissue constituents, along with active signaling activities within and among the involved cells involved. Future research should prioritize the use of larger animal models such as rabbits and minipigs, and the development of stress fracture models that more accurately replicate the clinical pathogenesis of stress fractures. Although the efficacy of anti-osteoporotic agents, non-steroidal anti-inflammatory drugs (NSAIDs), and low-intensity pulsed ultrasound (LIPUS) have been reported, future research should explore additional physical therapy modalities to elucidate their specific role in the management of stress fractures and underlying mechanisms. Overall, by reviewing the latest research advances in the pathogenesis and treatment of stress fractures and exploring targeted therapeutic strategies, this article holds the promise to offer novel insights into their prevention and management, thereby driving improvements and innovations in clinical treatment approaches and demonstrating significant translational potential.
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Chagas disease (CD), once found mainly in underdeveloped countries, is becoming a public health problem in the developed world. Although the drug benznidazole (BZN) is effective in the acute phase of the disease, it causes toxicity due to the formation of reactive substances resulting from presystemic metabolism, which have the ability to bind to DNA structures. This study conducts experimental tests with the epimastigote and trypomastigote species of the parasite, followed by drug-target interaction analyses through molecular docking against the enzymes trypanothione reductase, cruzain, and TcGAPDH, as well as pharmacokinetic prediction based on MPO analyses. In vitro tests revealed CPN4F's significant efficacy in reducing host cell viability and inhibiting parasite growth. Molecular docking indicated CPN4F's favorable energy ordering and superiority to BZN against the cruzain target (ΔG < -6.0 kcal mol-1), while molecular dynamics simulations showed that the complex remains stable in the 500 ns range. Pharmacokinetic estimates suggested high cell permeability (P app > 10 × 10-6 cm/s) but potential metabolic stability concerns (CLint,u > 8 mL/min/kg), showing good oral bioavailability, although with moderate metabolism. The CPN4F molecule demonstrates potent in vitro efficacy against Chagas disease, outperforming BZN in molecular docking studies targeting cruzain. Despite concerns about metabolic stability due to its high cell permeability and lipophilic nature, CPN4F exhibits low acute oral toxicity, highlighting its potential as a safe and effective treatment option.
Rheumatoid arthritis (RA) is driven in part by hyperactivated fibroblast-like synoviocytes (FLS) that invade articular structures. Iguratimod (IGU), a conventional synthetic DMARD, is clinically effective, but its direct molecular target and impact on synovial cell-cell crosstalk remain unclear. We aimed to elucidate how IGU regulates FLS invasiveness and inflammatory signaling, identify its upstream target within the JAK-STAT pathway, and develop a prodrug with improved pharmacokinetics while preserving disease-modifying activity. We combined in vitro assays in MH7A cells and rat RA-FLS with RNA sequencing and conditioned-medium fast-astral DIA proteomics to characterize IGU's effects on TNF-α-induced migration, invasion, and signaling. STAT1 dependence was interrogated by siRNA knockdown, phosphorylation-deficient mutant reconstitution and IFN-γ rescue. Integrated single-cell RNA-seq of RA and healthy synovium, together with CellChat analysis and complement component 3a (C3a) stimulation of THP-1-derived macrophages, was used to define FLS-macrophage crosstalk. Reverse virtual screening, molecular docking, thermal shift assays, cellular thermal shift assays, kinase assays, and molecular dynamics simulations were applied to characterize IGU-TYK2 interactions. A sulfonamide N-acyl IGU prodrug (AD811) was rationally designed and evaluated for pH-dependent stability, plasma and microsomal metabolism, pharmacokinetics, efficacy, and short-term safety in collagen-induced arthritis rats. IGU suppressed TNF-α-induced FLS migration and invasion without cytotoxicity by selectively inhibiting STAT1 Y701 phosphorylation and nuclear translocation, while sparing STAT1 Y727 phosphorylation and STAT2 Y690 phosphorylation. Bulk and single-cell transcriptomic analyses revealed STAT1 hyperactivation in RA lining-layer FLS and uncovered a STAT1-C3-TNFα feedback loop in which FLS-derived C3/C3a enhances macrophage TNF-α production, thereby reinforcing FLS activation; IGU disrupted this loop by reducing STAT1 activity, C3 transcription, and C3a-driven macrophage TNF-α induction. Biochemical and biophysical studies showed that IGU directly engages the TYK2 JH2 pseudokinase domain, alters its thermal behavior, and inhibits kinase activity of a TYK2 construct containing JH2 and JH1, while not measurably inhibiting the isolated JH1 catalytic domain, consistent with JH2-dependent allosteric modulation of TYK2 output. The prodrug AD811 exhibited pH-sensitive stability, rapid plasma conversion to IGU, favorable oral bioavailability, and therapeutic efficacy, joint protection, and preliminary hepatic and gastric safety comparable to equimolar IGU in vivo. In FLS-centered experimental systems, IGU reduces RA-FLS invasiveness by targeting TYK2 JH2 and disrupting a STAT1-C3-TNFα feedback loop between lining-layer FLS and macrophages, thereby attenuating both intrinsic fibroblast aggressiveness and inflammatory crosstalk. The prodrug AD811 maintains these disease-modifying actions while improving pharmacokinetic properties, nominating AD811 as a promising candidate for further translational development in RA. This study mechanistically links IGU, a clinically used csDMARD, to selective modulation of TYK2 JH2 and downstream STAT1 signaling in synovial lining-layer FLS. By showing that, in FLS-centered models, IGU disrupts a STAT1-C3-TNFα feedback loop between FLS and macrophages and thereby reduces FLS invasiveness and inflammatory crosstalk, our data provide a concrete cellular and molecular basis for its disease-modifying effects in rheumatoid arthritis. Furthermore, the rationally designed prodrug AD811 exhibits improved pharmacokinetic properties and a favorable short-term safety profile in vivo, supporting its further evaluation as a potential oral small-molecule candidate.
Understanding the electronic structure of amino acids is crucial to understanding protein stability, folding mechanisms, and molecular interactions. In this study, we introduce fragment-wise mutual information (FMI) as a quantum information-based tool to quantify interatomic correlations in peptides. By extending mutual information (MI) analysis to amino acid fragments, FMI provides a detailed map of electronic interactions beyond classical descriptors, such as van der Waals forces. We first validated FMI on 400 dipeptides, demonstrating a correlation with the atomization and bonding energies. Expanding this approach to the 10-mer Neh2 peptide, we analyze molecular dynamics (MD) simulations and reveal how interatomic correlations evolve during folding. Our results show that FMI distinguishes stabilizing interactions such as salt bridges and variable hydrogen-bond strengths, providing deeper insight into peptide stability. These findings suggest that FMI could enhance molecular modeling and force-field development by incorporating quantum electronic effects into biomolecular analysis.
Osteoblasts are bone-building cells that drive osteogenesis by producing osteoid and promoting its mineralization during development and remodeling. Although ginsenosides from Panax species can enhance bone formation and inhibit resorption, the role of ginsenoside F1 in osteoblast differentiation and bone metabolism has not been defined. This study aimed to elucidate the molecular mechanism by which ginsenoside F1 promotes osteoblast differentiation and evaluate its therapeutic potential in an ovariectomy-induced osteoporosis model. Bone marrow-derived mesenchymal stem cells and primary osteoblasts were treated with ginsenoside F1. Osteogenic differentiation was analyzed through gene and protein expression of key markers, including Runx2, Sp7 and Alpl. RNA-sequencing, molecular docking, and siRNA-mediated gene silencing were performed to identify and validate F1's target signaling pathway. The in vivo efficacy of F1 was assessed in ovariectomized mice using micro-computed tomography, histological staining, and biochemical assays. Gene and protein expression analyses showed higher levels of osteogenic transcription factors in F1-induced osteoblasts than in untreated cells. RNA-sequencing analysis and molecular docking studies revealed an association between bone morphogenetic protein receptor type 1b (BMPR1b) and SMAD proteins important for mediating osteoblast differentiation following F1 induction. Furthermore, BMPR1B knockdown attenuated the inhibition of downstream SMAD1/5/9 signaling, indicating that BMP-activated SMAD signaling was required for the pre-osteogenic action of F1. In addition, F1 treatment increased bone mass in ovariectomy-induced osteoporosis. Collectively, these findings suggest that ginsenoside F1 enhances osteoblast differentiation and promotes bone formation under osteoporotic conditions, highlighting its therapeutic potential for bone metabolism disorders.
Cold stress (CS) is a significant obstacle in tobacco (Nicotiana tabacum L.) farming, significantly affecting plant development, photosynthetic activity, and cellular redox balance. In recent decades, bio-stimulants have created environmentally friendly substances that make the plant resistant to abiotic stresses, such as cold stress. The recent developments highlight bio-stimulants as a sustainable solution to improve cold stress tolerance in tobacco production. These substances promote plant growth, thereby increasing plant resilience to unfavorable temperature conditions. This review assesses the role of bio-stimulants in improving cold stress tolerance in tobacco, focusing on physiological, biochemical, and molecular responses. It summarizes the effects of various bio-stimulants on plant growth, antioxidant defense systems, and photosynthetic performance under low-temperature conditions. The enhancement of enzymatic antioxidants and non-enzymatic antioxidants by bio-stimulants helps overcome oxidative damage. Evidence in molecular biology studies to understand bio-stimulant-mediated regulation of stress responsive genes is also critically discussed in order to understand the role bio-stimulants play in enhancing the genetic potential of tobacco to cold stress. This review presents an integrated scheme of the multifarious functions of bio-stimulants in improving cold stress tolerance of tobacco. It also highlights existing knowledge gaps and provides research directions on how to explore efficient, sustainable, and climate resilient tobacco production systems in the future.
Although the efficacy of molecular targeted therapies varies across actionable genomic alterations in NSCLC, comparisons within a single real-world cohort remain limited. We conducted a retrospective multi-institutional study of 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy from 2017 to 2023. Patients were classified into the following three genomic groups: EGFR mutations (group A), ALK/ROS1/RET fusion oncogenes (group B), and others, including MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations (group C). Treatment efficacy and safety were compared across the groups. Treatment outcomes differed between the subgroups. Group B demonstrated the highest objective response rate (85.8%) and the longest median real-world progression-free survival (rwPFS; 42.5 mo); median overall survival (OS) was not reached. Group A had intermediate outcomes. Group C exhibited the shortest rwPFS (9.2 mo), poorer OS, and higher rates of treatment discontinuation due to adverse events. Such hierarchical differences were observed in patients with baseline central nervous system metastases and in those receiving first-line treatment. In multivariate analysis, genomic subgroup remained associated with rwPFS and OS, with fusion-driven tumors maintaining superior outcomes irrespective of other factors. This large real-world analysis yielded a hierarchy of therapeutic benefits across actionable genomic alterations in NSCLC. Patients with fusion-driven tumors benefited from targeted therapy, whereas those with EGFR-mutated tumors had intermediate outcomes. Treatment of patients with MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations had limited efficacy and higher toxicity, underscoring the need for improved therapeutic strategies.
Lathyrol, a bioactive natural compound derived from plants of the Euphorbiaceae family, exhibits antitumor activity, and its molecular targets and underlying mechanisms remain incompletely understood. In this study, thermal proteome profiling (TPP) was applied to systematically identify lathyrol-binding proteins in non-small cell lung cancer (NSCLC) cells. TPP analysis identified glucose-6-phosphate dehydrogenase (G6PD) as a candidate target of lathyrol. A cellular thermal shift assay (CETSA) confirmed increased thermal stability of G6PD upon treatment. Molecular docking indicated a potential interaction between lathyrol and G6PD. The peptide-centric local stability assay (PELSA) revealed localized conformational changes in the C-terminal region of G6PD consistent with the predicted interaction interface. Enzymatic assays showed reduced G6PD activity accompanied by decreased intracellular NADPH levels. Quantitative proteomics indicated alterations in the pathways associated with glucose metabolism and redox regulation. These findings identify G6PD as a functional target of lathyrol in NSCLC cells and link its inhibition to disruption of cellular redox balance and metabolic homeostasis.