Search Results (1,451)

Cancer progression is driven by dysregulated kinase signaling and apoptotic evasion across multiple malignancies. Although targeted kinase inhibitors have improved outcomes, resistance and toxicity remain major challenges. Natural phytochemicals offer promising multi-target therapeutic potential. Persea americana contains diverse bioactive compounds; however, its role in multi-cancer kinase targeting remains underexplored. This study aimed to identify and validate anti-cancer kinase targets of Persea americana phytoconstituents across five cancers: lung, breast, cervical, colorectal, and prostate, using integrated network pharmacology and molecular simulation approaches. Cancer-associated genes were retrieved from the Open Targets Platform and prioritized through Gene Ontology analysis. Overlapping targets with 208 predicted human targets of Persea americana were identified. Protein–protein interaction networks revealed hub genes, followed by TCGA-based validation. Twenty-five phytoconstituents were docked against SRC and GSK3β, and top complexes underwent 100 ns molecular dynamics simulations. Enrichment highlighted kinase activity and apoptosis. SRC emerged as a pan-cancer hub, while GSK3β was prominent in breast cancer. Luteolin showed strongest binding to SRC (−11.9 kcal/mol), outperforming the co-crystal inhibitor, while valencene showed affinity toward GSK3β (−8.8 kcal/mol). Simulations confirmed stable interactions. Luteolin exhibits strong multi-target kinase inhibition, particularly against SRC, supporting its potential as a pan-cancer therapeutic candidate. Full article

Brain-derived neurotrophic factor (BDNF) is a key mediator of central sensitization and chronic pain through activation of TrkB receptors. Although the Pannexin 1 (Panx1) channel has been implicated in chronic pain, its involvement in BDNF-TrkB signaling remains unclear. Here, we investigated the functional relationship between TrkB activation and Panx1 using a BDNF-induced pain model in rats. Animals received a single intrathecal administration of BDNF, and mechanical nociception was assessed using the Randall–Selitto test. Behavioral analyses were combined with pharmacological interventions, Western blotting, confocal microscopy, YOPRO-1 uptake assays, and ATP quantification in spinal cord tissue. Intrathecal BDNF induced a robust mechanical hyperalgesia that persisted for up to 10 days. Blockade of Panx1 with 10Panx significantly attenuated BDNF-induced hyperalgesia. BDNF increased Src416 phosphorylation, Panx1 phosphorylation, and YOPRO-1 uptake in dorsal horn neurons, indicating enhanced channel activation. These effects were prevented by the TrkB antagonist ANA12, demonstrating that Panx1 acts downstream of BDNF-TrkB signaling. Inhibition of Src-family kinases with PP2 reduced both hyperalgesia and Panx1 activation, supporting a TrkB-Src-Panx1 signaling cascade. Furthermore, BDNF enhanced ATP release from spinal cord slices, an effect abolished by ANA12, PP2, and 10Panx. Together, these findings identify Panx1 as a downstream effector engaged by BDNF-TrkB signaling during the onset of mechanical hyperalgesia. While persistent TrkB activation appears to be required for the prolonged nociceptive state, the Src family kinase-Panx1 pathway contributes primarily to the early phase of BDNF-induced sensitization. Full article

The Shared Metacognition Questionnaire (SMQ) is widely used to assess metacognition in collaborative online learning environments. Prior work has supported its two broad dimensions of self-regulation of cognition (SRC) and co-regulation of cognition (CRC), but the lower-order monitoring and managing subdimensions theorized within SRC and CRC have not been empirically supported. The present study used a split-sample exploratory and confirmatory factor analytic approach with graduate students (N = 348) enrolled in 25 fully online courses. For SRC, the results provided tentative support for a two-factor monitoring–managing structure, with the managing factor performing more strongly than the monitoring factor. For CRC, neither the theorized structure nor an empirically informed alternative reached marginally acceptable fit, and item-level diagnostics pointed to potential issues of item clarity, redundancy, and content clustering. The findings (1) provide additional validity evidence supporting the use of SMQ to measure self-monitoring and self-managing; (2) extend the original SMQ development study and broader theoretical models of self- and co-regulation; and (3) offer practical guidance on the current use of the SMQ and suggestions for refining the CRC items. Full article

Sport-related concussion (SRC) rehabilitation has advanced toward active, multidomain management, yet recovery may still be judged largely through symptom resolution and broad clinical indicators that may not fully capture persistent functional deficits. Emerging evidence suggests subtle disturbances in postural control, gait, and sensorimotor coordination may persist beyond apparent clinical recovery, raising the possibility that unresolved asymmetries represent an underrecognized dimension of dysfunction. This Viewpoint proposes symmetry restoration as a potential rehabilitative construct in SRC management and explores how biofeedback-guided approaches may provide a conceptual framework for identifying, monitoring, and retraining symmetry-related deficits. Drawing from concussion research, motor control theory, rehabilitation science, and biofeedback applications, this article discusses postural and movement asymmetries as possible markers of incomplete recovery, examines visual, wearable, neuromuscular, and auditory biofeedback strategies as potential mechanisms for symmetry-informed rehabilitation, and outlines clinical implications and future research priorities. Rather than proposing symmetry as a stand-alone determinant of recovery, this Viewpoint advances the conceptual proposition that symmetry-oriented approach may complement existing multidomain models by serving as an additional layer of functional assessment alongside symptom reporting, neurocognitive evaluation, vestibular and oculomotor examination, exertional testing, and routine clinical assessment. Within this framework, symmetry-related measures are envisioned not as independent clearance criteria, but as potentially informative indicators of residual sensorimotor function that may help guide rehabilitation progression and contribute to more functionally informed return-to-sport decision making through adjunctive measures such as center-of-pressure behavior, center-of-mass displacement, gait symmetry, stance and swing time asymmetry, limb-loading patterns, interlimb coordination, and muscle activation symmetry. Full article

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), limiting the durability of targeted therapy. Bardoxolone methyl (CDDO-Me) has been reported to exert anti-inflammatory and anti-cancer activities. However, its role in acquired EGFR-TKI resistance remains unclear. Here, we found that CDDO-Me significantly enhanced sensitivity of resistant NSCLC cells to gefitinib, with combination index analysis confirming a synergistic interaction between CDDO-Me and gefitinib. Mechanistically, CDDO-Me induced mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, thereby activating Caspase-3 mediated apoptosis and GSDME-dependent pyroptosis, as evidenced by increased lactate dehydrogenase (LDH) release. Network pharmacology and molecular docking analyses identified Src as a potential target of CDDO-Me. Cellular thermal shift assay (CETSA) confirmed cellular engagement between CDDO-Me and Src, and Western blot analysis showed that CDDO-Me suppressed Src/STAT3 signaling. Consistently, Src knockdown reduced the inhibitory effect of combined CDDO-Me and gefitinib treatment on colony formation and attenuated changes in apoptosis and pyroptosis regulatory proteins induced by the combination treatment. Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC. Full article

Mitochondria coordinate cellular energy production, metabolism, and signalling through the organization of the electron transport chain (ETC) and formation of respiratory supercomplexes. These structures facilitate efficient electron transfer and enable coenzyme Q (CoQ) channelling, allowing differential regulation of NADH- and succinate-driven respiration while modulating reactive oxygen species (ROS) production. Beyond their damaging potential, ROS act as key signalling molecules that regulate mitochondrial function through redox-sensitive modifications. Mitochondrial protein kinases add an additional layer of control, with Src-family kinases playing a central role. In particular, the mitochondrial tyrosine-kinase Fgr is activated by H₂O₂ and promotes phosphorylation of succinate dehydrogenase, boosting complex II activity, delivering more electrons to CoQ and inducing reverse electron transfer (RET) through CI, in a ROS-induced ROS generation amplification cycle. This induces a metabolic rewiring aimed at supporting stress adaptation, immune cell activation, and macrophage polarization. Overall, the interplay between supercomplex organization, ROS signalling, and kinase activity is critical for metabolic flexibility and represents a promising target for therapeutic intervention. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a chronic multifactorial metabolic disorder requiring multi-target therapeutic strategies. This study aimed to predict the potential material basis, key targets and molecular mechanisms by which PuRenDan (PRD) may act against T2DM through an integrated network pharmacology and molecular simulation approach. Methods: Active compounds of PRD were screened from TCMSP, HERB 2.0 and the literature, and compound-related targets were predicted using TCMSP, SwissTargetPrediction and PharmMapper. T2DM-associated targets were collected from OMIM, DrugBank, DisGeNET, HPO, ClinPGx and GeneCards to obtain drug–disease intersection targets. Cytoscape was used to construct herb–compound–target and protein–protein interaction (PPI) networks, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking was performed using AutoDock Vina1.1.2, and representative ligand–receptor complexes were further assessed by 100 ns molecular dynamics (MD) simulations and molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) binding free-energy analysis. Results: A total of 163 active compounds, 597 PRD-related targets, 9138 T2DM-associated targets and 483 intersection targets were identified. β-sitosterol, emodin, quercetin, kaempferol and formononetin were predicted as major active compounds, whereas AKT1, TP53, SRC, IL6, TNF, EGFR and ESR1 were identified as disease-related network hubs. KEGG enrichment highlighted the PI3K-Akt, MAPK, HIF-1, FoxO, mTOR, AGE-RAGE and TNF signalling pathways. Docking predicted a comparatively favourable multi-target binding tendency for β-sitosterol. MD and MM/PBSA analyses further suggested favourable dynamic stability for β-sitosterol-TNF, β-sitosterol-AKT1, β-sitosterol-SRC and emodin-EGFR complexes, with β-sitosterol-TNF showing the lowest predicted binding free energy among the simulated systems. Conclusions: These in silico findings suggest that PRD may regulate T2DM-related inflammatory, insulin-signalling, oxidative-stress and metabolic networks through coordinated multi-compound, multi-target and multi-pathway actions. β-sitosterol may represent an important candidate material basis of PRD, with TNF, AKT1, SRC and EGFR as potential key targets. These conclusions remain predictive and require validation in biochemical, cellular and animal experiments. Full article

The extracellular matrix (ECM) is increasingly recognized as an active regulator of breast cancer progression rather than a passive structural scaffold. This narrative review examines how ECM remodeling contributes to tumor aggressiveness through changes in matrix composition, collagen architecture, tissue stiffness, mechanotransduction, stromal permissiveness, immune and metabolic programs, invasion, metastasis and therapeutic response. A structured narrative search of literature published from 1981 to June 2026 was used to support this synthesis. Evidence from breast cancer studies indicates that collagens, fibronectin, laminins, proteoglycans, matricellular proteins, ECM-remodeling enzymes, and matrix-crosslinking pathways regulate integrin–FAK/Src, RhoA–ROCK, PI3K–AKT, MAPK, TGF-β/SMAD, Wnt/β-catenin, and YAP/TAZ signaling. Spontaneous canine mammary tumors are discussed as complementary comparative models that may preserve selected tumor–stroma–ECM interactions under naturally occurring disease conditions while requiring cautious interpretation due to species-specific biological and clinical differences. Proteomics, lipidomics, metabolomics, spatial omics, digital pathology, and artificial intelligence may support ECM-informed biomarker discovery and response prediction. However, translational application requires standardized pathology, reproducible assays, harmonized metadata, external validation, model interpretability, and clinically meaningful endpoints. Overall, ECM-informed comparative oncology is best viewed as a framework grounded in rigorous validation for identifying matrix-defined tumor phenotypes and prioritizing future biomarker and therapeutic strategies. Full article

Biomass torrefaction represents a highly promising thermochemical pathway for upgrading low-density agricultural residues into high-value solid biofuels. However, optimizing reactor operations requires resolving the conflict between product energy enrichment and mass loss under transient heat transfer limitations. In this work, a transient kinetics-coupled Pareto optimization and techno-economic framework is developed for the torrefaction of rice husk residues (Oryza sativa), with pine wood (Pinus sp.) as a validation reference. The framework connects a transient 1D radial finite-difference heat transfer model in a cylindrical particle to a two-stage sequential chemical kinetics scheme, which was successfully calibrated against experimental thermogravimetric analysis (TGA) data. The physical model outputs (instantaneous species concentrations, temperature profiles, and process thermal demand) are dynamically coupled to an economic module to calculate the Levelized Cost of Torrefaction (LCOT). A grid sweep with Pareto non-dominance filtering is conducted on the active torrefaction design space (using a product quality constraint $Y_{BT}\le 0.96$ to avoid degenerate zero-conversion limits) to identify the Pareto frontier that minimizes LCOT while maximizing the efficiency index ($\eta$). To evaluate the financial and technical stability of the Pareto operating point for rice husk (523 K, 30 min), a global sensitivity and uncertainty analysis (GSA) is executed using 250 Latin Hypercube Sampling (LHS) Monte Carlo simulations coupled with Standardized Regression Coefficients (SRCs). The results show a baseline LCOT of 6.49 USD/GJ for rice husk at its 1 dry t/h pilot Pareto knee point (523 K, 30 min), which is projected to decrease to 4.12 USD/GJ under an industrial-scale techno-economic scenario (50 dry t/h). Under uncertainty, LCOT displays a mean value of $6.486\pm 0.565$ USD/GJ (95% CI: $5.517$–$7.644$ USD/GJ), which is heavily dominated by the raw feedstock acquisition cost ($\beta =0.7430$, $p<0.001$) and CAPEX contingency multiplier ($\beta =0.6129$). The efficiency index exhibited limited variability (mean $91.40\%\pm 0.96\%$, 95% CI: $89.80\%$–$93.26\%$), governed primarily by the particle diameter $d_p$ ($\beta =0.7828$) and secondary convective heat transfer coefficient h ($\beta =-0.5929$, $p<0.001$). This work successfully demonstrates that coupling transient transport phenomena to a techno-economic cash-flow layer provides a physics-informed framework for techno-economic evaluation and scale-up of thermochemical bioreactors. Full article

This study aimed to use quantitative phosphoproteomics to explore phosphorylation characteristics in Klebsiella pneumoniae (Kpn)-induced liver abscess (KPLA) formation and liver injury. The Kpn strain LA-Kpn006 was phenotypically and genotypically characterized. A murine model of KPLA was established via intragastric inoculation. Phosphoproteomics and bioinformatic analyses were conducted to identify and quantify phosphosites and phosphoproteins. LA-Kpn006 displayed a hypermucoviscous phenotype, serotype K1, ST23 genotype, and harbored six major virulence genes. Inoculation induced liver colonization and typical histopathological abscess lesions. We quantified 3017 phosphoproteins covering 12,798 phosphosites (dominated by serine phosphorylation); 1723 proteins were upregulated and 425 downregulated. Bioinformatic analyses revealed remodeling in metabolism, stress response, signal transduction, and cytoskeleton organization. Upregulated proteins converged on fatty acid elongation, inositol phosphate metabolism, and the tricarboxylic acid cycle; downregulated proteins were enriched in PI3K–Akt, IL-17 signaling, and T-cell differentiation. Protein–protein interaction network analysis identified 10 key proteins (Src, Rac1, Actb, Hsp90aa1, Hsp90ab1, Egfr, Rps6, Pik3CA, Itgb1, and Fyn) that mediate inflammatory signaling, cytoskeleton remodeling, and immune infiltration. Dysregulated phosphorylation networks drive pathological metabolic adaptation, suppressed immune homeostasis, and cytoskeletal disorganization, collectively facilitating KPLA progression. The identified hub proteins and pathways represent high-value mechanistic targets and candidate therapeutic vulnerabilities for KPLA. Full article

Lung cancer is the most common malignant tumor worldwide in terms of both incidence and mortality, and the development of highly effective, low-toxicity therapeutic strategies remains an urgent clinical challenge. Here, we report that Salvianolic acid A (SAA), a natural compound extracted from Salvia miltiorrhiza Bunge, inhibits the proliferation of non-small cell lung cancer (NSCLC) cells and induces ferroptosis. Mechanistically, SAA acts as an SRC kinase inhibitor, blocking SRC autophosphorylation at Tyr416, thereby disrupting the SRC-YAP interaction and preventing YAP nuclear translocation. This leads to GPX4 downregulation and subsequently triggers ferroptosis, characterized by increased reactive oxygen species (ROS), Fe²⁺ accumulation, and lipid peroxidation. Overexpression of YAP abrogates the effects of SAA, while inhibiting SRC or YAP enhances its activity. SAA inhibits tumor growth and downregulates key effector molecules in vivo. In summary, this study reveals a novel mechanism by which SAA induces ferroptosis via the SRC/YAP/GPX4 axis, supporting its further development as a candidate therapeutic agent for NSCLC. Full article

CD36 is a multifunctional scavenger receptor involved in long-chain fatty acid (LCFA) uptake, binding of oxidized lipids, and interactions with extracellular matrix proteins such as thrombospondin-1. Through association with Src family kinases, integrins, and adaptor proteins, it also modulates signaling, migration, inflammation, angiogenesis, and phagocytosis. Hypoxia, a common feature of solid tumors, inflamed tissues, and ischemic organs, remodels CD36 expression, localization, and function through hypoxia-inducible factor (HIF) signaling and stress-activated kinases. These effects change cellular metabolism, intercellular lipid trafficking, and cell behavior (migration, phagocytosis, angiogenesis, immune phenotype) in a manner that is highly dependent on tissue type, duration of hypoxia, and metabolic context, with important implications for disease progression. In acute hypoxia, CD36 regulation often contributes to rapid metabolic adaptation, whereas in chronic hypoxia, it may promote sustained lipid accumulation, inflammation, maladaptive remodeling, or tumor progression. In this review, we aim to highlight the regulation and function of CD36 in hypoxia in different tissues, conditions, and metabolic states, emphasizing the distinct roles of CD36 in acute versus chronic hypoxia and its potential therapeutic implications. For example, hypoxia typically downregulates CD36 in ischemic cardiomyocytes to limit lipotoxic fatty acid influx, whereas in hepatocytes, adipocytes, and tumor-associated macrophages, it upregulates CD36-mediated lipid uptake to sustain steatotic, inflammatory, or protumorigenic metabolism, illustrating the tissue-specific nature of this regulation. Full article

We propose a lattice structure and space group symmetry, Pmmm (No. 47), for the QCD condensate ground state, whose Wyckoff positions are occupied by the four light quarks and antiquarks $u$, $d$, $\tilde{u}$, $\tilde{d}$. These serve as the fundamental building blocks of both the condensate lattice ground state and the baryonic and leptonic particle excitations embedded within it as topological defects of the nominal Wyckoff occupation, offering a more structured alternative to the QCD instanton liquid picture. Building on Bloch quark wave solutions of a tight-binding Hamiltonian defined on this lattice, we propose a generalization of Einstein’s Equivalence Principle: composite particles embedded in the lattice and propagating by tunnelling cannot distinguish acceleration by gravity, the strong, weak, or electromagnetic forces, or curvature of the lattice itself, arising from local variation in unit cell shape. We derive an eight-by-eight tight-binding Hamiltonian that decouples into two four-by-four blocks separating the quark and antiquark sectors. Electrons, positrons, protons, neutrons, deuterons, and α-particles are embedded in the lattice as defect-induced deviations from the nominal Wyckoff occupation, with their spin and helicity emerging structurally from this picture. We further propose that the lattice’s unit cells carry a small nonzero rest mass, whose collective gravitational effect across a galactic halo may account for the discrepancy between visible mass and rotation curves, identifying the Pmmm condensate as a dark matter candidate. Finally, we outline a mechanism near black hole horizons by which local melting of the condensate lattice followed by quark reactions that conserve the number and flavor of the quarks could yield a new route to baryon asymmetry. We propose a framework that goes several steps beyond the Standard Model by introducing a Pmmm space group unit cell for the QCD condensate ground state, built from the four light quarks and antiquarks $u$, $d$, $\tilde{u}$, $\tilde{d}$. We further propose that topological defects of the Pmmm condensate lattice are the geometric origin of particle excitations. Full article

Despite the growing use of brief self-report measures of creativity in digital higher education, no Polish adaptation of the Self-Rated Creativity Scale (SRCS) has been psychometrically evaluated. The present study translated and evaluated the Polish SRCS as an online assessment instrument for higher education. The sample comprised 406 university students studying in Poland (age range = 18–57 years; M = 22.04, SD = 4.01; 72.4% women) from artistic and non-artistic majors. The sample was randomly divided for exploratory factor analysis (EFA; n = 203) and confirmatory factor analysis (CFA; n = 203). Participants completed the Polish SRCS, the Openness subscale of the IPIP-NEO-PI-R, and the Cognitive Flexibility Scale. In the initial 12-item EFA, the six retained items had primary pattern loadings of 0.717–0.819; in the re-estimated brief solution, primary loadings ranged from 0.688 to 0.842 with negligible secondary loadings. CFA favored correlated two-factor models over one-factor models for both the full and brief versions, with excellent fit for the 6-item model (CFI = 1.000, RMSEA = 0.000, SRMR = 0.017). Internal consistency was good (Cronbach’s α = 0.80–0.84; McDonald’s ω = 0.80–0.84), scalar invariance was supported across gender and study major, and correlations with openness and cognitive flexibility ranged from r = 0.34 to 0.44 (all p < 0.001). The 6-item Brief Polish Self-Rated Creativity Scale (BSRCS-6_PL) appears to be a reliable and efficient measure of creativity-related self-beliefs for online research and group-level screening in higher education; however, its educational utility requires direct implementation and predictive validity studies. Full article

Tetrabromobisphenol A mono(2-hydroxyethyl) ether (TBBPA-MHEE) is an important byproduct during the production of tetrabromobisphenol A (TBBPA) and its related derivatives. Although it has been detected in aquatic environments, its in vivo developmental toxicity and underlying mechanisms remain poorly understood. In this study, zebrafish were used as a model organism to evaluate the early developmental toxicity, neurobehavioral toxicity, and candidate molecular responses associated with TBBPA-MHEE. The 96 h median lethal concentration (96 h-LC₅₀) of TBBPA-MHEE for zebrafish embryos/larvae was 1.684 mg/L. Sublethal nominal exposure concentrations (2, 20, and 200 μg/L) caused developmental abnormalities, including reduced body length, pericardial edema, impaired swim bladder development, and significantly inhibited spontaneous motor activity as well as the response to light–dark transition and mechanical stimulation. Transgenic reporter assays further showed shortened motor neuron projections, reduced brain-region fluorescence in Tg(gad1b:mCherry) larvae, and downregulated the expression of neurodevelopment-related genes. Network toxicology analysis suggested that MTOR, SRC, MAPK3, and GSK3B were identified as candidate targets potentially associated with TBBPA-MHEE-induced neurotoxicity, with significant enrichment of the ErbB signaling pathway and possible perturbation of PI3K/Akt/mTOR-related responses. In addition, TBBPA-MHEE exposure increased the accumulation of reactive oxygen species (ROS) in the larval brain and induced inflammatory and apoptotic responses. Quercetin intervention partially alleviated ROS accumulation and inflammation and improved the developmental and motor phenotypes. Collectively, these findings indicate that TBBPA-MHEE induces neurodevelopmental toxicity in zebrafish, possibly associated with altered transcriptional responses related to ErbB signaling and the PI3K/Akt/mTOR axis, accompanied by oxidative stress, inflammatory responses, and apoptosis-related events. Because exposure concentrations were not analytically verified, all treatment levels are reported as nominal concentrations. This study provides experimental evidence for the toxicological assessment and environmental risk evaluation of TBBPA derivative pollutants. Full article