Search Results (6,971)

Warfarin is one of the most used oral anticoagulants, even after the arrival of non-vitamin K oral anticoagulants. Warfarin has been implicated in approximately one-third of emergency hospitalizations for adverse drug events among older adults in national U.S. data. Warfarin dose has been shown to vary between patients with up to 10 times the standard dose. This variability is due to multiple factors such as age, gender, diet, body size, co-medications, and the genetic background of the patient, where the genetic background accounts for 50% of warfarin dose variability among Europeans. Sadly, these findings do not apply to Caribbean Hispanic populations such as Puerto Ricans due to them having an admixed genetic profile. In the field of pharmacogenomics (PGx), the utility of machine learning (ML) has been used to predict individual drug responses by analyzing complex genetic and clinical data, which helps personalize medicine by tailoring treatments to a patient’s genetic makeup. Inclusion of ethno-specific variants has demonstrated improvement on the application of ML to a specific population. This study compares eight ML methods to predict warfarin sensitivity in Puerto Rican Caribbean Hispanics. This study is a secondary analysis of genetic and clinical data from 217 Puerto Rican patients treated with warfarin for thromboembolic disorders. After quality control filtering and exclusion of participant records with incomplete genetic and clinical data, 146 participants are retained for analysis. Data are divided into 65% and 35% to be used as training and test sets. Model performance is determined by comparing the precision and accuracy metrics, computed through the corresponding confusion matrixes. A gradient boosting classifier (GDB) achieves the highest overall accuracy (0.7500) and weighted precision of (0.7642); however, sensitivity for detecting warfarin-sensitive patients remains low. Feature importance analysis suggests that rs202201137 could contribute to model predictions, although overall detection of warfarin-sensitive individuals remains limited. Full article

Background/Objective: Di-2-ethylhexyl phthalate and its bioactive metabolite mono-2-ethylhexyl phthalate (MEHP) are ubiquitous endocrine-disrupting chemicals implicated in carcinogenesis. However, the molecular mechanisms linking MEHP exposure, host genetic susceptibility, and prostate cancer progression remain incompletely defined. Methods: We integrated transcriptomic profiling of MEHP-exposed human prostate epithelial cells with a genetic association study of 630 patients with prostate cancer receiving androgen deprivation therapy. MEHP-responsive genes were identified from public microarray datasets and subjected to pathway enrichment analyses. Germline single-nucleotide polymorphisms (SNPs) in MEHP-regulated genes were evaluated for their association with progression-free survival, overall survival, and cancer-specific survival. The clinical and functional relevance of the key genes was further assessed using large-scale public prostate cancer expression datasets. Results: MEHP exposure induced widespread transcriptional reprogramming, prominently suppressing focal adhesion and cell–matrix interaction pathways. Genetic analyses identified multiple prognostically relevant SNPs within MEHP-responsive genes, with anoctamin 4 (ANO4) variants showing consistent associations across all clinical endpoints. The minor allele of rs17485225 in ANO4 was significantly associated with reduced all-cause and prostate cancer-specific mortality. Pooled analyses revealed reduced ANO4 expression levels in prostate cancer tissues and improved survival in patients with high ANO4 expression levels. Pathway analyses linked low ANO4 expression levels with enhanced cell cycle activity and compromised cell adhesion. Conclusions: Our findings suggest that ANO4 may act as a mediator of MEHP-associated prostate cancer progression and support a gene–environment interaction model in which environmental toxicant exposure and germline variation converge on focal adhesion dysregulation to potentially contribute to aggressive disease. Full article

Polypropylene fibers provide an innovative solution for enhancing the crack resistance of tunnel lining segments. However, existing macro-models obscure the distinct effects of fibers on the mortar and ITZ, while explicit meso-modeling remains computationally prohibitive. This study develops a multi-scale modeling framework to investigate PFRC segment fracture under bending. The framework integrates a 3D meso-scale module for calibrating fracture-related material properties, a 3D macro-scale module for predicting global displacements, and a 2D meso-scale module for resolving local fracture processes. A full-scale bending test was performed to validate the framework and to examine the effects of fiber content at both scales. Both the full-scale test and numerical simulations show that the segment response exhibits three stages: elastic, damage development, and cracking at the design load. Numerical simulations further reveal that an optimal fiber content of 0.4% reduces the vertical displacement at the load point by 9.8% and the horizontal displacement at the edge point by 2.9% relative to the fiber-free case. Meso-scale simulations show that 0.4% fibers decrease the bottom crack width from 0.0868 to 0.0770 mm (−11.29%) and limit internal crack connectivity. Although fibers may locally promote ITZ cracking due to reduced mortar–aggregate bonding, a strengthened mortar matrix suppresses crack penetration and connected crack networks. A pronounced high-damage peak in the ITZ near the failure threshold confirms the ITZ as the governing weak link; therefore, further improvements may require ITZ-strengthening strategies. Full article

Hypertension-induced renal injury is a major cause of chronic kidney disease and end-stage renal disease. Increasing evidence indicates that disease progression is not driven solely by hemodynamic stress but results from the interplay of multiple molecular mechanisms. In this review, we propose a stage-structured and network-based framework to systematically integrate current mechanistic insights into hypertension-induced renal injury. Early events, mainly including endothelial dysfunction and renal hypoxia, establish a permissive microenvironment for disease progression. These insults activate amplifying pathways such as the renin–angiotensin–aldosterone system (RAAS) overactivation, oxidative stress, immune and inflammatory responses, and sympathetic nervous system hyperactivity, which interact through cross-talk and positive feedback loops. Ultimately, these signals converge on fibrotic programs characterized by epithelial–mesenchymal transition (EMT), fibroblast activation, and extracellular matrix deposition, leading to irreversible structural remodeling and functional decline. Furthermore, epigenetics, the gut–kidney axis, autophagy dysfunction and renal aging also contribute to this process. We highlight two critical and underappreciated aspects: the existence of a permissive ‘early-window’ dominated by endothelial dysfunction and hypoxia, which sets the stage for later amplification; and the hierarchical interplay between amplifying mechanisms where cross talk creates self-reinforcing loops that may explain therapeutic resistance. In addition, this review highlights emerging biomarkers for early diagnosis and disease monitoring, and discusses therapeutic advances that extend beyond blood pressure control to disease-modifying interventions that confer renoprotective effects. By integrating molecular mechanisms with diagnostic and therapeutic perspectives, this review provides a comprehensive framework for early detection and precision intervention in hypertension-induced renal injury. Full article

Cardiovascular diseases (CVDs) remain the leading cause of global mortality, with aortic pathologies such as atherosclerosis and thoracic aortic aneurysm posing significant risks due to their asymptomatic nature and potential fatal complications. This study investigates molecular mechanisms underlying CVDs by examining key cellular components of the aortic wall—vascular smooth muscle cells (VSMCs), fibroblasts, and macrophages—and their responses to low-density lipoproteins (LDLs). Using in vitro models, we analyzed phenotypic characteristics, LDL internalization capacity, and secretion/expression of pro-inflammatory mediators (IL-6, IL-8, IL-1β, CCL2) in primary VSMCs (from tunica intima and media), fibroblasts (977hTERT), and THP-1 macrophages. Fluorescence staining with BDP 630/650 revealed that all cell types internalize LDLs, with macrophages showing the highest lipid accumulation. ELISA and RT-qPCR demonstrated cell-specific patterns of cytokine secretion and gene expression, both in control conditions and after LDL exposure. The results indicate that VSMCs and fibroblasts, normally involved in vascular tone maintenance and extracellular matrix (ECM) synthesis, acquire pro-inflammatory features under pathological conditions, including increased secretion of IL-6, IL-8, and CCL2. Macrophages exhibited enhanced expression of the scavenger receptor CD36 and pro-inflammatory cytokines (especially IL-1β) after LDL treatment. Full article

The aim of this study was to investigate the effect of hemp protein addition on the structural, rheological, textural, color, and bioactive properties of gelatin hydrogels. Composite systems containing 0–20% hemp protein were analyzed to clarify the mechanism of interaction with the gelatin matrix and to determine whether hemp protein acts as a passive filler or an active structure-forming component. In all formulations, the gelatin concentration was kept constant at 5% (w/w), while hemp protein was added at increasing levels without replacing the gelatin phase, resulting in systems with increasing total solid content. The addition of hemp protein significantly enhanced water-holding capacity and gel strength, as confirmed by rheological measurements and texture profile analysis. Thermorheological analysis revealed a gradual transition from a classic thermoreversible gelatin gel to reinforced composite networks, with the viscoelastic response increasingly governed by the hemp protein structure at higher concentrations (15–20%). Frequency- and amplitude-sweep tests demonstrated improved mechanical stability and reduced frequency dependence. FTIR analysis indicated reorganization of hydrogen bonding and an increasing contribution of hydrophobic interactions related to the lipid fraction of hemp protein. Furthermore, the addition of hemp protein led to a marked increase in antioxidant activity (ABTS and FRAP) and significant changes in color parameters. These results demonstrate that hemp protein functions as an active structural and functional component in gelatin hydrogels, enabling the development of materials with tailored mechanical properties and enhanced bioactivity. Full article

Artocarpin, a prenylated flavonoid isolated from Artocarpus altilis heartwood, has emerged as a promising multi-targeted bioactive compound for combating UV-induced skin aging. This review provides a comprehensive overview of the molecular mechanisms and photoprotective efficacy of artocarpin across in vitro, in vivo and clinical study, based on the peer-reviewed literature published between 2012 and 2025, retrieved from PubMed, Scopus, and Web of Science. Delivery strategies designed to overcome the inherent physicochemical limitations of artocarpin on skin penetration are also discussed. Artocarpin demonstrates antioxidant effects through both direct free radical scavenging and activation of the Nrf2-ARE pathway, providing sustained cellular defense. Its anti-inflammatory properties target multiple signaling cascades, including the NF-κB and MAPK pathways, effectively mitigating UV-induced inflammatory response. The compound maintains dermal matrix homeostasis by inhibiting matrix metalloproteinase-1 (MMP-1) expression while preserving collagen synthesis and fibroblast mechanical function. Additionally, artocarpin exhibits selective apoptosis modulation, being cytoprotective in normal keratinocytes while acting as pro-apoptotic in damaged or abnormal cells, thereby supporting tissue homeostasis. It also inhibits melanogenesis through anti-inflammatory mechanisms rather than direct tyrosinase inhibition. Furthermore, artocarpin has been shown to induce autophagic cell death in certain cell lines; however, its role in UV-induced skin damages remains to be clarified. Despite these promising biological activities, the poor water solubility (<0.1 mg/mL) and high lipophilicity (log P ≈ 5) of artocarpin significantly limit its skin penetration. Lipid-based delivery systems, including liposomes, transfersomes, ethosomes, and nanostructured lipid carriers (NLCs), are presented as effective strategies to enhance transepidermal delivery, with each system offering distinct mechanistic advantages. Further investigations should prioritize the safety of artocarpin within each delivery system, as well as the synergistic co-encapsulation with complementary natural antioxidants to simultaneously target multiple mechanisms involved in UV-induced skin damage, thereby broadening its application in the cosmeceutical industry. Full article

This study presents an efficient, environmentally benign approach for synthesizing chitosan-entrapped titanium dioxide (TiO₂) nanocomposites utilizing aqueous orange peel extract playing its role in reduction and stabilization of the nanoparticles and exploring its anticancer activity in vitro. TiO₂ nanoparticles were initially synthesized via a modified sol-gel method incorporating the orange peel extract. Subsequently, these nanoparticles were entrapped within a chitosan matrix. The orange peel extract was thoroughly characterized using analysis of phytochemicals present, and Gas Chromatography–Mass Spectrometry (GC–MS) analysis of a reconstructed methanolic extract to identify potential biomolecules responsible for the reduction and capping processes. The synthesized chitosan-entrapped TiO₂ nanoparticles were subjected to comprehensive characterization using various analytical techniques, like UV–visible spectroscopy, Dynamic Light Scattering (DLS) and Zeta Potential analysis, X-ray Diffraction (XRD), FTIR, High-Resolution Scanning Electron Microscopy (HR-SEM) and Energy-Dispersive X-ray Spectroscopy (EDAX). An absorption peak was observed at 296 nm, a hydrodynamic diameter of 400 nm, a+ 35.88 mV zeta potential, and an SEM image showing a diameter in the range of 300–645 nm, indicating polymer entrapment with enhanced size. Brine shrimp assay, MTT assay using normal fibroblasts, 3T3-L1, and zebrafish embryo assay were done to observe the biocompatibility of the synthesized nanostructure. The concentration of 50 μg/mL was found to be inert in both in vitro and in vivo. Furthermore, cervical cancer cells, SiHa, were treated with the nanoparticles to exhibit their cancer-killing capability with an IC₅₀ value of 30.74 μg/mL. The results demonstrate the effectiveness of orange peel extract as a sustainable agent for TiO₂ nanoparticle synthesis and the successful formation of a stable chitosan-entrapped nanocomposite. This approach offers a promising pathway for producing functional metal oxide nanomaterials with reduced environmental impact and enhanced properties for diverse biomedical applications. Future studies using other types of cancer cells and animal models for cancerous tumors need to be explored. Full article

In this study, red cabbage-based intelligent/active composite films loaded with different concentrations of clove essential oil were prepared using red cabbage slurry as the matrix, polyvinyl alcohol as the binder, glycerol as the plasticizer, and Tween 80 as the emulsifier via the casting method. The physicochemical properties, color response behavior, and antioxidant and antibacterial activities of the films were systematically evaluated and their application in fish freshness monitoring was further investigated. The results showed that the incorporation of clove essential oil significantly enhanced the antioxidant and antibacterial properties of the films and optimized their mechanical properties within a certain concentration range. Although high concentrations slightly reduced the pH response sensitivity of the films, all composite films exhibited significant color-changing ability, achieving a visible transition from red to yellow-green within the pH range of 2–12. In fish preservation experiments, the composite films not only reflected the freshness status of fish in real time through color changes but also effectively inhibited the increase in total volatile basic nitrogen, total bacterial count, and pH value, thereby delaying spoilage. In this study, a green packaging material with an intelligent indicating function was successfully developed, providing a novel solution for the quality monitoring of high-value aquatic products. Full article

This study investigates the synergistic effect of functionalized carbon nanotubes (CNTs), graphene nanoplatelets (GNPs), and carbon fibers (CFs) on the mechanical performance of cement-based composites through a multivariate optimization approach. All carbon allotropes were covalently functionalized via acid treatment to enhance dispersion and interfacial bonding with the cement matrix. A face-centered central composite design (FCCD) combined with response surface methodology (RSM) was employed to systematically evaluate the influence of the three reinforcements, each varied between 0.033 wt.% and 0.067 wt.%, with a total carbon content not exceeding 0.2 wt.% of cement. The statistical analysis revealed a negligible correlation between reinforcement content and flexural strength (explained variance ≈ 1%), whereas fracture energy and compressive strength showed stronger dependencies, with explained variances of 25% and 66%, respectively. The maximum experimental fracture energy reached 18.1 J, corresponding to an increase of nearly 800% compared to plain cement, obtained at the highest combined reinforcement content. Compressive strength improved up to 48 MPa (≈32% higher than the reference), with the model predicting potential enhancements up to 40% under optimized compositions. The regression analysis highlighted the dominant role of quadratic and interaction terms, indicating that mechanical performance is governed more by synergistic effects than by the linear contribution of individual components. These findings demonstrate that controlled co-dispersion of multiple functionalized carbon allotropes enables significant enhancement of cement mechanical properties at very low total carbon contents, providing a cost-effective strategy for the design of high-performance cementitious composites. Full article

Catalytic ozonation often suffers from a low ozone utilization rate and incomplete mineralization of organic pollutants. To address these challenges, we designed and prepared a novel catalyst via a one-step thermal polymerization method, anchoring single-atom manganese on a glucose-derived carbon network-modified C₃N₅ framework (Mn/C-C₃N₅). Aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC-HAADF-STEM) on an FEI Titan Themis Z microscope confirmed the atomic dispersion of Mn sites, while Raman spectroscopy using a Renishaw inVia Reflex laser micro-Raman spectrometer verified the successful incorporation of a graphitic carbon network within the C₃N₅ matrix. Moreover, electrochemical analyses, including electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) performed on a Bio-Logic SP-150 electrochemical workstation, demonstrated that the integration of the conductive carbon matrix substantially enhanced the interfacial charge transfer capability. The optimized Mn/C-C₃N₅ catalyst demonstrated exceptional performance in phenol mineralization, achieving a 97% total organic carbon (TOC) removal within 60 min, a remarkable improvement compared to pristine C₃N₅ (30%). Furthermore, the catalyst exhibited excellent operational stability, preserving more than 95% of its original activity over five repeated runs. Mechanistic investigations, including electron paramagnetic resonance (EPR) spectroscopy and radical quenching experiments, revealed that the Mn/C-C₃N₅ system accelerated the generation of multiple oxidizing radicals (•O₂⁻, ¹O₂, and •OH), with •OH identified as the predominant reactive species responsible for complete mineralization. This work establishes an integrated catalytic platform and provides fundamental insights into electronic structure modulation for designing advanced oxidation catalysts. Full article

The implementation of Australia’s 2024 waste export ban has increased pressure on domestic recycling systems, resulting in an additional 650,000 tonnes of waste annually. This emphasises the urgent need for high volume landfill waste material recovery, especially in sustainable construction materials such as geopolymer concrete (GPC). Geopolymer concrete is recognised as a sustainable construction material; however, the scientific understanding of the compatibility between landfill waste and the geopolymer matrix, particularly under harsh environments, remains unknown. This paper presents an experimental investigation on five types of geopolymer concrete (GPC) mixes. The study included a control mix with natural stone chips and four additional mixes in which stone chips were 100% replaced with waste materials including shredded plastic, cardboard, crushed glass, and granular crumb rubber as fine aggregates. The mechanical performance, durability behaviour and stress-strain characteristics of these mixes were evaluated. Concrete samples were exposed to normal air, a saline environment with 10% salinity, and a hygrothermal environment at 60 °C and 98% humidity for four months to assess durability performance. The results demonstrate that GPC is compatible with landfill waste aggregates and enables the production of a workable mixture. As a result of saline environments, waste aggregate-based geopolymer concrete reduces compressive strength by 15%, while natural stone chips-based geopolymer concrete decreases strength by 45% during the same period, indicating that waste aggregates are more appropriate than natural aggregates in marine environments. Although the inclusion of waste aggregates reduces the strength and stiffness of the GPC, the materials continue to meet the mechanical property requirements for non-structural applications. A theoretical model considering the elastic modulus, ultimate strength and corresponding strain has been developed to predict compressive stress–strain behaviour of waste-based GPC. High modulus aggregates, typically ranging from approximately 10.0 GPa to 85.0 GPa such as stone chips and glass sand demonstrate parabolic stress–strain behaviour. In contrast low modulus aggregates, generally ranging from 1.0 GPa to 5.0 GPa including plastic, cardboard, and crumb rubber, exhibit a bilinear stress–strain response. Full article

Endothelial cells are key regulators of vascular homeostasis, and their dysfunction plays a central role in the development of atherosclerosis and other cardiovascular diseases. Multinucleated variant endothelial cells (MVECs) have been described in pathological vascular regions; however, their functional properties remain poorly characterized. The aim of the present study was to compare lipid handling, inflammatory activation, barrier-associated features, and secretory profiles of typical endothelial cells (TECs, EA.hy926 line) and MVECs under low-density lipoprotein (LDL) exposure. MVECs were generated by polyethylene glycol-induced fusion of EA.hy926 cells and incubated with LDL under standardized conditions. Intracellular cholesterol accumulation was assessed biochemically, cytokine secretion was quantified by ELISA, gene expression of inflammatory, endothelial, junctional, and vasoactive markers was analyzed by quantitative real-time PCR, and the endothelial secretome was characterized using data-independent acquisition liquid chromatography–tandem mass spectrometry (DIA-LC-MS). MVECs demonstrated enhanced cholesterol accumulation compared with TECs following LDL exposure. At the transcriptional level, MVECs were characterized by elevated basal expression of proinflammatory markers, including IL1B, IL6, and NFKB1, and showed a markedly amplified IL6 and IL8 response to LDL. In parallel, MVECs exhibited reduced expression of genes associated with antioxidant defense (SOD1), barrier integrity (TJP1), and hemostatic function (VWF). Consistent with transcriptional data, mass spectrometry-based secretome analysis revealed decreased secretion of von Willebrand factor (vWF), vascular endothelial growth factor C (VEGFC), and endothelin-1 (EDN1) by MVECs, accompanied by increased secretion of tissue-type plasminogen activator (t-PA). Functional enrichment analysis of secretome-associated proteins highlighted pathways related to extracellular matrix–receptor interaction, focal adhesion, cell adhesion molecules, complement and coagulation cascades, and leukocyte transendothelial migration. In contrast, TECs demonstrated a more pronounced transcriptional response in EDN1, consistent with their role in vascular tone regulation. Immunocytochemical analysis further revealed altered subcellular distribution of the tight junction protein ZO-1 in MVECs, indicating junctional destabilization. Taken together, these results indicate that MVECs represent a distinct endothelial phenotype characterized by enhanced lipid accumulation, sustained proinflammatory activation, altered secretory signaling, and reduced barrier and hemostatic potential. Such features suggest that MVECs may contribute to the maintenance of chronic endothelial dysfunction and vascular inflammation under conditions of lipid overload. Full article

The growing demand for environmentally responsible lubricants motivates the use of bio-based base stocks and benign solid additives. This study assesses the tribological performance of two Amazonian vegetable oils, Carapa guianensis (andiroba) and Copaifera spp. (copaiba resin) and a paraffinic mineral oil (PNL30) formulated with different zinc oxide (ZnO) particles, namely nanocrystals and microcrystals, at 0.01, 0.05, and 0.10 wt.%. Reciprocating sliding tests, coupled with 3D profilometry, viscosity, and sedimentation analyses, were used to link dispersion stability with friction and wear responses. A preliminary stability screening constrained the practical loading window to ≤0.10 wt.% for reproducible suspensions. Performance depended on the interplay between particle type and base-oil chemistry. Andiroba exhibited the most pronounced gains, with ZnO microcrystals near 0.05 wt.% delivering the best friction outcomes and the largest wear reductions (up to ~35%). In copaiba resin oil, nanocrystals produced small, sometimes non-significant improvements, whereas microcrystals tended to worsen wear consistent with abrasive third-body effects in a less polar matrix. In PNL30, the overall benefits were modest: nanocrystal additions generally increased wear, whereas microcrystals particularly at the highest loading 0.10 wt.% achieved a 36.4% reduction in SWR, representing a measurable and statistically significant improvement in wear resistance. These results highlight that eco-efficient lubricant design should co-optimize particle characteristics and dosage with base-oil polarity and film-forming tendencies, prioritizing dispersion stability alongside tribological targets. Full article

Postbiotics produced by beneficial bacteria are emerging as safe dietary approaches to intestinal inflammation. We evaluated intestinal bacterial metabolites (IBM), a cell-free fermented soybean extract generated by co-culturing 31 Lactobacillus/Bifidobacterium-related strains, for prophylactic protection in 3% dextran sulfate sodium (DSS)-induced colitis. Male C57BL/6NJ mice received oral IBM (0.4 or 2 mL/kg/day) or vehicle for 7 days before and during 7 days of DSS. Disease activity index (DAI), colon length, and histopathology were assessed, and endpoint serum cytokines were quantified by a multiplex bead assay. DSS-independent responses were examined in healthy mice after 7 days of IBM by rectal RNA sequencing and cecal 16S rDNA profiling, and direct epithelial effects were tested in HCT-116 and DLD-1 cells treated with 2% IBM. IBM attenuated colitis, improving DAI, preventing colon shortening, and ameliorating histopathology, with decreased IL-23 and IL-17A and increased IFN-β and GM-CSF. Rectal transcriptomics showed modulation of circadian programs, upregulation of mucosal/barrier genes, and reduced extracellular-matrix remodeling signatures. IBM increased junctional proteins and barrier-related transcripts in vitro and shifted the microbiota, increasing Lactobacillus and Roseburia while decreasing Streptococcus and Staphylococcus. These coordinated clinical, immunological, transcriptomic, epithelial, and microbiome changes support prophylactic protection by IBM against DSS colitis. Full article