Search Results (29,039)

Developing eco-friendly metal oxide nanoparticles (NPs) with plant-based reducing and stabilizing agents offers a sustainable alternative to traditional chemical methods. Nonetheless, the detailed mechanisms by which phytochemicals influence NPs formation, antimicrobial properties, and cytocompatibility remain poorly understood, especially in systems mediated by Vaccinium. This study aimed to synthesize TiO₂ NPs and ZnO NPs using Vaccinium corymbosum (blueberry) extract, analyze their structural and surface characteristics, assess their antimicrobial effectiveness and cytotoxicity, and explore potential molecular mechanisms through computational docking. ZnO NPs were produced via alkaline precipitation (pH 12) from ZnCl₂, while food-grade TiO₂ was mixed with blueberry extract. A comprehensive characterization was carried out using techniques like X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, transmission and scanning electron microscopy (TEM/SEM), dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC) for polyphenol profiling. The antimicrobial activity was tested against Escherichia coli and Salmonella Typhimurium, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined. Cytotoxicity was assessed using Gallus gallus domesticus leukocytes and Artemia salina bioassays, and molecular docking simulations were performed to examine polyphenol interactions with the bacterial DNA gyrase subunit B (GyrB). XRD analysis confirmed the presence of wurtzite ZnO (with a crystallite size of 18.2 nm) and anatase TiO₂ (12.8 nm after functionalization). HPLC identified key polyphenols, including quercetin, cyanidin, malvidin, and cyanidin-3-glucoside, with patterns indicating stronger adsorption onto TiO₂ NPs surfaces. ZnO NPs showed higher antimicrobial effectiveness (>90% inhibition at 2 mg/mL; MIC 0.5–1 mg/mL) compared to TiO₂ (72% inhibition at 16 mg/mL; MIC 8–16 mg/mL). Cytotoxicity results indicated concentration-dependent effects. Molecular docking simulations revealed favorable binding energies (−6.2 to −8.4 kcal/mol) for blueberry polyphenols with GyrB, suggesting potential synergistic antimicrobial effects and ROS production. The study highlights a successful green synthesis of bioactive TiO₂ NPs and ZnO NPs using Vaccinium corymbosum extract, where polyphenol surface functionalization enhances both colloidal stability and biological activity. This comparative research offers mechanistic insights into how polyphenol-coated NPs work and supports the development of eco-friendly antimicrobial oxide nanomaterials. Full article

Antibody–drug conjugates (ADCs) are a rapidly evolving class of oncology therapeutics that enable precise delivery of potent cytotoxic agents to tumor cells while minimizing systemic toxicity. While HER2-targeted ADCs such as trastuzumab deruxtecan (T-DXd) in HER2-mutant, Datopotamab deruxtecan (Dato-Dxd) in EGFR-mutant, and telisotumumab vedotin (Teliso-V) in MET IHC 3+ expressing lung cancer have already established a clinical role in non-small cell lung cancer (NSCLC), multiple ADCs targeting alternative antigens, including additional TROP2 ADCs, HER3, MET, CEACAM5, B7-H3, Nectin-4, and others, are now in advanced clinical development. This review synthesizes the current evidence for non-HER2 ADCs in NSCLC, highlighting mechanisms of action, clinical efficacy, safety profiles, biomarker strategies, and emerging resistance mechanisms. Key safety concerns, including interstitial lung disease (ILD), ocular toxicity, and peripheral neuropathy, are emphasized alongside approaches for re-challenge following toxicity. We further discuss next-generation ADC platforms, including bispecific and conditionally activated constructs, as well as combination strategies with immunotherapy. Collectively, ADCs beyond HER2 are poised to reshape treatment paradigms in NSCLC, offering hope for patients with limited therapeutic options. This review identifies current gaps, highlights ongoing research priorities, and proposes practical considerations for integrating these therapies into clinical practice. Full article

Multiple mycotoxins in feed threaten animal health and food safety, demanding sustainable mitigation strategies. This study evaluated acid-modified mangosteen peel (AMP), an agricultural by-product, as a potential multi-mycotoxin adsorbent. Physicochemical characterization using scanning electron microscopy (SEM), Brunauer–Emmett–Teller (BET) surface area analysis, and Fourier transform infrared spectroscopy (FTIR) analyses demonstrated that acid modification increased surface area (1.9 to 9.03 m²/g), pore volume (0.005 to 0.027 cm³/g), and surface negativity, indicating enhanced adsorption properties. In vitro binding experiments assessed adsorption of aflatoxin B₁ (AFB₁), zearalenone (ZEA), ochratoxin A (OTA), T-2 toxin, deoxynivalenol (DON) and fumonisin B₁ (FB₁) under different pH conditions. AMP exhibited high adsorption efficiencies for AFB₁, ZEA, OTA, and T-2 toxin, particularly at pH 3, whereas DON and FB₁ showed limited binding. Adsorption behavior was dose-dependent and best described by Langmuir and Freundlich isotherm models. Simulated gastrointestinal digestion indicated stable binding of AFB₁ and ZEA under gastric conditions, with partial release of some toxins at neutral pH. Cytotoxicity assessment in porcine intestinal epithelial cells (IPEC J2) showed no apparent cytotoxic effects at 0.25–1 mg/mL. Therefore, AMP demonstrated improved multi-mycotoxin adsorption compared to the untreated material and showed no apparent cytotoxic effects in vitro within the tested concentration range, indicating its potential as a promising feed additive candidate. Full article

Bone metastasis remains a major cause of morbidity in advanced cancer, driven not only by tumor–bone crosstalk but also by profound immune remodeling within the marrow. Myeloid-derived suppressor cells (MDSCs), including polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subsets, are increasingly recognized as central effectors of this process, integrating inflammatory signals with metabolic and stromal cues to enforce immune suppression and support skeletal colonization. In this review, we synthesize current evidence that bone metastases transform the bone marrow into an “MDSC amplifier,” where vascular and endosteal niches, CXCL12-rich stromal compartments, hypoxia, and adipocyte-derived lipids collectively promote MDSC recruitment, persistence, and functional maturation. We discuss the dominant suppressive programs deployed by MDSCs in bone (e.g., arginase-1 activity, reactive oxygen/nitrogen species, and checkpoint ligand expression), and how these mechanisms converge to impair cytotoxic T-cell and NK-cell responses while fostering regulatory T-cell dominance. Importantly, because the marrow is a hematopoietic organ, bone lesions can also generate systemic consequences through myeloid spillover, providing a mechanistic basis for reduced responsiveness to immune checkpoint blockade in bone-dominant disease. We then evaluate pharmacologic strategies to target MDSCs in the context of bone metastasis, including approaches that block trafficking (e.g., CCR2/CXCR2 axes), deplete or reprogram suppressive myeloid states (e.g., STAT3-directed strategies, differentiation therapy), and disrupt bone-resorptive feedback loops (e.g., receptor activator of NF-κB ligand (RANKL) inhibition and bisphosphonates), emphasizing rational combinations and sequencing to limit marrow toxicity. Finally, we highlight emerging single-cell and spatial profiling tools that can resolve bone-specific heterogeneity in MDSCs and guide biomarker-driven, mechanism-informed therapeutic development. Full article

The mezcal industry in Mexico generates substantial volumes of vinasse, a waste product rich in organic material and bioactive compounds, yet its environmental impact and potential valorization in the food and biotechnological field remain underexplored. This study presents a comprehensive physicochemical and functional characterization of mezcal vinasse derived from mezcal production, including antioxidant activity and cytotoxicity assessment. Proximate analysis revealed high moisture content (96%) and a carbohydrate-rich profile (87.58% dry basis), with notable fiber fractions predominantly composed of insoluble dietary fiber (9.10% dry basis). Low-molecular-weight carbohydrate analysis identified fructose (60.46%) and glucose (10.48%) as the major components, and the hydrolyzed sample showed a monomeric profile with arabinose (31.98%) and glucose (24.14%) as the predominant sugars. Vinasse was found to provide antioxidant activity, as assessed by DPPH (296.3 µmol TE/g) and ABTS (465.3 µmol TE/g) colorimetric assays. Undesirable and antinutritional compounds such as tannins (15.3 mg catechin/g), oxalates (14.6 mg sodium oxalate/g), hydroxymethyl furfural (HMF) (3830.0 mg/L), and furfural (160.0 mg/L) were also quantified, highlighting potential environmental and nutritional concerns due to its mutagenic character at high concentrations. Despite these challenges, vinasse exhibited no cytotoxicity in Caco-2 cells at tested concentrations (25 to 100 mg/mL of phenolic extract), suggesting feasibility for further biotechnological applications. Full article

CAR-T cell therapy remains ineffective in most solid tumours because effector cells infiltrate poorly, undergo exhaustion, and face antigen escape within an immunosuppressive microenvironment. To address this, we developed a hybrid framework that combines a mechanistic spatiotemporal model with machine learning for limited individual-level mechanistic personalisation under data constraints. At its core, we employed a reaction–diffusion–chemotaxis model describing functional and exhausted CAR-T cells, antigen-positive and antigen-negative tumour subpopulations, a chemoattractant, an immunosuppressive factor, and hypoxia. Gradient boosting combined with nested cross-validation was used to recover model-consistent latent-parameter pseudo-labels generated by a limited inverse problem. Within this surrogate-target setting, parameters characterising the tumour microenvironment and CAR-T cell exhaustion were reproduced most robustly, whereas antigen escape and individualised initial conditions were substantially less well constrained. As an auxiliary reference point, we also considered a direct empirical baseline for binary clinical outcomes. This baseline indicated that the observed clinical features contained a more stable signal for disease control than for objective response. A favourable response was associated with high CAR-T cell infiltration and cytotoxic potency, whereas resistance was linked to exhaustion, antigen escape, and a suppressive microenvironment. Overall, the proposed approach should be interpreted as an internally validated, hypothesis-generating proof-of-concept platform for mapping clinical features to mechanistically interpretable surrogate latent targets, rather than as evidence for validated recovery of true patient-specific biological parameters. Full article

Polybrominated diphenyl ethers (PBDEs), widely used as brominated flame retardants, are known to exert persistent adverse effects on the immune systems of humans and other organisms. Previous studies have demonstrated that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a prevalent congener, induces apoptosis, impairs phagocytic function, and triggers aberrant immune-inflammatory reactions in RAW264.7 macrophages via the induction of elevated intracellular reactive oxygen species (ROS). However, the underlying regulatory mechanism remains unclear. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is a key cellular defense system against oxidative stress. In this study, we investigated the role of the Nrf2/ARE pathway in BDE-47-induced macrophage immunotoxicity. Network toxicology analysis identified Nrf2 as a hub gene within the BDE-47-associated immunotoxicity network. Molecular docking and molecular dynamics simulations suggested a potential interaction between BDE-47 and the Keap1-Nrf2 complex, with moderate binding affinity. Experimental studies in RAW264.7 cells showed that BDE-47 exposure activated the Nrf2/ARE pathway, as evidenced by Nrf2 nuclear translocation and the differential upregulation of downstream genes (GCLC, GCLM, HO-1, NQO1, SOD1, and CAT). Importantly, Nrf2 knockdown via lentiviral shRNA or pharmacological inhibition with brusatol significantly exacerbated BDE-47-induced apoptosis and immune dysfunction, including enhanced pro-inflammatory cytokine production and impaired phagocytosis. These results demonstrate that Nrf2/ARE pathway activation represents an adaptive antioxidant response and contributes to limiting BDE-47-induced cytotoxicity and immune impairment in macrophages. Full article

Microplastics (MPs), i.e., plastic particles <5 mm, and nanoplastics (NPs), i.e., plastic particles <1 µm, are widespread in the environment. MPs and NPs (MNPs) have also been detected in human tissues. Environmental MNPs exhibit diverse physicochemical properties such as size, shape, and surface degradation. However, most experimental studies have used pristine MNPs, which poorly represent real-world conditions, and only a limited number of studies have focused on preparing environmentally relevant MNPs. Therefore, we focused on the key physicochemical properties of MNPs, particularly their shape, size, and surface degradation, using polyvinyl chloride (PVC) as the model polymer. In this study, fragment and spherical PVC-MNPs were utilized, and surface degradation was introduced through exposure to vacuum ultraviolet (VUV) radiation at a wavelength of 172 nm. Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) analysis revealed the formation of additional carbonyl groups after VUV exposure. We investigated the cytotoxic effects of the degraded and non-degraded PVC-MNPs on A549, Caco-2, and THP-1 cells. The results indicated that the degraded PVC-MNP-treated groups induced higher cytotoxic effects than those in the non-degraded groups. Notably, the degraded PVC-NPs induced stronger cytotoxicity than the degraded PVC-MPs. These findings highlight the potential health risks associated with environmental MNPs. Full article

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer Full article

RNA viruses exhibit high mutation rates, necessitating antivirals targeting conserved infection mechanisms. In this study, viral hemorrhagic septicemia virus (VHSV), a non-human pathogenic negative-sense RNA virus, was used as a surrogate model to enable high-throughput antiviral screening under reduced biosafety conditions. A recombinant VHSV expressing enhanced green fluorescent protein was used to screen 17,265 compounds, 2000 plant extracts, and 100 marine extracts. Among the candidates, the leaf extract of Phellodendron amurense Rupr. (PL extract) exhibited antiviral activity with low cytotoxicity (selectivity index ≈ 10). The extract reduced viral infectivity in a dose-dependent manner and showed cross-activity against snakehead rhabdovirus. Mechanistic analyses indicated that the PL extract acts primarily at early stages of infection. Virucidal assays demonstrated direct, time-dependent inactivation of viral particles, while pre-treatment reduced host cell susceptibility. Time-of-addition experiments confirmed that antiviral activity was restricted to early infection, suggesting interference with viral attachment or entry rather than intracellular replication. Fractionation revealed that activity was associated with the non-polar n-hexane fraction, implicating lipophilic compounds that may disrupt viral envelope integrity or membrane interactions. These findings suggest that P. amurense leaf extract is a promising candidate for broad-spectrum antivirals targeting conserved entry processes in enveloped RNA viruses. Full article

Oxicam derivatives, a class of nonsteroidal anti-inflammatory drugs (NSAIDs), are important scaffolds for developing biologically active compounds. In this study, arylpiperazine oxicam derivatives (PR24–PR50) were examined for membrane interactions, cytotoxic activity, cyclooxygenase inhibition, and potential binding to COX-2 protein. Membrane interactions were examined using differential scanning calorimetry (DSC) in phospholipid bilayers formed from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). All compounds altered the thermotropic properties of the lipid bilayer, showing concentration-dependent decreases in phase transition temperature, indicating incorporation to bilayer and partial disruption of lipid organization. Cytotoxicity, assessed using the MTT assay in breast cancer (MCF-7, MCF-7/DX), colorectal cancer (LOVO, LOVO/DX), and normal V79 cell lines, showed moderate effects, particularly against colorectal cancer cells. Cyclooxygenase inhibition was rather weak, with IC₅₀ values in the high micromolar range, indicating limited anti-inflammatory potential compared with reference COX inhibitors, although docking studies suggested possible interactions with the COX-2 active site. The obtained results indicate that the biological activity of the arylpiperazine oxicam derivatives is primarily associated with cytotoxicity and membrane effects rather than COX inhibition. These limitations should be considered in the design of future membrane-targeted bioactive compounds. Full article

Electrospun poly(ε-caprolactone) (PCL) membranes incorporating Triticum vulgare extract (TVE) were developed as biomimetic scaffolds for periodontal regeneration. Using a ternary solvent system, two experimental formulations (µF-P10 and µF-P10T1) were fabricated and compared against a commercial dermal matrix. SEM analysis revealed bimodal fiber distributions (0.77–1.74 µm) and a surface porosity of 29.86% for TVE-loaded membranes, significantly higher than that of the commercial control (25.26%). FT-IR confirmed that the PCL chemical integrity was preserved, while mechanical testing showed that extract incorporation reinforced the matrix, increasing the Young’s modulus from 2.90 × 10³ Pa to 3.54 × 10³ Pa. UHPLC–MS identified ferulic acid as the primary bioactive component (90%), with release kinetics following a first-order model (R² = 0.998) over 48 h. Biological assays with human gingival fibroblasts (HGF) confirmed non-cytotoxicity (>70% viability). While both membranes supported healing, the µF-P10 formulation showed superior performance, with 80.2% proliferation and 60.6% wound closure, approaching control levels. These findings demonstrate that PCL-TVE electrospun scaffolds effectively combine favorable morphology and controlled release, offering a promising alternative for subepithelial connective tissue regeneration. Full article

The design of multitargeted drug candidates has recently emerged as a highly attractive area of research. Numerous heterometallic compounds have been developed to enhance both the biological efficacy and physicochemical properties of monometallic metallodrugs. Combining classical transition metals with established antitumor activity, such as Pt, Ru, and Au, with other metal-based fragments offers the potential to generate complex compounds with improved pharmacokinetic and pharmacodynamic profiles. Incorporating different bioactive metal cations within a single molecular framework may enhance anticancer activity through metal-specific interactions with distinct biological targets or through improved physicochemical characteristics of the resulting heteronuclear complexes. Recent studies have underscored the significant progress and promising impact of this multitargeted strategy, particularly in systems that combine ruthenium with other biologically active metal centers. This approach may enable selective biological targeting and help overcome drug resistance. This review compiles and analyzes reported ruthenium-based heteronuclear complexes, offering a comprehensive and critical assessment of recent advances in the rational design and synthesis of novel multinuclear compounds as potential chemotherapeutic agents. Particular emphasis is placed on understanding structure–activity relationships, mechanistic pathways, and the role of metal–metal and metal–ligand interactions in modulating biological responses. The findings summarized herein highlight the remarkable efficacy of a wide range of multinuclear ruthenium anticancer complexes and support the hypothesis that synergistic and/or cooperative interactions between distinct metal-based fragments can significantly enhance pharmacological performance, including improved selectivity, stability, and cellular uptake. Furthermore, emerging insights into their modes of action, resistance profiles, and potential for targeted delivery underscore their promise as viable alternatives to conventional therapies. Overall, this dynamic and rapidly evolving field is poised to inspire continued interdisciplinary research and drive the development of next-generation metallodrugs with improved therapeutic indices and clinical potential. Full article

Advanced gastric (GAC) or gastroesophageal junction (GEJAC) adenocarcinoma continues to carry a poor prognosis. Understanding GAC/GEJAC at the molecular level has provided a new understanding and the basis for individualized approaches to treatment. The current biomarker-driven therapy focuses on four areas: microsatellite instability (MSI), human epidermal growth factor receptor-2 (HER2), programmed death ligand-1 (PD-L1) combined positive score, and claudin 18.2 (CLDN18.2). However, because of improving technology, the focus has shifted to cancer cell-surface proteins and peptides. Each of these GAC/GEJAC subgroups provides a different treatment pathway. The agents utilized to treat advanced GAC/GEJAC include immune checkpoint inhibitors (ICIs), chemotherapy, monoclonal antibodies (mAbs), and antibody–drug conjugate (ADC) therapy, as well as bispecific antibodies (BsAbs), but they are certainly not limited to the above. Drug development has shifted in recent years to establish different mechanisms that are attempting more sophisticated and targeted approaches, such as BsAbs and ADCs. Meanwhile, the development of cytotoxics has tapered off. Along with these developments in drug therapy, more therapies directed at CLDN18.2, HER2, MSI, EGFR, HER3 and trophoblast cell-surface antigen 2 (TROP2) are underway. Here we review future areas in advanced GAC, including zanidatamab’s potential role in HER2-positive advanced GAC and deciphering the abundance of anti-CLDN18.2, extending beyond investigative therapies. Full article

The CD33 rs12459419 (C>T; Ala14Val) single-nucleotide polymorphism (SNP) has been reported to modulate treatment response and survival in pediatric patients with acute myeloid leukemia (AML) receiving gemtuzumab ozogamicin (GO), an anti-CD33 antibody linked to the cytotoxic compound calicheamicin. However, it remains unclear whether this SNP also affects CD33 expression on leukemic blasts. Moreover, its prognostic significance in adult AML patients treated with standard chemotherapy without GO has not been investigated. In this study, we retrospectively genotyped 184 adult AML patients who received standard induction chemotherapy for the CD33 rs12459419 SNP genotype and collected CD33 expression data. The observed genotype distribution was 46% (n = 85) CC, 43% (n = 79) CT, and 11% (n = 20) TT. CD33 expression was detected in significantly higher proportions of leukemic blasts in patients with the CC genotype than those with the TT genotype (p = 0.0009). A similar trend was observed between the CT and TT genotypes (p = 0.06). No significant differences in clinical outcome were detected among the three genotype cohorts. Grouping CC and CT genotypes together based on their similar CD33 expression and comparing them to patients with the TT genotype also revealed no differences in overall survival (OS), event-free survival (EFS), or relapse-free survival (RFS). Using a proportion of 90% CD33-positive blasts to define high versus low expression groups also failed to identify a meaningful impact on OS, EFS, or RFS, either across genotypes or independent of genotype. In conclusion, our findings indicate that the CD33 rs12459419 SNP does not affect outcomes or survival in adult AML patients receiving standard chemotherapy in the absence of GO. Furthermore, no association was seen between CD33 expression and clinical outcomes between the three genotypes. To our knowledge, this is the first study to investigate the prognostic impact of the CD33 rs12459419 SNP per se on outcome and survival in adult AML patients treated with chemotherapy without GO. Validation in larger patient cohorts is required to conclusively rule out a prognostic role of the CD33 rs12459419 SNP in AML. Full article