Search Results (406)

Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

Donor–acceptor (D–A) molecular systems are gaining increasing attention in cancer imaging and phototherapy due to their tunable optical properties and high photosensitizing efficiency. Encapsulation of such D–A molecules in nano-sized polymeric carriers can enhance the efficiency of antitumor therapy by passive tumor accumulation and controlled drug release. Here, we synthesized two D–A molecules—TTDCV and TTInd—based on triphenylamine with thiophene π-spacers and electron-withdrawing dicyanovinyl or indene-1,3-dione moieties. These molecules were used to preparate nanoparticles (NPs) via nanoprecipitation with amphiphilic polymers—poly(ethylene glycol)-block polylactide methyl ether (PEG-b-PLA) and polyethylene oxide-polypropylene oxide (PEO-PPO-PEO, Pluronic^® F-127). The resulting NPs had spherical morphology, core–shell structure and a tunable mean size (66–139 nm), depending on the polymer type used. Photothermal and photodynamic properties of the NPs were confirmed by intracellular reactive oxygen species generation and efficient heating even under 530 nm low dose irradiation (1 J/cm²), leading to substantial in vitro cytotoxicity against Sk-Br-3 and MCF-7 human breast cancer cells. Pluronic-encapsulated systems showed the strongest effect, reducing IC₅₀ values down to 0.99 µg/mL and achieving phototoxicity indices up to 22, accompanied by increased intracellular accumulation studied by confocal microscopy and flow cytometry. This study establishes relationships between molecular design, encapsulation approaches, and the biological performance of nanoparticles, enabling the rational engineering of D–A-derived nanotherapeutics for precision cancer treatment. Full article

The protective effect of arzanol, a natural prenylated phloroglucinol α-pyrone from the Helichrysum microphyllum subsp. tyrrhenicum, was investigated in HaCaT keratinocytes exposed to two inflammatory stimuli: lipopolysaccharide (LPS, 0.5–75 µg/mL), a component of gram-negative bacteria, and polyriboinosinic-polyribocytidylic acid (poly I:C, 0.5–50 µg/mL), a synthetic viral RNA analog. LPS and poly I:C significantly decreased HaCaT cell viability (18–93% reduction in the 5–75 μg/mL LPS range and 25% at 50 μg/mL poly I:C, MTT assay) and increased apoptosis and cell death (NucView 488 and propidium iodide assay) after 3 h and 24 h of exposure. Arzanol (1 h of pre-incubation, 5–25 μM) showed a significant protective effect against LPS and poly I:C-induced damage, preserving cell viability (25% of viability increase at 5 μg/mL LPS concentration, and 30% at 50 μg/mL of poly I:C) and decreasing apoptosis/cell death. Western blot analysis demonstrated the ability of arzanol (5 μM) to reduce the apoptotic protein Bax and the inflammatory cytokine IL-1β levels in HaCaT keratinocytes exposed for 3 h to 5 and 10 μg/mL LPS. Moreover, scratch assay showed the arzanol reparative effect on HaCaT cells. Our results qualified arzanol as a protective drug for dermatological applications in human skin diseases. Full article

Cutaneous lupus erythematosus (CLE) is an autoimmune disease in which type I interferon (IFN) has been well-established as a central pathogenic factor. It presents with diverse cutaneous manifestations that markedly impair patients’ quality of life. Therapeutic options for CLE remain limited and are often insufficient, highlighting the need for novel treatment strategies. The aryl hydrocarbon receptor (AHR) is a transcription factor that modulates immune responses and has recently attracted attention as a potential therapeutic target for autoimmune diseases. We previously confirmed that treatment of normal human epidermal keratinocytes with IFNα and Poly I:C upregulated the expression of the CLE-like inflammatory cytokines IFNκ, CXCL10, and IL6, as well as the B-cell activating factor. In the present study, we demonstrated by quantitative PCR and Western blotting that pretreatment with the AHR agonist tapinarof suppressed the upregulation of IFNκ and CXCL10. Mechanistically, we demonstrated that tapinarof suppresses IFNκ expression by inhibiting STAT1 phosphorylation in an AHR-dependent manner, thereby attenuating the nuclear translocation of ISGF3. Overall, we show that tapinarof suppresses CLE-like inflammation in human keratinocytes in an AHR-dependent manner, suggesting that it may represent a novel therapeutic agent for CLE. Full article

Icing phenomena on wind turbine blades and components are a major problem, causing downtimes that increase maintenance costs, reducing the blade’s lifespan, or in severe cases, even leading to component damage. A nanofiber-based bi-layer liquid-infused surface (BLIS) coating was prepared and characterized, combining good adhesion to wind turbine blades with low ice adhesion. The BLIS coating was produced by a new method combining electrospinning and a heat treatment step, containing a poly ethyl-2-cyanoacrylate (PECA)-based adhesive layer, a slippery layer of poly vinylidene fluoride-co-hexafluoropropylene (PVDF-HFP) copolymer, and an infiltrated perfluoropolyether lubricant. Thermogravimetric analysis (TGA) was used to ensure the thermal stability of the polymers in the nanofiber coating layers and to optimize the heat treatment process of the layers. Microstructural changes were studied by scanning electron microscopy (SEM) and surface roughness measurements. Contact angle measurements and sliding velocity tests on wind turbine blade segments at icing conditions of 0 °C and +5 °C indicate that the water sliding properties of the BLIS coating were improved compared to uncoated blades. In addition, coated blade segments showed a 50% lower ice adhesion strength than uncoated blades. Full article

The reduction of antibiotic use in livestock production necessitates the development of reliable in vitro models for evaluating alternative immunomodulatory compounds. In this study, porcine hepatocyte–non-parenchymal (NP) cell co-cultures and small intestinal explants exposed to pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), lipoteichoic acid (LTA), flagellin and polyinosinic–polycytidylic acid (poly I:C), were established as inflammatory models. Hepatic co-cultures exhibited pronounced inflammatory responses, with LPS and LTA increasing hepatocellular interleukin (IL)-4, IL-6, IL-8 and tumor necrosis factor (TNF)-α release, alongside elevated extracellular lactate dehydrogenase activity and maintained metabolic activity, indicating membrane perturbation without marked cytotoxicity. Poly I:C was found to be cytotoxic, accompanied by an altered cytokine profile. All PAMPs enhanced reactive oxygen species production without remarkable lipid peroxidation in most cases. In contrast, intestinal explants showed high resilience with unchanged viability and limited cytokine responses. Only IL-6 and IL-8 were detectable, with LPS elevating IL-8, while poly I:C and flagellin increased IL-6 levels. These findings demonstrate marked tissue-specific differences in inflammatory responsiveness. The hepatic co-culture model provides a sensitive system for studying robust inflammatory reactions, whereas intestinal explants are suitable for investigating moderate, gut-specific immune responses. In conclusion, these complementary models offer valuable tools for evaluating antibiotic alternatives in swine. Full article

Background: Glioblastoma (GBM) remains a lethal malignancy due to temozolomide (TMZ) resistance and limited drug penetration across the blood–brain barrier, largely driven by hyperactive DNA damage repair mechanisms such as poly (ADP-ribose) polymerase (PARP). To address these challenges, we developed folic acid-targeted PLGA–zein hybrid core–shell nanoparticles for the codelivery of the alkylating agent TMZ and the natural PARP inhibitor Ellagic acid (FA-TMZ/EA-PZ-CS NPs), thereby enabling simultaneous enhancement of drug delivery and suppression of chemoresistance pathways. Methods and Results: The dual-drug nanoplatform was fabricated using a double-emulsion solvent evaporation method and functionalized via EDC/NHS-mediated folic acid conjugation to promote receptor-mediated uptake. Physicochemical characterisation confirmed uniform spherical morphology, high colloidal stability, efficient drug encapsulation, and sustained biphasic drug release consistent with a core–shell diffusion mechanism. In LN229 glioblastoma cells, folic acid conjugation significantly enhanced cellular internalisation and cytotoxic efficacy compared to free drugs and non-targeted nanoparticles. Combination index analysis revealed strong synergism between TMZ and ellagic acid, resulting in markedly reduced IC₅₀ values. Mechanistic studies demonstrated apoptosis induction, increased DNA damage, inhibition of cell migration at sub-cytotoxic concentrations, and downregulation of PARP gene expression. Conclusion: Overall, this study establishes a targeted core–shell nanotherapeutic strategy that integrates chemotherapy with DNA repair inhibition to overcome TMZ resistance, offering a mechanistically sound strategy that serves as a foundational framework for future translational research. Full article

Superhydrophobic fiber films, as a typical superhydrophobic material, have advantages such as self-cleaning, non-wettability, and pollution resistance. They can be widely used in oil-water separation, antibacterial, anti-pollution, anti-icing, and self-cleaning fields. Traditional electrospun superhydrophobic fiber films face difficulties in fabricating fibers with large contact angles due to the non-Newtonian fluid flow and Taylor cone jet trajectory limitations. To address this challenge, this study develops a novel ultrasonic-magnetic field coupling electrospinning strategy for fabricating poly(methyl methacrylate)-polystyrene (PMMA-PS) fibrous films with enhanced superhydrophobicity. Physical, chemical, and contact angle measurements were used to analyze the morphology, composition, and hydrophobic properties of the fabricated films. The results showed that by controlling the blend ratio of PMMA and PS and optimizing the electrospinning process with ultrasonic vibration and magnetic field coupling, PMMA-PS fibers with better fiber refinement, closer spindle-shaped arrangements, and significantly increased roughness were successfully fabricated. When using 15% PMMA and 15% PS solutions, the static contact angle of the resulting fiber films reached 173.1°, demonstrating the best superhydrophobicity. The study suggests that optimizing the surface morphology of the nanofibers is an effective method to improve hydrophobicity and provides a new approach for fabricating superhydrophobic fiber films. Full article

In rheumatoid arthritis (RA), activated synovial tissue-derived mesenchymal stem cells (MSC) acquire a pathogenic phenotype and produce pro-inflammatory cytokines, chemokines, metalloproteinases, pro-osteoclastic and pro-angiogenic factors. The acquisition of this aggressive phenotype might be due to modified expression of micro-RNAs. We aimed to clarify the role of specific micro-RNAs (miR-146a-5p, miR-221-3p, miR-34a-3p, miR-150, miR-203a-3p and miR-155-3p) in an in vitro model of RA. Methods: Micro-RNA expression was determined in RA patient plasma and in commercial human synovial tissue-derived MSC-like cells stimulated with a panel of pro-inflammatory mediators (poly I:C, TNF-α, IL-1β, IFN-γ) to mimic the rheumatoid arthritis pathogenic setting. Next, unstimulated cells or TNF-α stimulated cells were transfected with miR-146a-5p mimic or miR-221-3p mimic. Protein and/or mRNA expressions of chemokines, cytokines, VEGF, MMPs and RANKL were determined by ELISA or qRT-PCR. MiR-34a-3p, miR-146a-5p, miR-150, miR-221-3p and miR-203a-5p were upregulated in RA patient plasma versus healthy controls. Moreover, synovial tissue-derived MSC-like cells expressed miR-146a-5p and miR-221-3p in response to pro-inflammatory mediators. Overexpression of miR-146a-5p increased CCL2 and CXCL8 expression and miR-221-3p increased IL-1β and IL-6 expression in synovial tissue-derived MSC-like cells stimulated with TNF-α. Conclusion: Overexpression of miR-146a-5p and miR-221-3p might favour inflammation and participate in rheumatoid arthritis pathogenesis. Full article

Inflammation is associated with metabolic alterations that can lead to the release of volatile organic compounds (VOCs) reflecting cellular biochemical activity. Profiling these volatile metabolites may provide insight into cellular responses to inflammatory stimuli, although their characterization in skin-derived cells remains limited. In this exploratory proof-of-concept study, we investigated the volatile metabolite profiles of human skin fibroblasts exposed to different inflammatory stimuli. Fibroblast cell lines were stimulated with polyinosinic:polycytidylic acid (Poly I:C), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharide (LPS) to model viral-, cytokine-, and bacterial-associated stress conditions. Headspace solid-phase microextraction coupled with comprehensive two-dimensional gas chromatography and time-of-flight mass spectrometry (HS-SPME-GC×GC-TOFMS) was applied to analyze volatile metabolites released from the cell cultures, enabling exploratory profiling of the fibroblast volatilome. A data-processing workflow including pairwise comparisons between experimental groups and statistical filtering was implemented to identify volatile features associated with the different conditions. Several VOCs were tentatively identified, mainly belonging to alcohol, ester, and hydrocarbon classes, and showed differential abundance patterns between stimulated and control samples. Multivariate analysis indicated a separation between stimulated and non-stimulated groups, suggesting stimulus-associated differences in the volatile profiles of fibroblast cultures. While these observations may reflect metabolic responses occurring under inflammatory stimulation, the chemical identity and biochemical origins of several detected features remain to be confirmed. All in all, this study demonstrates the feasibility of applying HS-SPME-GC×GC-TOFMS-based volatilome profiling to investigate stimulus-associated changes in fibroblast cultures. The detected VOC patterns should therefore be considered preliminary observations requiring further chemical characterization and independent validation. Future studies including larger sample numbers, complementary biological verification of the inflammatory response, and more physiologically relevant experimental models will be necessary to further assess the robustness and potential relevance of these volatile signatures in the context of inflammatory processes. Full article

Shoseiryuto (SST) is a Kampo medicine widely used to treat respiratory diseases. We previously showed that SST attenuates lipopolysaccharide (LPS)-induced tight junction (TJ) barrier disruption in human bronchial epithelial (16HBE) cells. However, the underlying mechanisms remain unclear. This study aimed to clarify the mechanisms underlying the protective effects of SST. SST attenuated inflammatory responses (increased IL-6 protein and mRNA levels) and TJ disruption (decreased transepithelial electrical resistance, increased sodium fluorescein permeability, and decreased occludin mRNA and protein expression) induced by LPS, hydrogen peroxide (H₂O₂), tumor necrosis factor-α (TNF-α), and polyinosinic–polycytidylic acid (Poly I:C). Further analyses using the Poly I:C model confirmed that the effects of SST were comparable to those of the nuclear factor κB (NF-κB) inhibitors SC-514 and BAY11-7085. SST reduced the activation of NF-κB signaling (increased phosphorylation of NF-κB and IκB), similar to BAY11-7085. SST components, isoliquiritigenin (ILQG) and glycyrrhizin (GL), also attenuated inflammation, barrier dysfunction, and NF-κB signaling activity. These findings suggest that (1) activation of the NF-κB signaling pathway might be associated with both inflammatory responses and TJ barrier disruption; (2) SST could reduce these effects, potentially through modulation of NF-κB signaling; and (3) ILQG and GL may contribute, in part, to these activities. Overall, this study provides the first evidence suggesting that SST may exert anti-inflammatory and epithelial barrier-protective effects, possibly via the suppression of the NF-κB signaling pathway. Full article

Background/Objectives: Poly(ADP-ribose) polymerase 1 (PARP1) is an important therapeutic target in DNA repair-deficient cancers, but discovery of new inhibitors remains constrained by scaffold convergence, tolerability limits, and acquired resistance. This study aimed to develop an interpretable, reliability-stratified cheminformatics workflow for PARP1 potency prioritization and structure-based follow-up. Methods: A curated ChEMBL dataset of 3339 PARP1 inhibitors was encoded using RDKit 2D descriptors and Avalon fingerprints (1143 initial features), then reduced to 132 informative variables by Random Forest-based feature selection. Five regression models were optimized, including a stacked ensemble. Model interpretation was performed using permutation feature importance and SHAP. External near-domain corroboration was assessed using a stringent PubChem similarity expansion (Tanimoto > 0.90) around sub-10 nM seed compounds, followed by comparison with retrievable experimental PARP1 activity values. Top scaffold-diverse candidates were further evaluated by complementary docking against PARP1 (PDB: 4R6E) using AutoDock Vina and cavity-guided docking through the SwissDock platform. Results: The stacked ensemble achieved the best held-out performance (test R² = 0.723; RMSE = 0.610 pIC₅₀ units), with 83.7% of test predictions within ≤0.75 pIC₅₀ units and only 2.7% exceeding 1.5 pIC₅₀ units. PubChem similarity expansion retrieved approximately 32,450 analogs, of which 3349 were predicted to have IC₅₀ ≤ 10 nM. Among 366 compounds with retrievable experimental PARP1 activity values, predicted versus experimental pIC₅₀ showed a positive association (R² = 0.124; Pearson r = 0.479), with RMSE = 0.491 and MAE = 0.330 pIC₅₀ units. Three ligands—CID 168873053, CID 175154210, and CID 172894737—showed the strongest complementary docking support and pocket-consistent poses relative to niraparib. Conclusions: This workflow provides a transparent and practically useful framework for near-domain PARP1 inhibitor prioritization. The combined QSAR, explainability, external corroboration, and docking strategy supports shortlist generation for experimental follow-up. Full article

Background: Cancer is a major health concern that significantly impacts the global population. Selective chemotherapeutic delivery is needed to improve the efficacy of cancer therapy while minimizing side effects in healthy cells. This study investigated the potential of gold nanoclusters (AuNCs) functionalized with poly(amidoamine) dendrimers (PAMAM) and folic acid (FA) to selectively deliver doxorubicin (DOX) to cancer cells that express the folate receptor (FR). Methods: AuNC synthesis was confirmed via UV–visible and Fourier transform infrared spectroscopy, nanoparticle tracking analysis, and transmission electron microscopy. Folic acid (FA) was incorporated for cell surface receptor targeting, while the triphenylphosphonium cation (TPP⁺) was added to improve mitochondrial localization. Cytotoxicity (MTT), apoptosis, caspase 3/7, mitopotential, and oxidative stress assays were assessed using human MCF-7 (breast adenocarcinoma), HeLa (cervical carcinoma), Caco-2 (colon adenocarcinoma), MDA-MB-231 (epithelial breast cancer), and the embryonic kidney (HEK293) cells. Results: Favorable DOX loading (>78%), with more than 90% of the drug released at pH 4.5, was achieved. A dose-dependent increase in cytotoxicity was observed, with IC50 values lower in cancer cells than HEK293 cells, indicating selective toxicity and minimal off-target effects. Targeting nanocomplexes produced the best responses in the mitopotential, caspase, and oxidative stress assays in HeLa and MCF-7 cells. Conclusions: The improved cytotoxicity in cancer cells may be due to folate-receptor-mediated cellular uptake, as well as the mitochondrial uptake of TPP⁺ nanocomplexes. This highlighted the potential of the drug–AuNC nanocomplexes to limit systemic side effects, proposing a potential novel strategy for drug delivery to cancer cells. Full article

The design, production, and study of new poly[ADP-ribose] polymerase 1 (PARP-1) inhibitors have emerged as an interesting exploration area, since PARP-1 is an overexpressed enzyme in several carcinomas. In this sense, menadione, or vitamin K3, is well known for its use in correct blood clotting, and for the generation of reactive oxygen species, but it is important to mention that it has been used as an antineoplastic agent against several cell lines. Related to the last commentary, in this work, four novel molecules (2–5) were produced from menadione through a Michael addition protocol, using 1,2-ethanedithiol, cysteamine, benzene-1,4-dithiol, and 4-aminobenzenethiol as nucleophiles, and menadione (1) as substrate, to evaluate them as plausible candidates to inhibit PARP-1. It is convenient to note that after their production and spectroscopic characterization, both docking and theoretical studies for each compound were conducted, using density functional theory (DFT) with the hybrid method B3LYP with the 6-311G(d,p) basis set. As a complement, the reactivity properties determined by DFT calculations were obtained for all compounds; the results revealed that 2 has the best properties to bind with PARP-1, and 3 offered good results. Hence, the target compounds were evaluated in vitro, determining their activity against PARP-1, using olaparib as a reference. Molecules 2 and 3 displayed the free binding energy values −7.97 and −9.35 kcal/mol, respectively, but 2 has the best IC₅₀ value, 13.76 µM. It is important to highlight that 2 and 3 must be considered as potential new inhibitor agents against PARP-1, exhibiting competitive IC₅₀ values with olaparib. Full article

Background/Objectives: Acalypha monostachya is used in rural communities in Mexico as a traditional remedy for cancer, and we previously observed cytotoxic activity of its extracts against MDA-MB-231 and HeLa cells. Methods: Because lipophilic plant fractions disperse poorly in water, we encapsulated the hexane leaf extract (LHE) of A. monostachya in poly (lactic-co-glycolic acid) (PLGA) nanoparticles prepared by nanoprecipitation, characterized them physicochemically, and evaluated their in vitro cytotoxicity. Results: The selected extract/polymer ratio (5/50, w/w) produced nanoparticles with a mean diameter of 131.4 ± 0.5 nm and a PDI of 0.122 ± 0.028, with an encapsulation efficiency of 92.03% and a loading of 8.43%. We next evaluated cytotoxicity by MTT after 24 h in HeLa and MDA-MB-231 cells and compared the response with non-tumorigenic HaCaT keratinocytes. Encapsulation increased potency relative to free LHE, yielding IC₅₀ values of 30 µg/mL (HeLa), 60 µg/mL (MDA-MB-231), and 95 µg/mL (HaCaT). These values corresponded to selectivity indices of 3.2 (HaCaT/HeLa) and 1.6 (HaCaT/MDA-MB-231). Conclusions: Overall, encapsulation of LHE in PLGA nanoparticles yields an aqueous PLGA nanoparticle suspension and is associated with improved in vitro potency while maintaining measurable selectivity against cancer cells. Full article