Search Results (5,420)

Skin cells exposed to ultraviolet (UV) radiation may experience reduced elasticity in skin tissue due to the production of reactive oxygen species (ROS) and the overexpression of collagen type I-degrading enzymes (MMP-1). Beyond preventing UV exposure with sunscreen, components that protect the inner surface of skin tissue may suppress the expression of ROS and their subsequent effects. In this study, the suppression of ROS production from UV-A-irradiated normal human dermal fibroblasts (NHDFs) using Chaga-derived polyphenol decoction (CPD) was examined with confocal laser scanning microscopy. Pretreatment with CPD reduced ROS expression to less than 5% compared to the blank. The evaluation of MMP-1 expression levels induced by ROS production from UV-A-irradiated NHDFs using an ELISA showed that MMP-1 expression in CPD-pretreated NHDFs was suppressed by more than 30% compared to untreated NHDFs. Furthermore, three-dimensional collagen gels containing NHDFs were prepared, and a dynamic mechanical analysis of the elasticity of UV-A-irradiated gels revealed that pretreatment with CPD maintained elasticity at more than five times that of the CPD-untreated gel. These findings suggest that CPD may be promising as a functional food for protecting skin tissue. Full article

Vernal keratoconjunctivitis (VKC) is a chronic condition that causes remodeling of the cornea and conjunctiva through recurring episodes of allergic inflammation of the ocular surface. This can lead to corneal scarring, keratoconus, and chronic conjunctival papillae. However, the details of the immunopathological processes behind these remodeling changes are not completely understood. Despite involving IgE-modulated mechanisms, about half of patients with VKC test negative on systemic allergy tests. This calls for the need to understand the common and novel inflammatory mediators involved in the pathogenesis of VKC development and severity levels. Eye rubbing stimulates the release of inflammatory cytokines TNF-alpha, IL-4, IL-5, and IL-13 and remodeling enzymes MMP-1, MMP-3, MMP-9, and MMP-10, which drive a dysregulated cycle of stromal tissue remodeling that leads to progressive ectasia. Eosinophilic activity is driven by CCL11 and ICAM-1 and eye rubbing, which leads to degranulation and the release of EMBP, ECP, and MMP-9. These inflammatory mediators drive the remodeling changes that lead to corneal scarring and ectasia. The purpose of this comprehensive review paper is to shed light on common and novel immunological mediators that help us further understand VKC and eventually lead to the discovery of more effective and targeted treatment options. Full article

Osteosarcoma remains the most common primary malignant bone tumor in adolescents and is characterized by aggressive metastasis, resistance to therapy, and extensive bone microenvironment remodeling. Therefore, the identification of novel multi-target therapeutic agents capable of simultaneously inducing ferroptosis and disrupting tumor-supportive signaling is urgently needed. This study employed a multi-omics-guided approach to investigate the anti-osteosarcoma potential of metabolites derived from the sea cucumber Holothuria scabra. LC–MS/MS profiling identified major bioactive constituents, including holothurins, scabrasides, fucosterol, desmosterol, and 24-methylenecholesterol. Integrated transcriptomic analysis of the GSE42352 dataset revealed key ferroptosis- and bone microenvironment-associated targets, including CXCR4, CTSK, RUNX2, VEGFA, and TFRC. In silico pharmacological prediction and molecular docking demonstrated favorable anticancer properties and strong binding affinities of several metabolites toward these targets, with fucosterol and holothurin A exhibiting the most promising interactions. Functional validation in MG-63 osteosarcoma cells showed concentration-dependent reductions in cell viability and migration following H. scabra treatment. Furthermore, treatment decreased GPX4, NRF2, and GSH levels while increasing TFRC and MDA, indicating activation of ferroptotic cell death. In a MG-63/RAW264.7 co-culture model, H. scabra suppressed RANKL, VEGFA, MMP9, and TRAP-positive osteoclast formation, suggesting inhibition of osteoclastogenesis, angiogenesis, and metastatic potential. Collectively, these findings identify H. scabra as a promising marine source of multi-target compounds for osteosarcoma management through coordinated induction of ferroptosis and remodeling of the bone tumor microenvironment. Full article

Objective: Lung cancer (LC) remains a leading cause of cancer mortality worldwide. Thymoquinone (TQ), a bioactive compound derived from Nigella sativa, possesses anti-inflammatory and antioxidant properties, but its precise mechanisms concerning miRNA regulation in LC are poorly defined. This study investigates the anti-cancer potential of TQ through modulation of microRNA signaling in LC. Methods: We employed an integrated approach combining bioinformatic predictions with rigorous experimental validation in A549 lung adenocarcinoma cells and SHP-77 human small-cell lung carcinoma (SCLC) cells. Bioinformatic analyses predicted miRNA targets, and experimental techniques included dual-luciferase reporter assays, miRNA inhibition, TaqMan RT-qPCR, cell-based ELISA, and Western blotting to dissect the molecular pathway. Results: We identified the transcription factor BACH1 as a direct and novel target of hsa-miR-155-5p. TQ potently suppressed interferon-γ-induced expression of both hsa-miR-155-5p and its target, BACH1. This TQ-mediated suppression led to subsequent downregulation of the key metastasis-promoter Matrix Metalloproteinase-9 (MMP-9). Genetic inhibition of miR-155-5p or direct BACH1 inhibition phenocopied the effects of TQ, confirming the functional significance of this axis. Thus, we define a novel oncogenic signaling cascade—the hsa-miR-155-5p/BACH1/MMP-9 axis that is effectively disrupted by TQ. Conclusions: This represents the first evidence that TQ exerts its anti-cancer effects in LC through the modulation of the critical signaling cascade (hsa-miR-155-5p → BACH1 → MMP-9). Our findings establish TQ as a multi-targeted agent capable of simultaneously inhibiting miRNA-mediated oncogenic signaling and protein-level effectors. The dual therapeutic action of TQ represents a novel therapeutic strategy and underscores its potential for synergistic combination therapies. Full article

Mitochondrial toxicity is a major concern in drug development and safety assessment. Machine learning models trained on mitochondrial membrane potential (MMP) assay data offer promising toxicity predictions, but cross-scaffold and cross-assay transferability remain uncharacterized. We evaluated classical machine learning and deep learning architectures across six molecular representations and both random and scaffold-based splitting strategies, assessing performance on an internal MMP test set and an independent external set comprising flux and glucose–galactose assay data. Across all model configurations, we observed a consistent cross-assay generalization gap, independent of model type, feature choice, or augmentation strategy. Mordred descriptors provided the most transferable predictive signal, outperforming fingerprint-based representations on the external set. SHAP analysis of the best CatBoost and Random Forest models identified autocorrelation-family descriptors as dominant predictors. C3SP3 contributed through feature interactions while ATS5i showed positive association with toxicity across assays. Motif-level and descriptor-level associations proved to be strongly assay-dependent, supporting a mechanism in which mitochondrial toxicity arises from multivariate physicochemical interactions rather than single structural alerts. Full article

The emergence and global dissemination of pandrug-resistant (PDR) Acinetobacter baumannii represents a critical public health crisis. This One Health study provides comprehensive surveillance and molecular characterization of carbapenem-resistant, extensively drug-resistant (XDR), and PDR A. baumannii isolates isolated from hospitalized patients and diseased chickens/environment in Egypt. We investigated cross-species clinical and pathological impacts, characterized resistance genes, and analyzed potential transmission links. Of 145 samples, 48 A. baumannii isolates were identified. Resistance profiling revealed an alarming prevalence, with PDR (56.3%) being the dominant phenotype, followed by XDR (43.7%), all exhibiting high multiple antibiotic resistance (MAR) indices (≥0.67). Chickens and humans infected with PDR A. baumannii suffered from increased neutrophilia, anemia, elevated inflammatory markers (CRP and procalcitonin), renal and liver impairment, and upregulation of MMP-9 and IL-8 response genes. Molecular analysis showed that all PDR isolates co-harbored multiple carbapenemase genes, including Class D beta-lactamases (bla_OXA-23 (most prevalent), bla_OXA-48, bla_OXA-58, bla_OXA-24) and Class B metallo-beta lactamase (bla_VIM, bla_IMP, bla_NDM). A substantial proportion also carried bla_KPC (44.4%) and the carO gene (81.48%). Genotyping using ERIC PCR and Multilocus Sequence Typing (MLST) identified a high diversity (23 ERIC types, DI = 0.986). Significantly, two ERIC types (ET19 and ET20) contained isolates from both human and chicken sources. MLST confirmed this interspecies correlation, with isolates from both hosts clustering into Sequence Types (STs) ST1410 and ST1828. These findings confirm the rapid and alarming spread of highly virulent, multi-carbapenemase-producing PDR A. baumannii strains across the human–animal interface in Egypt. The detection of shared STs between clinical and poultry isolates underscores a potential zoonotic or environmental transmission route, necessitating integrated One Health surveillance and urgent infection control interventions. Full article

Osteoarthritis (OA) is a chronic, debilitating degenerative joint disease whose prevalence is rising markedly with the rapid aging of the global population. In this study, we investigated the chondroprotective efficacy of NP-2007, an enzymatically hydrolyzed low-molecular-weight collagen from Cervi cornu, using IL-1β-stimulated SW1353 human chondrocyte cells and a medial meniscal transection (MMT)-induced OA rat model. In SW1353 cells, NP-2007 considerably suppressed the expression of inflammatory mediators (iNOS, COX-2) and cytokines (TNF-α, IL-6) without cytotoxicity. Crucially, it restored matrix homeostasis by downregulating catabolic enzymes (MMP-3, MMP-13, and ADAMTS-5) and upregulating anabolic markers (COL2A1, aggrecan), a process associated with the modulation of the Wnt/β-catenin and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathways and the recovery of the master chondrogenic factor SOX9. These in vitro findings were consistent with the in vivo results from the MMT model, where oral administration of NP-2007 (50 and 200 mg/kg) for 8 weeks effectively preserved articular cartilage structure and proteoglycan content while markedly reducing serum levels of catabolic biomarkers, including MMP-13 and COMP. Collectively, our findings demonstrate that NP-2007 exerts potent chondroprotective effects by modulating the balance between cartilage degradation and synthesis, suggesting its potential as a therapeutic candidate for the management of OA. Full article

Background/Objectives: Pelvic organ prolapse (POP) is increasingly recognized as a localized extracellular matrix (ECM) remodeling disorder. Conventional clinical predictors do not fully explain interindividual variation in tissue quality or surgical durability. This study aimed to characterize the ECM failure phenotype in surgically obtained pelvic support tissue and to derive an exploratory tissue-based ECM Vulnerability (ECM-V) score. Methods: This single-center exploratory translational biomarker derivation study included 121 women: 60 undergoing primary reconstructive surgery for POP with or without concomitant stress urinary incontinence, and 61 benign gynecological controls. Standardized intraoperative anterior vaginal wall biopsies and preoperative plasma samples were obtained. Seven ECM biomarkers (COL1, COL3, ELN, MMP1, MMP2, MMP3, MMP9) were quantified in both compartments. Receiver operating characteristics (ROC) analysis adjusted logistic regression and stratified 10-fold cross-validation were performed. An exploratory integer-weighted ECM-V score was derived from COL3, MMP2 and MMP9 tissue values. Results: Tissue biomarkers demonstrated substantially stronger discrimination than plasma biomarkers. Surgical cases showed reduced COL1 (AUC 0.898) and ELN (AUC 0.846), elevated COL3 (AUC 0.818), MMP2 (AUC 0.958) and MMP9 (AUC 0.977) (all p < 0.001). The compact COL3-MMP2-MMP9 tissue model achieved a cross-validated AUC of 0.986 ± 0.035, substantially outperforming the best plasma model (AUC 0.719). The ECM-V score demonstrated derivation-level AUC of 0.995, sensitivity of 0.967 and specificity of 0.967. Tissue MMP9 and MMP2 correlated strongly with POP-Q severity and validated symptom scores (rho up to 0.806, p < 0.001). Conclusions: Women undergoing primary POP surgery demonstrate a distinct localized ECM failure phenotype. The exploratory COL3-MMP2-MMP9 framework provides a biologically coherent basis for the ECM-V score requiring prospective validation with longitudinal recurrence outcomes. Full article

This study investigated the protective effect of an optimized naturally derived formulation extract against ultraviolet-induced skin photoaging and its preliminary potential for topical formulation development. A mouse model was established by combined UVA + UVB irradiation and D-galactose administration. Skin phenotype, histopathology, oxidative stress, and inflammation-related indicators were evaluated, and representative constituents were identified by HPLC. The loading level of the active extract was screened using a DPPH radical-scavenging assay, and lotion and cream formulations were optimized through emulsification-condition screening and response surface methodology. The final products were further evaluated for appearance, pH, short-term physical stability, moisture-retention performance, and DPPH radical-scavenging capacity. The extract significantly alleviated skin roughness, wrinkle deepening, epidermal thickening, and collagen fiber disorganization in mice, increased SOD, GSH-Px, and CAT activities, and reduced MDA, ROS, 8-oxoG, TNF-α, IL-6, and MMP-3 levels. HPLC identified representative constituents including 6-gingerol, ferulic acid, senkyunolide, ligustilide, atractylenolide, cinnamaldehyde, quercetin, amygdalin, and sarsasapogenin. The optimal loading level was 1.6 μg/mL. The optimized lotion and cream exhibited acceptable appearance, suitable pH, and short-term physical stability under the tested conditions, while retaining measurable DPPH radical-scavenging capacity. These findings indicate that the naturally derived formulation extract exerts anti-photoaging effects by alleviating oxidative damage, suppressing inflammatory responses, and improving extracellular matrix abnormalities, and that it has preliminary potential for topical formulation development. Full article

Oral mucosal repair is a redox-regulated process that may be impaired by diabetes, chronic inflammation, infection, and chemotherapy- or radiotherapy-induced oral mucositis. Reactive oxygen species (ROS) support host defense, epithelial migration, angiogenesis, extracellular matrix remodeling, and adaptive repair when their production is transient and compartmentalized. In contrast, persistent ROS promote lipid, protein, and DNA oxidation, mitochondrial dysfunction, and extracellular matrix damage. Photobiomodulation (PBM) is increasingly used to support oral tissue repair, but its effects should be interpreted as dose- and context-dependent redox modulation rather than as simple antioxidant activity. This narrative review synthesizes oxidative stress biomarkers and redox-sensitive pathways relevant to oral mucosal repair and PBM, including oxidant–antioxidant balance, lipid and protein oxidation, oxidative DNA damage, antioxidant defense, thiol/disulfide homeostasis, mitochondrial and NADPH oxidase-derived ROS, Nrf2/HO-1, NF-κB, HIF-1α/VEGF, MAPK/ERK, PI3K/Akt, and MMP/TIMP signaling. The review emphasizes the distinction between transient mitochondrial ROS/nitric oxide signaling and sustained NADPH oxidase-driven oxi-inflammatory stress. It proposes a practical redox-guided framework for biomarker selection, PBM response interpretation, and future study design, while noting that this framework remains conceptual and is not yet a validated clinical decision algorithm. Full article

Breast cancer is among the most commonly diagnosed malignancies in women and remains difficult to treat due to therapy resistance and the adverse effects associated with conventional chemotherapeutic regimens. In this study, the anticancer activity of the ethanolic root extract of Salvadora persica (S. persica), commonly known as Miswak, was evaluated in human breast cancer cells using a combination of in vitro assays, phytochemical profiling, and computational analyses. HRLC-MS/MS characterization revealed a wide range of bioactive constituents, including alkaloids, flavonoid derivatives, glucosinolates, and fatty acid–based molecules detected under both ionization modes. The extract exhibited a concentration-dependent cytotoxic effect on breast cancer MCF-7 and MDA-MB-231 cells, with IC₅₀ values of 144.1 and 176.3 µg/mL, respectively, as determined by the MTT assay, while exerting negligible toxicity toward normal Vero cells. Miswak extract enhanced intracellular ROS production, disruption of MMP, nuclear condensation, and increased apoptotic cell populations, along with S-phase cell cycle arrest, pointing toward activation of mitochondrial-mediated apoptosis. In silico docking results indicated that key phytoconstituents exhibit strong binding interactions with multiple breast cancer–relevant targets such as ERα, PR, EGFR, HER3, IGF-1R, and GPER. Additionally, pharmacokinetic and toxicity predictions suggested favorable drug-like properties with minimal safety concerns. Thus, these findings support its potential as a promising plant-derived therapeutic candidate for breast cancer. Full article

Deep high-temperature and high-pressure (HTHP) oil reservoirs have limited experimental MMP data, large differences between reservoir and saturation pressures, low gas–oil ratios, and pressure-sensitive CO₂–oil phase behavior, which make both minimum miscibility pressure (MMP) prediction and miscibility-mechanism identification challenging. To address these gaps, this study determines the MMP of a CO₂–oil system by integrating slim-tube experiments, empirical formula methods, the Multiple Mixed-Cell (MMC) method, the Method of Characteristics (MOC), compositional numerical simulation, and three intelligent algorithm models (GWO-RBF, GWO-LSSVM, and GWO-SVM). The slim-tube MMP of 44.13 MPa at 140 °C is used as the experimental reference for comparing prediction errors, whereas PVTsim and literature data are used for consistency checks and model benchmarking. The results show that when the injected CO₂ mole fraction exceeds 0.88, the formation oil under original reservoir conditions cannot achieve first-contact miscibility with CO₂, and the maximum dissolved CO₂–oil molar ratio is 7.3:1. Supercritical CO₂ forms dual displacement mechanisms, including front-end vaporizing miscible drive and rear-end condensing miscible drive, but the dominant mechanism for this CO₂–oil system is vaporizing miscible drive. During the vaporizing gas drive, the CO₂ + N₂ + C₁ content in the liquid phase increases from less than 60% to nearly 90%, indicating significant CO₂ dissolution into oil and associated density and viscosity reduction; meanwhile, the C₇₊ content in the gas phase increases to nearly 10%, indicating extraction of heavy components. Relative to the slim-tube reference at 140 °C, the deviations of MMC, GWO-SVM, GWO-LSSVM, compositional numerical simulation, GWO-RBF, MOC, and empirical formula methods are 2.97%, 3.08%, 3.40%, 4.24%, 4.26%, 11.62%, and 19.74%, respectively. The MMC method is the most suitable approach for this specific HTHP oil system, while intelligent algorithms should be regarded as supplementary predictors whose reliability depends on training-domain coverage and independent validation. Full article

This study characterized the basic structure of partridge tea leaves polysaccharides and comparatively analyzed the in vitro lipid-lowering activity of total partridge tea polysaccharide (PTPS) and its two purified homogeneous fractions, namely PTPS-I (13,560 Da) and PTPS-III (30,935 Da). In terms of structural composition, PTPS-I and PTPS-III share identical monosaccharide types but differ significantly in monosaccharide proportions, glycosidic linkages and backbone structures. In vitro experiments demonstrated that PTPS, PTPS-I, and PTPS-III could effectively reduce intracellular lipid levels and oxidative stress in free fatty acids (FFA)-injured L02 cells and alleviate the decline of mitochondrial membrane potential in damaged hepatocytes. At the high concentration of 400 μg/mL, PTPS-III showed a superior effect in reducing triglyceride (TG) content compared with the other two samples, with the value reaching 0.31 ± 0.024 mmol/mg prot. Additionally, 400 μg/mL PTPS markedly decreased total cholesterol (TCHO) content and enhanced superoxide dismutase (SOD) activity, which were 0.55 ± 0.039 mmol/mg prot and 29.92 ± 0.22 μmol/mg prot, respectively. PTPS-I of 400 μg/mL significantly reduced malondialdehyde (MDA) content to 1.31 ± 0.288 μmol/mg prot and inhibited the decline of mitochondrial membrane potential (MMP) by 9.67%. The three polysaccharide fractions could elevate the mRNA expression of Nrf2, NQO1 and HO-1 in the Nrf2/HO-1 signaling pathway and the gene expression of PPARα, CPT-1 and ACOX1 in the lipid metabolism pathway, and ultimately regulate lipid accumulation in L02 cells. This study validated the in vitro antilipid activities of partridge tea leaves polysaccharide and provided fundamental data for research on its bioactivity and functional components. Further in vivo assays and mechanism exploration will be conducted to evaluate its potential application in fatty liver intervention product development. Full article

Adequate placental development and function, prerequisites for the development of a healthy fetus, rely on controlled trophoblast invasion into the decidua and remodeling of the spiral arteries. These tightly regulated processes involve epithelial–mesenchymal transition (EMT) and endovascular differentiation of trophoblast cells. Taxifolin (dihydroquercetin), a natural flavonoid with various pharmacological effects, previously showed cytoprotective, antioxidant, and anti-inflammatory activity on trophoblast cells. Given that the literature indicates that this flavonoid suppresses EMT and can affect angiogenesis across different cell types, we investigated the potential of taxifolin (10 and 100 µM) to modulate invasion and endothelial-like differentiation in human extravillous trophoblast HTR-8/SVneo cells by functional tests. Expression of different molecular markers relevant to these processes was evaluated at the mRNA and protein levels. Our results showed that taxifolin inhibited invasion of HTR-8/SVneo cells, involving downregulation of integrin α5 subunit and modulation of MMP-2 and MMP-9 mRNA expression and secretion. No changes in the concentrations of secreted TIMP-1 and TIMP-2 were observed following taxifolin treatment. Furthermore, downregulation of N-cadherin and vimentin in treated trophoblast cells indicated suppression of EMT. Taxifolin inhibited endothelial-like differentiation of HTR-8/SVneo cells, as evidenced by reduced tube formation and downregulation of VE-cadherin in treated cells. Moreover, expression of TGFB1 was upregulated in treated cells, as were levels of phosphorylated SMAD2/3, indicating involvement of TGF-β signaling in TF-induced effects on trophoblast cells. The in vitro effects of taxifolin on suppression of trophoblast invasion, EMT, and endothelial-like differentiation highlight its potential impact on placental development processes. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD⁺/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in Aβ42-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality. Full article