Search Results (35,131)

Reactive oxygen species (ROS) generated by ultraviolet (UV) radiation accelerate skin aging by activating matrix metalloproteinase-1 (MMP-1) and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, antioxidants that can suppress ROS generation and downstream signaling cascades are considered promising anti-aging agents. In this study, five methoxyflavones were isolated from Kaempferia parviflora (black ginger) rhizomes—5,7,3′,4′-tetramethoxyflavone (1), 3,5,7,4′-tetramethoxyflavone (2), 5,7,4′-trimethoxyflavone (3), 3,5,7,3′,4′-pentamethoxyflavone (4), and 5,7-dimethoxyflavone (5)—using LC–MS-guided fractionation and identified via NMR and LC–MS analysis. Their biological activities were evaluated in tumor necrosis factor-α (TNF-α)-stimulated normal human dermal fibroblasts (NHDFs). All methoxyflavones, except compound 3, significantly suppressed TNF-α-induced ROS generation, while compounds 3–5 markedly reduced MMP-1 secretion. Among them, compounds 4 and 5 exerted the strongest protective effects by modulating distinct MAPK pathways: compound 4 selectively inhibited p38 phosphorylation, whereas compound 5 selectively suppressed ERK phosphorylation. Both compounds attenuated ECM degradation and enhanced antioxidant defenses in a concentration-dependent manner. Collectively, these findings highlight the mechanistic significance of methoxyflavones 4 and 5 as dual-acting antioxidant and ECM-protective agents that counteract skin aging through selective regulation of MAPK signaling. Their potential as natural anti-photoaging ingredients warrants further validation in in vivo models and clinical studies for future skincare applications. Full article

Benzophenone-3 (BP-3), a widely used ultraviolet absorber in various scenarios, exhibits estrogenic toxicity at environmental concentrations—as demonstrated in our prior work. Given the importance of hepatic metabolism and the limitations of previous hepatotoxicity research (high-dose models, lack of mammalian data, etc.), we evaluated BP-3’s hepatic effects on postpartum mice at environmentally relevant levels. Postpartum mice were exposed to BP-3 via drinking water from postpartum day 1 (PPD1) to PPD35. Groups solvent control (0.001% DMSO), 10–1000 nM BP-3, and diethylstilbestrol (DES) were established. Basic growth performance, histopathological changes, and a range of molecular indicators were assessed. The results showed that BP-3 exposure induced dose-dependent increases in liver weight, histopathological alterations (sinusoidal dilation, hepatocyte edema, and necrosis), and significant upregulation of oxidative stress markers (Ros, Mda), chemokines (Ccl27a/b), and inflammatory factors (Tnf-α, Il-6, Nf-κb) at the mRNA level (all p < 0.05). Conversely, levels of antioxidant enzymes (Cat, Sod1/2) and anti-inflammatory factor Ho-1 were markedly decreased (p < 0.05). A clear dose-effect relationship was confirmed using the Integrated Biomarker Response (IBR) framework. This pioneering study establishes the hepatotoxicity of environmentally relevant BP-3 levels in mammals and offers methodological insights for endocrine disruptor assessment. Full article

Multiple sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease that causes disability in patients. Cladribine is an oral treatment that is used in relapsing–remitting and active secondary progressive MS. T and B lymphocytes are especially sensitive to cladribine, which are transiently depleted upon short treatment courses. However, cladribine crosses the blood–brain barrier (BBB), supporting the hypothesis that cladribine may affect central nervous system (CNS)-resident cells. In this study, we used human primary cells and human cell lines to test the effect of cladribine, at therapeutic concentrations, on cells of the CNS. In these conditions, cladribine did not affect survival, proliferation and the capacity of producing cytokines of human microglial cells (HMC3 cell line) or primary human astrocytes but enhanced the production of oxygen reactive species in both cell types. The initial differentiation of primary human neuronal progenitor cells was impaired when continuously exposed to the maximum therapeutic concentration of cladribine, but not when lower concentrations were used. However, cladribine protected differentiated SH-SY5Y human neuroblastoma cell line from oxidative stress-related cell death. In conclusion, using different in vitro cell models, we demonstrate that cladribine maintains the normal function of CNS glia and protects neuronal cells from oxidative stress damage. Full article

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta along with the aggregation of α-synuclein in Lewy bodies. Among the pathological mechanisms involved is the alteration of iron homeostasis, which promotes oxidative stress and neuronal damage. Despite therapeutic advances, today, no treatment is available to modify the course of the disease. In this study, we investigated for the first time the neuroprotective potential of bovine lactoferrin (bLf) in both its Native (Nat-) and Holo forms, using rotenone-treated N1E-115 cells to mimic PD phenotype. The results showed that the Nat-bLf was more effective than Holo-bLf in counteracting rotenone-induced cytotoxicity and neurite retraction, preserving neuronal morphology and promoting neuritogenesis, as evidenced by increased β3-Tubulin and Growth-Associated Protein-43 markers (GAP-43). Both forms of bLf preserved Tyrosine Hydroxylase (TH) levels, crucial for dopamine synthesis, reduced the DNA damage marker γ-H2Ax and prevented rotenone-induced downregulation of Divalent Metal Transporter-1 (DMT-1) and Ferroportin (Fpn), key proteins involved in iron uptake and release, thereby limiting intracellular iron accumulation. Notably, only Nat-bLf reduced the levels of α-synuclein and markers of oxidative damage. Conversely, Holo-bLf exhibited pro-oxidant effects and increased α-synuclein accumulation even in absence of rotenone. Overall, these results highlight the differential neuroprotective effects of both Nat- and Holo-form, resulting from their distinct iron saturation level and their ability to modulate protein expression, with the native form emerging as a promising candidate for therapeutic strategies to counteract PD-associated neurodegeneration. Full article

Aquatic species are exposed to several long-chain per- and polyfluoroalkyl substances (PFASs) in the environment but their potential toxicity is not well studied. In this study, we assessed the effects of perfluoroundecanoic acid (PFUnDA) exposure on developing zebrafish. To do this, we investigated the potential for oxidative stress and neurotoxicity by measuring reactive oxygen species, apoptosis, gene expression, and locomotor activity. Mortality was evident in fish exposed to 1000 µg/L PFUnDA, and apoptosis was indicated in fish exposed to 100 µg/L PFUnDA via an increase in casp3 transcription. No change in reactive oxygen species in 7-day-old larval fish exposed to 0.01 up to 1000 µg/L PFUnDA was detected. Visual motor response analysis revealed hypoactivity in different light–dark periods that occurred in a concentration-specific manner. At the transcriptional level, several neurotoxicity-related genes (casp3, bdnf, gfap, gmfb, nkx2-2a) were significantly upregulated, further supporting neurotoxic effects. Overall, these findings indicate that PFUnDA disrupts neurodevelopment and behavior in zebrafish larvae, raising concerns for this long-chain PFAS. Full article

The increasing prevalence of antibiotic resistance necessitates the development of novel antimicrobial agents and therapeutic strategies. This study reports the extracellular biosynthesis of silver selenide nanoparticles (Ag₂Se NPs) using Meyerozyma guilliermondii PG-1 and evaluates their antimicrobial and antibiofilm efficacy, both alone and in combination with gentamicin. The NPs were thoroughly characterized, confirming their nanoscale size, crystallinity, and biomolecule-mediated stability. Ag₂Se NPs exhibited broad-spectrum antibacterial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Escherichia coli) pathogens and showed strong synergy with gentamicin, particularly against P. aeruginosa and E. coli, as demonstrated through checkerboard and time–kill assays. The NPs also significantly inhibited biofilm formation and disrupted pre-formed biofilms. Mechanistic studies revealed that the antibacterial effects involved membrane disruption, ATP leakage, and elevated oxidative stress, while gene expression analysis in S. aureus indicated triggered stress responses related to biofilm formation. These findings suggest that biosynthesized Ag₂Se NPs represent a promising synergistic agent for enhancing antibiotic efficacy and combating biofilm-related infections. Full article

Background/Objectives: Approximately 50% of infertility cases are attributable to male factors; yet conventional semen examination can not identify the molecular abnormalities that hinder sperm functionality. Extracellular vesicles (EVs) derived from sperm, such as testicular EVs, prostasomes, and epididymosomes, have become important modulators of oocyte activation, sperm maturation, capacitation, acrosome stability, motility, and early embryonic development. This study aimed to evaluate the potential diagnostic and translational uses of sperm-associated extracellular vesicles (EVs) in male infertility and assisted reproduction, while also consolidating recent insights on their origins, composition, and functional significance. Methods: A focused narrative search of PubMed (2000–2025) was conducted using backward and forward citation tracking. Studies that qualified included human clinical cohorts, functional sperm extracellular vesicle tests, and omics analyses using MISEV-aligned extracellular vesicle isolation and characterisation methodologies. When human mechanistic understanding was constrained, knowledge from animal research was selectively integrated. Results: The cargo signatures specific to the source identified in sperm-derived and seminal EVs encompass proteins, small RNAs, lipids, and enzymatic modules that govern sperm maturation, capacitation, acrosome reaction, redox balance, calcium signalling, zona binding, and DNA integrity. Density-resolved seminal extracellular vesicle subfractions (EV-H/EV-M/EV-L) have unique functional and proteomic characteristics linked to progesterone-induced hyperactivation, oxidative stress, and motility. Asthenozoospermia and oligoasthenoteratozoospermia are associated with changes in extracellular vesicle composition, reduced embryonic developmental potential, compromised oocyte activation (related to PLCζ), and increased sperm DNA fragmentation. Numerous EV-related miRNA and protein signatures may predict TESE results, identify functional sperm anomalies not recognised by conventional semen analysis, and differentiate between obstructive and non-obstructive azoospermia. Conclusions: The available findings indicate that sperm-derived extracellular vesicles are significant functional regulators of sperm physiology and may serve as valuable non-invasive indicators for male infertility. The standardisation of EV isolation, characterisation, and clinical validation is essential prior to widespread use; nonetheless, their integration into liquid biopsy methods and assisted reproductive technology processes represents a significant improvement. Full article

Background: The combination of manganese porphyrins (MnPs) and ascorbate (ASC) represents a promising redox-based therapeutic approach for selectively targeting cancer cells. We investigated the cytotoxic effects of two structurally distinct MnPs (MnTPPS and MnF₂BMet) with differing lipophilicity and potential membrane permeability in combination with ASC. Methods: Cancer cell lines (MCF-7, PANC-1, U87, T98G, AT-2) and normal human dermal fibroblasts (HDFs) were treated with MnTPPS and MnF₂BMet in the absence or presence of ASC. Viability, migration potential, and intracellular oxidative stress were assessed using single-cell methods. Results: MnPs alone exhibited no intrinsic cytostatic or cytotoxic activity, as confirmed by proliferation, viability, and motility assays. When combined with ASC, both MnTPPS and MnF₂BMet significantly enhanced ASC-induced oxidative stress, leading to lipid peroxidation, glutathione depletion, mitochondrial dysfunction, and cell membrane disruption. Time-lapse microscopy revealed rapid necrotic cell death under co-treatment. Catalase fully abolished cytotoxicity, indicating the essential role of hydrogen peroxide. In contrast, dehydroascorbate (DHA), which increases intracellular ASC levels, did not induce the same toxicity, suggesting that extracellular ROS generation contributes predominantly to the observed effects. Normal fibroblasts were minimally affected, supporting the MnPs–ASC system’s selectivity toward cancer cells. Conclusions: MnTPPS and MnF₂BMet enhance extracellular oxidation of ascorbate and subsequent ROS production, leading to selective oxidative-stress-mediated cancer cell death. This study supports the potential of MnPs–ASC redox catalysis as a complementary oxidative-stress-based anticancer strategy and highlights the need for further mechanistic and structure–activity investigations. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor that controls the antioxidant response to oxidative stress, especially after exposure to ionizing radiation (IR). This review examines NRF2’s emerging role as a complementary biomarker in radiobiological dosimetry for assessing radiation exposure and its potential health effects. When cells encounter IR, the resulting reactive oxygen species (ROS) interfere with the NRF2 repressor KEAP1, leading to NRF2 activation and the expression of cytoprotective genes such as HO-1, NQO1, and GCLC. Evidence suggests that NRF2 levels increase in a dose- and time-dependent manner, primarily at low to moderate radiation doses, highlighting its potential for early detection of radiation exposure. However, at high doses (>8 Gy), NRF2 activation may be suppressed due to apoptosis or irreversible damage, which limits its reliability in those situations. The review also compares NRF2 with other biomarkers used in biodosimetry, discussing its advantages, such as sensitivity and early response, along with its limitations, including variability in activation at high doses and expression influenced by other oxidative factors. The authors introduce a comprehensive radiobiological model that illustrates how low-dose IR exposure affects NRF2 expression patterns, thereby improving the understanding of dose-dependent oxidative stress mechanisms. Additionally, the role of NRF2 in inflammation and general health risk assessment is emphasized, suggesting broader applications beyond biodosimetry. Overall, NRF2 holds significant promise for use in evaluating radiation exposure, developing radioprotection strategies, and informing future radiobiological research frameworks. Full article

Rosacea is a chronic inflammatory skin disorder of multifactorial pathogenesis, in which dysregulated innate immunity, neurovascular dysfunction, oxidative stress, and microbiome imbalance are central contributors. Recent molecular studies have revealed altered cytokine expression (e.g., IL-1β, IL-6, IL-36 family), aberrant activation of signaling pathways (STAT3, NF-κB, MAPKs), and enhanced expression of innate immune receptors such as TLR2,b TLR4, and TLR7, all of which promote chronic inflammation, angiogenesis, and barrier dysfunction. This systematic review was performed according to PRISMA guidelines. A total of 1425 records were retrieved from PubMed, Scopus, and Web of Science, and 14 studies met the inclusion criteria. The included studies comprised both clinical cohorts and translational experimental investigations using human samples. Reported findings consistently confirmed systemic and tissue-specific inflammatory activity, with elevated circulating monocytes, indoleamine 2,3-dioxygenase, and inflammatory indices, as well as tissue expression of STAT3, NF-κB, MAPKs, and cathelicidin fragments. Oxidative stress markers (TOS, OSI, AOPP, MMP-9) and hypoxia-related molecules (HIF-1α) were significantly increased in patients, correlating with disease severity and vascular manifestations. Taken together, these results highlight that rosacea involves both cutaneous and systemic molecular alterations. The evidence identifies multiple biomarkers with diagnostic potential and provides mechanistic insights into immune, vascular, and metabolic dysregulation. Future research should aim to validate these findings in larger cohorts, establish standardized biomarker panels, and explore novel therapeutic strategies targeting key molecular pathways. Full article

Root pruning has been proposed as a practical method to regulate growth and metabolite accumulation in horticultural crops, yet its physiological and metabolic consequences in hydroponically grown lettuce remain poorly understood. In this study, we examined the effects of root pruning, applied two days before harvest, on biomass production, oxidative stress responses, and metabolite accumulation in red leaf lettuce. Root pruning suppressed root growth and reduced root water content in a severity-dependent manner. Shoot fresh weight also declined, whereas shoot dry weight was significantly reduced only under severe pruning. Young leaves of pruned plants exhibited transient reddish coloration, which was most pronounced under severe pruning. Quantitative analyses revealed that anthocyanin content increased up to 4.5-fold compared with the control, while total phenolic content also rose significantly. These metabolic changes were accompanied by pronounced oxidative stress, as indicated by elevated hydrogen peroxide accumulation and enhanced lipid peroxidation. In addition, leaf nitrate concentration decreased significantly in both moderate and severe pruning treatments. Collectively, these findings demonstrate that root pruning acts as a controllable stressor that triggers oxidative stress signaling, enhances antioxidant metabolite accumulation, and reduces nitrate content, highlighting its potential as a pre-harvest strategy for improving the nutritional and functional quality of hydroponic lettuce. Full article

Microplastics (MPs) are increasingly reported as contaminants in sewage sludge, with wastewater treatment plants retaining approximately 10³–10⁶ particles kg⁻¹ of dry sludge. Anaerobic digestion (AD), widely applied for sludge stabilization and energy recovery, does not consistently remove these particles; MPs frequently persist and, at elevated or sensitive loadings, have been shown to affect methane production, microbial communities and sludge quality. In parallel, thermal hydrolysis and related pretreatments are being implemented at full scale to enhance sludge biodegradability, exposing embedded MPs to high temperature and pressure prior to AD. This review compiles and analyzes experimental studies on MPs in sludge pretreatment and AD systems, with an emphasis on how pretreatment severity, MP type, particle size and concentration influence MP transformation and process performance. Reported data indicate that intensified pretreatment accelerates MP aging, causing fragmentation, oxidative surface modification and additive release, while subsequent AD generally induces limited further MP degradation but can be negatively affected through reduced methane yields, shifts in microbial consortia and altered behavior of co-contaminants. Mechanisms implicated include leaching of plastic additives, enhanced oxidative and physiological stress, and formation of plastisphere biofilms that perturb syntrophic interactions. Mitigation approaches, including optimized thermal hydrolysis–AD configurations and the use of carbonaceous sorbents, are assessed with regard to their effects on MP-associated inhibition and their practical constraints. Analytical limitations, uncertainties in MP mass balances and environmental fate, and key research needs for evaluating MP risks and designing MP-resilient sludge treatment and biosolid management strategies are identified. Full article

Citalopram, a common selective serotonin reuptake inhibitor (SSRI), has been increasingly detected in aquatic environments due to ineffective removal and improper disposal. Although developmental exposure to SSRIs is linked to neurotoxicity, little is known about the persistence of gene expression alterations following limited exposure periods. Zebrafish embryos were exposed from 2 to 24 h post-fertilization (hpf) at concentrations of citalopram hydrobromide spanning surface water to therapeutic serum levels (0.03, 0.9, 50, and 250 μg/L), followed by removal of the citalopram and development until 48 hpf. Whole-embryo RNA sequencing at 48 hpf revealed a non-linear dose–response wherein the lowest dose resulted in the induction of the highest number of differentially expressed genes (DEGs). Gene set enrichment analyses (GSEA) and overrepresentation analyses (ORAs) showed that 0.03 μg/L citalopram caused upregulation of metabolic and developmental pathway genes, but suppressed synaptic membrane genes, whereas 0.9 μg/L resulted in strong downregulation of key neurotransmitter receptors. At 50 μg/L, genes linked to oxidative stress (glutathione metabolism and ferroptosis) were upregulated, and at 250 μg/L, stress and apoptotic processes were increased, while glutamate receptor genes were repressed. All four citalopram doses suggested synaptic and neurotransmitter alterations, implying that persistent neurodevelopmental impacts resulted from a limited early window of exposure. These data highlight that transient, low-level SSRI exposures shape long-term embryonic gene expression. Full article

The review article critically evaluates the application of edible plant extracts as natural preservatives in food systems, with a particular focus on environmentally sustainable extraction methodologies. It examines green extraction methods designed to enhance the yield of bioactive compounds responsible for plants’ strong antibacterial properties. The biochemical mechanisms underlying antibacterial activity are studied, namely disruption of bacterial cell walls and membranes; inhibition of metabolic enzymes; interference with nucleic acid synthesis; induction of oxidative stress; and suppression of quorum sensing, biofilm formation, efflux pumps, and β-lactamase activity, along with standardized methodologies for efficacy assessment and extracts’ incorporation into food matrices. Recent research demonstrates the potential of plant extracts to extend the shelf life of meat, seafood, dairy, and fresh products while meeting consumer demand for clean-label products. Although large-scale application remains limited due to challenges, future research should focus on optimizing green extraction approaches, establishing standardized evaluation protocols, and developing regulatory frameworks to facilitate their safe and sustainable use in the food industry. Full article

Stroke is the leading cause of death and long-term disability worldwide, with ischemic stroke accounting for nearly 87% of all cases. Vascular occlusion, a key pathological event in ischemic stroke, has been reliably reproduced in preclinical studies using permanent ischemic stroke models. This study demonstrated the neuroprotective effect of NXC736, a functional antagonist of sphingosine-1-phosphate receptor 4 (S1P₄, currently in phase II clinical trials for alopecia areata), against acute injury in mice with permanent middle cerebral artery occlusion (pMCAO). pMCAO-challenged mice received oral NXC736 1 h after occlusion. NXC736 demonstrated substantial therapeutic activity against permanent ischemic stroke by attenuating pMCAO-induced acute brain infarction, neurological deficits, and apoptosis. Additionally, NXC736 reduced blood–brain barrier disruption and edema in the injured brain. Moreover, NXC736 reduced microglial activation and proliferation, oxidative stress, and suppressed pro-inflammatory cytokine expression, suggesting that the efficacy of NXC736 in permanent ischemic stroke is associated with the suppression of neuroinflammatory responses. Mechanistically, we found that NXC736-mediated neuroprotective effects were dependent on the inactivation of NF-κB and MAPKs, including ERK1/2, JNK, and p38. Collectively, our findings indicate that NXC736 is an effective neuroprotective drug for permanent ischemic brain stroke, highlighting S1P₄ as a promising therapeutic target for ischemic stroke. Full article