Search Results (10,205)

The potential hazards of triazole fungicides to non-target organisms necessitate environmental risk assessment. This study, therefore, focused on characterizing the differential toxicity of the enantiomers of Ipfentrifluconazole (IFZ), a new triazole fungicide, in zebrafish larvae using a multi-endpoint approach. Acute toxicity tests determined the LC₅₀ values of 1.709 mg/L for rac-IFZ, 1.531 mg/L for (+)-IFZ, and 1.809 mg/L for (−)-IFZ, indicating a higher toxicity of the (+)-enantiomer. To avoid overt mortality while revealing organ-level effects, we chose a concentration of approximately 20% of the LC50 of (+)-IFZ, which is 340 μg/L, as the exposure concentration. Exposure to IFZ induced developmental defects, including swim bladder malformation, cardiac blood pooling, and metabolic disturbances during the early developmental stage of zebrafish. Additionally, cardiac and hepatic development and function were disrupted in zebrafish larvae following IFZ exposure. Biochemical and transcriptomic analyses revealed distinct toxic mechanisms: (+)-IFZ primarily disrupted lipid metabolism through alterations in PPAR signaling pathway and fatty acid degradation, while (−)-IFZ significantly impaired cardiac function by affecting adrenergic signaling in cardiomyocytes and cardiac muscle contraction. Rac-IFZ mainly influenced drug metabolism, particularly cytochrome P450-related pathways. These findings demonstrated the toxic effects of IFZ, emphasizing the need for evaluating environmental and health risks of chiral pesticides. The study provides valuable insights into the molecular mechanisms underlying IFZ toxicity. Full article

Fumonisin B1 (FB1) is a prevalent mycotoxin in moldy grains and feeds, highly toxic to livestock and compromising product quality while threatening food safety. Poultry exhibit low susceptibility to FB1, but the underlying tolerance mechanisms remain unclear. Traditional 3D chicken intestinal organoid models cannot simulate direct interaction between the epithelial monolayer and FB1, limiting the study of FB1–chicken intestinal crosstalk. Here, we established a 2D chicken intestinal organoid monolayer model, derived from intestinal crypts of 18-day-old specific pathogen-free chicken embryos, to systematically explore poultry’s resistance mechanisms against FB1. Using this model, we compared FB1-induced effects with those in a porcine intestinal epithelial cell model. Results showed that FB1 exposure did not reduce transepithelial electrical resistance, induce abnormal expression of tight junction genes, or cause significant fluctuations in inflammatory factor levels in chicken intestinal organoid monolayers. Mechanistically, FB1 enhances chicken intestinal stem cell function by activating the Wnt/β-catenin pathway, thereby promoting epithelial regeneration and renewal to increase FB1 resistance and decrease toxin sensitivity in chickens. This study reveals a strategy for enhancing FB1 tolerance in poultry by promoting intestinal stem cell function, providing a new perspective for developing mycotoxin prevention and control strategies. Full article

The urinary bladder is a primary target organ for environmental toxicants such as arsenic. The objects of this study were two-fold. First, we constructed a novel 3D urinary bladder mucosa model (3D-UBMM) composed of an overlying epithelium and a supporting subepithelial layer. Primary human bladder urothelial and fibroblast cells were immortalized by introducing the human CDK4^R24C and TERT genes. The construction of the 3D-UBMM involved incorporating immortalized fibroblast cells into a collagen raft, while immortalized urothelial cells were cultured at the air-liquid interface. This 3D-UBMM closely resembles the human bladder epithelium in terms of morphology and marker protein expression, including uroplakin 1b, P63, and cytokeratin 5. Second, using the 3D-UBMM we investigated the cytotoxicity of sodium arsenite (iAs^III) and dimethylarsenic acid (DMA^V). Exposure to iAs^III and DMA^V resulted in increased urothelial necrosis, increased γ-H2AX-positive cells, and reduced P63-positive cells, all in a dose–response manner. These findings affirm that this novel 3D-UBMM resembles the human bladder epithelium and offers a practical in vitro model for evaluating bladder toxicants and carcinogens, identifying mechanisms of carcinogenesis, and supporting hazard identification and risk assessment. Full article

This study systematically explores the mechanisms and application potential of biochar in remediating heavy metal-contaminated soils. Particular emphasis is placed on the role of raw materials and pyrolysis conditions in modulating key physicochemical properties of biochar, including its aromatic structure, porosity, cation exchange capacity, and ash content, which collectively enhance heavy metal immobilization. The direct remediation mechanisms are categorized into six pathways: physical adsorption, electrostatic interactions, precipitation, ion exchange, organic functional group complexation, and redox reactions, with particular emphasis on the reduction in toxic Cr⁶⁺ and the oxidation of mobile As³⁺. In addition to direct interactions, biochar indirectly facilitates remediation by enhancing soil carbon sequestration, improving soil physicochemical characteristics, stimulating microbial activity, and promoting plant growth, thereby generating synergistic effects. The study evaluates combined remediation strategies integrating biochar with phytoremediation and microbial remediation, highlighting their enhanced efficiency. Moreover, practical challenges related to the long-term stability, ecological risks, and economic feasibility in field applications are critically analyzed. By synthesizing recent theoretical advancements and practical findings, this research provides a scientific foundation for optimizing biochar-based soil remediation technologies. Full article

The increasing environmental presence of metal oxide nanoparticles (NMOPs) raises concerns regarding their influence on biological wastewater treatment. This study comparatively evaluates the structural and biological effects of zinc oxide (ZnO-NPs) and titanium dioxide (TiO₂-NPs) nanoparticles on activated sludge from a wastewater treatment plant. Experimental exposure covered nanoparticle concentrations of 0.05–0.3 g/L and contact times up to 180 min, with analysis of enzymatic activity (dehydrogenase activity, TTC-SA method), sludge settleability, and particle size distribution. Inhibition of microbial metabolic activity was observed in a clear dose- and time-dependent manner, with ZnO-NPs showing stronger toxicity than TiO₂-NPs. At the highest dose (0.3 g/L), enzymatic activity nearly disappeared after 90 min (0.04 µg TPF/mg MLSS). Both nanoparticles caused floc fragmentation, decreased sludge volume index (SVI), and increased the proportion of ultrafine particles (<0.3 µm). ZnO-NPs induced more severe destabilization, while TiO₂-NPs showed partial re-aggregation of suspended particles at higher concentrations. Additionally, particle size distribution in the supernatant was analyzed, revealing distinct aggregation and fragmentation patterns for ZnO- and TiO₂-NPs. These structural and functional alterations suggest potential risks for treatment efficiency, including reduced nutrient removal and impaired sludge settleability. The study provides a comparative contribution to understanding toxicity mechanisms of ZnO- and TiO₂-NPs and emphasizes the need to monitor NMOPs in wastewater and to develop mitigation strategies to ensure stable plant operation Full article

Dioryctria abietella (Lepidoptera: Pyralidae) is a destructive forest pest for coniferous trees. Bacillus thuringiensis has been widely applied in forestry as a biological control agent to control it. However, the mechanisms of Bt-induced mortality in D. abietella, particularly its effects on gene expression and enzyme activities, remain unclear. Here, bioassay, enzyme assay, transcriptome sequencing, and gene expression profiling were employed to explore the relationship between the toxin-receptor, defense, and lethal mechanisms of D. abietella after Bt exposure. In a toxicity bioassay, Bacillus thuringiensis galleriae 05041 strain (Bt05041) was the most toxic insecticide to the larvae of D. abietella, with LC₅₀ values of 3.15 × 10⁸ Colony-Forming Units (CFUs) mL⁻¹ at 72 h after treatment. Transcriptome analysis revealed that the gene expression patterns of D. abietella after 8 h of Bt05041 exposure (Bt8) varied considerably from the Bt05041-treated for 2 h group (Bt2). In the Bt2 group, differentially expressed genes were significantly enriched in cellular and bioenergy pathways of lysosome, insulin signaling, cGMP-PKG signaling, etc. Immune-related pathways were activated, namely cAMP, AMPK, MAPK, Rap1, IMD, and Toll pathways. Meanwhile, Bt8 treatment caused metabolic changes in basic substances such as amino acids, glucose, nucleic acids, and fatty acids. Bt05041 exposure activated the activities of defense enzymes and induced gene expression changes in D. abietella larvae. Among them, most Bt-receptor genes had higher expression levels than defense enzyme genes. Overall, these findings reveal a possible mechanism underlying Bt-mediated death in D. abietella larvae. This work provides valuable information in terms of biological control strategies. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor and leads to high human malignancy and mortality. Because PDAC is highly drug-resistant and current treatments have adverse reactions, exploring novel approaches for PDAC prevention and therapy is urgently needed. Methods: Antitumor activities of Salecan were evaluated on multiple human pancreatic adenocarcinoma cells in vitro. Cell viability, colony formation, migration and invasion, flow cytometry, caspase-3 activity, qRT-PCR and Western blotting were monitored. RNA-seq was conducted to clarify the mechanism underlying Salecan’s inhibition of pancreatic cancer cell progression. Results: Here we show that Salecan, a naturally occurring polysaccharide of β-glucan, can significantly inhibit pancreatic cancer cell proliferation and exhibit no toxicity in normal cells. We find that Salecan impedes pancreatic cancer cell migration and invasion via the epithelial-to-mesenchymal transition (EMT) pathway. Mechanistically, through RNA sequencing, we reveal that Salecan induces pancreatic cancer cell necroptosis, instead of apoptosis. Moreover, Salecan’s anti-pancreatic cancer bioactivity is attributed to its promotion of the receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase-like (MLKL) signaling pathway. Conclusions: Salecan can inhibit pancreatic cancer cell proliferation, migration and invasion in vitro and accelerate cell death by inducing the necroptosis via the MLKL/RIPK1 pathway. These findings identify that Salecan may become a potential functional food component for preventing and treating PDAC. Full article

Reactive oxygen species (ROS) function as critical signaling molecules in cancer biology, promoting proliferation, angiogenesis, and metastasis at controlled levels while inducing lethal damage when exceeding the cell’s buffering capacity. To survive under this state of chronic oxidative stress, cancer cells become dependent on a hyperactive antioxidant shield, primarily orchestrated by the Nrf2, glutathione (GSH), and thioredoxin (Trx) systems. These defenses maintain redox homeostasis and sustain oncogenic signaling, notably through the oxidative inactivation of tumor-suppressor phosphatases, such as PTEN, which drives the PI3K/AKT/mTOR pathway. Targeting this addiction to a rewired redox state has emerged as a compelling therapeutic strategy. Pro-oxidant therapies aim to overwhelm cellular defenses, with agents like high-dose vitamin C and arsenic trioxide (ATO) showing significant tumor-selective toxicity. Inhibiting the master regulator Nrf2 with compounds such as Brusatol or ML385 disrupts the core antioxidant response. Disruption of the GSH system by inhibiting cysteine uptake with sulfasalazine or erastin potently induces ferroptosis, a non-apoptotic cell death driven by lipid peroxidation. Furthermore, the thioredoxin system is targeted by the repurposed drug auranofin, which irreversibly inhibits thioredoxin reductase (TrxR). Extensive preclinical data and ongoing clinical trials support the concept that this reliance on redox adaptation is a cancer-selective vulnerability. Moreover, novel therapeutic strategies, including the expanding field of redox-active metal complexes, such as manganese porphyrins, which strategically leverage the differential redox state of normal versus cancer cells through both pro-oxidant and indirect Nrf2-mediated antioxidative mechanisms (triggered by Keap1 oxidation), with several agents currently in advanced clinical trials, have also been discussed. Essentially, pharmacologically tipping the redox balance beyond the threshold of tolerance offers a rational and powerful approach to eliminate malignant cells, defining a novel frontier for targeted cancer therapy. Full article

Shikonin, a dietary naphthoquinone phytochemical from the roots of Lithospermum erythrorhizon, has gained attention for its anticancer potential. Preclinical studies show that shikonin regulates multiple programmed cell death pathways, including apoptosis, necroptosis, ferroptosis, and pyroptosis, through mechanisms involving reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and kinase-mediated signalling. Beyond cytotoxicity, shikonin suppresses metastasis by blocking epithelial–mesenchymal transition (EMT) and downregulating matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). It also disrupts tumour metabolism by targeting pyruvate kinase isoform M2 (PKM2) and modulating the Warburg effect. Evidence further indicates that shikonin can enhance the efficacy of chemotherapy, targeted therapy, immunotherapy, and radiotherapy, thereby contributing to the reversal of therapeutic resistance. To address limitations related to solubility and bioavailability, novel formulations such as nanoparticles, liposomes, and derivatives like β,β-dimethylacrylshikonin have been developed, showing improved pharmacological profiles and reduced toxicity in experimental models. Overall, the current literature identifies shikonin as a promising dietary phytochemical with diverse anticancer activities, therapeutic synergy, and formulation advances, while highlighting the need for clinical studies to establish its translational potential. Full article

This study aims to elucidate the neurodevelopmental toxicity and molecular mechanisms of endocrine-disrupting chemicals (EDCs) in neurodevelopmental disorders (NDDs) through a network toxicology approach, using triclosan exposure as a case example. Potential targets of triclosan were identified via comparative analysis of toxicogenomics databases such as the Comparative Toxicogenomics Database (CTD), Similarity Ensemble Approach (SEA), SwissTargetPrediction, and TargetNet. NDD-related targets were retrieved from GeneCards, Disease Gene Network (DisGeNET), and Online Mendelian Inheritance in Man (OMIM), resulting in 633 overlapping genes associated with disease pathology and triclosan effectors. Protein–protein interaction networks were constructed using STRING and Cytoscape, applying median-based algorithms to identify six core genes: AKT1, TP53, EGFR, FN1, SRC, and ESR1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses via Metascape revealed that triclosan-induced NDDs are primarily associated with endocrine signaling disruption and activation of the PI3K-Akt pathway. Molecular docking with CB-Dock2 demonstrated strong binding affinities between triclosan and the core targets, while YASARA molecular dynamics simulations confirmed stable interactions, notably with EGFR, exhibiting high binding stability. Collectively, these findings delineate the potential molecular mechanisms underlying triclosan-induced NDDs and underscore the utility of network toxicology, molecular docking, and molecular dynamics simulations in assessing neurotoxicity and related molecular pathways. This research provides novel insights for future investigations, enhances understanding of the potential impact of neurodevelopmental disorders on health, and lays a scientific foundation for the development of preventive and therapeutic strategies. Full article

Tumor immunotherapy, a revolutionary cancer treatment, is hindered by inadequate immune cell activation, immunosuppressive tumor microenvironment (TME), and off-target toxicities of immunotherapeutics. These bottlenecks necessitate innovative strategies to enhance efficacy and reduce side effects. Marine polysaccharides have garnered significant attention due to their potential to enhance immune cell activity and regulate the tumor microenvironment, among other benefits. Due to their excellent biocompatibility, modifiability, and relatively low cost, polysaccharides are increasingly being explored as materials for drug delivery systems. The development of marine polysaccharide-based drug delivery systems represents an opportunity for advancing tumor immunotherapy. This review focuses on the application of marine polysaccharide drug delivery systems in tumor immunotherapy, exploring the mechanisms underlying the bioactivity of marine polysaccharides, the design of drug delivery systems, and the interactions between these systems and tumor immunotherapy, aiming to provide a framework for advancing marine polysaccharide-based therapeutics, accelerating the clinical translation of effective, safe, and targeted tumor immunotherapy strategies. Full article

Nanoplastics have emerged as significant global pollutants, drawing worldwide concern. Due to their small particle size, large specific surface area, and high surface activity, nanoplastics can combine with other environmental contaminants, including environmental nanoparticles, persistent organic pollutants, antibiotics, and endocrine-disrupting chemicals. This review summarizes recent progress on the environmental behavior of nanoplastics and their complex effects on food safety when co-exposed to various contaminants. These composite pollutants accumulate in foods and the environment, and are ultimately taken up by humans, posing potential toxic effects on human health. In the future, the interaction mechanisms between environmental NPs and various co-contaminants, as well as their transfer routes from food to humans, should be addressed. Full article

Even though Pt(II)-based drugs represent the standard in cancer therapy, their use is seriously limited by severe side-effects (renal toxicity, allergic reactions, gastrointestinal disorders, hemorrhage and hearing loss), drug resistance and a grim prognosis. This review presents the results of multiple studies showing different nanoparticle-based platforms as delivery agents in order to overcome these drawbacks. The approach of using nanoparticle-based drug delivery systems of Pt drugs and prodrugs is promising due to key advantages like specific targeting and thereby reduced toxicity to healthy cells; increased stability in the bloodstream; multiple mechanisms of action such as stimulating anti-tumor immunity, responding to environmental stimuli (light, pH, etc.), or penetrating deeper into tissues; enhanced efficacy by their combination with other therapies (chemotherapy, gene therapy) to amplify the anti-tumor effect. However, certain challenges need to be overcome before these solutions can be widely applied in clinics. These include issues related to biocompatibility, large-scale production, and regulatory approvals. In conclusion, using nanoparticles to deliver Pt-based drugs represents an advanced and highly promising strategy to make chemotherapy more effective and less toxic. Nonetheless, further studies are required for the better understanding of intracellular mechanisms of action, toxicity and the pharmacokinetics of nanoparticles, and physical–chemical standardization. Full article

The secondary contamination of nodularin disinfection by-products (NOD-DBPs) is a problem worthy of attention. In this study, prototypical NOD-R-DBPs were prepared, and their toxicity was assessed using conventional protein phosphatase (PPs) inhibition assay, confirming that structural changes in “Adda³” during chlorination are key factors leading to a significant reduction in NOD-R toxicity. However, some NOD-R-DBPs still exhibit certain levels of toxicity (2.8–81% of NOD-R). To elucidate the mechanism underlying the potential inhibitory effect of NOD-R-DBPs on protein phosphatase 2A (PP2A), molecular simulations were employed to establish interaction models between prototypical NOD-R-DBPs and PP2A using homology modeling strategies, and molecular docking was used to obtain candidate interaction parameters between prototypical NOD-R-DBPs and PP2A. Structural changes in “Adda³” weakened the hydrogen bonds “Adda³”Asn₁₁₇ and “Adda³”His₁₁₈. Subsequently, the disruption of “Adda³” altered key interactions between NOD-R-DBPs and PP2A (hydrogen bond Mdhb⁵ ← Arg₈₉, ionic bond Glu⁴-Arg₈₉, metal bond His₂₄₁-Mn₁²⁺, etc.). The changes in these interactions further altered the interactions between conserved amino acids and the catalytic center Mn²⁺ (ionic bond Asp₅₇-Mn₂²⁺), thereby increasing Mn²⁺ exposure. Meanwhile, the retained interactions promoted the binding of -PO₄ with the conserved amino acids His₁₁₈ and Arg₈₉. Prototypical NOD-R-DBPs retained the aforementioned key interactions and thus exhibit potential inhibitory effects on PP2A. The varying degrees of damage to the Adda³ structure led to significant differences in the inhibitory effects of different NOD-R-DBPs on PP2A. Full article