Toxicology Research最新文献

The genus Aconitum L. is widely used in the treatment of rheumatoid arthritis, tumors, and cardiovascular diseases due to its prominent pharmacological properties. However, increasing scientific attention has been directed toward its neurotoxicity. Diester-diterpenoid alkaloids (DDAs), such as aconitine (AC), mesaconitine (MA), and hypaconitine (HA), have been identified as the principal toxic constituents of Aconitum. Although disruption of calcium homeostasis has been demonstrated to mediate DDAs-induced neurotoxicity, the key neurotoxic components and their underlying molecular mechanisms remain unclear. Our study employed both in vivo and in vitro to compare the neurotoxic effects of structurally similar DDAs (AC, MA, and HA) to screen for the key effector substance for further investigation. Experiments conducted in both zebrafish and SH-SY5Y cells revealed that AC exerted more significant regulatory effects on mitophagy, calcium homeostasis, and two-pore channels (TPCs) than MA and HA. Consequently, subsequent mechanistic studies focused on the role of the TPCs-Ca²⁺-mitophagy axis in AC-induced neurotoxicity. Treatment with the TPCs inhibitor Ned-19 suppressed mitochondrial-lysosomal fusion and reversed the AC-induced upregulation of LC3B-II/I and Parkin, thereby attenuating the overactivation of mitophagy markers in SH-SY5Y cells. Similarly, the calcium chelator BAPTA-AM diminished mitochondrial-lysosomal colocalization and LC3B-II/I protein levels. In summary, AC disrupts lysosomal TPCs-mediated calcium homeostasis, leading to excessive mitophagy more pronounced than that of MA and HA. These findings not only deepen our understanding of the intrinsic mechanisms underlying AC-induced neurotoxicity, but also provide new experimental evidence supporting the identification of AC as the primary neurotoxic component in the genus Aconitum L.

Plastic pollution and childhood health are two significant public health issues worldwide. However, there is a lack of corresponding toxicological studies to confirm this association, and the molecular pathological mechanism behind it remains unknown. Here, we utilized DIDP as a proxy to examine the association. A mouse model of autism-like behaviors was successfully constructed using the early social deprivation (ESD) approach. Social deficits were evaluated through the three-chamber social preference test, while cognitive impairments were assessed using the Morris water maze test. Various metrics, including oxidative stress (ROS, GSH, MDA, and 8-OHdG), inflammatory response (IL-6/TNF-α), and pathological impairments in brain tissue, were examined. Additionally, we explored the mediation of oxidative stress signaling pathways as molecular pathological mechanisms and investigated the preventive and therapeutic effects of vitamin E (VitE) on social disorders. The results indicate that mice exposed to the plasticizer DIDP exhibited oxidative stress, pathological damage, and inflammatory responses in the hippocampal region of the brain. Additionally, behavioral tests revealed that these mice displayed social deficits and cognitive impairments. However, upon administration of VitE, the mice exhibited significant improvement in social deficits and cognition impairments. The study finds that exposure to the plasticizer DIDP exacerbates autism in mice, possibly through the molecular pathological mechanisms of oxidative stress and inflammation in brain tissue. Furthermore, VitE is found to have a noteworthy protective effect against the worsening of autism caused by exposure to the plasticizer DIDP.

Type 2 diabetes mellitus is closely associated with male reproductive dysfunction driven by oxidative stress, hormonal imbalance, and testicular cell damage. This study evaluated the effects of tirzepatide, a dual agonist of the glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptors, on diabetes-induced reproductive impairment in male Wistar rats, compared with metformin. Sixty rats were allocated into control, diabetic control, tirzepatide-treated diabetic, metformin-treated diabetic, and pair-fed diabetic control groups to distinguish weight-dependent from weight-independent effects. Diabetes was induced using a high-fat diet combined with low-dose streptozotocin, and treatments were administered for eight wk. Metabolic, hormonal, sperm, oxidative stress, histological, and gene-expression parameters were assessed. Diabetic rats exhibited hyperglycemia, insulin resistance, reduced reproductive hormones, impaired sperm quality, increased lipid peroxidation, and downregulation of antioxidant and steroidogenic genes. Tirzepatide markedly improved glucose homeostasis, restored testosterone and gonadotropin levels, enhanced antioxidant defenses via activation of the Nrf2/Keap1 pathway, normalized steroidogenic gene expression, preserved testicular architecture, increased PCNA expression, and reduced caspase-3-mediated apoptosis. These effects were superior to those of metformin and largely independent of weight reduction. Overall, tirzepatide ameliorates diabetes-associated male reproductive dysfunction through coordinated metabolic, antioxidant, and steroidogenic mechanisms.

Niobium pentoxide nanoparticles (NINPs) are increasingly used in technological and biomedical applications due to their chemical stability, biocompatibility, and osteoconductive properties. However, despite their promising use in clinical materials, limited information is available regarding their potential genotoxic effects, particularly in vivo. In this study, we evaluated the genotoxicity of crystalline and amorphous NINPs using the Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. Third instar larvae from both standard (ST) and high bioactivation (HB) crosses were exposed to NINPs at concentrations ranging from 0.25 to 4.0 mg/mL. Survival rates were assessed, and mutant spots were scored in adult wings to detect somatic mutation and recombination events. Crystalline NINPs induced a significant increase in the frequency of mutant spots in both ST and HB crosses, indicating genotoxic activity through both mutagenic and recombinagenic mechanisms. In contrast, amorphous NINPs did not show any genotoxic effect under the same conditions. The survival rates remained above 70% for crystalline and above 80% for amorphous NINPs, suggesting that neither form caused systemic toxicity. These results highlight the influence of crystallinity, on nanomaterial biological activity, and reinforce the importance of detailed physicochemical characterization in toxicological assessments.

Water pollutants represent a growing environmental concern, yet their specific mechanisms in gastric cancer (GC) remain poorly understood. This study comprehensively investigates the multi-target mechanisms through which water pollutants promote gastric carcinogenesis using an integrated computational and bioinformatic approach. We screened 69 U.S. EPA-listed water contaminants for carcinogenicity using ADMETlab 3.0, ProTox-3, and IARC classifications, identifying seven high-risk pollutants. Their potential targets were predicted using five databases, and GC-related genes were identified from the GSE54129 dataset. Shared targets underwent functional enrichment, PPI network construction, and three machine learning algorithms to identify key targets. Diagnostic and prognostic analyses, immune infiltration, and single-cell sequencing explored tumor microenvironment remodeling, while molecular docking validated pollutant-target interactions. Results identified EGFR, MMP9, and CXCR4 as high-priority candidate key targets with significant diagnostic and prognostic value. These targets were implicated in cancer-related pathways and associated with immune cell infiltration. Molecular docking confirmed strong binding affinities between key pollutants and these targets. Our integrated analysis suggests that exposure to certain water pollutants may potentially contribute to gastric carcinogenesis through predicted interactions with EGFR, MMP9, and CXCR4, disrupting cancer-related signaling and remodeling the tumor microenvironment. These findings offer a computational framework for generating hypotheses regarding environmental risk assessment and may inform future investigations into therapeutic targets.

Invasive aspergillosis (IA) is a severe fungal infection with complex pathogenesis, and the role of ferroptosis, an iron-dependent regulated cell death, in IA remains largely unexplored. This study investigates the association between ferroptosis and IA using a bioinformatics approach. We analyzed the GSE78000 dataset to assess ferroptosis activity and identify differentially expressed genes (DEGs). Ferroptosis-related genes (FRGs) were curated from literature, and protein-protein interaction (PPI) networks and functional enrichment analyses (GO and KEGG) were performed. Three machine learning algorithms (SVM, LASSO, and Random Forest) identified five core FRGs (KIF20A, PEBP1, HMOX1, MTF1, QSOX1), which exhibited excellent diagnostic potential (AUCs: 0.884-0.981). IA patients were categorized into two ferroptosis-related subtypes (C1 and C2), characterized by distinct molecular profiles and pathway enrichments, such as ribosome biogenesis and DNA replication. Immune cell infiltration analysis, using ssGSEA, revealed significant alterations in IA, with increased innate immune cells (macrophages, neutrophils) positively correlating with core FRG expression, while adaptive immune cells (B cells, T cells) were decreased. Our findings indicate that ferroptosis is critically involved in IA pathogenesis, with identified core FRGs serving as promising diagnostic biomarkers. The revealed heterogeneity among IA patients and the interaction between ferroptosis and the immune microenvironment provide new insights into the disease's molecular mechanisms and potential therapeutic targets for further investigation.

Environmental toxins such as sodium arsenite induce oxidative stress, disrupt redox homeostasis, and trigger oncogenic signaling, providing a model for studying natural redox modulators. This study investigated the protective effects of Tapinanthus globiferus fractions (butanol, methanol, and ethyl acetate) on sodium arsenite-exposed Drosophila melanogaster. Biochemical, behavioral, and molecular assays were employed to assess oxidative stress markers, enzyme activities, locomotor performance, cell viability, and gene expression. Sodium arsenite exposure significantly decreased acetylcholinesterase activity, total thiols, glutathione (GSH), glutathione-S-transferase (GST), and nitric oxide, while increasing hydrogen peroxide, lipid peroxidation, protein carbonyls, and metabolic hyperactivity. These alterations were effectively ameliorated by T. globiferus fractions, with the methanol and butanol fractions producing the most consistent improvements (P < 0.05). Behavioral assessment revealed that sodium arsenite reduced negative geotaxis performance to 39% climbing ability, which improved to 55% following butanol fraction treatment. Molecular analysis demonstrated that sodium arsenite suppressed p53 and SOD1 expression while inducing Ras and CNcC overexpression. Treatment with T. globiferus fractions restored p53 and SOD1 expression, suppressed Ras overexpression, and normalized CNcC transcription factor levels. These findings provide the in vivo evidence that T. globiferus mitigates arsenic-induced oxidative stress and genetic dysregulation through coordinated biochemical and transcriptional modulation. The dual ability to restore redox homeostasis and reprogram oncogenic signaling underscores its potential as a natural redox therapeutic against toxin-induced and carcinogenesis-linked pathologies.

Polymyxin B remains a first-line therapeutic option against Gram-negative bacterial infections; however, its clinical utility is substantially limited by dose-limiting toxicity, the mechanisms of which remain incompletely elucidated. Within a network toxicology framework, this study systematically investigated the potential toxic characteristics and underlying molecular mechanisms of Polymyxin B, with a specific focus on three key adverse effects: acute kidney injury, neurotoxicity, and skin pigmentation. Potential targets associated with Polymyxin B exposure and these toxicities were initially identified through integrated data mining of the SuperPred, SEA, GeneCards, and OMIM databases. A protein-protein interaction (PPI) network was subsequently constructed and analyzed using the STRING database and Cytoscape software. Functional enrichment analyses, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, were performed using Metascape. Furthermore, a compound-target-pathway network and Sankey diagram were generated to identify major active components, followed by molecular docking between these components and proteins encoded by the key targets. Molecular docking and molecular dynamics simulations confirmed strong binding affinities between Polymyxin B and core target proteins, namely STAT3, NF-κB, PRKACA, and HIF1A. Notably, both PMB1 and PMB2 exhibited high binding affinity for NF-κB. Consistent with these findings, in vivo studies in mice demonstrated that Polymyxin B treatment significantly enhanced the activation of the NF-κB pathway in renal tissues. Conversely, co-administration of the NF-κB pathway inhibitors PDTC and JSH-23 markedly attenuated Polymyxin B-induced nephrotoxicity. In conclusion, these experimental results indicate that hyperactivation of NF-κB is a critical mechanism underlying Polymyxin B-induced renal toxicity.

The use of paraquat as a pesticide exposes users to a high risk of death and morbidity in various organ systems. In Iran, poisoning from this deadly chemical occurs frequently as a result of suicide or accidental use. As such, knowledge about paraquat is essential for this region, and in this study, we conducted a systematic review of the available evidence on paraquat poisoning in Iran. We utilized databases including PubMed, Google Scholar, Web of Science, and ResearchGate to conduct a systematic literature review on paraquat poisoning in Iran up to June 2025. Studies involving human subjects who reported paraquat poisoning in any province of Iran were included in this systematic review. Two independent researchers searched and extracted the results using a predefined table in Microsoft Excel. After screening 14 studies including 752 cases in this review, we concluded that the mortality rate was about 40% and the first symptoms were typically nausea and vomiting. Also, the main side effects were renal and respiratory failure. All reported paraquat poisoning cases in the Iranian population were included in this systematic review, including an overview of the patient population, symptoms, comorbidities, hospital stays, and treatments. The data revealed a lack of an effective antidote and highlighted the urgent need for prevention strategies in Iran, offering actionable insights for health authorities. This review may also serve as a useful guide for clinicians in diagnosing, preventing, and treating paraquat poisoning.

[This corrects the article DOI: 10.1093/toxres/tfaf177.].