Genotoxicity is a fundamental biological process linked to the development of numerous diseases, particularly cancer, due to its impact on the integrity and stability rof genetic material. In this context, natural compounds with antigenotoxic properties have gained increasing attention as potential agents for preventing or mitigating DNA damage. Species of the genus Lippia (Verbenaceae) have emerged as a relevant source of bioactive metabolites with promising genoprotective effects. This review provides a comprehensive analysis of the antigenotoxic activity of Lippia spp., focusing on key species such as Lippia alba, Lippia citriodora, Lippia graveolens, and Lippia sidoides. Special emphasis is placed on their phytochemical composition, particularly flavonoids and phenolic acids, including quercetin, luteolin, apigenin, caffeic acid, and rosmarinic acid, which are responsible for their biological activity. Evidence from in vitro and in vivo studies indicates that Lippia extracts exhibit low genotoxic potential and can reduce DNA damage induced by chemical and physical agents. The molecular mechanisms underlying these effects involve reactive oxygen species scavenging, activation of endogenous antioxidant systems, modulation of DNA repair pathways, metal chelation, and regulation of cellular signaling and epigenetic processes. Additionally, potential applications in chemoprevention, environmental health, and nutraceutical development are discussed. Overall, Lippia species represent a valuable source of natural antigenotoxic compounds; however, further studies in complex biological models and clinical settings are required to validate their efficacy, safety, and applicability in human health.

Zishangan Granule (ZSG) is a plant-derived formulation containing Taxus, Astragalus, Asparagus, and licorice. Its phytochemical composition and oral toxicological safety remain insufficiently characterized. This study profiled ZSG constituents and evaluated acute and subchronic oral toxicity in Kunming mice using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and in vivo safety assessments. UPLC-MS/MS detected 15 candidate serum-detectable constituents in ZSG and post-administration mouse serum, including Salvianolic acid L, Lithospermic acid B, Taxine A, Liquiritin, Hyperin, and Calycosin-7-O-glucoside. In the acute study, no mortality occurred after 14 days of ZSG administration at 0.43-27.52 g/kg/day. No abnormal clinical signs were observed up to 3.44 g/kg/day; however, higher doses (6.88-27.52 g/kg/day) produced dose-related reductions in food intake, slower body-weight gain, hypoactivity, and piloerection. In the 90-day subchronic study, repeated administration at the no-observed-adverse-effect level (NOAEL; 3.44 g/kg/day) caused no treatment-related changes in body weight, food intake, organ coefficients, hematology, serum biochemistry, or histopathology. These findings indicate a wide oral safety margin for ZSG at up to eight-fold the recommended mouse dose and support further preclinical development, while additional genotoxicity, reproductive toxicity, and longer-duration studies remain needed.

Over the past three decades, artificial intelligence (AI) and machine learning (ML) have revolutionized computational toxicology, providing powerful tools for predicting chemical toxicity and supporting safer assessments for human health and the environment. This review offers a critical 30-year synthesis (1995-2025) that distinguishes itself from narrower prior works through its interdisciplinary integration of historical evolution, multi-omics data fusion, nanotoxicity challenges, regulatory frameworks, multi-stakeholder perspectives, and emerging hybrid and generative models. Key findings reveal a clear progression: from early artificial neural networks capturing non-linear patterns in the 1990s to modern deep learning architectures such as convolutional neural networks and graph neural networks that have achieved over 85% accuracy, primarily in retrospective benchmarks on ToxCast and Tox21 datasets for endpoints including hepatotoxicity, cardiotoxicity, and nanotoxicity. However, prospective validation on novel compounds remains limited, representing a critical translational gap. Traditional machine learning methods (random forests and support vector machines) effectively handle imbalanced high-throughput screening data, facilitating multi-omics integration and applications across pharmaceuticals, pesticides, cosmetics, and nanoparticles. These approaches strengthen read-across strategies, Integrated Approaches to Testing and Assessment (IATA), and Threshold of Toxicological Concern (TTC) frameworks. Regulatory acceptance, guided by OECD principles, increasingly emphasizes explainable AI to ensure transparency and validation.In conclusion, AI/ML approaches can substantially reduce animal testing, accelerate safety evaluations, and address data gaps, yet require ongoing attention to biases, model opacity, and limited prospective performance. Hybrid mechanistic-AI models, federated learning, and strengthened cross-sector collaboration represent the most promising path forward.

Oscillatory reactions involving periodical oxido-reduction reactions are commonly found in life-sustaining processes. The purpose of this study consisted in using the luminol-KSCN-H2O2-Cu(II) oscillator to probe the capacity of known environmental xenobiotics to alter these oscillatory reactions. The above oscillator was studied in the presence of increasing concentrations of ascorbate (a reducer), cerium (Ce IV; an oxidant), samarium oxide (SmO), nanocerium (nCeO2), zinc oxide nanoparticles (nZn), polyethylene nanoplastics (PE), cadmium tellurium quantum dots (CdTe) and copper-zinc-iron composite (nCuZnFeO) to monitor changes in the cyclic luminescent profiles. In normal conditions, 4 amplitude changes were generated during the first 15 min with luminescence spikes occurring at each 2.5-3 min. Following Fourier transformation, the amplitudes of the major oscillations were obtained for the first 9 frequencies were obtained and showed negative slope β between amplitudes and frequencies, which is related to the fractal dimension fD. The addition of the above compounds in the reaction media produced characteristic changes in oscillations with the appearance of amplitudes at higher frequencies at various intensity thereby decreasing the slope β and increasing the fD. The data also revealed that the fD followed the reported toxicity values of these compounds in fish suggesting that electron flow occurring in increased fD is associated to toxicity. Although more research is needed, the use of chemical oscillators based on oxido-reduction reactions to probe various xenobiotics could serve as a proxy to identify potential toxicity of xenobiotics.

The functional nutraceutical Spirulina (SP) was evaluated against alcohol intoxication in mice livers, concurrently striving to elucidate its protective mechanisms in cellular death pathways: necroptosis and pyroptosis. Ethanol (ET) intoxication was induced via intake of 5% ethanol in drinking water for 10 days, succeeded by a substantial dose of 50% ethanol (4 g/kg, i.p.) on day 11. SP (250 and 300 mg/kg, p.o.) were administered to the ET-intoxicated mice one hour prior to ethanol consumption for 11 days. The two submaximal doses effectively modulated the ET-instigated hepatic abnormalities. Both doses restored the disrupted hepatic function and architecture. SP mitigated serum liver biomarkers: ALT, AST and ALP, in addition to improving survival. SP substantially modified hepatic oxidative stress by inhibiting the lipid peroxidation product MDA and elevating the antioxidant levels of SOD and GSH. Meanwhile, SP counteracted the ET-induced elevated levels of hepatic TNF-α, the necroptosis-related molecular signals; RIPK1/RIPK3/MLKL and the pyroptosis biomarkers: NLRP3/caspase-1/IL-1β. However, no extra benefit was detected with the higher dose. These findings robustly imply the hepatoprotective properties of Spirulina in alcoholism at a dose correspondent to 250 mg/kg via revoking hepatic cell death chains: necroptosis and pyroptosis. Thereby, opens a new avenue for assisting cellular repair mechanisms.

Triclosan (TCS), a synthetic broad-spectrum antimicrobial and novel persistent organic pollutant, is detected in over 75% of human urine samples, yet its molecular targets in ulcerative colitis (UC) remain unclear. We integrated network toxicology, multi-cohort machine learning, molecular docking, 100-ns all-atom molecular dynamics (MD) simulation, and single-cell transcriptomics to address this gap.Intersecting UC differentially expressed genes with database-derived TCS targets yielded 479 shared candidate targets; because these databases include indirect and probabilistic associations,this set was treated as hypothesis-generating. KEGG enrichment identified the AGE-RAGE signaling pathway, PPAR signaling, and TNF signaling among the top enriched pathways. LASSO regression and random forest algorithms distilled a 10-gene diagnostic signature that achieved cross-cohort AUC of 0.910-1.000 across six independent GEO datasets, consistent with strong discriminative performance.Molecular docking predicted Vina scores of -7.1 kcal/mol (CYP3A4) and -7.0 kcal/mol (DPP7);redocking and decoy analyses supported protocol specificity but not biochemical binding or inhibition. Over 100 ns of MD simulation, the docked poses remained stable for both targets. Single-cell RNA sequencing GSE214695 independently corroborated cell-type-specific CYP3A4 downregulation in epithelial cells and broad DPP7 upregulation across immune subsets in UC.CellOracle-based in silico perturbation predicted that CYP3A4 suppression would impair cytoplasmic translation, while DPP7 suppression would polarize innate inflammation toward an IL-1β-driven phenotype. Together, these analyses computationally prioritize CYP3A4 and DPP7 as candidate TCS-relevant targets in UC and generate testable hypotheses for future experimental validation; they do not by themselves establish direct target engagement, inhibition, or causal contribution to UC.

Nanoplastics (NPs), a subfraction of microplastics (MPs) smaller than 1 μm, are increasingly recognized for their ability to cross biological barriers and induce organ-level toxicity; however, their systemic histopathological effects remain fragmented across individual studies. This review summarizes current in vivo mammalian evidence on NP-induced cellular toxicity and organ-specific histopathological changes based on a structured literature search of PubMed, Scopus, and Web of Science covering studies published between 2000 and 2024. The findings were narratively organized by organ system. Across the nervous, respiratory, gastrointestinal, hepatobiliary/renal, and reproductive systems, NPs consistently induce common pathological signatures, including immune cell infiltration, apoptosis, fibrosis, epithelial barrier disruption, and ultrastructural organelle damage. These lesions indicate conserved mechanisms involving oxidative stress, inflammatory signaling, impaired cellular homeostasis, and organ-organ crosstalk, such as gut-liver and hepato-renal interactions, which may amplify systemic toxicity. Collectively, the evidence demonstrates that NPs act as system-wide toxicants capable of multi-organ histopathological disruption, distinct from larger MPs or other nanoparticles, underscoring the need for further mechanistic and pathology-driven evaluation.

Following the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) multidisciplinary guideline M7 (R2), in silico prediction, in vitro and in vivo genotoxicity evaluations were used to evaluate the potential genotoxic risk of (-)-scopolamine hydrobromide trihydrate (SHT), the main impurity of scopolamine butylbromide in the Chinese Pharmacopeia (ChP). The 2018 in silico models for genotoxicity (Derek Nexus and Sarah Nexus) predicted SHT to be a Class 4 impurity. Subsequent in vitro and in vivo genotoxicity tests (bacterial reverse mutation test, in vitro mammalian chromosomal aberration test, in vitro mammalian cell gene mutation test and mammalian erythrocyte micronucleus test) showed no positive findings, indicating that SHT has no evidence of genotoxic potential under the tested conditions. Therefore, SHT could be tentatively categorized as a Class 5 impurity according to the ICH multidisciplinary guideline M7 (R2), with a threshold according to ICH quality guideline Q3B (R2). In silico prediction in 2026 confirmed this classification, demonstrating the high reliability of the Nexus software database for classification according to ICH multidisciplinary guideline M7 (R2). In the ChP, the SHT threshold in scopolamine butylbromide falls between the identification thresholds and the qualification thresholds of ICH quality guideline Q3B (R2), which is accurate and reasonable.

Vancomycin (VM) therapy is one of the cornerstone options in the treatment of resistant Gram-positive bacterial infections. However, its drawback is associated with the side effect hepatotoxicity during optimal high doses. It is unknown whether quercetin (Que), a natural bioactive flavonoid, could protect the liver against VM-induced hepatotoxicity. The study thus aimed to explore the potential protective effects of Que on VM-induced hepatotoxicity in male Wistar rats. Rats were randomized into groups and administered VM (200 mg/kg body weight, twice a day) and/or Que (100 mg/kg body weight) for 7 consecutive days. The VM injection induced liver dysfunction revealed via significantly elevated serum activities of ALT, AST, and GGT compared to the control group (p < 0.001). VM markedly decreased hepatic activities of SOD, CAT and GPx, while MDA level increased compared to the control group (p < 0.001). Additionally, VM increased TNF-α levels while decreasing IL-10 levels. There were considerable increases in the hepatic expression of caspase-3, NF-κB, Keap1, NOX4, 4-HNE and NLRP3, whereas the expression of HO1, Nrf2, PI3K, p-Akt decreased significantly as revealed by qRT-PCR and immunohistochemical analyses (p < 0.001). Interestingly, the Que administration attenuated the VM-induced alterations on the liver enzymes and antioxidant enzymes, including the MDA and 4-HNE. Que exerted prominent modulatory effects on the mechanistic proteins and mRNA expression in a manner comparable to the control. Overall, the present findings suggest that quercetin may mitigate vancomycin-induced hepatotoxicity in rats by modulating oxidative stress, inflammatory signaling, and apoptosis-related pathways.

Per- and polyfluoroalkyl substances (PFAS) are persistent surfactants with ingestion as a major exposure route, positioning the intestine as a primary site of contact. This narrative review integrates mechanistic toxicology, multi-omics microbiology, and human observational studies to evaluate whether PFAS-associated disruption of intestinal homeostasis could contribute to colorectal cancer (CRC). In vitro epithelial systems and animal models indicate that selected PFAS can impair barrier function through altered membrane properties and reduced tight-junction expression, increasing paracellular permeability and luminal antigen translocation. PFAS may also perturb goblet-cell secretion and mucus organization, in part through endoplasmic reticulum (ER) stress and altered autophagy, thereby facilitating mucosa-associated bacterial adherence. Stress signaling can converge on mitochondrial dysfunction and reactive oxygen species (ROS) generation that primes inflammasome activity and cytokine-mediated inflammation. In colon cell models, PFOA and PFOS have been associated with modulation of Wnt/β-catenin signaling and downstream transcriptional programs linked to proliferative and invasive phenotypes. At the community level, exposure-associated dysbiosis includes loss of butyrate-producing taxa and disruption of bile acid pools, consistent with reduced short-chain fatty acids (SCFAs) and altered farnesoid X receptor signaling. However, epidemiologic findings remain inconsistent, including null and inverse associations that may reflect reverse causation from occult bleeding, exposure misclassification, residual dietary confounding, non-monotonic dose responses, congener heterogeneity, and species-specific toxicokinetics. We propose priorities for future work including long-lag prospective sampling, physiologically based pharmacokinetic (PBPK)-informed exposure reconstruction, and adverse outcome pathway (AOP)-anchored multi-omics endpoints for causal inference and regulation.

Electronic cigarettes are widely used by individuals in their reproductive years, yet polymer materials in pods, wicks, seals, and casings remain underexamined as possible contributors to inhaled particulate exposure. This narrative review evaluates whether e-cigarette device components could plausibly generate microplastics or nanoplastics during use and whether such particles, if present, could have reproductive relevance. Evidence from device-material studies, polymer degradation chemistry, aerosol physics, inhalation toxicology, and reproductive microplastic models was synthesized. Current devices place polycarbonate, polydimethylsiloxane, nylon, and other polymers near heating and aerosolization zones, where thermal cycling, solvent contact, and mechanical stress could theoretically promote oxidation, chain scission, embrittlement, or fragmentation. However, no study has chemically identified or quantified device-derived microplastics or nanoplastics in e-cigarette aerosols using polymer-resolving methods. Thus, links between e-cigarette use, inhaled polymer particles, and reproductive harm remain hypothetical. Evidence from non-e-cigarette models shows that micro- and nanoplastics can induce oxidative stress, inflammation, endocrine disruption, barrier interaction, and cellular injury, but these findings cannot be extrapolated without confirming particle formation, polymer identity, dose, and biodistribution. Future research should prioritize polymer-resolved aerosol testing under realistic puffing regimens, including unused and aged devices, e-liquids, condensates, and emitted aerosols. Key endpoints should include polymer identity, particles per puff, particles per mL of e-liquid consumed, particle size distribution, polymer mass, pulmonary deposition, systemic translocation, and reproductive or placental effects. Device-derived microplastics should be treated as a plausible particle-safety concern requiring direct experimental evaluation.

Cisplatin resistance remains a major limitation in the treatment of oral squamous cell carcinoma (OSCC), often associated with altered oxidative stress. This study aimed to evaluate whether matrine can enhance cisplatin sensitivity in OSCC cells and explore its potential underlying mechanisms.Bioinformatics analysis and molecular docking were used to predict potential targets and pathways. In vitro experiments were conducted using CAL27 and cisplatin-resistant CAL27/DDP cells. Cell viability was assessed by CCK-8 assay, and drug interaction was evaluated using combination index (CI). Colony formation, reactive oxygen species (ROS), glutathione (GSH), apoptosis, and protein expression were analyzed.A total of 104 matrine-related targets and 21 overlapping genes were identified. Enrichment analysis suggested that oxidative stress-related pathways may be involved. Matrine alone showed limited cytotoxicity, while it significantly enhanced cisplatin sensitivity, reducing IC50 from 8.340 μM to 2.703 μM (p < 0.01) with CI values <1. Combined treatment decreased GSH and increased ROS (p < 0.001), accompanied by increased apoptosis (p < 0.001). The expression of Nrf2-related antioxidant proteins was reduced, while apoptotic protein levels were increased.Matrine enhances cisplatin sensitivity in OSCC cells, which may be associated with the regulation of oxidative stress and apoptosis. These findings suggest that matrine may serve as a potential chemosensitizing agent.

Etoxazole (ETX) is a widely used organofluorine acaricide/insecticide applied to many food crops, and its residues have been detected in food matrices at levels of concern for human dietary exposure. However, its hepatotoxic and nephrotoxic potential following subchronic oral exposure remains insufficiently characterized. This study investigated the dose-dependent effects of repeated oral ETX administration on serum biochemical parameters, hepatic and renal antioxidant enzyme activities, lipid peroxidation, and histopathological features in Wistar albino rats. Six groups of seven female rats each received normal control (NC) or ETX at 25, 100, 250, 500, or 750 mg/kg/day by gavage for 28 consecutive days. At the end of the exposure period, serum parameters (AST, ALT, ALP, GGT, creatinine, uric acid, glucose, total cholesterol, triglycerides, HDL, LDL), catalase (CAT), glutathione S-transferase (GST), reduced glutathione (GSH), and malondialdehyde (MDA) levels in liver and kidney tissues, and histopathological changes were evaluated. ETX caused significant, dose-dependent increases in AST and ALT from ETX100, in ALP and GGT from ETX500, and in creatinine and uric acid at higher doses, indicating progressive hepatic and renal injury. Hepatic and renal CAT, GST, and GSH activities significantly decreased, whereas MDA levels significantly increased in the higher-dose groups, demonstrating oxidative stress-mediated disruption of antioxidant defenses. Histopathological evaluation revealed dose-dependent liver injury and significant tubular damage in kidneys. The tentative NOAEL and LOAEL were estimated at 25 and 100 mg/kg/day, respectively. These findings demonstrate that ETX induces dose-dependent hepatorenal toxicity in rats through an oxidative stress-mediated mechanism and provide relevant data for dietary risk assessment.