Hepatocellular carcinoma (HCC) is the primary type of liver malignancy, which stands as the third leading contributor to cancer-related death worldwide. Sodium butyrate (NaB), a gut microbiota-derived short-chain fatty a...Hepatocellular carcinoma (HCC) is the primary type of liver malignancy, which stands as the third leading contributor to cancer-related death worldwide. Sodium butyrate (NaB), a gut microbiota-derived short-chain fatty acid with known anticancer activity, remains poorly understood in HCC. This study aimed to elucidate the effects and underlying mechanisms of NaB-induced cuproptosis in HCC cells. 200 mg/kg NaB inhibits HCC tumor growth by 73.9% and induced a 1.83- and 6.83-fold increase in the Cu content and SLC31A1 protein expression, respectively. Furthermore, 5 mmol/L NaB inhibits cell viability by 35.4% and induced a 1.52-, 2.20-, 7.96-, 2.34-, and 2.24-fold increase in the cell number in G1 phase, Cu content and protein expression of SLC31A1, FDX1 and lipoic DLAT, respectively. NaB inhibits viability and cell cycle progression and promotes cuproptosis in HCC cells, which were revised by SLC31A1. NaB induces SLC31A1 expression by inhibiting HDAC1-induced decrease in the levels of H3K27ac, thus inhibiting HepG2 cell growth and promoting cuproptosis. SLC31A1 mRNA is positively correlated with Cu concentration, while HDAC1 mRNA is negatively correlated with both Cu concentration and SLC31A1 mRNA in patients with HCC. In conclusion, our findings indicate that NaB inhibits the HCC cell growth by targeting HDAC1-SLC31A1 axis-dependent cuproptosis.
Microplastics (MPs) are emerging environmental contaminants detected in biological fluids, including blood and follicular fluid, raising concern about their potential effects on mammalian reproduction. The present study...Microplastics (MPs) are emerging environmental contaminants detected in biological fluids, including blood and follicular fluid, raising concern about their potential effects on mammalian reproduction. The present study investigated whether polyethylene microplastics (PE-MPs; 10-30 μm), at concentrations reported in vivo, affect bovine oocyte maturation and subsequent embryonic development. Bovine cumulus-oocyte complexes were matured in vitro for 24 h in the presence of 0, 0.025, 0.5, or 1.5 μg/mL PE-MPs. Nuclear maturation, mitochondrial distribution, mitochondrial content, mitochondrial membrane potential (ΔΨm), intracellular glutathione (GSH) in oocytes, progesterone secretion by cumulus cells, and embryo development after in vitro fertilization were evaluated. PE-MPs exposure significantly impaired meiotic progression. Mitochondrial content decreased at all concentrations, accompanied by abnormal mitochondrial aggregation and altered distribution, particularly at intermediate concentration, whereas ΔΨm remained unchanged. Intracellular GSH levels were reduced at 0.5 and 1.5 μg/mL. In contrast, progesterone secretion and early embryo development were not affected. Nuclear maturation, mitochondrial aggregation and migration and GSH levels exhibited quadratic dose-response patterns, suggesting a non-monotonic response consistent with adaptive cellular stress rather than overt cytotoxicity. The combination of preserved bioenergetic activity with mitochondrial redistribution and oxidative imbalance indicates activation of mitochondrial quality-control mechanisms. These findings support an endocrine-disruptor-like mode of action affecting regulatory pathways controlling meiotic maturation rather than steroidogenic capacity. In conclusion, PE-MPs disrupt bovine oocyte maturation by targeting mitochondrial organization and redox homeostasis without compromising overall cellular viability or embryonic competence. The oocyte therefore represents a highly sensitive early indicator of reproductive toxicity.
A growing public health concern is the increased lung cancer incidence and mortality in women. Lung cancer prevalence in young non-smoking women and sex-specific disparities in clinical characteristics suggest other etio...A growing public health concern is the increased lung cancer incidence and mortality in women. Lung cancer prevalence in young non-smoking women and sex-specific disparities in clinical characteristics suggest other etiologic factors. Several studies have substantiated the pivotal role of estrogen and estrogen receptors (ER) in lung cancer initiation and progression. Therefore, investigating the impact of ubiquitous estrogen-mimicking chemicals in today's environment on lung cancer progression is pertinent. Here, we have used bisphenol A (BPA) as a representative xenoestrogen to treat human A549 lung cancer cell line. In addition to BPA, A549 cells have been treated with either pre- or post-menopausal estradiol (E2) concentrations (30 and 100 pg/mL), administered either concomitantly or cells have been pre-treated with E2 followed by BPA treatment. Cell proliferation, migration, ER expressions were measured. We have also measured the expressions of pEGFR, PI3K, p-Akt levels in response to E2 and BPA treatment. The ability of BPA to induce lung carcinogenesis has also been demonstrated in vivo in male and female Swiss Albino mice. The results obtained in this study demonstrate the involvement of BPA in lung cancer pathogenesis in vitro and in vivo. The study also showed increased lung cancer progression by BPA in presence of E2.
Risk assessments of genotoxic carcinogens often rely on deterministic approaches with unknown conservatism. Full probabilistic risk assessments include the quantification of uncertainties and population variability, but...Risk assessments of genotoxic carcinogens often rely on deterministic approaches with unknown conservatism. Full probabilistic risk assessments include the quantification of uncertainties and population variability, but are time- and data-intensive. The APROBA-Plus tool offers a (semi-)probabilistic alternative to quantify and visualize uncertainties in risk assessment. This paper evaluates the APROBA-Plus tool's applicability to the risk assessment of genotoxic carcinogens, by comparing deterministic and probabilistic approaches. The results show that APROBA-Plus effectively visualizes key uncertainties in risk assessments of genotoxic carcinogens. It can also compare exposure groups or separate components of mixtures. For the probabilistic approach, APROBA-Plus provides insight into the magnitude of uncertainty, the degree of conservativeness, the population coverage and possibilities for uncertainty reduction. Deterministic approaches are generally more conservative compared to the probabilistic approaches for the same substances, and do not provide these insights. In particular for genotoxic carcinogens, where uncertainty may be large, insight into these aspects may provide risk managers with more information, supporting decision taking on risk-reducing measures. Overall, APROBA-Plus can be the first tier in probabilistic risk assessment and will therefore facilitate the transition from deterministic to probabilistic risk assessment by providing a rapid, user-friendly means to incorporate uncertainty prior to more comprehensive analyses.
The ABCB1 polymorphisms may influence risperidone-induced extrapyramidal symptoms (EPS) in schizophrenia. This cross-sectional study examined the relationships among ABCB1 variants, clinical factors, and objective, subje...The ABCB1 polymorphisms may influence risperidone-induced extrapyramidal symptoms (EPS) in schizophrenia. This cross-sectional study examined the relationships among ABCB1 variants, clinical factors, and objective, subjective EPS in 150 patients receiving risperidone at Kasr al-Ainy Hospital, Cairo University, who were genotyped for ABCB1 (rs1045642) and assessed via BARS, SAS, and LUNSERS. The genotype frequencies were CC (44.7%), CT (40.7%), and TT (14.7%). EPS occurred more frequently in TT (59.1%) and CT (52.5%) carriers than in CC carriers (29.9%). Results revealed increased EPS risk for TT (OR = 3.39, P = 0.016) and CT (OR = 2.59, P = 0.010). In multivariate analysis, TT (OR = 15.77, 95% CI: 3.11-79.89, P = 0.001) and CT (OR = 5.51, 95% CI: 1.77-17.16, P = 0.003) remained independent predictors, whereas longer illness duration increased risk (OR = 1.089, 95% CI: 1.022-1.161, P = 0.008) and smoking was protective (OR = 0.31, 95% CI: 0.12-0.80, P = 0.015). The ABCB1 genotype significantly impacted subjective (LUNSERS; p = 0.012) and objective (SAS; p = 0.009), whereas objective (BARS) showed no significant association (p = 0.281). The ABCB1 TT and CT genotypes increase susceptibility to risperidone-induced EPS. These findings support using pharmacogenomic screening to guide personalized therapy and reduce EPS risk.
Pulmonary hypertension (PH) is a chronic and complex condition characterized by structural alterations in the pulmonary vasculature, leading to vascular remodeling, increased pulmonary vascular resistance, and heightened...Pulmonary hypertension (PH) is a chronic and complex condition characterized by structural alterations in the pulmonary vasculature, leading to vascular remodeling, increased pulmonary vascular resistance, and heightened vasoreactivity. Although nicotine exposure is demonstrated to adversely affect the structure and function of pulmonary arteries, the underlying molecular mechanisms remain incompletely elucidated. After eight weeks of nicotine exposure, right ventricular systolic pressure (RVSP) increased in a concentration-dependent manner with nicotine doses, accompanied by a progressive reduction in tricuspid annular plane systolic excursion (TAPSE). Nicotine-treated mice exhibited a significant increase in respiratory frequency, whereas expiratory flow at 50%, peak inspiratory flow, peak expiratory flow, and tidal volume showed concentration-dependent decreases. Furthermore, pulmonary arteries from nicotine-exposed mice displayed enhanced concentration-dependent contractions in response to vasoconstrictor. Notably, partial smooth-muscle Cx43 deficiency not only depressed the changes of RVSP, TAPSE and the pulmonary function parameters but also reduced pulmonary artery hyperreactivity. Additionally, nicotine treatment significantly inhibited the contractile response of pulmonary arteries to (4-AP), which was associated with decreased protein levels of Kv1.2 and Kv2.1. Importantly, partial smooth-muscle Cx43 deficiency reversed the nicotine-induced changes in pulmonary arterial hyperreactivity, Kv1.2 and Kv2.1 expression. Collectively, Cx43 upregulation, with subsequent downregulation of Kv1.2 and Kv2.1, drives nicotine-induced pulmonary arterial dysfunction.
BACKGROUND: Hepatic steatosis is increasingly prevalent in the U.S., alongside widespread exposure to per- and polyfluoroalkyl substances (PFAS), volatile organic compounds (VOCs), and heavy metals (HMs). While these tox...BACKGROUND: Hepatic steatosis is increasingly prevalent in the U.S., alongside widespread exposure to per- and polyfluoroalkyl substances (PFAS), volatile organic compounds (VOCs), and heavy metals (HMs). While these toxins have individually been linked to hepatic steatosis, few studies assess their combined effects. This study evaluates the association between multi-toxin exposure and hepatic steatosis. METHODS: NHANES 2017-2020 data were analyzed to identify participants with hepatic steatosis (FibroScan® CAP™ ≥238 dB/m). PFAS, VOCs, and HMs were measured in blood and urine. Hierarchical clustering generated four toxin-combination models, followed by logistic regression unadjusted and adjusted for confounders. Sensitivity analyses included bootstrap resampling and Firth logistic regression. RESULTS: In Model 4, clusters 1 and 2 had the highest odds of hepatic steatosis (OR 8.62 and 9.37, p < 0.001 vs. cluster 3), with elevated PFAS (cluster 1) and PFAS plus HMs (cluster 2). Higher risk was associated with female sex, Mexican American and Non-Hispanic Asian ethnicity, and higher income. Sensitivity analyses were consistent. CONCLUSION: Combined exposure to PFAS and HMs is linked to increased hepatic steatosis risk. Targeted public health interventions are needed to reduce these exposures.
Cavalcanti BC, Magalhães IL, Barreto FS
… +7 more, Dos Santos CAL, de Araújo Monteiro AA, de Andrade Neto JB, Magalhães HIF, de Oliveira Ferreira JR, Barros LM, de Moraes MO
Haloperidol (HP), an antipsychotic, has been associated with toxicological effects beyond its therapeutic actions. This study investigated its cytotoxic, genotoxic, mutagenic and oxidative stress potential in human lung...Haloperidol (HP), an antipsychotic, has been associated with toxicological effects beyond its therapeutic actions. This study investigated its cytotoxic, genotoxic, mutagenic and oxidative stress potential in human lung fibroblasts (MRC-5 cells) and in Drosophila melanogaster as an alternative in vivo model. In MRC-5 cells, HP reduced viability and increased lactate dehydrogenase release, accompanied by lipid and protein oxidation. HP also induced DNA strand breaks and oxidative DNA lesions (Fpg-sensitive sites), and elevated micronucleus formation with greater effects in the presence of the S9 fraction, suggesting the involvement of reactive metabolites. Furthermore, no mutagenicity was observed in Salmonella typhimurium. In D. melanogaster, chronic exposure to HP (7 days of treatment) impaired locomotor activity and decreased sulfhydryl group levels only at the highest concentration. These data on redox imbalance in D. melanogaster suggest there may be compensatory antioxidant mechanisms involved in the overall defense against oxidative stress. Molecular docking analysis revealed a stable interaction between HP and the mitochondrial complex I of D. melanogaster, suggesting that HP may cause disruption of electron transport and energy production. Collectively, these results demonstrate that HP triggers cytotoxic, genotoxic and mutagenic responses in MRC-5 cells along with redox imbalance in mammalian cells and in D. melanogaster.
Fluorides are widely used in oral care products to prevent dental caries. However, toxicological data on Olaflur, a relatively new fluoride compound in China, is limited. Three types of Olaflur were selected as test subs...Fluorides are widely used in oral care products to prevent dental caries. However, toxicological data on Olaflur, a relatively new fluoride compound in China, is limited. Three types of Olaflur were selected as test substances: cetylamine Olaflur, stearylamine Olaflur and oleylamine Olaflur. Skin irritation and sensitization tests were performed using reconstructed human epidermis models and the '2 out of 3' approach, respectively. For oral mucosal irritation testing, animal models were employed. The results showed that, at concentrations of 0.515% and 1.97%, none of the three compounds exhibited skin irritation. None of the three compounds showed sensitization potential. In oral mucosal irritation tests, at concentrations of 0.515% and 1.97%, all three compounds showed minimal or no irritation. Overall, under reasonable conditions of use, all three types of Olaflur are considered safe for use in oral care products.
INTRODUCTION: In the European Union (EU), the total use of diisocyanates is 2.5 million tons per year. Diisocyanates are highly reactive chemicals, containing two isocyanate functional groups. Diisocyanates are the main...INTRODUCTION: In the European Union (EU), the total use of diisocyanates is 2.5 million tons per year. Diisocyanates are highly reactive chemicals, containing two isocyanate functional groups. Diisocyanates are the main cause of occupational asthma in EU. The aim of this study was to assess metabolic changes in human plasma after occupational exposure to diisocyanates. METHODS: This study used samples and data provided by the EU project HBM4EU. The study population was recruited from Finland and Belgium, including 81 diisocyanate exposed workers and 40 controls. Non-targeted metabolomics was used to assess metabolic changes in plasma samples. Samples were analyzed with two distinct chromatographic retention mechanisms in both positive and negative ionization mode, measured with a high-resolution mass spectrometer. RESULTS: Differences in metabolite profiles between workers and controls were observed. Diisocyanate exposure was associated with higher 5-aminovaleric acid betaine, tetradecenoylcarnitine, lysophosphocholine 18:1 and lower N1-methyl-4-pyridone-3-carboxamide levels. Additionally, variations were observed in metabolite profiles between Finnish and Belgian individuals. CONCLUSIONS: This study is the first to assess metabolite changes in human plasma samples after occupational exposure to diisocyanates. These preliminary results suggest that exposure to diisocyanates may affect fatty acid metabolism, but the observations need to be validated in future studies.
Acrylamide (AA) is a contaminant present in foods cooked at high temperatures, and its formation is associated with the Maillard reaction. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon mucosa wit...Acrylamide (AA) is a contaminant present in foods cooked at high temperatures, and its formation is associated with the Maillard reaction. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon mucosa with a complex pathogenesis. This study investigated the effects of AA exposure on UC and its potential mechanisms. First, network toxicology was employed to identify genes that are targets associated with both the toxicity of AA and the pathogenesis of UC, which are enriched in pathways associated with inflammatory cascades and immune cell recruitment. Then, Mendelian randomization was employed to identify two risk proteins (CCL5 and CXCL10) associated with AA and UC. Molecular docking and molecular dynamics simulations revealed that CXCL10 exhibits the strongest binding affinity with AA, and the complex is stable. Furthermore, animal studies have found that AA exposure alone does not induce typical colitis manifestations in mice. However, AA exposure exacerbated the colitis phenotype in the DSS-induced model. CXCL10 has been identified as a potential key target in the process by which AA increases susceptibility to UC. These findings provide scientific grounds for reassessing the safety of AA and offer new insights into understanding the environmental risks of UC and potential intervention targets.
In our previous work, we isolated a novel bisphenol named capillarisenol C (Cap C) from Artemisia capillaris. The preliminary activity screening study showed that Cap C can cause cytotoxicity to hepatocellular carcinoma...In our previous work, we isolated a novel bisphenol named capillarisenol C (Cap C) from Artemisia capillaris. The preliminary activity screening study showed that Cap C can cause cytotoxicity to hepatocellular carcinoma cells, but its mechanism is still largely unclear. In this study, we confirmed that Cap C sharply reduced the viabilities of HepG2 and Huh7 cells in a concentration- and time-dependent manner by using CCK8 assay. We aimed to investigate the molecular mechanism underlying the cytotoxicity of Cap C in liver cancer cells. The mechanism study results showed that the apoptosis inhibitor z-vad-fmk had no significantly effects on Cap C-induced HepG2 cell death. Further mechanistic studies showed that MAP1LC3-II (LC3-II) expression, LC3 puncta and GFP-p62 puncta were increased under Cap C treatment. In addition, Cap C-induced cell death was attenuated by treatment with chloroquine (CQ) or knockdown of autophagy-related gene 7 (ATG7). Western blot analysis showed that Cap C treatment led to activation ER stress protein sensors EIF2AK3/PERK and ERN1/IRE1 as well as EIF2A/eIF2α phosphorylation which have been reported to promote cytotoxic autophagy in cancer cells. Moreover, Cap C-induced cell death was abrogated with the ER stress inhibitor 4-phenylbutyrate (4-PBA) treatment. Our results demonstrated that Cap C led to autophagic cell death in liver cancers potentially by activating ER stress-related PERK- eIF2α axis and IRE1 upregulation.
Exposure to certain pesticides remains a significant environmental and public health concern due to their capacity to induce oxidative damage in vital organs. Deltamethrin (DEL), a widely used synthetic pyrethroid, disru...Exposure to certain pesticides remains a significant environmental and public health concern due to their capacity to induce oxidative damage in vital organs. Deltamethrin (DEL), a widely used synthetic pyrethroid, disrupts hepatic function primarily through oxidative stress-mediated mechanisms. This study investigated the protective effects of spinosin (SP) and carvacrol (CAR), administered individually or in combination, against DEL-induced liver toxicity and explored the underlying molecular pathways. Hepatic injury was induced in male Swiss albino mice by oral gavage of DEL (15 mg/kg bw). SP and CAR were administered at 50 mg/kg bw, either alone or in combination, while silymarin (50 mg/kg bw) served as a reference compound. All treatments were administered once daily for 28 consecutive days. DEL exposure significantly reduced SOD, CAT, GSH, and PGE2 levels, accompanied by downregulation of HO-1, Nrf2, and Bcl-2 expression. Conversely, levels of ALP, ALT, AST, MDA, NO, TNF-α, IL-1β, IL-6, Bax, and Cas-3 were significantly increased. Treatment with SP and CAR ameliorated these alterations, with combined administration demonstrating greater efficacy than monotherapy. Overall, the findings suggest that SP and CAR co-treatment may exert enhanced hepatoprotective effects, potentially through coordinated regulation of oxidative stress, inflammation, apoptosis, and activation of the Nrf2/HO-1 signaling pathway.
Currently, sulfonylureas, a class of medications used in type 2 diabetes mellitus (T2DM) treatment, are widely applied, but the problem of secondary failure isn't fully understood. This study aims to explore the potentia...Currently, sulfonylureas, a class of medications used in type 2 diabetes mellitus (T2DM) treatment, are widely applied, but the problem of secondary failure isn't fully understood. This study aims to explore the potential mechanisms of secondary failure of sulfonylureas (SFS) and to identify reliable predictive biomarkers. In this study, 16S rDNA sequencing technology and non-targeted metabolomics were used to analyze the differences in gut microbiota and metabolic products between the SFS and sulfonylurea effective (SE) groups. The results of 16S rDNA sequencing indicated that there are differences in composition between two groups. Seventeen different bacterial types were identified, including six types from SFS patients and eleven from SE. SFS might be linked to disturbances in energy metabolism, amino acid metabolism, nucleotide metabolism, and lipid metabolism within the gut microbiota. Metabolomics results showed 66 different metabolites between two groups (49 metabolites were upregulated, and 17 metabolites were downregulated). Correlation analysis between gut bacteria and fecal metabolites revealed that 4 types of gut bacteria were significantly linked to 5 types of metabolites. This study reveals distinct gut microbiota composition in patients with sulfonylurea secondary failure, helping us understand changes in gut metabolites and providing new biomarkers for personalized treatment.
The potential health impacts of nanoplastic exposure have attracted significant scientific interest, with emerging evidence linking their presence to various human diseases. Alarmingly, polystyrene nanoplastics (PS-NPs)...The potential health impacts of nanoplastic exposure have attracted significant scientific interest, with emerging evidence linking their presence to various human diseases. Alarmingly, polystyrene nanoplastics (PS-NPs) have been detected in brain tissues, showing their capability to penetrate the blood-brain barrier (BBB). However, most previous animal studies used high-dose acute exposures, which may not properly reflect the common long-term, low-dose exposure scenarios in real-world. Thus, we conducted a 17-month exposure study in mice using PS-NPs with significantly lower dosage and assessed their behavior and brain damage. Our results demonstrated that prolonged exposure induced oxidative stress in the brain with significantly elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as activated immune responses, including microglial activation (Iba1+) and increased release of inflammatory cytokines, indicating a chronic inflammatory state in the brain. In behavioral experiments, only the elevated plus maze (EPM) showed significant differences, however, pathways linked to neurodegenerative diseases like Parkinson disease were notably upregulated. This unfavorable molecular network restructuring may heighten the risk for such disorders. These findings provide critical evidence for the adverse neural effects of long-term, low-dose PS-NPs exposure, thus laying the ground for further more detailed investigation and offering insights for future health interventions and preventive strategies.
Chronic arsenic (As)-exposure leads to behavioral and biochemical changes both in humans and laboratory animals. However, post-exposure self-recovery after prolonged As-exposure remains unclear. This study evaluated the...Chronic arsenic (As)-exposure leads to behavioral and biochemical changes both in humans and laboratory animals. However, post-exposure self-recovery after prolonged As-exposure remains unclear. This study evaluated the effects of As-exposure via drinking water (5 mg/kg body-weight/day) for 60 days and post-exposure self-recovery at 30-, 45-, and 60-days on behavioral and biochemical alterations in a mouse model. As-exposure mice exhibited augmented anxiety, impaired memory, and decreased motor coordination compared to controls. Furthermore, diminished cholinesterase and antioxidant environment, increased inflammation, and elevated Fe levels were observed in brains of As-exposed mice. However, after stopping drinking As-contaminated water, recovery groups showed less anxiety, improved memory, and motor coordination. Moreover, levels of Nrf2, HO-1, and GSH, and activities of SOD, AChE, and BChE were significantly increased in brains of 45- and 60-days recovery groups compared to As-exposed group. Besides, remarkably reduced Fe and MDA levels, concurrent with increased GPx4 activities in brains of the 45- and 60-days recovery groups, indicate attenuation of ferroptosis. Additionally, 45- and 60-days recovery groups showed decreased levels of IL-1β and IL-6, while increased IL-10 levels indicated reduced inflammation. These results suggest that stopping As-intake facilitates the attenuation of oxidative stress-mediated anxiety, cognitive, and motor coordination impairment in As-exposed mice.
This study explored the molecular mechanisms underlying zearalenone (ZEA)-induced damage in porcine intestinal epithelial cells (IPEC-J2), focusing on oxidative stress and inflammatory pathways. Cells were exposed to ZEA...This study explored the molecular mechanisms underlying zearalenone (ZEA)-induced damage in porcine intestinal epithelial cells (IPEC-J2), focusing on oxidative stress and inflammatory pathways. Cells were exposed to ZEA (0-100 μM), and assessments included cell viability (CCK-8 assay), oxidative stress markers (ROS, SOD, CAT, GSH-Px, MDA), inflammatory cytokines (ELISA, RT-qPCR), and Nrf2/NF-κB pathway proteins (Western blot). RESULTS: ZEA dose-dependently reduced viability, elevated ROS and MDA, and suppressed antioxidant enzyme activities. It also upregulated TNF-α, IL-1β, IL-6, and IL-8 expression. Mechanistically, ZEA inhibited Nrf2 nuclear translocation and downstream antioxidant genes (HO-1, NQO1) while promoting NF-κB p65 activation. Notably, NAC pretreatment alleviated ZEA-induced inflammation, and BAY11-7082 reduced oxidative stress, indicating pathway crosstalk. CONCLUSIONS: ZEA disrupts intestinal homeostasis by suppressing Nrf2-mediated antioxidant defense and triggering NF-κB-driven inflammation. These insights enhance understanding of ZEA toxicity and support the development of targeted protective strategies.
Dimyricetin-yl-diselenide (DMS; 3,5,7-trihydroxy-8-[[3,5,7-trihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chromen-8-yl]diselanyl]-2-(3,4,5-trihydroxyphenyl)chromen-4-one) is a structurally defined organoselenium flavonoid di...Dimyricetin-yl-diselenide (DMS; 3,5,7-trihydroxy-8-[[3,5,7-trihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chromen-8-yl]diselanyl]-2-(3,4,5-trihydroxyphenyl)chromen-4-one) is a structurally defined organoselenium flavonoid dimer in which two dihydromyricetin units are linked via a diselenide (Se-Se) bond. Due to the potential redox activity and thiol reactivity of certain selenium species, a systematic genotoxicity evaluation is required prior to further application. Therefore, in the present study, the genotoxic potential of DMS was assessed using a bacterial reverse mutation (Ames) assay and two in vivo assays in mice, namely the mammalian erythrocyte micronucleus test and the bone marrow chromosomal aberration test, in accordance with relevant Chinese and OECD Test Guidelines. The selected in vivo dose levels were based on acute oral toxicity data showing that the LD of DMS was greater than 5 g/kg BW in mice, thereby supporting the use of high-dose settings for genotoxicity assessment. In the Ames test, DMS (625-5000 μg/plate) did not increase revertant colony counts in five Salmonella typhimurium strains (TA97a, TA98, TA100, TA102, and TA1535), either in the presence or absence of S9 metabolic activation, while all positive controls showed expected responses. In the in vivo micronucleus assay, DMS (1.25-5.0 g/kg body weight, BW) did not affect the PCE/RBC ratio and did not increase the frequency of micronucleated polychromatic erythrocytes in either sex. In the bone marrow chromosomal aberration test, DMS (0.625-2.5 g/kg BW) did not increase the frequency of aberrant metaphase cells compared with the negative control, whereas cyclophosphamide induced marked increases in chromosomal aberrations. Collectively, DMS did not exhibit mutagenic, clastogenic, or aneugenic effects under the experimental conditions employed. These findings provide initial evidence supporting the safety profile of DMS and its potential for further development as a functional food ingredient or therapeutic candidate.
Api AM, Bartlett A, Belsito D
… +31 more, Botelho D, Bruze M, Bryant-Friedrich A, Burton GA, Cancellieri MA, Chon H, Cronin M, Crotty S, Dagli ML, Dekant W, Deodhar C, Farrell K, Fryer AD, Jones L, Joshi K, Lapczynski A, Laskin DL, Lavelle M, Lee I, Moustakas H, Muldoon J, Penning TM, Piersma AH, Ritacco G, Sadekar N, Schember I, Schultz TW, Siddiqi F, Sipes IG, Sullivan G, Thakkar Y