Toxicology and applied pharmacology最新文献

{"title":"Integrative analysis of levofloxacin-induced liver injury: Insights from pharmacovigilance, human liver organoids, and extracellular vesicle proteomics","authors":"Shiyi Tan ,&nbsp;Yun Yang ,&nbsp;Yu-Han Cai ,&nbsp;Yuepu Pu ,&nbsp;Zhongze Gu ,&nbsp;Juan Zhang","doi":"10.1016/j.taap.2025.117576","DOIUrl":"10.1016/j.taap.2025.117576","url":null,"abstract":"<div><h3>Background</h3><div>Levofloxacin (LVX), a widely used fluoroquinolone antibiotic, is generally considered to have low hepatotoxic potential compared to its analog trovafloxacin (TVX). Although considered relatively safe, LVX has been implicated in Drug-induced liver injury (DILI) cases, prompting the need for a comprehensive mechanistic assessment.</div></div><div><h3>Methods</h3><div>This study employed an integrated strategy combining real-world pharmacovigilance analysis based on FDA Adverse Event Reporting System (FAERS), human liver organoid modeling, and extracellular vesicle (EV) proteomics to systematically assess LVX-associated DILI risks and mechanisms.</div></div><div><h3>Results</h3><div>A total of 1671 LVX-related DILI cases were identified in FAERS, with a predominance in males and individuals aged 45–65. Disproportionality analysis revealed statistically significant signals indicative of cholestatic liver injury phenotypes, including mixed liver injury, cholestasis, and conjugated hyperbilirubinemia, etc. Furthermore, liver organoid assays revealed that LVX induced moderate hepatocellular injury, which was less severe than that caused by TVX. EV proteomic analysis from LVX-exposed organoids identified glycolysis as the most significantly enriched pathway, with notable upregulation of phosphoglycerate kinase 1 (PGK1), lactate dehydrogenase A (LDHA), and fructose-bisphosphate aldolase A (ALDOA). The expression of these three key glycolysis-related targets was further validated by RT-qPCR and proteomic analysis, and molecular docking demonstrated strong binding affinities between LVX and these proteins. Collectively, these findings suggest that glycolytic reprogramming may contribute to the pathogenesis of LVX-induced liver injury.</div></div><div><h3>Conclusions</h3><div>This study presents a multidimensional strategy to investigate LVX-induced liver injury by integrating real-world pharmacovigilance data with a human liver organoid model. Together, these findings provide a translational framework for elucidating DILI.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117576"},"PeriodicalIF":3.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress and apoptotic pathways mediate BDE-47-induced reproductive dysfunction and offspring skeletogenesis disruption in zebrafish","authors":"Xiaoling Shi ,&nbsp;Han Xie ,&nbsp;Yimin Zhang ,&nbsp;Xingbo Wang ,&nbsp;Congying Luo ,&nbsp;Kusheng Wu ,&nbsp;Wenlong Huang","doi":"10.1016/j.taap.2025.117575","DOIUrl":"10.1016/j.taap.2025.117575","url":null,"abstract":"<div><div>2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47) has been recognized as a potential hazard to the reproductive systems of organisms. However, the reproductive toxicity and transgenerational effects of BDE-47 in female remain insufficiently characterized. In this study, we systematically investigated the reproductive performance, sex hormone levels, ovarian morphology, expression of genes associated with the hypothalamic-pituitary-gonadal (HPG) axis, and ovaries apoptotic responses following a 21-day exposure to BDE-47 in female zebrafish. Furthermore, we examined the intergenerational impacts of BDE-47 on unexposed F1 larvae by evaluating craniofacial skeletons and vertebrae development, oxidative stress responses, and apoptotic activity. In female zebrafish, our findings indicate that exposure to BDE-47 significantly compromised somatic indices (CF and GSI), diminished levels of steroid hormones (FSH, LH, T, and E₂), and disrupted ovarian histoarchitecture and oocyte development. These deleterious effects are likely attributable to the dysregulation of genes associated with the HPG axis and the exacerbation of apoptotic processes specifically within ovarian tissue. In F1 larvae, maternal BDE-47 exposure altered the transcriptional levels of genes involved in bone development (<em>dlx2a, col2a1, sp7</em>), resulting in malformations of the craniofacial skeleton and vertebrae. Additionally, BDE-47 exposure upregulated the activity of antioxidant enzyme (CAT), and modified the expression of oxidative stress-related genes (<em>sod</em>, <em>cat</em>, <em>gpx</em>) and apoptosis-related genes (<em>bcl2a</em>, <em>baxa</em>), indicating the activation of oxidative stress and apoptotic pathways. Collectively, our study suggest that exposure to BDE-47 not only compromises female reproductive health but also has lasting effects on offspring health, likely through mechanisms involving oxidative stress and apoptosis. The transgenerational impact, especially regarding skeletal and developmental malformations, highlights the possible hazards associated with environmental contaminants like BDE-47 on aquatic organisms and potentially, on human health.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117575"},"PeriodicalIF":3.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative potential and cellular toxicity of carbonaceous aerosols undergoing aging in an atmospheric simulation chamber","authors":"Virginia Vernocchi ,&nbsp;Marco Brunoldi ,&nbsp;Silvia Canepari ,&nbsp;Emanuela Corsini ,&nbsp;Tommaso Isolabella ,&nbsp;Lorenzo Massimi ,&nbsp;Federico Mazzei ,&nbsp;Gloria Melzi ,&nbsp;Marco Paglione ,&nbsp;Sofia Pantaleoni ,&nbsp;Paolo Prati ,&nbsp;Marco Rapuano ,&nbsp;Matteo Rinaldi ,&nbsp;Caterina Tiraboschi ,&nbsp;Dario Massabò","doi":"10.1016/j.taap.2025.117573","DOIUrl":"10.1016/j.taap.2025.117573","url":null,"abstract":"<div><div>This study investigates how chemical composition, atmospheric aging, and environmental conditions affect the oxidative potential (OP) and cellular toxicity of soot particles using an atmospheric simulation chamber (ASC). In the ASC ChAMBRe were simulated real-world summer and winter scenarios, exposing pure soot particles (generated by using the mini-inverted soot generator) and various secondary aerosol precursors (i.e., toluene, 2,5-dimethylfuran and α-pinene) alternatively to light or dark conditions and different oxidants. OP was assessed using multiple assays (namely, 2′,7′-dichlorofluorescein – DCFH, Dithiothreitol - DTT and Ascorbic Acid – AA), revealing that soot particles exposed to light, especially in presence of toluene, exhibited higher OP. The presence of toluene also increased cellular reactive oxygen species (ROS) production, leading to elevated cytotoxicity, DNA damage, and release of the proinflammatory cytokine interleukin-8 (IL-8) in BEAS-2B cells. Ammonium sulfate addition reduced OP and do not enhance toxicological responses, suggesting that non-toxic components in aged particulate matter (PM) may mitigate some harmful effects. Toxicological assessment showed increased cytotoxicity, genotoxicity, oxidative stress, and inflammatory responses in soot generated under high irradiance conditions typical of summer and traffic environments, compared to low irradiance winter scenarios. Strong correlations were observed between OP and toxicological endpoints, such as ROS formation, LDH release, micronuclei formation, and IL-8 secretion underscoring the role of chemical composition and environmental aging in determining PM toxicity. The study highlights OP assays as a reliable tool for predicting PM-induced oxidative stress and potential health effects, emphasizing the importance of considering soot chemical composition and aging processes in urban air pollution assessments.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117573"},"PeriodicalIF":3.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoflurane aggravates cognitive deficits in aged rats via lncRNA GABPB1-AS1/miR-361-3p-mediated NLRP3 inflammasome activation","authors":"Guorui Miao ,&nbsp;Yiwei Zhang ,&nbsp;Hui Wang","doi":"10.1016/j.taap.2025.117571","DOIUrl":"10.1016/j.taap.2025.117571","url":null,"abstract":"<div><h3>Objective</h3><div>Postoperative cognitive dysfunction (POCD) following isoflurane (ISO) anesthesia in elderly patients is associated with neuroinflammation, but the molecular mechanisms remain unclear. This study aimed to elucidate the role and mechanism of long non-coding RNA (lncRNA) GA binding protein beta 1 subunit antisense RNA 1 (GABPB1-AS1) in ISO-induced POCD.</div></div><div><h3>Methods</h3><div>Aged rats were exposed to ISO to establish a POCD model. Cognitive deficits were assessed via morris water maze tests. Hippocampal expression of GABPB1-AS1, microglial activation markers (Iba1), pro−/anti-inflammatory cytokines, and NLRP3 inflammasome components was quantified using quantitative Reverse Transcription-PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blotting. In vitro, BV-2 microglia treated with ISO were analyzed for polarization markers and cytokine secretion. Dual-luciferase assays validated interactions between GABPB1-AS1, microRNA-361-3p (miR-361-3p), and NLR family pyrin domain containing 3 (NLRP3).</div></div><div><h3>Results</h3><div>ISO upregulated hippocampal GABPB1-AS1 in aged rats, correlating with prolonged escape latency, reduced target quadrant time, and elevated pro-inflammatory cytokines. GABPB1-AS1 knockdown reversed these effects. In microglia, ISO increased GABPB1-AS1 expression, M1 polarization markers, and NLRP3 inflammasome activation, while suppressing M2 markers and miR-361-3p. GABPB1-AS1 acted as a competing endogenous RNA (ceRNA) to sponge miR-361-3p, relieving translational inhibition of NLRP3 and activating the NLRP3 inflammasome. GABPB1-AS1 knockdown restored miR-361-3p expression, suppressed NLRP3 inflammasome activation, and attenuated ISO-induced microglial M1 polarization and neuroinflammatory responses.</div></div><div><h3>Conclusion</h3><div>ISO induces POCD via the GABPB1-AS1/miR-361-3p/NLRP3 axis, driving microglial M1 polarization and neuroinflammation. Targeting this axis may offer therapeutic strategies to mitigate anesthesia-related cognitive decline in elderly patients.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117571"},"PeriodicalIF":3.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lutein inhibits ferroptosis and reduces neuronal cell death induced by Parkinson's disease through the NRF2-HMOX2 signaling axis","authors":"Jiabin Duan ,&nbsp;Wenbin Duan ,&nbsp;Xiaomin Pu ,&nbsp;Changdi Ma ,&nbsp;Huai Huang ,&nbsp;Zhenghu Xu","doi":"10.1016/j.taap.2025.117570","DOIUrl":"10.1016/j.taap.2025.117570","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the role of lutein in the inhibition of ferroptosis in neurons induced by Parkinson's disease (PD) and the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>PD animal and cellular models were established by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and treatment with 1-methyl-4-phenylpyridinium (MPP⁺) in SH-SY5Y cells. Behavioral tests, immunohistochemistry, and hematoxylin–eosin (HE) staining were employed to evaluate motor function and neuronal damage. Oxidative stress and ferroptosis-related markers were assessed using commercial assay kits and flow cytometry.</div></div><div><h3>Results</h3><div>Lutein treatment significantly alleviated MPTP-induced motor deficits in PD model mice and increased the number of tyrosine hydroxylase (TH)-positive neurons. Furthermore, lutein attenuated MPTP/MPP⁺-induced neuronal ferroptosis, as indicated by decreased Fe²⁺ and ACSL4 levels and elevated FTH1 and SLC7A11 expression—all of which were reversed by the ferroptosis activator erastin. Molecular docking and Western blot analyses demonstrated that lutein upregulated SOD1/2 and GPX1/2/3 expression. Notably, lutein treatment increased SOD and GSH levels while reducing MDA and ROS levels, indicating its neuroprotective role via antioxidant activation. Mechanistically, exposure to MPTP/MPP⁺ markedly suppressed NRF2 and HMOX2 expression, whereas lutein restored these levels; this protective effect was diminished by the NRF2 inhibitor ML385, which counteracted the suppression of oxidative stress and ferroptosis by lutein.</div></div><div><h3>Conclusion</h3><div>Lutein reduces dopaminergic neuronal death by promoting the expression of SOD1/2 and GPX1/2/3 and inhibiting PD ferroptosis through the activation of the NRF2–HMOX2 signaling pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117570"},"PeriodicalIF":3.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effects of berberine on hyperammonemia-associated neuroinflammation in thioacetamide-induced hepatic encephalopathy","authors":"Syed Afroz Ali ,&nbsp;Ashok Kumar Datusalia","doi":"10.1016/j.taap.2025.117569","DOIUrl":"10.1016/j.taap.2025.117569","url":null,"abstract":"<div><div>Persistent hyperammonaemia and neuroinflammation are the hallmarks of hepatic encephalopathy (HE), a severe central nervous system (CNS) disorder. Berberine (BBR) showed potent anti-inflammatory activities in various diseases. However, its underlying mechanisms and potential therapeutic benefits in HE remain unclear, necessitating further mechanistic studies. In the current investigation, we evaluated the therapeutic effects of BBR on neurobehavior, blood-brain barrier (BBB) permeability and brain histology in TAA-induced HE rats. The animal model of HE was induced by three repeated doses of TAA 300 mg/kg <em>i.p.</em> Animals were treated with BBR 100 mg/kg orally once daily for 3 days. The administration of TAA aggravated neurobehavioral alterations, ammonia, cerebral edema and impaired BBB permeability. The cortex and hippocampus tissue showed significant microglial and astrocyte activation, increased inflammatory markers such as IL-1β, TNF-α, IL-6, and NLRP3 inflammasome signalling cascade (caspase-1, ASC, NLRP3, and NF-κB) in TAA group compared to control. Moreover, increased tissue injury and expression of gasdermin-D and reduced neuronal markers (NeuN and MAP-2) were detected in cortex and hippocampus of TAA group. To this end, BBR post-treatment averted the TAA-induced behavioral alterations, cerebral edema and BBB leakage. Additionally, BBR reduced the TAA-induced aforementioned neuroinflammatory and histopathological changes in the cortex and hippocampus. In conclusion, this study demonstrates that BBR post-treatment significantly inhibits the progression of HE by modulating HMGB1/NF-κB/NLRP3 signalling pathway. Overall, these findings highlight the potential of BBR as a promising therapeutic agent to manage HE.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117569"},"PeriodicalIF":3.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicokinetics and in vivo genotoxicity after single dose oral gavage and intravenous administration of N-Nitrosonornicotine in Sprague Dawley rats","authors":"Mamata De ,&nbsp;Ashley Fields ,&nbsp;Guy Lagaud","doi":"10.1016/j.taap.2025.117572","DOIUrl":"10.1016/j.taap.2025.117572","url":null,"abstract":"<div><div>N-Nitrosonornicotine (NNN) is a tobacco specific nitrosamine (TSNA) and a known human carcinogen. NNN is mutagenic in bacterial mutation assay. The dose response and a correlation between its exposure and genotoxic mode of action is not well characterized. In this study, we evaluated the toxicokinetics (TK) of NNN via oral gavage (PO) and intravenous (IV) administration. In addition, genotoxicity assays, such as comet assay and micronucleus assay were conducted using different tissues as a toxicodynamic endpoints. The genotoxicity of NNN in the select target organs of toxicity in vivo was studied in rats following NNN exposure. A single dose of 0.24 μg/kg, 2.4 μg/kg, or 24 μg/kg of NNN (mixture of 70 % R and 30 % S) and 0.9 % saline (vehicle control) was acutely administered in male Sprague-Dawley (SD) rats (9–10 weeks age) via PO and IV administrations. Plasma, urine, and tissue specimens were collected at designated timepoints and analyzed for levels of NNN and its major metabolites, (<em>R</em>, <em>S</em>)-Nornicotine (NN) and N′-nitrosonornicotine-1-N-oxide (NNN-N-Oxide); and DNA from various tissues were evaluated for the genotoxic potential of NNN using in vivo alkaline comet assay. Following IV administration, tail migration increased compared to that of the vehicle control in peripheral blood, bronchoalveolar lavage (BAL), liver, kidney, and bone marrow. These increases were mostly dose dependent. Similar changes were seen for tail moments in peripheral blood lymphocytes (PBLs), BAL, and liver. Similarly to the IV administration, tail migration showed treatment related effects following PO administration. Tail migration in liver, kidney, duodenum, bone marrow, and BAL showed statistically significant increase in length compared to that of the vehicle control. TK data analysis indicated that NNN was rapidly absorbed and metabolized to NNN-N-Oxide after NNN administration via the two routes as shown by the short half-life (T_1/2 = 1.25–2.5 h). While NNN concentration was not quantifiable in plasma at low dose, systemic exposure as indicated by C_max and AUC was found to be increased in a dose proportional manner between the mid and high NNN exposure groups in the plasma samples following the PO and IV administration. Similarly, urinary excretions of NNN showed a dose proportional increase between the mid and high NNN after PO and IV administrations. Overall, the results suggest that the different tissue-specific genotoxic profiles are mainly due to the different effective doses of NNN resulting from the route of administration. First pass metabolism may play a role in enhancing NNN genotoxicity via the PO route as indicated by positive comet assay results from different target organs of toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117572"},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrahydroxy stilbene glucoside for alleviating osteoporosis: Elevating autophagy to attenuate osteoblast dysfunction mediated by the AMPK/mTOR/ULK1 pathway","authors":"Wenqi Jin ,&nbsp;Manying Wang ,&nbsp;Yu Wang ,&nbsp;Jing Wang ,&nbsp;Chunlei Ji ,&nbsp;Shuai Zhang ,&nbsp;Liwei Sun","doi":"10.1016/j.taap.2025.117562","DOIUrl":"10.1016/j.taap.2025.117562","url":null,"abstract":"<div><div>Osteoporosis, a systemic metabolic disease, typically leads to osteogenic dysfunction with aging, which is the primary mechanism underlying the decrease in bone mass and strength. <em>Polygonum multiflorum</em> Thunb., a Chinese botanical drug known for kidney-tonifying and bone-fortifying effects, comprises 2,3,5,4′-Tetrahydroxy stilbene-2-O-β-d-glucoside (TSG) as its key component, which demonstrates potential for preventing and managing osteoporosis. However, its specific role in oxidative stress-induced osteoblast dysfunction remains unclear. Here, we constructed osteoblasts model of oxidative damage and a mouse model of senile osteoporosis. Alkaline phosphatase (ALP) and Alizarin Red S staining analysis, as well as histological, trabecular microstructure and indexes of bone metabolism were used to evaluate osteogenic function. Flow cytometry, western blot and qRT-PCR were employed to identify apoptosis and autophagy pathways affected by TSG. The results showed that TSG pretreatment significantly reduced apoptosis and suppressed mitochondrial apoptosis pathway proteins in H₂O₂-exposed osteoblasts, thereby mitigating oxidative damage. TSG also increased ALP expression, mineralization, and the expression of osteogenic factors. Furthermore, TSG aggravated autophagy induced by H₂O₂, while the anti-apoptotic and mineralization-promoting effects were inhibited by 3-methyladenine and enhanced by rapamycin. Mechanistically, TSG resulted in the activation of the AMPK/mTOR/ULK1 pathway, which was partially reversed by AMPK inhibition, thereby ameliorating osteoblast dysfunction. Finally, we confirmed that TSG treatment reversed bone loss by improving trabecular microstructure, balancing bone metabolic factors, and enhancing bone morphogenetic protein expression. Collectively, our findings provide a potential therapeutic strategy for alleviating osteoporosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117562"},"PeriodicalIF":3.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotoxicity and effects of gut microbiota in chicks exposed to low doses of deoxynivalenol and 15-acetyl-deoxynivalenol","authors":"Wandi Bu ,&nbsp;Xinyao Wu ,&nbsp;Zhihang Zhong ,&nbsp;Yaping Fang ,&nbsp;Shuang Chen ,&nbsp;Jun Jiang ,&nbsp;Yiqun Deng","doi":"10.1016/j.taap.2025.117568","DOIUrl":"10.1016/j.taap.2025.117568","url":null,"abstract":"<div><div>Deoxynivalenol (DON) contamination in animal feed threatens livestock health due to chronic low-dose exposure and masked forms. 15-acetyl-deoxynivalenol (15ADON), a major masked form, exhibits stronger toxicity than DON in cell models, yet <em>in vivo</em> data, particularly in poultry, remain scarce. To address this gap, 1-day-old chickens were fed diets containing 3 mg/kg DON, 3 mg/kg 15ADON, or a combination of 1.5 mg/kg each. Immunotoxicity and cecal microbiota were evaluated through immune parameters and 16S rRNA sequencing. To examine cumulative effects, chickens were also exposed to low-dose DON at different developmental stages. Both DON and 15ADON induced evident immunotoxicity, including immune organ damage. Compared with controls, 15ADON reduced antibody titers against infectious bronchitis and Marek's disease viruses by 30 % and IgM levels by 50 % during early immune development. Co-exposure produced no synergistic effects, whereas prolonged low-dose DON exposure initially enhanced antibody production but later caused a 20–50 % decline relative to controls. Microbiota analysis revealed an increased abundance of Lactobacillus in DON and 15ADON treated groups, while overall microbial richness and diversity remained unchanged. These findings demonstrate that 15ADON exerts comparable immunotoxicity to DON, highlight the importance of exposure timing and duration, and reveal masked mycotoxins as underappreciated risks in poultry production. Our results provide valuable <em>in vivo</em> evidence to support the reassessment of regulatory limits and further investigation into masked mycotoxin toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117568"},"PeriodicalIF":3.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emodin enhances the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived extracellular vesicles in acute pancreatitis-induced lung injury","authors":"Beiyun Dong ,&nbsp;Xiong Liu ,&nbsp;Xiaodong Huang ,&nbsp;Siyao Liu ,&nbsp;Jun Hu ,&nbsp;Xianwei Huang ,&nbsp;Jiyan Lin","doi":"10.1016/j.taap.2025.117566","DOIUrl":"10.1016/j.taap.2025.117566","url":null,"abstract":"<div><div>Acute pancreatitis (AP) frequently leads to acute lung injury, a major contributor to AP-related mortality. Emodin, a natural anti-inflammatory compound, shows therapeutic promise. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) also exhibit intrinsic therapeutic properties against AP-associated lung injury. This study investigated whether encapsulating emodin into these EVs (EVs-Emodin) enhances their protective effects in alleviating lung injury caused by AP-triggered systemic inflammation.EVs-Emodin were encapsulated into hUC-MSC-EVs and compared with free emodin in vitro using TNF-α-treated BEAS-2B lung epithelial cells and in vivo using a sodium taurocholate (STC)-induced AP mouse model. Cell viability, apoptosis, ROS production, inflammatory cytokine release, mitochondrial morphology, and pyroptosis markers were assessed using CCK-8, flow cytometry, ELISA, qPCR, transmission electron microscopy, Western blotting, and immunostaining.EVs-Emodin exhibited effective uptake and significantly improved BEAS-2B cell viability compared to emodin or hUC-MSC-EVs alone. They also more effectively reduced TNF-α-induced apoptosis, ROS accumulation, inflammatory cytokine production, and pyroptotic signaling. In AP mice, EVs-Emodin administration is more efficient in preserving lung tissue structure, restoring lung epithelial proliferation, and reducing inflammation and pyroptosis.Encapsulation of emodin in hUC-MSC-EVs significantly enhances their therapeutic efficacy against AP-induced lung injury. EVs-Emodin represent a promising strategy for targeted treatment of inflammatory complications in AP.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117566"},"PeriodicalIF":3.4,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}