Toxicology and applied pharmacology最新文献

{"title":"Celastrol delays the progression of hepatocellular carcinoma by suppressing SLC1A5-mediated glutamine dependence","authors":"Simeng Xiao ,&nbsp;Yun Zhao ,&nbsp;Zhiguo Chen ,&nbsp;Yangkun Xiong ,&nbsp;Dingmei Zhang ,&nbsp;Gang Zhou ,&nbsp;Cong Zhang","doi":"10.1016/j.taap.2025.117690","DOIUrl":"10.1016/j.taap.2025.117690","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the <em>Tripterygium wilfordii</em> Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells <em>in vitro</em> and <em>in vivo</em>. Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117690"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769301","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":"In Silico, in vitro, and in vivo studies of a 2-substituted quinazolin-4(3H)-one in T-cell acute lymphoblastic leukemia","authors":"Giorgio Antoniolli ,&nbsp;Gilberto Carlos Franchi Junior ,&nbsp;Keli Lima ,&nbsp;Rayssa de Mello Lopes ,&nbsp;Euzebio Guimarães Barbosa ,&nbsp;João Agostinho Machado-Neto ,&nbsp;Carmen Silvia Passos Lima ,&nbsp;Tiago Rodrigues ,&nbsp;Fernando Coelho","doi":"10.1016/j.taap.2025.117667","DOIUrl":"10.1016/j.taap.2025.117667","url":null,"abstract":"<div><div>This study reports the synthesis, physicochemical characterization, and preliminary pharmacological evaluation of a novel 2-substituted quinazolin-4(3<em>H</em>)-one, Qona11. The compound was synthesized from 2-aminobenzamide and 1<em>H</em>-benzo[<em>d</em>]imidazole-2-carbaldehyde in dimethyl sulfoxide with a 55 % yield, in a catalyst-free, atom-efficient process that adheres to Green Chemistry principles. Structural confirmation was achieved through IR (1667 cm⁻¹, carbonyl), ¹H NMR (13.50 and 12.50 ppm, NH protons), and ¹³C NMR (161.17 ppm, carbonyl carbon). <em>In silico</em> analysis suggested Qona11 possesses favorable oral bioavailability, high intestinal absorption, limited CYP450 inhibition, and predicted blood-brain barrier permeability. Toxicity predictions highlighted potential hepatotoxicity, neurotoxicity, and respiratory toxicity, while no significant risks for cardiotoxicity, carcinogenicity, immunotoxicity, or cytotoxicity were found. Comparative analysis with idelalisib revealed similar toxicity profiles to Qona11, distinct from vincristine. Biological evaluation in acute leukemia models demonstrated concentration- and time-dependent cytotoxicity, with Jurkat T-ALL cells being more sensitive (IC₅₀ 2.3 μM) than NB4 APL cells (IC₅₀ 12.7 μM). Flow cytometry confirmed apoptosis induction in Jurkat cells <em>via</em> mitochondrial permeabilization and caspase 3 activation. <em>In vivo</em> studies in NOD/SCID mice bearing Jurkat xenografts showed that Qona11 (100 mg.kg⁻¹) was well tolerated with no systemic toxicity, although it did not inhibit leukemia cell proliferation in immune-independent models. Overall, Qona11 exhibits promising anticancer activity and low systemic toxicity, warranting further preclinical investigation in solid tumor models and combination therapies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117667"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696370","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":"Pioglitazone attenuates cardiovascular remodeling cadmium-induced through the MAPK pathway","authors":"Victor Enrique Sarmiento-Ortega ,&nbsp;Diana Moroni-González ,&nbsp;José Everardo Avelino-Cruz ,&nbsp;Miguel Garcia-Gonzalez ,&nbsp;Rubén Vázquez-Roque ,&nbsp;Eduardo Brambila ,&nbsp;Samuel Treviño","doi":"10.1016/j.taap.2025.117691","DOIUrl":"10.1016/j.taap.2025.117691","url":null,"abstract":"<div><div>Cadmium (Cd) is an environmental pollutant increasingly linked to cardiovascular morbidity. While its toxic effects have been well documented at high doses, the impact of chronic exposure to the minimal risk level remains underexplored. This study aimed to investigate the mechanistic basis of Cadmium-induced cardiotoxicity at low doses and to evaluate the cardioprotective potential of pioglitazone, a PPARγ agonist with anti-inflammatory and antioxidant properties. Male Wistar rats were exposed chronically to Cd in drinking water (Cd, 15 mg/L) for 3 and 5 months, with or without pioglitazone co-treatment (2.5 mg/kg bw/day). Hemodynamic parameters, serum biomarkers (hs-TnI, NT-proBNP, sST2, IL-6, TNF-α), ventricular morphometry, histology, and activation of MAPK signaling (p-ERK1/2, p-JNK, p-p38) were evaluated. At 5 months, Cd exposure significantly increased systolic and diastolic blood pressure, hs-TnI, and NT-proBNP, without affecting CK-MB or hs-PCR. Structural changes included selective left ventricular hypertrophy, increased cardiomyocyte size, and elevated HW/BW and LVW/BW ratios. Cadmium also disrupted the IL-33/sST2 axis, elevating IL-6 and TNF-α, which indicates the presence of chronic inflammation. Mechanistically, Cd activated the MAPK pathway, with marked increases in p-p38 and p-JNK. Pioglitazone partially reversed these alterations by reducing inflammatory cytokines, restoring IL-33 levels, downregulating MAPK activation, and attenuating cardiac remodeling. Chronic exposure to the minimal risk of cadmium dosage induces subclinical yet progressive cardiotoxicity through inflammatory and MAPK-dependent pathways. Pioglitazone confers partial protection by modulating these mechanisms, underscoring its therapeutic potential in mitigating environmentally induced cardiovascular injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117691"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769304","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":"Establishment of a real-time monitored animal model to evaluate novel therapeutic strategies for organophosphorus nerve agent poisonings","authors":"Sofia Jonasson,&nbsp;Åsa Gustafsson,&nbsp;Johanna Qvarnström,&nbsp;Marcus Carlsson,&nbsp;Nina Forsgren,&nbsp;Fredrik Ekström,&nbsp;Linda Elfsmark","doi":"10.1016/j.taap.2025.117694","DOIUrl":"10.1016/j.taap.2025.117694","url":null,"abstract":"<div><div>Preclinical evaluation of oximes as antidotes for organophosphorus nerve agent (OPNAs) poisoning is predominantly based on protection ratio of the antidote against lethal doses. Developing protection indexes involves considerable animal distress and, due to the limited precision, requires large animal cohorts. This study aimed to establish an <em>in vivo</em> model for evaluating new therapeutic substances more aligned with the 3R principles that also enables detailed quantification of specific biological effects to better understand the impact of treatment.</div><div>Anesthetized Sprague-Dawley rats were tracheostomized and connected to a small animal ventilator allowing simultaneous registration of respiratory function. Rats were exposed to 1xLD₅₀ VX or tabun, and progression of poisoning was monitored in real-time through measurements of respiratory resistance (R_RS) over a 30-min period. Additional assessments included clinical symptoms and acetylcholine esterase (AChE) inhibition in blood. Pre-treatment with oxime (obidoxime, HI-6, RS194B) or atropine were used to validate the model.</div><div>Exposure to OPNAs resulted in rapid increases in R_RS to 250–300 % above baseline. HI-6 and obidoxime were the most effective treatments, mitigating both respiratory and enzymatic effects of OPNA poisoning, while RS194B treatment delayed onset of symptoms but did not fully reverse toxicity. Tabun-inhibited AChE was generally more resistant to reactivation with oximes than VX- inhibited enzymes. The findings indicate that maintaining AChE activity above 15–20 % is sufficient to restore respiratory function and alleviate symptoms to levels comparable to unexposed controls.</div><div>This study highlights the value of high-sensitivity, real-time monitoring of physiological metrics like respiratory resistance in evaluating novel antidotes for OPNA poisoning.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117694"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800769","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":"Unveiling the therapeutic potential and leukemia risk of PD-166866 in sepsis via an integrated computational-experimental strategy","authors":"Mingkai Chang ,&nbsp;Ye Shang ,&nbsp;Jianing Zheng ,&nbsp;Wenfei Wang ,&nbsp;Tingting Zhao","doi":"10.1016/j.taap.2025.117702","DOIUrl":"10.1016/j.taap.2025.117702","url":null,"abstract":"<div><div>Objective: This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology.Methods: In terms of druggability, network pharmacology was used to screen drug-disease common targets and conduct enrichment analysis. Meanwhile, transcriptome sequencing was performed on the LPS-induced Raw264.7 cell model for target validation. In terms of toxicology, network toxicology was applied to predict the potential toxicity of small molecules, which was further verified by gene expression and survival analysis using the TCGA and Kaplan-Meier Plotter databases.Results: A total of 39 common targets between PD-166866 and sepsis were identified. The core pathways include the Rap1 signaling pathway, and the core targets are SRC, EGFR, and CCND1; molecular docking showed stable binding between PD-166866 and these targets. Transcriptomic analysis confirmed that PD-166866 can significantly regulate the expression of inflammation-related genes and inhibit the Rap1 pathway. Network toxicology indicated a significant risk of hematological toxicity associated with this drug. Transcriptome sequencing revealed that PD-166866 treatment led to the downregulation of IRAK3 and IKBKE, and the low expression of these two genes was significantly associated with poor prognosis in leukemia patients, confirming the potential hematological toxicity of PD-166866.Conclusion: This study confirms that PD-166866 exerts anti-sepsis effects by regulating pathways such as Rap1, but it also has the potential risk of inducing leukemia. More importantly, this study successfully established a comprehensive evaluation framework integrating in silico and in vitro experiments. It provides a feasible methodological reference for systematically evaluating the dual attributes of “efficacy-risk” in the early stage of drug development and reducing the initial reliance on traditional animal models.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117702"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889392","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":"Benign cardiac troponin I release induced by elevated beat rate is associated with membrane bleb formation","authors":"Jomana Hatahet ,&nbsp;Hannah J. Nonarath ,&nbsp;Mark T. Zafiratos ,&nbsp;Geena Jasiek ,&nbsp;Rebecca Kohnken ,&nbsp;Jessica Treadway ,&nbsp;C. Michael Foley","doi":"10.1016/j.taap.2025.117701","DOIUrl":"10.1016/j.taap.2025.117701","url":null,"abstract":"<div><div>Cardiac troponin I (cTnI), a key regulatory protein of cardiomyocyte contraction, serves as a clinical biomarker for cellular necrosis. Measuring circulating cTnI in preclinical studies is used to assess cardiotoxicity of new chemical entities (NCEs) and gate their advancement into clinical trials. Recent studies showed benign troponin release due to reversible myocyte injury post-exercise, that could be primarily driven by sustained elevations in heart rate. However, mechanisms linking increased heart rate to troponin release without necrotic damage remain undetermined. In this study we investigated the relationship between sustained beat rate increases and cTnI release using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and zebrafish models. Beat rate was increased in hiPSC-CMs with forskolin, and a concomitant increase in cTnI release was observed without impacting cell viability. To evaluate the translatability of benign troponin release from <em>in vivo</em> contexts, we established methods for quantifying systemic troponin levels in zebrafish and evaluated the effects of forskolin on heart rate and troponin release. Similarly, forskolin treatment increased heart rate and circulating troponin in zebrafish. To investigate the molecular mechanisms involved, hiPSC-CMs were co-treated with forskolin and (±)-blebbistatin, a Myosin II and membrane blebbing inhibitor. We found (±)-blebbistatin to significantly reduce cTnI release, suggesting membrane bleb formation as a possible mechanism of benign troponin release triggered by elevated beat rates. These findings provide a better understanding of troponin release mechanisms in cardiomyocytes. Further, these results may support refinement of cardiotoxicity assessment of NCEs, preventing misinterpretations that might lead to unnecessary termination of promising therapeutics.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117701"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889404","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":"Gastrodin alleviates alcohol-induced developmental and neurotoxic effects in zebrafish larvae by suppressing ferroptosis via regulating the Nrf2/GPX4 signaling pathway","authors":"Ruijing Li ,&nbsp;Weili Yang ,&nbsp;Lijuan Zheng ,&nbsp;Xingxue Yan ,&nbsp;Cuihua Liu ,&nbsp;Yaodong Zhang ,&nbsp;Jitong Li","doi":"10.1016/j.taap.2025.117684","DOIUrl":"10.1016/j.taap.2025.117684","url":null,"abstract":"<div><div>Prenatal alcohol exposure is a leading cause of developmental abnormalities and neurobehavioral deficits, collectively known as fetal alcohol spectrum disorder (FASD). The underlying molecular mechanisms, however, are not fully elucidated, hindering the development of effective therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key pathological process in various diseases. Gastrodin (GAS), the primary bioactive component of <em>Gastrodia elata</em>, has demonstrated potent antioxidant and neuroprotective properties. This study aimed to investigate the protective effects of GAS against alcohol-induced developmental and neurotoxic damage and to elucidate the underlying molecular mechanisms. Using a zebrafish larval model, we found that exposure to 200 mM alcohol from 2 to 24 hours post-fertilization (hpf) induced significant developmental toxicity, including a decreased hatching rate, body length and eye diameter, and increased morphological malformations in larvae. Alcohol-exposed larvae also exhibited severe neurobehavioral deficits, characterized by a reduction in movement distance and average velocity in dark conditions. Mechanistically, alcohol exposure triggered ferroptosis, evidenced by an increase in intracellular Fe²⁺, malondialdehyde (MDA), and reactive oxygen species (ROS) levels, alongside a decrease in the levels of glutathione (GSH) and reduced glutathione peroxidase 4 (GPX4) and the nuclear factor erythroid 2-related factor 2 (Nrf2) activities. Co-treatment with GAS (200 mg/L) significantly ameliorated these alcohol-induced developmental and neurobehavioral defects. GAS administration effectively suppressed the hallmarks of ferroptosis by restoring the ROS level and altering the expression of genes related to oxidative stress. In addition, GAS suppressed alcohol-induced cell apoptosis, downregulated <em>caspase3b</em>, <em>bax</em>, <em>caspase8</em>, and upregulated <em>bcl2</em> in mRNA levels. Molecular analysis revealed that GAS exerts its anti-ferroptotic effect by activating Nrf2/GPX4 signaling pathway, which was suppressed by alcohol. Our findings indicate that ferroptosis plays a key role in alcohol-induced developmental neurotoxicity, and GAS provides protection by activating the Nrf2/GPX4 axis. This suggests that GAS could be a potential therapeutic option for reducing the negative effects of prenatal alcohol exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117684"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726274","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":"Ditrioxzin synergizes with 2-deoxy-d-glucose to induce redox-dependent metabolic crisis in gastric cancer through dual targeting of peroxiredoxin 3 and glycolysis","authors":"Nan Su ,&nbsp;Lulu Pan ,&nbsp;Xiaojing Shi ,&nbsp;Ying Liu ,&nbsp;Xiaxia Fan ,&nbsp;Shilin Liu ,&nbsp;Yong-Cheng Ma","doi":"10.1016/j.taap.2025.117666","DOIUrl":"10.1016/j.taap.2025.117666","url":null,"abstract":"<div><div>Emerging evidence demonstrates that dual inhibition of glycolysis and mitochondrial function represents a potent anticancer strategy. Here, we report that Ditrioxzin (DTO), a synthetic <em>ent-</em>kaurane diterpenoid analog, selectively disrupts mitochondrial redox homeostasis by targeting peroxiredoxin 3 (Prx3) to induce hydrogen peroxide (H₂O₂) accumulation, thereby depolarizing mitochondrial membrane potential (MMP) and impairing oxidative phosphorylation (OXPHOS) in gastric cancer cells. DTO synergized with the glycolytic inhibitor 2-deoxy-<span>d</span>-glucose (2-DG) to deplete ATP through dual metabolic blockade. In vitro studies revealed that DTO exerted selective cytotoxicity against gastric cancer cells (IC₅₀ 3.82–6.10 μM) but spared normal gastric epithelial cells (GES-1). Mechanistically, DTO directly bound Prx3, elevating H₂O₂ levels (&gt;3-fold at 8 μM), oxidizing mitochondrial peroxiredoxins, and triggering redox-dependent mitochondrial dysfunction. Combined DTO/2-DG treatment promoted ATP depletion and apoptosis (69.6 % vs 24.1 % DTO alone) via ROS-dependent pathways, an effect abrogated by <em>N</em>-acetylcysteine. In vivo, DTO (10 mg/kg) and 2-DG (500 mg/kg) synergistically suppressed tumor growth (66 %, <em>P</em> &lt; 0.001) in xenograft models without body weight loss or histopathological changes in kidney/heart. Our findings establish DTO as a novel Prx3-targeted agent that synergizes with 2-DG to induce metabolic crisis, providing a high-safety-profile therapeutic strategy for gastric cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117666"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683525","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":"Evaluation of 2-isopropyl-N-2,3-trimethylbutyramide by a comprehensive toxicity study using gpt delta rats","authors":"Tatsuya Mitsumoto ,&nbsp;Yuji Ishii ,&nbsp;Norifumi Takimoto ,&nbsp;Shinji Takasu ,&nbsp;Moeka Namiki ,&nbsp;Takeshi Toyoda ,&nbsp;Kumiko Ogawa","doi":"10.1016/j.taap.2025.117686","DOIUrl":"10.1016/j.taap.2025.117686","url":null,"abstract":"<div><div>2-Isopropyl-<em>N</em>-2,3-trimethylbutyramide (ITB) is a food-flavoring agent classified as an aliphatic amide. In 2016, the Joint FAO/WHO Expert Committee on Food Additives evaluated ITB and concluded that additional data on toxicity and <em>in vivo</em> genotoxicity are required for its safety evaluation. In this study, we comprehensively investigated ITB toxicity using reporter gene transgenic animals. Male F344 <em>gpt</em> delta rats were administered ITB by oral gavage at doses of 0, 5, 50, or 500 mg/kg/day for 13 weeks. Neurological symptoms were observed in the early phase of treatment at doses ≥50 mg/kg. Periportal hepatocellular vacuolation was observed histopathologically at doses ≥50 mg/kg, along with increased liver weight and serum alanine aminotransferase levels. Kidney weight increased and serum chloride levels decreased at doses ≥5 mg/kg, indicating that ITB exerted potential nephrotoxic effects at lower doses. Accordingly, the lowest observed adverse effect level in the present study was at 5 mg/kg/day. No significant changes in <em>gpt</em> and <em>red</em>/<em>gam</em> mutant frequencies were detected in the liver or kidney, demonstrating a lack of ITB genotoxicity. Immunohistochemical analysis of GST-P-positive foci also suggested that ITB showed no hepatocarcinogenic potential. Overall, our findings demonstrate that ITB induces hepatic and renal toxicity but shows no evidence of <em>in vivo</em> genotoxicity or hepatocarcinogenic potential, providing essential information for safety assessment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117686"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744578","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":"Rupestonic acid targets ENO1 to exert antitumor activity and synergizes with paclitaxel in hepatocellular carcinoma","authors":"Shulipan Mulati ,&nbsp;Maierdan Maimaitiming ,&nbsp;Jianing Ma ,&nbsp;Miaomiao Zhang ,&nbsp;Rongsong Jiang ,&nbsp;Silafu Aibai ,&nbsp;Xieraili Tuerxun","doi":"10.1016/j.taap.2025.117688","DOIUrl":"10.1016/j.taap.2025.117688","url":null,"abstract":"<div><div>Rupestonic acid, a sesquiterpene, has protective properties against liver damage, inflammation, and tumor formation. Despite these known effects, its specific role and mechanism of action in combating hepatocellular carcinoma (HCC) remain insufficiently understood. This study aimed to investigate the anti-HCC effects of rupestonic acid and to identify its potential molecular targets. We employed cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays to assess its impact on cell viability, proliferation, and apoptosis in HCC cell lines. Additionally, target fishing, cellular thermal shift assays (CETSA), ribonucleic acid interference, and Western blot (WB) were employed to identify rupestonic acid's protein targets in HCC cells. Our results showed that rupestonic acid significantly inhibited HCC cell proliferation, induced G0/G1 phase cell cycle arrest, and promoted apoptosis through the mitochondrial pathway. Target engagement studies employing an alkyne–rupestonic acid probe combined with mass spectrometry identified enolase 1 (ENO1) as a direct binding target, with CETSA confirming its destabilization. Furthermore, rupestonic acid inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box protein O (FOXO) signaling pathway, and rupestonic acid demonstrated a synergistic cytotoxic effect with paclitaxel (PTX). These findings suggest that rupestonic acid is a promising candidate for HCC treatment. They also underscore the potential of rupestonic acid in the design and development of lead compounds for HCC treatment and identify ENO1 as a viable therapeutic target.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117688"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744638","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}