Toxicology and applied pharmacology最新文献

{"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":"2025-12-14","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":"Corrigendum to “Toxicokinetics and in vivo genotoxicity after single dose oral gavage and intravenous administration of N-Nitrosonornicotine in Sprague Dawley rats” [Toxicology and Applied Pharmacology 505 (2025), 117572]","authors":"Mamata De,&nbsp;Ashley Fields,&nbsp;Guy Lagaud","doi":"10.1016/j.taap.2025.117689","DOIUrl":"10.1016/j.taap.2025.117689","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117689"},"PeriodicalIF":3.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757836","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":"2025-12-11","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}

{"title":"Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis","authors":"Sultan Alrashdi ,&nbsp;Shimaa K. Mohamed ,&nbsp;Mohamad Elbaz ,&nbsp;Elsayed K. El-Sayed","doi":"10.1016/j.taap.2025.117687","DOIUrl":"10.1016/j.taap.2025.117687","url":null,"abstract":"<div><div>Bladder ischemia, frequently associated with vascular insufficiency, contributes to lower urinary tract symptoms via oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial defect, and apoptosis. Ischemia-reperfusion (I/R) injury exacerbates these effects by generating excessive reactive oxygen species. Trimetazidine (TMZ), an anti-ischemic agent, has shown protective effects in several I/R models; however, its role in bladder injury remains insufficiently characterized. This study investigated the protective effect of TMZ against bladder I/R injury in rats, focusing on oxidative stress, inflammation, ER stress, mitochondrial biogenesis, microRNA regulation, and apoptosis. Forty rats were allocated into four groups: sham control, I/R, and two TMZ-pretreated groups (10 or 20 mg/kg/day, p.o., for 14 days) prior to I/R induction. Controls received Tween 80 vehicle. Bladder tissues were collected for biochemical, molecular, and histopathological analyses. TMZ showed protection by lowering MDA (∼43.5–60.8 %) and enhancing GSH (∼2–2.6 fold) and SOD activity (∼2–3.2 fold). ER stress was attenuated, with reduced p-PERK (∼29.4–63 %) and CHOP (∼29.1–60 %), alongside upregulation of mirR-211 (∼1.4–1.9 fold). TMZ restored mitochondrial biogenesis through increased SIRT1 (∼1.9–2.4 fold), PGC1α (∼2.1–4.3 fold), p-AMPK (∼3–6.3 fold), and ATP (∼2–2.8 fold). It also downregulated pro-apoptotic (Bax, Caspase 3) and pro-inflammatory (TNF-α, IL-1β) mediators. Histopathology revealed marked preservation of bladder architecture, particularly at 20 mg/kg. TMZ exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective effects in bladder I/R injury via modulation of oxidative stress, ER stress, mitochondrial pathways, and the mirR-211/CHOP axis. These findings suggest that TMZ may represent a promising therapeutic candidate for ischemia-associated bladder dysfunction, providing a mechanistic basis for future translational and clinical investigation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117687"},"PeriodicalIF":3.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145737639","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":"2025-12-09","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":"Duloxetine-induced inhibition of voltage-gated K+ 3.1 (Kv3.1) channels and underlying electrophysiological mechanisms","authors":"Jin Ryeol An ,&nbsp;Junsu Jeong ,&nbsp;Hye Ryung Kim ,&nbsp;Sooa Lee ,&nbsp;Armin Sultana ,&nbsp;Raju Das ,&nbsp;Joohan Woo ,&nbsp;Seong Woo Choi ,&nbsp;Young Min Bae ,&nbsp;Yeji Lim ,&nbsp;Hongzoo Park ,&nbsp;Mi Seon Seo ,&nbsp;Won Sun Park","doi":"10.1016/j.taap.2025.117685","DOIUrl":"10.1016/j.taap.2025.117685","url":null,"abstract":"<div><div>Duloxetine is a serotonin-norepinephrine reuptake inhibitor that has been widely used to treat major depression; however, it has also been associated with severe neuropsychiatric side effects, including hallucinations, confusion, and suicide attempts. Nevertheless, the electrophysiological mechanisms underlying these adverse effects remain poorly understood. In this study, we investigated the effect of duloxetine on cloned neuronal rat voltage-gated K⁺ (Kv) channel subunit Kv3.1, stably expressed in Chinese hamster ovary (CHO) cells. Duloxetine inhibited the Kv3.1 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC₅₀) of 2.04 ± 0.27 μM (approximately 5-fold higher than the peak therapeutic plasma concentration of 0.4 μM) and a Hill coefficient of 0.94 ± 0.08. This inhibitory effect was associated with accelerated current inactivation. The association and dissociation rate constants for duloxetine were 43.43 ± 4.57 μM⁻¹·s⁻¹ and 122.12 ± 68.2 s⁻¹, respectively. In addition, duloxetine shifted the voltage dependence of Kv3.1 steady-state inactivation toward a more negative direction and led to use-dependent inhibition upon repetitive stimulation (1 and 2 Hz). Duloxetine also slowed recovery from inactivation. Docking analysis predicted that duloxetine binds to the central pore and interface between the voltage-sensing and pore domains on Kv3.1 channel, supporting the inhibitory mechanisms of duloxetine. Furthermore, duloxetine inhibited Kv3.1-mediated currents in SH-SY5Y human neuroblastoma cells. Taken together, our results indicate that duloxetine inhibits Kv3.1 expressed in CHO cells in concentration-, time-, and use (open and inactivated states)-dependent manners, independently of its anti-depressive effects.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117685"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726257","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":"Targeting sonic hedgehog (shh) signaling pathways by the concentration–dependent topical resveratrol for protection from cyclophosphamide-induced alopecia in a mouse model","authors":"Aml A. El-Din,&nbsp;Dina M. Tahoon,&nbsp;Maaly A. Abd Elmaaboud,&nbsp;Fleur F. Abd Elmoniem,&nbsp;Amany A. Abdin","doi":"10.1016/j.taap.2025.117681","DOIUrl":"10.1016/j.taap.2025.117681","url":null,"abstract":"<div><h3>Background</h3><div>Chemotherapy-induced alopecia (CIA) is a common and inevitable side effect of systemic cancer treatment. There is an urgent need for novel therapies for cancer patients suffering from hair loss to improve their quality of life. This study aimed to investigate the potential protective effect of concentration-dependent topical resveratrol on hair follicles via targeting sonic hedgehog (Shh) signaling and its related downstream regulatory (Sirt-1), proliferative (Ki-67), and apoptotic status (caspase-3 and Bcl-2) pathways in cyclophosphamide-induced alopecia in female C57BL/6 mice model. Methods: All animals were subjected to depilation at the start of the experiment, then mice were divided into 5 equal groups as follows: Control group, cyclophosphamide (CPA)-untreated alopecia group, minoxidil (MXL) + CPA-alopecia, Resveratrol low concentration (RSV L10) + CPA-alopecia, Resveratrol high concentration (RSV H80) + CPA-alopecia. The effects of these drugs on hair coverage score, Shh signaling, Sirt-1, proliferation, and apoptosis were assessed. Results: Low concentration of topical RSV showed a significant increase in hair coverage score. Shh, Sirt-1, immunohistochemical expression levels of Ki-67, and Bcl-2 were significantly elevated, significantly decreasing caspase-3 expression in skin tissue. Moreover, the superiority extended to include histopathological findings and dermatoscopic skin monitoring compared to the groups that received either topical minoxidil 2 % or RSV at high concentration. Conclusion: Topical low-dose resveratrol protects against CIA by activating Shh signaling and modulating follicular proliferative and apoptotic pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117681"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726284","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":"Andrographolide-induced PANoptosis underlies its multiple organ toxicity in mice","authors":"Na Lu ,&nbsp;Yuan-wen Cai ,&nbsp;Qi-hai Cai ,&nbsp;Xiu-wen Liang ,&nbsp;Nuo Sun ,&nbsp;On-kei Chan ,&nbsp;Zi-jian Shi ,&nbsp;Bo Hu ,&nbsp;Xian-hui He ,&nbsp;Qing-bing Zha ,&nbsp;Dong-yun Ouyang","doi":"10.1016/j.taap.2025.117682","DOIUrl":"10.1016/j.taap.2025.117682","url":null,"abstract":"<div><div>Andrographolide (Andro), the major bioactive component of <em>Andrographis paniculata</em>, exhibits potent anti-inflammatory properties but has raised safety concerns due to reported organ toxicity. This study aimed to investigate the mechanisms underlying Andro's <em>in vitro</em> and <em>in vivo</em> toxicity. In mice, single dose (≤100 mg/kg) Andro administration showed no acute toxicity, with no overt histopathological organ injury. But repeated administration of the same dose of Andro triggered damage in lung, liver, uterus, and kidney, characterized by pulmonary alveolar disruption, renal tubular edema, and elevated serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Concurrent with systemic injury, PANoptosis was induced by Andro in these organs, as evidenced by the activation of caspase-1/−8/−3 (apoptosis), gasdermin D/E (GSDMD/E, pyroptosis), and MLKL (necroptosis), indicating the correlation between PANoptosis and organ toxicity. <em>In vitro</em>, Andro caused lytic cell death in macrophages and other cells in a time- and dose-dependent manner. During this process, Andro induced rapid activation of caspase-8, followed by caspase-1/−3 and GSDME cleavage and phosphorylation of MLKL (p-MLKL), indicative of the activation of the PANoptosis signaling pathway. Consistent with this, Andro induced lytic cell death was markedly attenuated by caspase-1 inhibitor VX-765, pan-caspase inhibitors (IDN-6556, <em>Z</em>-VAD-FMK) and GSDMD/E inhibitor (disulfiram). In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117682"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726262","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":"2025-12-08","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":"Exposure to a PFAS mixture alters cholesterol lipoprotein subfractions and induces a foam cell-like aortic macrophage expression profile in hyperlipidemic LDLr−/− mice","authors":"Katherine Roth ,&nbsp;Zhao Yang ,&nbsp;Manisha Agarwal ,&nbsp;Katherine Gurdziel ,&nbsp;Michael C. Petriello","doi":"10.1016/j.taap.2025.117683","DOIUrl":"10.1016/j.taap.2025.117683","url":null,"abstract":"<div><div><em>Per</em>- and polyfluoroalkyl substances (PFAS) have been associated with elevated cholesterol, a clinically-relevant risk factor for atherosclerosis. Macrophages are key mediators of atherosclerosis progression through their polarization to various subsets including inflammatory macrophages and foam cells. However, studies examining impacts of PFAS on macrophages in the context of atherosclerosis are lacking. Here, we investigate the impact of PFAS mixtures on cholesterol subfractions and transcriptional profiling of aortic macrophages during early atherosclerosis. Male low density lipoprotein receptor (Ldlr) deficient mice were fed an atherogenic diet and exposed via their drinking water to a mixture of 5 PFAS (i.e., PFOA, PFOS, PFNA, PFHxS, and GenX), each at a concentration of 2 mg/L, for 7 weeks. Circulating cholesterol subfractions and subclasses were analyzed, and aortic macrophages were isolated using immuno-magnetic beads for RNA-sequencing. Total circulating cholesterol was significantly elevated by 10 % following PFAS exposure which was predominately due to a 25 % increase in intermediate-density lipoprotein (IDL). The densest subfraction of low-density lipoprotein, LDL7, also increased by 206 %. RNA sequencing of aortic macrophages revealed PFAS downregulated 389 and upregulated 593 genes; many related to lipid metabolism and foam cell development. Specifically, expression of inflammatory mediators chemokine (C-X-C motif) ligand 2 (<em>Cxcl2</em>) and chemokine (C-X-C motif) ligand 17 (<em>Cxcl17</em>) were significantly increased due to PFAS (2.4 log2 fold change and 10.4 log2 FC respectively) and levels of lipid metabolism and transport genes fatty acid binding protein 4 (<em>Fabp4</em>) and fatty acid synthase (<em>Fasn</em>) were similarly increased (3 log2 FC and 5.2 log2 FC respectively). This work provides additional mechanistic information related to PFAS-mediated acceleration of atherosclerosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117683"},"PeriodicalIF":3.4,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715979","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}