Toxicology and applied pharmacology最新文献

{"title":"Maternal ozone exposure and differential cardiometabolic outcomes in aging male and female offspring","authors":"Brendan Yoo ,&nbsp;Janice A. Dye ,&nbsp;Mehdi S. Hazari ,&nbsp;Aimen K. Farraj ,&nbsp;Erica J. Stewart ,&nbsp;Leslie C. Thompson ,&nbsp;Helen H. Nguyen ,&nbsp;Samantha J. Snow ,&nbsp;Michelle Fiamingo ,&nbsp;Anna A. Fisher ,&nbsp;Katherine L. O'Shaughnessy ,&nbsp;Colette N. Miller","doi":"10.1016/j.taap.2025.117669","DOIUrl":"10.1016/j.taap.2025.117669","url":null,"abstract":"<div><div>Fetal development is a vulnerable life stage for exposure to environmental stressors. Gestational exposure to ozone (O₃) has been shown to compromise fetal growth, predisposing offspring to increased risk of pulmonary and metabolic dysfunction later in life. However, the cardiovascular consequences of maternal O₃ exposure on offspring health remain uncharacterized. Herein, pregnant Long-Evans rats were exposed to 0.8 ppm O₃ for 4 h each day on gestation day (GD) 5 and 6. Following weaning, male and female offspring were monitored for cardiometabolic health for up to ∼5 months of age. Although there were little-to-no changes in most metabolic endpoints (<em>e.g.</em>, growth, food intake, body composition, or glucose tolerance), offspring from O₃ exposed dams had an altered respiratory exchange ratio at ∼4 months old that differed by sex. Furthermore, female offspring had adipocyte hyperplasia in the retroperitoneal depot, effects that were not evident in male offspring. Males from O₃-exposed dams had altered cardiac structure and function, including left ventricular wall thickening and increased ejection fraction and fractional shortening. Females from O₃-exposed dams, on the other hand, had decreased myocardial performance attributed to shortened aortic ejection. RNAseq on hearts from GD 21 fetuses revealed sexually dimorphic effects of maternal O₃ exposure on cardiac gene expression, consistent with altered structure and function that was present in adulthood. Collectively, these findings demonstrate that peri-implantation O₃ exposure increases the risk of multiple adverse effects, including cardiac dysfunction, in adulthood.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117669"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696433","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":"GSDMD inhibitor GI-Y1 alleviates doxorubicin-induced cardiotoxicity via the inhibition of mitochondrial dysfunction","authors":"Yucong Zhang ,&nbsp;Ruihan Zheng ,&nbsp;Minne Xie ,&nbsp;Yunxuan Chen ,&nbsp;Binbin Xia ,&nbsp;Zexin Yang ,&nbsp;Zhuoning Li ,&nbsp;Yuzheng Li ,&nbsp;Li Luo ,&nbsp;Weijian Huang ,&nbsp;Shanshan Dai ,&nbsp;Bozhi Ye ,&nbsp;Wenli Zhang","doi":"10.1016/j.taap.2026.117713","DOIUrl":"10.1016/j.taap.2026.117713","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to explore GI-Y1's (a GSDMD inhibitor) protective effect against doxorubicin (Dox)-induced cardiotoxicity (DIC) and clarify its molecular mechanisms.</div></div><div><h3>Methods</h3><div>In vivo, wild-type and Gsdmd⁻/⁻ mice received Dox (5 mg/kg/week for 4 weeks) and GI-Y1 (10 or 20 mg/kg/day). AAV9-mediated GSDMD overexpression verified target specificity. Cardiac function was assessed by echocardiography; myocardial injury via H&amp;E staining, TUNEL assay, and serum biomarkers (CK-MB, LDH, cTnT). In vitro, HL-1 cardiomyocytes were treated with Dox (0.5 μg/mL) and GI-Y1 (10 or 20 μM). Pyroptosis markers (GSDMD cleavage, IL-1β secretion, LDH release) and mitochondrial function were measured using Western blot, ELISA, JC-1 staining, and TEM.</div></div><div><h3>Results</h3><div>GI-Y1 improved survival and cardiac function in Dox-treated mice. It reduced serum cardiac injury biomarkers and alleviated myocardial histological damage. In vivo and in vitro, GI-Y1 inhibited Dox-induced cardiomyocyte pyroptosis, shown by reduced GSDMD cleavage, less IL-1β secretion, and decreased cell death. Mechanistically, GI-Y1 bound GSDMD, impairing its lipid-binding and pore-forming abilities. It also relieved Dox-induced mitochondrial dysfunction by reducing mitochondrial GSDMD-N, restoring MMP, boosting ATP, and inhibiting mtDNA release.</div></div><div><h3>Conclusion</h3><div>GI-Y1 alleviates DIC by directly targeting GSDMD, inhibiting pyroptosis and mitochondrial damage. This study highlights GI-Y1 as a promising therapy for chemotherapy-related cardiac injury and a valuable tool to study pyroptosis in cardiovascular diseases.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117713"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960412","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":"Aloperine mitigates cigarette smoke-induced inflammation and pyroptosis by inhibiting the BRD4/NLRP3/GSDMD pathway in chronic obstructive pulmonary disease","authors":"Xiaofeng Li ,&nbsp;Zhe Wang ,&nbsp;Tingting Zhang ,&nbsp;Xiaoli Zeng ,&nbsp;Xin Li ,&nbsp;Kai Liu ,&nbsp;Ping Huang ,&nbsp;Xiaoju Liu","doi":"10.1016/j.taap.2025.117704","DOIUrl":"10.1016/j.taap.2025.117704","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and progressive airflow limitation, primarily caused by cigarette smoke (CS) exposure. Current pharmacological interventions for COPD merely slow disease progression, which further underscores the urgent need for innovative therapeutics. Aloperine has demonstrated potent anti-inflammatory properties, yet its therapeutic potential in COPD remains unclear. In this study, we investigated the effects and mechanisms of aloperine using a CS-induced COPD mouse model and a cigarette smoke extract (CSE)-stimulated alveolar macrophage (AM; MH-S cell) model. Aloperine treatment significantly improved pulmonary function and alleviated emphysema in COPD mice. Furthermore, it suppressed CSE-induced alveolar macrophage pyroptosis and inflammatory responses both in vivo and in vitro. Mechanistically, the bromodomain-containing protein 4 (BRD4) inhibitor—JQ1—attenuated CSE-induced pyroptosis; however, this effect was partially reversed by the NLRP3 activator— nigericin. Comprehensive analyses, including results from molecular docking, molecular dynamics simulations, surface plasmon resonance, and in vivo and in vitro experiments, supported that aloperine interacts with BRD4 and attenuates NLRP3-mediated pyroptosis. Collectively, our findings indicate that aloperine alleviates CS-induced airway inflammation and pyroptosis potentially by modulating the BRD4/NLRP3/GSDMD signaling, positioning it as a promising therapeutic candidate for COPD.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117704"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900886","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":"Salidroside derivative SHPL-49 accelerates cutaneous wound healing in diabetic mice by modulating macrophage-mediated TGF-β1/Smad2/3 signaling pathway","authors":"Feiyun Wang ,&nbsp;Zhouyun Ma ,&nbsp;Anam Latif ,&nbsp;Changsen Zhan ,&nbsp;Chunxiao Cui ,&nbsp;Pei Zhang ,&nbsp;Qianfei Cui ,&nbsp;Jiange Zhang","doi":"10.1016/j.taap.2025.117699","DOIUrl":"10.1016/j.taap.2025.117699","url":null,"abstract":"<div><div>Impaired wound healing represents a major complication of diabetes, yet effective therapeutic options remain limited. Our research group has developed a salidroside derivative, SHPL-49, which exhibits antioxidant, anti-inflammatory, and pro-angiogenic properties. We hypothesized that SHPL-49 may promote diabetic wound healing through the modulation of macrophage-mediated immune responses and fibroblast activity. <em>In vivo</em> studies revealed that SHPL-49 significantly accelerated wound closure in diabetic mice, with enhanced granulation tissue formation and extracellular matrix (ECM) deposition. Mechanistically, SHPL-49 induced M2 polarization of wound-associated macrophages, which subsequently secreted TGF-β1 to activate the TGF-β1/Smad2/3 pathway in fibroblasts. <em>In vitro</em> experiments further confirmed that SHPL-49 directly promoted M2 polarization in RAW 264.7 macrophages, as evidenced by increased CD206 expression and TGF-β1 secretion. The conditioned medium from SHPL-49-activated macrophages promoted Smad2/3 phosphorylation in L929 fibroblasts, thereby stimulating their proliferation, migration, and upregulating the expression of collagen I/III, α-SMA, and TGFβRI. Collectively, our findings suggest that SHPL-49 is a promising therapeutic candidate for diabetic wound healing, functioning through a macrophage-to-fibroblast signaling axis: it polarizes macrophages toward an M2 phenotype, which subsequently release TGF-β1 to enhance fibroblast function <em>via</em> the Smad2/3 signaling pathway. This study establishes a theoretical foundation for the future exploration and development of novel therapeutic indications for SHPL-49.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117699"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900937","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":"Inhaled polystyrene nanoparticles may cause fibrotic lesions via immune dysregulation and energy metabolism disturbance","authors":"Wonkyun Jung ,&nbsp;Man S. Kim ,&nbsp;Beom-Geon Kim ,&nbsp;Sung-Min Hong ,&nbsp;Sanghyeon Yu ,&nbsp;Kanghyun Kwon ,&nbsp;Mi-Jin Yang ,&nbsp;Min Beom Heo ,&nbsp;Ik Hwan Kwon ,&nbsp;Seong-Jin Choi ,&nbsp;Hyosun Choi ,&nbsp;Ji Ae Lee ,&nbsp;Eun-Jung Park","doi":"10.1016/j.taap.2025.117695","DOIUrl":"10.1016/j.taap.2025.117695","url":null,"abstract":"<div><div>Microplastics have emerged as a major risk to human health. In this study, we dosed polystyrene nanoparticles (PS-NPs) via the pharynx for 90 days and assessed local and systemic toxicity. PS-NPs increased white blood cell counts and decreased blood potassium levels, and they were widely distributed in the lungs and hearts. The total count of pulmonary cells increased with dose, whereas the proportion of macrophages decreased. Levels of immune regulation-related cytokines increased markedly in the lungs of male and female mice exposed to PS-NPs, accompanied by infiltration of inflammatory cells and the aggregation of foamy macrophages. Collagen fiber-and lamellar body-like structures were notably observed in the lungs and hearts of PS-NP-treated mice, accompanied by elevations in both blood total cholesterol and pulmonary IL-11 levels. We also investigated cellular responses in alveolar macrophages (MH-S cells), bronchial epithelial cells (BEAS-2B), and cardiomyocytes (H9C2), which are considered primary target organs for inhaled PS-NPs. PS-NPs inhibited the proliferation of H9C2 cells but not that of BEAS-2B or MH-S cells. In addition, PS-NPs disrupted the expression of energy metabolism-related genes, including those involved in oxidative phosphorylation and respiratory electron transport, across all three cell types, inducing a proteotoxic stress response that involved both mitochondrial and endoplasmic reticulum stress. Based on these results, we propose that chronic inhalation of PS-NPs may lead to fibrotic lesions via immune dysregulation and energy metabolism dysfunction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117695"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145858117","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":"2026-02-01","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":"DEHP induces hepatic fibrosis through STAT3-SLC7A11-ROS axis","authors":"Siqin Liang ,&nbsp;Zhiliang Xu ,&nbsp;Xiaoxiang You ,&nbsp;Tinghao Yuan ,&nbsp;Jun He ,&nbsp;Lei Mao ,&nbsp;Anan Jin ,&nbsp;Xinwen Zhou ,&nbsp;Bo Yi ,&nbsp;Ming Li ,&nbsp;Qiang Tu ,&nbsp;Bin Xu","doi":"10.1016/j.taap.2025.117665","DOIUrl":"10.1016/j.taap.2025.117665","url":null,"abstract":"<div><div>Di-(2-ethylhexyl) phthalate (DEHP) is a pervasive environmental contaminant commonly found in daily life, and numerous studies have linked it to the progression of liver diseases and organ fibrosis. However, the precise molecular mechanisms by which DEHP induces liver fibrosis remain incompletely understood. This study aimed to investigate the effects of DEHP on liver fibrosis and its underlying mechanisms. We observed that 100 μM DEHP and 6 days of exposure significantly induced activated human hepatic stellate cells (HSCs) and upregulated the fibrosis marker α-smooth muscle actin (α-SMA). By integrating DEHP and liver fibrosis-related target information from various databases, followed by an assessment of the protein-protein interactome (PPI) network and corresponding functional pathway mapping, we predicted that DEHP-induced liver fibrosis is closely associated with the accumulation of reactive oxygen species (ROS). Molecular docking experiments revealed that DEHP spontaneously binds to STAT3, with GLU-638 identified as a critical amino acid residue for this interaction. Further functional experiments confirmed that DEHP promotes ROS accumulation by downregulating SLC7A11 expression, a process mediated by STAT3. In summary, DEHP facilitates intracellular ROS accumulation by mediating the STAT3-SLC7A11-ROS signaling axis, thereby triggering the formation of liver fibrosis. This research provides novel molecular targets and therapeutic strategies for the future prevention and treatment of liver fibrosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117665"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696394","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":"Nitazoxanide reverses pulmonary vascular remodeling in pulmonary hypertension by targeting the IMPA1-RAGE signaling axis","authors":"Di Wang ,&nbsp;Ning Huang ,&nbsp;Mingyuan Cai ,&nbsp;Ruihua Huang ,&nbsp;Xiaoyun Zhu ,&nbsp;Changping Hu","doi":"10.1016/j.taap.2025.117657","DOIUrl":"10.1016/j.taap.2025.117657","url":null,"abstract":"<div><div>Pulmonary hypertension (PH) is a life-threatening disorder characterized by excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), leading to pulmonary vascular remodeling, elevated pulmonary vascular resistance (PVR), and increased pulmonary artery pressure (PAP). These pathological changes ultimately induce right ventricular hypertrophy, right heart failure, and death. Current therapeutic approaches inadequately address the remodeling aspect of PH. Thus, novel therapeutic strategies targeting PASMCs proliferation and vascular remodeling are critically needed. Nitazoxanide, an FDA-approved antiparasitic agent with favorable safety and bioavailability, significantly reduced PAP and alleviated pulmonary vascular remodeling in experimental models of PH, including the SU5416/hypoxia and monocrotaline rat models. Utilizing drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), co-immunoprecipitation and Western blot analysis, we identified inositol monophosphatase 1 (IMPA1) as a novel direct molecular target of nitazoxanide. Mechanistically, nitazoxanide treatment inhibited the IMPA1-RAGE interaction, thereby suppressing downstream activation of the PI3K/Akt/mTOR signaling cascade and attenuating the enhanced glycolysis characteristic of PASMCs in PH. Collectively, our findings highlight nitazoxanide as a promising therapeutic candidate for pulmonary vascular remodeling and pulmonary hypertension.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117657"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145639937","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":"Doxorubicin-induced cardiotoxicity under 28 GHz 5G-band electromagnetic radiation in rats: Insights into the mitigative role of vitamin C","authors":"Atefeh Rahimi ,&nbsp;Ali Rafati ,&nbsp;S.M.J. Mortazavi ,&nbsp;Fahime Edalat ,&nbsp;Najme Jooyan ,&nbsp;Maryam Naseh ,&nbsp;Somaye Keshavarz ,&nbsp;Hadi Moatamed Jahromi ,&nbsp;Ardeshir Nabizadeh ,&nbsp;Sanaz Dastghaib ,&nbsp;Narges Karbalaei","doi":"10.1016/j.taap.2025.117703","DOIUrl":"10.1016/j.taap.2025.117703","url":null,"abstract":"<div><div>Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, induces cardiotoxicity through oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways. As millimeter-wave frequencies used in fifth-generation (5G) communication systems continue to expand, experimental data on potential biological interactions under clinically relevant conditions remain limited. This study investigated whether short-term 28-GHz electromagnetic radiation (EMR) modifies the cardiac response to DOX and evaluated the potential protective role of vitamin C. Thirty male Sprague–Dawley rats were assigned to five groups (<em>n</em> = 6): Sham, DOX, DOX + Vit C, DOX + 5G, and DOX + 5G + Vit C. DOX (15 mg/kg intraperitoneally, six injections) induced cardiotoxicity, while vitamin C (250 mg/kg orally) was administered daily for 14 days. EMR exposure consisted of three 10-min cycles per day at 28 GHz for 14 days. Cardiac injury was assessed using electrocardiography, serum cTnI, oxidative markers (MDA, GSH, SOD, CAT), apoptotic and inflammatory gene expression (BAX, CASP3, BCL-2, TNF-α), and design-based stereology.</div><div>DOX induced significant functional, biochemical, molecular, and structural alterations. Co-exposure to 28-GHz EMR amplified reductions in CAT (<em>p</em> &lt; 0.001), and enhanced pro-apoptotic BAX gene expression (<em>p</em> &lt; 0.0001), accompanied by QT interval prolongation (<em>p</em> &lt; 0.05). Vitamin C provided partial protection across these endpoints. Under the specific short-term pre-clinical conditions tested, these findings indicate that 28-GHz EMR can modulate the severity of DOX-induced cardiotoxicity, while vitamin C confers modest attenuation. Further long-term and clinical studies are needed to clarify mechanisms and refine translational relevance.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117703"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884331","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":"Saxagliptin mitigates doxorubicin-induced cardiotoxicity by modulating NLRP3/caspase-1/IL-1β and TLR-4/NF-κB pathways","authors":"Maha M. Abdel-Fattah,&nbsp;Yasmeen M. Abozaid,&nbsp;Basim Anwar Shehata Messiha,&nbsp;Marwa M. Khalaf","doi":"10.1016/j.taap.2025.117697","DOIUrl":"10.1016/j.taap.2025.117697","url":null,"abstract":"<div><div>Doxorubicin (DOX) is a powerful anthracycline utilized in the management of several malignant disorders, involving both solid and hematological tumors. Despite its effectiveness as cytotoxic agent, its therapeutic use is restricted as cardiac toxicity proportional to the drug dosage. Saxagliptin (SAXA) is a selective and potent member of the dipeptidyl peptidase (DPP)-IV inhibitor family utilized in the management of type two diabetes. It also possesses several biological actions, involving anti-inflammatory and antioxidant properties. This work sought to ascertain the underlying molecular mechanisms and determine the shielding role of SAXA against DOX-induced cardiotoxicity. Thirty-two rats were randomly assigned to four experimental groups, including a normal control group administered the vehicle only, a SAXA group receiving SAXA alone (10 mg/kg), a DOX control group receiving DOX (20 mg/kg) as a single dose, and a SAXA treatment group receiving SAXA plus DOX. Compared to DOX control group, pretreatment with SAXA (10 mg/kg) significantly reduced serum concentrations of CK-MB and CTnI by 37.11 % and 46.32 %, respectively, in addition to a marked improvement in the histopathological features of heart tissues. Moreover, SAXA significantly decreased MDA by 56.05 % and increased GSH and SOD in DOX-intoxicated rats by 493.28 % and 458.32 %, respectively. Additionally, western blot analysis revealed that SAXA pretreatment significantly down-regulated TLR-4 and NLRP3 by 34.9 % and 33.99 %, respectively. Furthermore, ELISA analysis showed that SAXA pretreatment significantly down-regulated NF-κB, caspase-1, and IL-1β by 44.04 %, 78.7 %, and 57.7 %, respectively. The findings of this study suggest that SAXA may exert a cardioprotective effect against DOX-induced toxicity, likely through its antioxidant and anti-inflammatory properties.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117697"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840717","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}