Toxicology and applied pharmacology最新文献_第7页

In Silico, in vitro, and in vivo studies of a 2-substituted quinazolin-4(3H)-one in T-cell acute lymphoblastic leukemia 2-取代喹唑啉-4(3H)- 1在t细胞急性淋巴细胞白血病中的体内、体外研究。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-04 DOI: 10.1016/j.taap.2025.117667

Giorgio Antoniolli , Gilberto Carlos Franchi Junior , Keli Lima , Rayssa de Mello Lopes , Euzebio Guimarães Barbosa , João Agostinho Machado-Neto , Carmen Silvia Passos Lima , Tiago Rodrigues , Fernando Coelho

This study reports the synthesis, physicochemical characterization, and preliminary pharmacological evaluation of a novel 2-substituted quinazolin-4(3H)-one, Qona11. The compound was synthesized from 2-aminobenzamide and 1H-benzo[d]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). In silico 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 via mitochondrial permeabilization and caspase 3 activation. In vivo 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.

本文报道了一种新型2-取代喹唑啉-4(3H)- 1 Qona11的合成、理化性质和初步药理评价。该化合物由2-氨基苯甲酰胺和1h -苯并[d]咪唑-2-乙醛在二甲亚砜中合成，收率为55% %，无催化剂，原子效率高，符合绿色化学原则。通过IR（1667 cm-1，羰基），1H NMR（13.50和12.50 ppm， NH质子）和13C NMR（161.17 ppm，羰基碳）进行结构确认。计算机分析表明Qona11具有良好的口服生物利用度、高肠吸收、有限的CYP450抑制作用和预测血脑屏障通透性。毒性预测强调了潜在的肝毒性、神经毒性和呼吸毒性，而没有发现显著的心脏毒性、致癌性、免疫毒性或细胞毒性风险。与ideelalisib的比较分析显示，Qona11的毒性特征与长春新碱不同。急性白血病模型的生物学评价显示出浓度和时间依赖性的细胞毒性，Jurkat T-ALL细胞比NB4 APL细胞（IC50为12.7 μM）更敏感（IC50为2.3 μM）。流式细胞术证实Jurkat细胞通过线粒体通透性和caspase 3活化诱导凋亡。在携带Jurkat异种移植物的NOD/SCID小鼠体内研究表明，Qona11（100 mg.kg-1）耐受性良好，无全身毒性，尽管它在免疫不依赖性模型中不抑制白血病细胞增殖。总体而言，Qona11表现出良好的抗癌活性和较低的全身毒性，值得在实体肿瘤模型和联合治疗中进一步进行临床前研究。

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引用次数: 0

Maternal ozone exposure and differential cardiometabolic outcomes in aging male and female offspring 母亲臭氧暴露和老龄男女后代的不同心脏代谢结果。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-04 DOI: 10.1016/j.taap.2025.117669

Brendan Yoo , Janice A. Dye , Mehdi S. Hazari , Aimen K. Farraj , Erica J. Stewart , Leslie C. Thompson , Helen H. Nguyen , Samantha J. Snow , Michelle Fiamingo , Anna A. Fisher , Katherine L. O'Shaughnessy , Colette N. Miller

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 (e.g., 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.

胎儿发育是一个易受环境压力影响的生命阶段。妊娠期暴露于臭氧（O3）已被证明会损害胎儿生长，使后代在以后的生活中容易增加肺部和代谢功能障碍的风险。然而，母体接触臭氧对后代健康的心血管后果仍不清楚。在本研究中，怀孕的龙-埃文斯大鼠在妊娠第5和第6天（GD）每天暴露于0.8 ppm O3 4 h。断奶后，对雄性和雌性后代进行心脏代谢健康监测，直至5 个月大。虽然大多数代谢终点（例如，生长、食物摄入、身体成分或葡萄糖耐量）几乎没有变化，但O3暴露的水坝的后代在~4 个月大时呼吸交换比率发生了变化，性别不同。此外，雌性后代在腹膜后储存库中有脂肪细胞增生，而在雄性后代中则不明显。暴露于o3的雄鼠心脏结构和功能发生改变，包括左心室壁增厚、射血分数增加和部分缩短。另一方面，暴露于o3的雌性水坝由于主动脉射血缩短，心肌功能下降。GD 21胎儿心脏的RNAseq显示母体暴露于O3对心脏基因表达的性别二态效应，与成年后存在的结构和功能改变一致。总的来说，这些发现表明，胚胎植入期暴露于O3会增加成年期多种不良反应的风险，包括心功能障碍。

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引用次数: 0

DEHP induces hepatic fibrosis through STAT3-SLC7A11-ROS axis DEHP通过STAT3-SLC7A11-ROS轴诱导肝纤维化。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-04 DOI: 10.1016/j.taap.2025.117665

Siqin Liang , Zhiliang Xu , Xiaoxiang You , Tinghao Yuan , Jun He , Lei Mao , Anan Jin , Xinwen Zhou , Bo Yi , Ming Li , Qiang Tu , Bin Xu

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.

邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种普遍存在于日常生活中的环境污染物，许多研究已将其与肝脏疾病和器官纤维化的进展联系起来。然而，DEHP诱导肝纤维化的确切分子机制仍不完全清楚。本研究旨在探讨DEHP对肝纤维化的影响及其潜在机制。我们观察到100 μM DEHP和6 天的暴露显著诱导活化的人肝星状细胞（hsc），并上调纤维化标志物α-平滑肌肌动蛋白（α-SMA）。通过整合来自各种数据库的DEHP和肝纤维化相关靶点信息，随后评估蛋白质-蛋白质相互作用组（PPI）网络和相应的功能通路作图，我们预测DEHP诱导的肝纤维化与活性氧（ROS）的积累密切相关。分子对接实验表明，DEHP可以自发地与STAT3结合，其中GLU-638被鉴定为这种相互作用的关键氨基酸残基。进一步的功能实验证实，DEHP通过下调STAT3介导的SLC7A11表达来促进ROS积累。综上所述，DEHP通过介导STAT3-SLC7A11-ROS信号轴促进细胞内ROS积累，从而引发肝纤维化的形成。本研究为今后肝纤维化的防治提供了新的分子靶点和治疗策略。

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引用次数: 0

Ditrioxzin synergizes with 2-deoxy-d-glucose to induce redox-dependent metabolic crisis in gastric cancer through dual targeting of peroxiredoxin 3 and glycolysis Ditrioxzin与2-脱氧-d-葡萄糖协同作用，通过双靶向过氧化物还氧蛋白3和糖酵解诱导胃癌氧化还原依赖性代谢危象

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-03 DOI: 10.1016/j.taap.2025.117666

Nan Su , Lulu Pan , Xiaojing Shi , Ying Liu , Xiaxia Fan , Shilin Liu , Yong-Cheng Ma

Emerging evidence demonstrates that dual inhibition of glycolysis and mitochondrial function represents a potent anticancer strategy. Here, we report that Ditrioxzin (DTO), a synthetic ent-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-d-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 (>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 N-acetylcysteine. In vivo, DTO (10 mg/kg) and 2-DG (500 mg/kg) synergistically suppressed tumor growth (66 %, P < 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.

新出现的证据表明糖酵解和线粒体功能的双重抑制是一种有效的抗癌策略。在这里，我们报道了Ditrioxzin (DTO)，一种合成的对kaurane二萜类似物，通过靶向过氧化氧还蛋白3 （Prx3）诱导过氧化氢（H2O2）积累，从而选择性地破坏线粒体氧化还原稳态，从而使线粒体膜电位（MMP）去极化并损害胃癌细胞的氧化磷酸化（OXPHOS）。DTO与糖酵解抑制剂2-脱氧-d-葡萄糖（2-DG）协同作用，通过双代谢阻断消耗ATP。体外研究表明，DTO对胃癌细胞具有选择性细胞毒性（IC50为3.82 ~ 6.10 μM），但对正常胃上皮细胞（GES-1）没有作用。从机制上说，DTO直接结合Prx3，提高H2O2水平（8 μM时提高3倍），氧化线粒体过氧化物还毒素，并引发氧化还原依赖的线粒体功能障碍。DTO/2-DG联合处理通过ros依赖途径促进ATP耗竭和细胞凋亡（69.6% vs 24.1%单独DTO）， n -乙酰半胱氨酸消除了这一作用。在体内，DTO （10 mg/kg）和2-DG （500 mg/kg）在异种移植模型中协同抑制肿瘤生长（66%,P < 0.001），无体重减轻或肾/心脏组织病理改变。我们的研究结果表明，DTO是一种新型的prx3靶向药物，可与2-DG协同诱导代谢危机，为胃癌提供了一种高安全性的治疗策略。

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引用次数: 0

Zingiberensis new saponin reverses sorafenib resistance by targeting lncRNA TCONS-00026762/AKR1C1 and modulating autophagy and ferroptosis in hepatocellular carcinoma 姜叶新皂苷通过靶向lncRNA tcon -00026762/AKR1C1并调节肝细胞癌的自噬和铁凋亡逆转索拉非尼耐药。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-28 DOI: 10.1016/j.taap.2025.117664

Liang Luo , Pingsheng Zhou , Keqing He

Introduction

Zingiberensis new saponin (ZnS) extracted from Dioscorea zingiberensis has antitumor activity. Our previous study found that Zns could exert anti- hepatocellular carcinoma (HCC) effects by regulating lncRNA TCONS-00026762. In addition, lncRNA TCONS-00026762 may act synergistically with AKR1C1. However, the relationship between them and their specific molecular mechanism underlying the anti-HCC effects of Zns has not been elucidated. This study aimed to investigate the role of TCONS-00026762/ AKR1C1 axis and ZnS in HCC cells from the perspective of autophagy, ferroptosis, and sorafenib resistance.

Methods

Bioinformatics analysis was used to assess the prognostic significance and expression level of AKR1C1 in TCGA liver cancer data. In vitro experiments, the effect of TCONS-00026762 knockdown or Zns on AKR1C1 expression, autophagy, and ferroptosis in HCC cells (Huh7) was investigated. Their function was further confirmed by rescue experiments. In addition, a sorafenib-resistant cell line (Huh7-SR) was constructed to explore the regulatory effects of TCONS-0026762 or Zns on cell viability.

Results

AKR1C1 was overexpressed in HCC and association with prognosis. It was involved in autophagy and ferroptosis related pathways. TCONS-00026762 knockdown inhibited AKR1C1 expression. TCONS-00026762 knockdown and Zns treatment suppressed the levels of autophagy marker (LC3) and ferroptosis markers (GPX4, SLC7A11) in Huh7 cell, as well as decreased the proliferation and invasion capacities of Huh7-SR cells after sorafenib treatment. Notably, these effects were eliminated by AKR1C1 overexpression or TCONS-00026762 overexpression.

Conclusions

Our findings suggest that ZnS inhibits autophagy, promotes ferroptosis, and enhances sensitivity to sorafenib in HCC cells through the TCONS-00026762/AKR1C1 axis.

摘要：从盾叶薯蓣中提取的盾叶新皂苷（ZnS）具有抗肿瘤活性。我们前期研究发现Zns可通过调控lncRNA TCONS-00026762发挥抗肝细胞癌（HCC）作用。此外，lncRNA TCONS-00026762可能与AKR1C1协同作用。然而，它们之间的关系及其在Zns抗hcc中的具体分子机制尚未阐明。本研究旨在从自噬、铁凋亡和索拉非尼耐药的角度探讨lncRNA TCONS-00026762/ AKR1C1和ZnS在HCC细胞中的作用。方法：采用生物信息学分析方法评估AKR1C1在TCGA肝癌资料中的预后意义及表达水平。体外实验研究tcon -00026762敲低或Zns对HCC细胞（Huh7）中AKR1C1表达、自噬和铁凋亡的影响。救援实验进一步证实了其功能。此外，构建索拉非尼耐药细胞株（Huh7-SR），探讨TCONS-0026762或Zns对细胞活力的调控作用。结果：AKR1C1在HCC中过表达并与预后相关。它参与了自噬和铁下垂相关的途径。TCONS-00026762敲低抑制AKR1C1表达。tcon -00026762敲除和Zns处理抑制Huh7细胞自噬标志物（LC3）和铁凋亡标志物（GPX4、SLC7A11）水平，降低索拉非尼处理后Huh7- sr细胞的增殖和侵袭能力。值得注意的是，这些影响被AKR1C1过表达或TCONS-00026762过表达消除。结论：我们的研究结果表明，ZnS通过lncRNA tcon -00026762/AKR1C1轴抑制HCC细胞自噬，促进铁凋亡，并增强对索拉非尼的敏感性。

{"title":"Zingiberensis new saponin reverses sorafenib resistance by targeting lncRNA TCONS-00026762/AKR1C1 and modulating autophagy and ferroptosis in hepatocellular carcinoma","authors":"Liang Luo , Pingsheng Zhou , Keqing He","doi":"10.1016/j.taap.2025.117664","DOIUrl":"10.1016/j.taap.2025.117664","url":null,"abstract":"<div><h3>Introduction</h3><div>Zingiberensis new saponin (ZnS) extracted from Dioscorea zingiberensis has antitumor activity. Our previous study found that Zns could exert anti- hepatocellular carcinoma (HCC) effects by regulating lncRNA TCONS-00026762. In addition, lncRNA TCONS-00026762 may act synergistically with AKR1C1. However, the relationship between them and their specific molecular mechanism underlying the anti-HCC effects of Zns has not been elucidated. This study aimed to investigate the role of TCONS-00026762/ AKR1C1 axis and ZnS in HCC cells from the perspective of autophagy, ferroptosis, and sorafenib resistance.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis was used to assess the prognostic significance and expression level of AKR1C1 in TCGA liver cancer data. In vitro experiments, the effect of TCONS-00026762 knockdown or Zns on AKR1C1 expression, autophagy, and ferroptosis in HCC cells (Huh7) was investigated. Their function was further confirmed by rescue experiments. In addition, a sorafenib-resistant cell line (Huh7-SR) was constructed to explore the regulatory effects of TCONS-0026762 or Zns on cell viability.</div></div><div><h3>Results</h3><div>AKR1C1 was overexpressed in HCC and association with prognosis. It was involved in autophagy and ferroptosis related pathways. TCONS-00026762 knockdown inhibited AKR1C1 expression. TCONS-00026762 knockdown and Zns treatment suppressed the levels of autophagy marker (LC3) and ferroptosis markers (GPX4, SLC7A11) in Huh7 cell, as well as decreased the proliferation and invasion capacities of Huh7-SR cells after sorafenib treatment. Notably, these effects were eliminated by AKR1C1 overexpression or TCONS-00026762 overexpression.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that ZnS inhibits autophagy, promotes ferroptosis, and enhances sensitivity to sorafenib in HCC cells through the TCONS-00026762/AKR1C1 axis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117664"},"PeriodicalIF":3.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649344","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}

引用次数: 0

High-density lipoprotein cholesterol protects against delayed encephalopathy after acute carbon monoxide poisoning 高密度脂蛋白胆固醇可预防急性一氧化碳中毒后的迟发性脑病。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-27 DOI: 10.1016/j.taap.2025.117663

Yuhang Mu , Nan Gao , Yutao Wang , Shaokun Wang , Li Pang

High-density lipoprotein cholesterol (HDL-C) plays a crucial role in neurological disorders. In this study, we aimed to elucidate the role of HDL-C in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), which presents with both neurological and psychiatric symptoms. Two-sample Mendelian randomization was employed on 201 lipid summary statistics to investigate potential causality. Data from the FinnGen database of 306,787 individuals were used. Mendelian randomization analysis results were screened using Bayesian model averaging. The results were validated in a multicenter cohort of 1368 patients, and the role of the antioxidant properties of high-density lipoprotein in DEACMP was examined. Mendelian randomization analysis identified six high-density lipoprotein-related variants significantly associated with DEACMP, with the cholesterol to total lipids ratio in medium high-density lipoprotein showing the strongest effect (marginal inclusion probability = 0.51, p = 1.00 × 10⁻³, false discovery rate = 6.00 × 10⁻³). Clinical validation confirmed HDL-C as an independent protective factor. Patients without DEACMP had higher high-density lipoprotein oxidant index values (1.23 [interquartile range: 1.02–1.36]) than those who developed DEACMP (0.84 [interquartile range: 0.66–0.90]); the high-density lipoprotein oxidant index declined significantly in postmenopausal women (p = 0.023). These findings demonstrate that HDL-C mitigates the risk of DEACMP through its antioxidant capacity. The integration of genetic evidence, clinical validation, and functional assays provides robust support for HDL-C as a predictive biomarker of neural recovery after carbon monoxide poisoning.

高密度脂蛋白胆固醇（HDL-C）在神经疾病中起着至关重要的作用。在这项研究中，我们旨在阐明HDL-C在急性一氧化碳中毒（DEACMP）后迟发性脑病中的作用，该疾病表现为神经和精神症状。采用双样本孟德尔随机化方法对201例血脂汇总统计数据进行分析，探讨潜在的因果关系。研究使用了FinnGen数据库中306,787人的数据。孟德尔随机化分析结果采用贝叶斯模型平均筛选。结果在1368例患者的多中心队列中得到验证，并检验了高密度脂蛋白抗氧化特性在DEACMP中的作用。孟德尔随机化分析确定六高密度lipoprotein-related变异与DEACMP显著相关,与总胆固醇脂质比例中高密度脂蛋白显示效果最强的(边际包含概率 = 0.51,p = 1.00  × 三分,错误发现率 = 6.00 × 三分)。临床验证证实HDL-C是一个独立的保护因素。无DEACMP患者的高密度脂蛋白氧化指数值（1.23[四分位数范围：1.02-1.36]）高于DEACMP患者（0.84[四分位数范围：0.66-0.90]）；绝经后妇女的高密度脂蛋白氧化指数明显下降（p = 0.023）。这些发现表明HDL-C通过其抗氧化能力减轻DEACMP的风险。遗传证据、临床验证和功能分析的整合为HDL-C作为一氧化碳中毒后神经恢复的预测性生物标志物提供了强有力的支持。

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引用次数: 0

Nanocapsule-based vitamin B12 as a novel strategy against vancomycin-induced nephrotoxicity: Targeting oxidative stress, ER stress, inflammation, and fibrosis in rats 基于纳米胶囊的维生素B12作为抗万古霉素诱导肾毒性的新策略：针对大鼠的氧化应激、内质网应激、炎症和纤维化

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-27 DOI: 10.1016/j.taap.2025.117662

Mahran Mohamed Abd El-Emam , Maha S. Kilany , Mohamed Ibrahim , Milad Reda Qelliny , Mahmoud Mostafa , Marwa Mohamed El Sayed , Tarek khamis , Rasha Ahmed Ahmed Agaga , Asmaa Monir Eltaweel , Mohamed Fouad Mansour

Vancomycin (VCM) is an essential glycopeptide antibiotic employed for treating methicillin-resistant Staphylococcus infections. However, its clinical use is limited by nephrotoxicity. Vitamin B12 (Vit B12) possesses antioxidant, anti-inflammatory, and anti-fibrotic properties that may protect against nephrotoxicity. However, Vitamin B12 bioavailability is inherently low. Therefore, nanotechnology-based approaches have been employed to overcome these limitations. Our research examined the formulation and preclinical assessment of Vitamin B12 nanocapsules (Vit B12 NC) against VCM-induced oxidative and, endoplasmic reticulum (ER) stress, inflammation, and fibrosis in rats. Nephrotoxicity was induced by administering VCM, followed by treatment with oral Vit B12 NC. Renal function, oxidative and ER stress markers, inflammatory cytokines, fibrosis markers, and histopathological changes in kidney tissue were evaluated. Vit B12 NC treatment reduced serum creatinine, uric acid, and urea levels, raised antioxidant enzyme activities (catalase and total antioxidant capacity), and decreased malondialdehyde (MDA) levels. It also downregulated ER stress markers, including inositol-requiring enzyme 1 (IRE1), TNF receptor-associated factor 2 (TRAF2), c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP). Inflammatory mediators such as Toll-like receptor 4 (TLR4), interleukin-17 (IL-17), and interleukin-18 (IL-18) were also repressed. Also, it reduced renal fibrosis as indicated by decreased expression of VIM, miR-382-5p, and miR-92a-3p. Furthermore, it reversed the histopathological alterations in renal tissues. These findings suggest that Vit B12 NC exhibits promising nephroprotective potential against VCM-induced nephrotoxicity.

万古霉素（VCM）是治疗耐甲氧西林葡萄球菌感染所必需的糖肽类抗生素。然而，其临床应用受到肾毒性的限制。维生素B12 （Vit B12）具有抗氧化、抗炎和抗纤维化的特性，可以防止肾毒性。然而，维生素B12的生物利用度本来就很低。因此，基于纳米技术的方法已经被用来克服这些限制。我们的研究检查了维生素B12纳米胶囊（Vit B12 NC）的配方和临床前评估，以对抗vcm诱导的大鼠氧化和内质网（ER）应激、炎症和纤维化。先给药VCM，再口服Vit B12 NC引起肾毒性。评估肾脏组织的肾功能、氧化应激和内质网应激标志物、炎症细胞因子、纤维化标志物和组织病理学变化。维生素B12 NC处理降低了血清肌酐、尿酸和尿素水平，提高了抗氧化酶活性（过氧化氢酶和总抗氧化能力），降低了丙二醛（MDA）水平。它还下调内质网应激标志物，包括肌醇要求酶1 （IRE1）、TNF受体相关因子2 （TRAF2）、C - jun n -末端激酶（JNK）和C/EBP同源蛋白（CHOP）。炎症介质如toll样受体4 （TLR4）、白细胞介素-17 （IL-17）和白细胞介素-18 （IL-18）也被抑制。此外，通过降低VIM、miR-382-5p和miR-92a-3p的表达，可以减少肾纤维化。此外，它逆转了肾组织的组织病理学改变。这些结果表明，Vit B12 NC对vcm引起的肾毒性具有良好的肾保护潜力。

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引用次数: 0

Drug screening reveals the mechanism of toyocamycin-induced apoptosis in triple-negative breast cancer organoids 药物筛选揭示了toyocamycin诱导三阴性乳腺癌类器官凋亡的机制。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-26 DOI: 10.1016/j.taap.2025.117659

Houshi Ma , Linlin Lu , Yuqing Tu , Xiaoran Chang , Huabin Jiang , Tianhang Yang , Shun Wang , Jinxian Wang , Jinbing Xue , Yan Chen , Gangyin Luo

Triple-negative breast cancer (TNBC) is characterized by high aggressiveness and molecular heterogeneity, limiting therapeutic efficacy and drug resistance, necessitating reliable preclinical models and novel therapeutic agents. This study utilized tumor tissues derived from breast cancer patients of various molecular subtypes, with a particular focus on TNBC, to construct patient-derived organoid models (PDOs). These models effectively recapitulate the in vivo characteristics of tumors and provide a cost-effective platform for high-throughput drug screening. The study employed a label-free in vitro drug screening system based on bright-field imaging, which continuously monitors changes in organoid area and brightness to assess the drug responses of 505 compounds. This approach avoids the interference associated with traditional cell viability assay reagents. Screening of the natural compound library using this system revealed that Toyocamycin effectively inhibits the growth of two TNBC organoid models, exhibiting significant dose-dependency. Further mechanistic studies demonstrated that Toyocamycin induces apoptosis in TNBC organoids by activating the p38 MAPK signaling pathway, specifically manifested by the upregulation of key genes such as TNFR, MAP3K7, MAP2K3, and DDIT3. It initially triggers cytotoxicity to suppress proliferation and subsequently induces sustained apoptosis. This process can be reversed by the p38 inhibitor Adezmapimod, further confirming that its apoptosis-inducing effect is dependent on the p38 MAPK pathway. This study not only validates the reliability of patient-derived organoids in personalized drug screening but also uncovers the potential therapeutic value of Toyocamycin for TNBC, providing a novel model and theoretical foundation for the precision treatment of TNBC.

三阴性乳腺癌（TNBC）的特点是高侵袭性和分子异质性，限制了治疗效果和耐药性，需要可靠的临床前模型和新的治疗药物。本研究利用来自不同分子亚型乳腺癌患者的肿瘤组织，特别关注TNBC，构建患者来源的类器官模型（PDOs）。这些模型有效地概括了肿瘤的体内特征，为高通量药物筛选提供了一个具有成本效益的平台。本研究采用基于亮场成像的无标记体外药物筛选系统，连续监测类器官面积和亮度的变化，评估505种化合物的药物反应。这种方法避免了与传统细胞活力测定试剂相关的干扰。利用该系统筛选天然化合物文库，发现Toyocamycin能有效抑制两种TNBC类器官模型的生长，并表现出明显的剂量依赖性。进一步的机制研究表明，丰霉素通过激活p38 MAPK信号通路诱导TNBC类器官凋亡，具体表现为上调TNFR、MAP3K7、MAP2K3、DDIT3等关键基因。它最初触发细胞毒性抑制增殖，随后诱导持续的细胞凋亡。这一过程可被p38抑制剂Adezmapimod逆转，进一步证实其诱导凋亡的作用依赖于p38 MAPK通路。本研究不仅验证了患者源性类器官在个体化药物筛选中的可靠性，也揭示了丰霉素对TNBC的潜在治疗价值，为TNBC的精准治疗提供了新的模型和理论基础。

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引用次数: 0

miR-207 mitigates silica-induced pulmonary fibrosis by suppressing fibroblast-to-Myofibroblast transition via multi-target modulation of the TGF-β1/SMADs signaling pathways in mice miR-207通过多靶点调节小鼠TGF-β1/SMADs信号通路，抑制成纤维细胞向肌成纤维细胞的转化，从而减轻二氧化硅诱导的肺纤维化。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-25 DOI: 10.1016/j.taap.2025.117661

Shu-ling Du , Yuan-yuan Cui , Xuan Zhou , Wei-Lei Gong , Zhao-qiang Zhang , Gui-zhi Han

TGF-β1/SMADs signaling pathway plays a vital role in development of silicosis, with SMADs serving as the core transducers. Accordingly, any fluctuation in SMAD abundance can decisively steer the disease trajectory. Our previous research revealed miR-207 suppresses the progression of silicosis fibrosis by targeting Smad3. Further bioinformatic analysis suggested that miR-207 could also bind to the sequences of genes of Smad2 and Smad7, raising the possibility that miR-207 functions as a coordinated rheostat of multiple SMADs. However, the specific regulatory mechanisms of miR-207 in silicosis remains unexplored. In this study, a mouse model of silicosis was established by administering a silica suspension (20 μg/μL, 80 μL) via nasal drip daily for 16 days. On day 17, the silica–dusted mice were transfected with either miR-207 mimics or inhibitors. Lungs samples were harvested on day 45 for histological assessment of injury. Then, the expression levels of miR-207, Smad2, and Smad7 were determined using RT-qPCR, and the levels of SMAD2 and 7, Collagen I and III, and indicators of fibroblast-to-myofibroblast transdifferentiation (FMT) (α-SMA, FAP-1, and Vimentin) were determined using Western blot. The results showed that miR-207 coordinately downregulated SMAD2 and upregulated SMAD7 at both the mRNA and protein levels in silica-exposed mice, with concomitant reductions in FMT indicators (α-SMA, FAP-1 and Vimentin) and collagen levels. Therefore, we concluded that miR-207 suppresses silicosis progression in mice by inhibiting FMT via modulation of the TGF-β1/SMADs signaling pathway by targeting SMADs.

TGF-β1/SMADs信号通路在矽肺的发生发展中起着至关重要的作用，其中SMADs是核心的转导器。因此，SMAD丰度的任何波动都可以决定性地引导疾病轨迹。我们之前的研究发现miR-207通过靶向Smad3抑制矽肺纤维化的进展。进一步的生物信息学分析表明，miR-207还可以结合Smad2和Smad7的基因序列，从而提高了miR-207作为多个smad的协调变阻器的可能性。然而，miR-207在矽肺中的具体调控机制仍未被探索。本实验采用每天滴鼻给药二氧化硅混悬液（20 μg/μL, 80 μL），连续16 d建立小鼠矽肺模型。在第17天，用miR-207模拟物或抑制剂转染硅粉小鼠。第45天采集肺样本用于损伤组织学评估。RT-qPCR检测miR-207、Smad2、Smad7的表达水平，Western blot检测Smad2、7、Collagen I、III的表达水平，检测成纤维细胞向肌成纤维细胞转分化（FMT）指标（α-SMA、FAP-1、Vimentin）的表达水平。结果显示，在硅暴露小鼠中，miR-207在mRNA和蛋白水平上协同下调SMAD2和上调SMAD7，同时降低FMT指标（α-SMA、FAP-1和Vimentin）和胶原水平。因此，我们得出结论，miR-207通过靶向smad，通过调节TGF-β1/SMADs信号通路抑制FMT，从而抑制小鼠矽肺的进展。

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引用次数: 0

Nomilin ameliorates perfluorooctanoic acid (PFOA)-induced impairment of zebrafish (Danio rerio) ocular development and visual function through PIK3CA activation 诺米林通过激活PIK3CA改善全氟辛酸（PFOA）诱导的斑马鱼（Danio rerio）眼部发育和视觉功能损伤

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-24 DOI: 10.1016/j.taap.2025.117660

Xing Liu , Mingzhu Xia , Xinyi Wu, Ruobing Chen, Yuting Peng, Yi Fan, Junjie Han, Yichun Zhao, Man Qu

Perfluorooctanoic acid (PFOA), a pervasive environmental contaminant, is implicated in ocular diseases through prenatal/embryonic exposure. This study investigated the protective effects of nomilin, a citrus-derived bioactive compound with therapeutic properties, against PFOA-induced ocular and visual impairments in zebrafish. Integrating network toxicology and molecular docking, we identified seven shared targets (including PIK3CA and mTOR) linking PFOA, nomilin, and ocular diseases. Experimental results demonstrated that PFOA exposure suppressed the PIK3CA/AKT/mTOR/pax6 axis, significantly downregulated (by approximately 0.23- to 0.65-fold) ocular development genes (rx1, vsx1, rpgra, lhx4), and induced structural defects (reduced eye size, lens diameter and retinal layer thickness) and visual dysfunction. Nomilin treatment dose-dependently reversed these effects by activating the PIK3CA/AKT/mTOR/pax6 axis, restoring the expression of ocular developmental related genes by 1.45- to 2.85-fold compared to the PFOA-exposed group, improving ocular morphology, and enhancing visual response behaviors. Furthermore, nomilin attenuated PFOA-induced apoptosis. These findings reveal that nomilin mitigates PFOA-mediated ocular toxicity via PIK3CA activation, offering novel therapeutic insights for environmental pollutant-related ocular disorders.

全氟辛酸（PFOA）是一种普遍存在的环境污染物，通过产前/胚胎暴露与眼部疾病有关。本研究研究了诺米林（一种柑橘衍生的具有治疗作用的生物活性化合物）对pfoa诱导的斑马鱼眼部和视力损伤的保护作用。结合网络毒理学和分子对接，我们确定了七个连接PFOA、nomilin和眼部疾病的共同靶点（包括PIK3CA和mTOR）。实验结果表明，PFOA暴露抑制PIK3CA/AKT/mTOR/pax6轴，显著下调眼发育基因（rx1, vsx1, rpgra, lhx4）（约0.23- 0.65倍），并诱导结构缺陷（眼睛尺寸减小，晶状体直径减小，视网膜层厚度减小）和视力障碍。诺米林通过激活PIK3CA/AKT/mTOR/pax6轴，与pfoa暴露组相比，恢复眼部发育相关基因的表达1.45- 2.85倍，改善眼部形态，增强视觉反应行为，从而剂量依赖性地逆转了这些影响。此外，诺米林可减弱pfoa诱导的细胞凋亡。这些研究结果表明，诺米林通过激活PIK3CA来减轻pfoa介导的眼部毒性，为环境污染相关眼部疾病的治疗提供了新的见解。

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引用次数: 0