Toxicology and applied pharmacology最新文献_第5页

Benign cardiac troponin I release induced by elevated beat rate is associated with membrane bleb formation 心率升高诱导的良性心肌肌钙蛋白I释放与膜泡形成有关。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.taap.2025.117701

Jomana Hatahet , Hannah J. Nonarath , Mark T. Zafiratos , Geena Jasiek , Rebecca Kohnken , Jessica Treadway , C. Michael Foley

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 in vivo 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 (Â±)-blebbistatin, a Myosin II and membrane blebbing inhibitor. We found (Â±)-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.

心肌肌钙蛋白I （cTnI）是心肌细胞收缩的关键调节蛋白，是细胞坏死的临床生物标志物。在临床前研究中测量循环cTnI用于评估新化学实体（NCEs）的心脏毒性，并将其推进临床试验。最近的研究表明，由于运动后可逆的肌细胞损伤，肌钙蛋白的良性释放可能主要是由心率的持续升高引起的。然而，心率增加与肌钙蛋白释放无坏死损伤之间的联系机制仍未确定。在这项研究中，我们利用人类诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）和斑马鱼模型研究了持续心率增加和cTnI释放之间的关系。加入forskolin后，hiPSC-CMs的心跳率增加，cTnI释放随之增加，但不影响细胞活力。为了评估体内良性肌钙蛋白释放的可翻译性，我们建立了定量斑马鱼全身肌钙蛋白水平的方法，并评估了福斯可林对心率和肌钙蛋白释放的影响。同样，福斯克林治疗增加了斑马鱼的心率和循环肌钙蛋白。为了研究其中的分子机制，hiPSC-CMs与forskolin和（Â±）-blebbistatin（一种肌球蛋白II和膜起泡抑制剂）共处理。我们发现（Â±）-blebbistatin显著降低cTnI释放，提示膜泡形成可能是心率升高引发良性肌钙蛋白释放的机制。这些发现有助于更好地理解肌钙蛋白在心肌细胞中的释放机制。此外，这些结果可能支持改进nce的心脏毒性评估，防止可能导致不必要终止有希望的治疗方法的误解。

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引用次数: 0

Doxorubicin-induced cardiotoxicity under 28 GHz 5G-band electromagnetic radiation in rats: Insights into the mitigative role of vitamin C 28 GHz 5g波段电磁辐射下阿霉素诱导的大鼠心脏毒性：维生素C的缓解作用

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.taap.2025.117703

Atefeh Rahimi , Ali Rafati , S.M.J. Mortazavi , Fahime Edalat , Najme Jooyan , Maryam Naseh , Somaye Keshavarz , Hadi Moatamed Jahromi , Ardeshir Nabizadeh , Sanaz Dastghaib , Narges Karbalaei

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 (n = 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.

DOX induced significant functional, biochemical, molecular, and structural alterations. Co-exposure to 28-GHz EMR amplified reductions in CAT (p < 0.001), and enhanced pro-apoptotic BAX gene expression (p < 0.0001), accompanied by QT interval prolongation (p < 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.

多柔比星（DOX）是一种有效的蒽环类化疗药物，通过氧化应激、线粒体功能障碍和凋亡通路的激活诱导心脏毒性。随着第五代（5G）通信系统中使用的毫米波频率不断扩大，临床相关条件下潜在生物相互作用的实验数据仍然有限。本研究研究了短期28 ghz电磁辐射（EMR）是否会改变心脏对DOX的反应，并评估维生素C的潜在保护作用。30只雄性Sprague-Dawley大鼠分为5组（n = 6）： Sham、DOX、DOX + Vit C、DOX + 5G和DOX + 5G + Vit C。DOX （15 mg/kg腹腔注射，6次注射）诱导心脏毒性，而维生素C （250 mg/kg口服）每天给药，持续14天。EMR暴露包括每天三次10分钟的28 GHz周期，持续14天。通过心电图、血清cTnI、氧化标志物（MDA、GSH、SOD、CAT）、凋亡和炎症基因表达（BAX、CASP3、BCL-2、TNF-α）和基于设计的体视学来评估心脏损伤。DOX诱导了显著的功能、生化、分子和结构改变。共暴露于28-GHz EMR可使CAT降低（p < 0.001），促凋亡BAX基因表达增强（p < 0.0001），并伴有QT间期延长（p < 0.05）。维生素C在这些终点提供了部分保护。在特定的短期临床前条件下，这些研究结果表明，28 ghz EMR可以调节dox诱导的心脏毒性的严重程度，而维生素C则具有适度的衰减作用。需要进一步的长期和临床研究来阐明机制和完善翻译相关性。

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引用次数: 0

Resveratrol mitigates TOCP-induced spinal cord neurotoxicity by suppressing ferroptosis, a process mediated through the p62/Keap1/Nrf2 pathway 白藜芦醇通过抑制p62/Keap1/Nrf2通路介导的铁凋亡来减轻tocp诱导的脊髓神经毒性。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-29 DOI: 10.1016/j.taap.2025.117698

Sangping Li, Shule Tan, Xiangsheng Tian, Yiquan Ou, Shujuan Hu, Weichao Zhao, Dingxin Long

This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin–eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe²⁺ levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.

本研究研究了白藜芦醇（Res）对三o-甲酰磷酸（TOCP）诱导的成年母鸡脊髓神经毒性的保护作用，重点研究了其通过p62/Keap1/Nrf2通路对铁死亡的调节作用。白藜芦醇是一种经典的神经保护化合物，具有抗氧化特性和激活Nrf2的能力。将成年母鸡分为对照组、TOCP组、他汀铁素-1 （fer1）组、他汀铁素-1 + TOCP组、白藜芦醇组和白藜芦醇+ TOCP组。脊髓组织采用行为OPIDN评分、组织学（苏木精-伊红和尼氏染色）、生化分析和Western blotting检测p62/Keap1/ nrf2相关蛋白。TOCP暴露诱导了严重的超微结构损伤，包括髓鞘破坏和神经元变性，同时丙二醛（MDA）和Fe2+水平升高，谷胱甘肽（GSH）和超氧化物歧化酶（SOD）活性降低。Western blot分析显示NCOA4、ACSL4、Nrf2、P62和LC3 II表达上调，GPX4、SLC7A11、FTH1和Keap1表达下调。白藜芦醇治疗显著减轻了这些分子、生化和组织病理学改变，减轻了氧化应激和铁的变化。

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引用次数: 0

Inhaled polystyrene nanoparticles may cause fibrotic lesions via immune dysregulation and energy metabolism disturbance 吸入聚苯乙烯纳米颗粒可通过免疫失调和能量代谢紊乱引起纤维化病变。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-27 DOI: 10.1016/j.taap.2025.117695

Wonkyun Jung , Man S. Kim , Beom-Geon Kim , Sung-Min Hong , Sanghyeon Yu , Kanghyun Kwon , Mi-Jin Yang , Min Beom Heo , Ik Hwan Kwon , Seong-Jin Choi , Hyosun Choi , Ji Ae Lee , Eun-Jung Park

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.

微塑料已成为人类健康的主要威胁。在这项研究中，我们通过咽部给药聚苯乙烯纳米颗粒（PS-NPs） 90 天，并评估局部和全身毒性。PS-NPs增加白细胞计数，降低血钾水平，广泛分布于肺和心脏。肺细胞总数随剂量增加而增加，巨噬细胞比例随剂量增加而减少。暴露于PS-NPs的雄性和雌性小鼠肺中免疫调节相关细胞因子水平显著升高，并伴有炎症细胞浸润和泡沫巨噬细胞聚集。ps - np处理小鼠的肺和心脏中明显观察到胶原纤维和板层状体样结构，同时血液中总胆固醇和肺中IL-11水平升高。我们还研究了肺泡巨噬细胞（MH-S细胞）、支气管上皮细胞（BEAS-2B）和心肌细胞（H9C2）的细胞反应，这些细胞被认为是吸入PS-NPs的主要靶器官。PS-NPs对H9C2细胞有抑制作用，对BEAS-2B和MH-S细胞无抑制作用。此外，PS-NPs破坏了能量代谢相关基因的表达，包括那些参与氧化磷酸化和呼吸电子传递的基因，在所有三种细胞类型中，诱导涉及线粒体和内质网应激的蛋白质毒性应激反应。基于这些结果，我们认为长期吸入PS-NPs可能通过免疫失调和能量代谢功能障碍导致纤维化病变。

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引用次数: 0

Dapagliflozin regulates kynurenine metabolism and microglial activation to alleviate diabetes-associated cognitive impairment 达格列净调节犬尿氨酸代谢和小胶质细胞激活以减轻糖尿病相关的认知障碍。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-24 DOI: 10.1016/j.taap.2025.117696

Yanhong Jia , Jiangxia Pang , Chen Sun , Puyun Wang , Qianqian Huang , Xueyun Zhao , Dongming Zhang

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown significant therapeutic potential in alleviating Diabetes-associated cognitive dysfunction (DACD). However, its specific effects on microglia remain to be further explored. In this study, a type 2 diabetes mellitus (T2DM) mouse model induced by a high-fat diet/streptozotocin (HFD/STZ) was used. It was found that dapagliflozin could significantly reduce fasting blood glucose levels, alleviate weight loss, and improve cognitive function performance in behavioral tests (Y-maze, Morris water maze, and novel object recognition). Histological and biochemical analyses indicated that dapagliflozin could reduce hippocampal neuronal damage, enhance antioxidant capacity (manifested as increased levels of superoxide dismutase and catalase, and decreased malondialdehyde content), and effectively inhibit neuroinflammation (significantly reduced levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6). Transcriptomic and metabolomic analyses revealed that dapagliflozin rebalanced the kynurenine pathway by down-regulating indoleamine 2,3-dioxygenase (IDO1) and kynurenine monooxygenase (KMO), while up-regulating kynurenic acid transaminase 1 (KYAT1), promoting the transformation of metabolic products from neurotoxic substances (such as 3-hydroxykynurenine and kynurenic acid) to neuroprotective substances (kynurenic acid). Additionally, in vitro experiments in high glucose (HG)-stimulated BV-2 microglia further verified that dapagliflozin exerted anti-inflammatory effects by inhibiting the Toll-like receptor/myeloid differentiation factor 88 (TLR/MyD88) signaling pathway and regulating kynurenine metabolic reprogramming. At the same time, overexpression of KMO reversed these effects. In conclusion, these results reveal the multi-dimensional neuroprotective mechanisms of dapagliflozin in DACD, providing substantial evidence for its potential as a therapeutic agent for diabetes-related cognitive dysfunction.

达格列净是一种钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂，在缓解糖尿病相关认知功能障碍（daca）方面显示出显著的治疗潜力。然而，其对小胶质细胞的具体作用仍有待进一步探索。本研究采用高脂饮食/链脲佐菌素（HFD/STZ）诱导的2型糖尿病（T2DM）小鼠模型。研究发现，达格列净可以显著降低空腹血糖水平，减轻体重，并改善行为测试（y迷宫、Morris水迷宫和新物体识别）中的认知功能表现。组织学和生化分析表明，达格列净能减轻海马神经元损伤，增强抗氧化能力（表现为超氧化物歧化酶和过氧化氢酶水平升高，丙二醛含量降低），有效抑制神经炎症（显著降低肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6水平）。转录组学和代谢组学分析显示，达格列净通过下调吲哚胺2,3-双加氧酶（IDO1）和犬尿氨酸单加氧酶（KMO），上调犬尿氨酸转氨酶1 (KYAT1)，重新平衡犬尿氨酸途径，促进代谢产物由神经毒性物质（如3-羟基犬尿氨酸和犬尿酸）转化为神经保护物质（犬尿酸）。此外，高糖（HG）刺激的BV-2小胶质细胞体外实验进一步验证了达格列净通过抑制toll样受体/髓样分化因子88 （TLR/MyD88）信号通路和调节犬尿氨酸代谢重编程发挥抗炎作用。同时，KMO的过表达逆转了这些作用。总之，这些结果揭示了达格列净在daca中的多维神经保护机制，为其作为糖尿病相关认知功能障碍治疗剂的潜力提供了有力证据。

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引用次数: 0

Saxagliptin mitigates doxorubicin-induced cardiotoxicity by modulating NLRP3/caspase-1/IL-1β and TLR-4/NF-κB pathways 沙格列汀通过调节NLRP3/caspase-1/IL-1β和TLR-4/NF-κB通路减轻阿霉素诱导的心脏毒性

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-24 DOI: 10.1016/j.taap.2025.117697

Maha M. Abdel-Fattah, Yasmeen M. Abozaid, Basim Anwar Shehata Messiha, Marwa M. Khalaf

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.

阿霉素（DOX）是一种强大的蒽环类药物，用于治疗多种恶性疾病，包括实体肿瘤和血液肿瘤。尽管其作为细胞毒性药物有效，但由于心脏毒性与药物剂量成正比，其治疗用途受到限制。沙格列汀（SAXA）是二肽基肽酶(DPP)-IV抑制剂家族的一种选择性和有效成员，用于治疗2型糖尿病。它还具有几种生物作用，包括抗炎和抗氧化特性。这项工作旨在确定潜在的分子机制，并确定SAXA对dox诱导的心脏毒性的屏蔽作用。将32只大鼠随机分为4个实验组，分别为正常对照组、SAXA单给药组（10 mg/kg）、DOX对照组（20 mg/kg）和SAXA治疗组（SAXA + DOX）。与DOX对照组相比，SAXA （10 mg/kg）预处理可显著降低血清CK-MB和CTnI浓度，分别降低37.11%和46.32%，并显著改善心脏组织的组织病理学特征。此外，SAXA显著降低dox中毒大鼠MDA 56.05%，使GSH和SOD分别升高493.28%和458.32%。此外，western blot分析显示，SAXA预处理可显著下调TLR-4和NLRP3，分别下调34.9%和33.99%。此外，ELISA分析显示，SAXA预处理可显著下调NF-κB、caspase-1和IL-1β，分别下调44.04%、78.7%和57.7%。本研究结果表明，SAXA可能通过其抗氧化和抗炎特性，对dox诱导的毒性发挥心脏保护作用。

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引用次数: 0

Shionone ameliorates pulmonary fibrosis by activating mitophagy via PINK1-Parkin pathway Shionone通过PINK1-Parkin通路激活线粒体自噬，改善肺纤维化

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-18 DOI: 10.1016/j.taap.2025.117693

Yijia Su , Qiang Fu , Xilin Wu , Xianhua Che , Zhe Jiang , Xuezheng Li

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited clinical treatment options. Shionone (SHI), a major active compound derived from Ligularia fischeri Turcz (LF), has shown pharmacological potential; however, its mechanism of action against PF remains unclear. This study investigates the anti-fibrotic effects and underlying pathways of SHI using a bleomycin (BLM)-induced PF mouse model and a Transforming Growth Factor-β (TGF-β)-stimulated A549 cell model. The results demonstrate that SHI treatment markedly alleviates BLM-induced alveolar damage, collagen accumulation, and inflammatory responses, while significantly improving survival rates in mice. At the molecular level, SHI activates the PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy pathway, leading to increased expression of autophagy-related proteins such as LC3II/LC3I and Beclin1, decreased levels of p62 and pro-fibrotic markers, enhanced clearance of dysfunctional mitochondria, restoration of mitochondrial membrane potential (MMP), and reduction of reactive oxygen species (ROS) accumulation. In vitro experiments further confirm that SHI inhibits fibrosis in TGF-β-challenged A549 cells through the same mechanism. This study is the first to elucidate that SHI mitigates PF by regulating mitophagy, offering a promising therapeutic target and potential drug candidate for PF. Future research may focus on optimizing the clinical application strategies of SHI.

肺纤维化（PF）是一种进行性和致死性间质性肺疾病，临床治疗选择有限。Shionone （SHI）是一种从黄舌属植物（Ligularia fischeri Turcz， LF）中提取的重要活性化合物，具有一定的药理潜力；然而，其对PF的作用机制尚不清楚。本研究采用博来霉素（BLM）诱导的PF小鼠模型和转化生长因子-β (TGF-β)刺激的A549细胞模型来研究SHI的抗纤维化作用及其潜在途径。结果表明，SHI治疗可显著减轻blm诱导的肺泡损伤、胶原积累和炎症反应，同时显著提高小鼠的存活率。在分子水平上，SHI激活pten诱导的推测的激酶1 (PINK1)-帕金森介导的线粒体自噬途径，导致自噬相关蛋白如LC3II/LC3I和Beclin1的表达增加，p62和促纤维化标志物水平降低，功能失调线粒体清除增强，线粒体膜电位（MMP）恢复，活性氧（ROS）积累减少。体外实验进一步证实，SHI通过相同的机制抑制TGF-β-激发的A549细胞的纤维化。本研究首次阐明了SHI通过调节线粒体自噬来减轻PF，为PF提供了一个有希望的治疗靶点和潜在的候选药物，未来的研究可能侧重于优化SHI的临床应用策略。

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引用次数: 0

Establishment of a real-time monitored animal model to evaluate novel therapeutic strategies for organophosphorus nerve agent poisonings 建立实时监测动物模型以评估有机磷神经毒剂中毒的新治疗策略。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-18 DOI: 10.1016/j.taap.2025.117694

Sofia Jonasson, Åsa Gustafsson, Johanna Qvarnström, Marcus Carlsson, Nina Forsgren, Fredrik Ekström, Linda Elfsmark

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 in vivo 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.

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.

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.

This study highlights the value of high-sensitivity, real-time monitoring of physiological metrics like respiratory resistance in evaluating novel antidotes for OPNA poisoning.

对氧肟作为有机磷神经毒剂（OPNAs）中毒解毒剂的临床前评价主要基于解毒剂对致死剂量的保护比率。制定保护指数涉及到相当大的动物痛苦，并且由于精度有限，需要大量的动物队列。本研究旨在建立一种体内模型，用于评估更符合3R原则的新治疗物质，也可以详细量化特定的生物效应，以更好地了解治疗的影响。麻醉后的Sprague-Dawley大鼠气管造口，并连接到一个小型动物呼吸机，以便同时记录呼吸功能。大鼠暴露于1ld50 VX或他本，并通过测量呼吸阻力（RRS）在30分钟内实时监测中毒的进展。其他评估包括临床症状和血液中乙酰胆碱酯酶（AChE）抑制。用肟（奥比多肟、HI-6、RS194B）或阿托品进行预处理，验证模型。暴露于OPNAs导致RRS迅速增加到比基线高250-300 %。HI-6和奥比肟是最有效的治疗方法，可减轻OPNA中毒的呼吸和酶作用，而RS194B治疗可延迟症状的发作，但不能完全逆转毒性。tabun抑制的AChE通常比VX抑制的酶更能抵抗肟的再激活。研究结果表明，将乙酰胆碱酯酶活性维持在15- 20% %以上，足以恢复呼吸功能，并将症状缓解到与未暴露对照组相当的水平。本研究强调了高灵敏度、实时监测呼吸阻力等生理指标在评估新型OPNA中毒解毒剂中的价值。

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引用次数: 0

CYP genetic polymorphism, and CYP3A inducers and inhibitors regulate apatinib metabolism: Consequences for drug exposure and toxicity risks cypp基因多态性和CYP3A诱导剂和抑制剂调节阿帕替尼代谢：药物暴露和毒性风险的后果。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-15 DOI: 10.1016/j.taap.2025.117692

Zhe Wang , Le-hao Jin , Ni-hong Pang , Jun-er Xu , Xiao-yu Xu , Wei Sun , Xiao-dan Zhang , Jian-chang Qian

Apatinib is a tyrosine kinase inhibitor metabolized by hepatic cytochromes P450 (CYPs). This study investigated how CYP genetic variations affect apatinib metabolism and response. We employed a multi-scale approach including enzyme kinetic studies with recombinant human CYP variants (n = 3), cellular proliferation assays in CYP3A4-overexpressing A549 cells (n = 3), and pharmacokinetic studies in rats treated with CYP3A modulators (n = 6 per group). CYP3A4*18, CYP2D6*10, and CYP2C9*3 variants showed markedly reduced metabolic activity. CYP3A4*18 overexpression enhanced apatinib's anti-proliferative effect in A549 cells. In rats, dexamethasone decreased apatinib exposure by inducing CYP3A expression, while ketoconazole increased exposure without altering CYP3A levels. Both CYP genetic polymorphisms and drug interactions significantly influence apatinib metabolism, highlighting the importance of personalized dosing strategies for optimizing therapy.

阿帕替尼是一种酪氨酸激酶抑制剂，由肝细胞色素P450 （CYPs）代谢。本研究探讨CYP基因变异如何影响阿帕替尼的代谢和反应。我们采用了多尺度方法，包括重组人CYP变异的酶动力学研究（n = 3），cyp3a4过表达的A549细胞的细胞增殖试验（n = 3），以及CYP3A调节剂处理大鼠的药代动力学研究（n = 6 /组）。CYP3A4*18、CYP2D6*10和CYP2C9*3变异体代谢活性明显降低。CYP3A4*18过表达增强了阿帕替尼在A549细胞中的抗增殖作用。在大鼠中，地塞米松通过诱导CYP3A表达减少阿帕替尼暴露，而酮康唑增加暴露，但不改变CYP3A水平。CYP遗传多态性和药物相互作用都显著影响阿帕替尼代谢，强调个性化给药策略对优化治疗的重要性。

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引用次数: 0

Celastrol delays the progression of hepatocellular carcinoma by suppressing SLC1A5-mediated glutamine dependence 雷公藤红素通过抑制slc1a5介导的谷氨酰胺依赖来延缓肝细胞癌的进展。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-14 DOI: 10.1016/j.taap.2025.117690

Simeng Xiao , Yun Zhao , Zhiguo Chen , Yangkun Xiong , Dingmei Zhang , Gang Zhou , Cong Zhang

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 Tripterygium wilfordii 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 in vitro and in vivo. 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.

肝细胞癌（HCC）因其高死亡率和罕见有效药物的特殊治疗策略而成为全球严重的公共卫生问题。谷氨酰胺作为维持细胞生命活动的重要营养物质，已成为HCC治疗的一个有希望的方向。雷公藤红素是从雷公藤中分离出来的萜类天然产物，因其具有抗hcc治疗潜力等多种药理活性而备受关注。然而，其调节谷氨酰胺代谢抑制HCC进展的作用尚未被研究。本研究以Hep3B和HepG2细胞为实验对象，研究了雷公藤酚对肝癌细胞的抑制作用。随后，在肝癌异种移植动物模型中研究了雷公藤红素的生物安全性和对肿瘤生长的抑制作用。结果表明，celastrol抑制了肝癌细胞的增殖，这与谷氨酰胺代谢通量的减少密切相关。从机制上说，雷公藤红素通过抑制SLC1A5的表达来减少肝癌细胞中谷氨酰胺代谢中间体的含量，从而中断细胞增殖的能量来源，从而限制谷氨酰胺的摄取。在移植的HCC肿瘤小鼠模型中也观察到类似的结果。有趣的是，SLC1A5的过表达逆转了celastrol降低谷氨酰胺代谢通量的作用，从而抑制肝癌细胞的体外和体内恶性增殖。总之，本研究提供了令人信服的证据，证明了雷公藤红素通过抑制slc1a5介导的谷氨酰胺依赖来抑制肝癌的发生，表明雷公藤红素作为一种天然活性化合物有望成为HCC的治疗药物。

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引用次数: 0