Toxicology and applied pharmacology最新文献_第6页

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

Pioglitazone attenuates cardiovascular remodeling cadmium-induced through the MAPK pathway 吡格列酮通过MAPK途径减弱镉诱导的心血管重构。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-14 DOI: 10.1016/j.taap.2025.117691

Victor Enrique Sarmiento-Ortega , Diana Moroni-González , José Everardo Avelino-Cruz , Miguel Garcia-Gonzalez , Rubén Vázquez-Roque , Eduardo Brambila , Samuel Treviño

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.

镉（Cd）是一种与心血管疾病日益相关的环境污染物。虽然高剂量的毒性作用已得到充分记录，但长期接触最低风险水平的影响仍未得到充分探讨。本研究旨在探讨低剂量镉致心脏毒性的机制基础，并评估吡格列酮（一种具有抗炎和抗氧化作用的PPARγ激动剂）的心脏保护潜力。雄性Wistar大鼠长期暴露于饮用水中的Cd (Cd, 15 mg/L) 3个月和5 个月，吡格列酮共处理（2.5 mg/kg bw/天）。评估血液动力学参数、血清生物标志物（hs-TnI、NT-proBNP、sST2、IL-6、TNF-α）、心室形态学、组织学和MAPK信号激活（p-ERK1/2、p-JNK、p-p38）。在5 个月时，Cd暴露显著增加收缩压和舒张压、hs-TnI和NT-proBNP，而不影响CK-MB或hs-PCR。结构改变包括选择性左心室肥厚，心肌细胞大小增加，高体重/体重和低体重/体重比升高。镉还破坏了IL-33/sST2轴，升高IL-6和TNF-α，这表明存在慢性炎症。在机制上，Cd激活了MAPK通路，p-p38和p-JNK显著增加。吡格列酮通过降低炎症细胞因子、恢复IL-33水平、下调MAPK激活和减轻心脏重塑来部分逆转这些改变。慢性暴露于镉剂量的最低风险通过炎症和mapk依赖性途径诱导亚临床但进行性的心脏毒性。吡格列酮通过调节这些机制提供部分保护，强调其在减轻环境诱导的心血管损伤方面的治疗潜力。

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引用次数: 0

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] “单次灌胃和静脉给药n -亚硝基索烟碱对大鼠体内的毒性动力学和遗传毒性”[毒理学与应用药理学505(2025),117572]。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-12 DOI: 10.1016/j.taap.2025.117689

Mamata De, Ashley Fields, Guy Lagaud

引用次数: 0

Rupestonic acid targets ENO1 to exert antitumor activity and synergizes with paclitaxel in hepatocellular carcinoma 鲁丙酮酸在肝细胞癌中靶向en1发挥抗肿瘤活性，并与紫杉醇协同作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-11 DOI: 10.1016/j.taap.2025.117688

Shulipan Mulati , Maierdan Maimaitiming , Jianing Ma , Miaomiao Zhang , Rongsong Jiang , Silafu Aibai , Xieraili Tuerxun

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.

鲁丙酮酸是一种倍半萜，具有防止肝损伤、炎症和肿瘤形成的保护作用。尽管有这些已知的作用，但其在对抗肝细胞癌（HCC）中的具体作用和作用机制尚不清楚。本研究旨在探讨鲁丙酮酸的抗hcc作用，并确定其潜在的分子靶点。我们采用细胞计数试剂盒-8 （CCK-8）、集落形成和流式细胞术检测来评估其对HCC细胞系细胞活力、增殖和凋亡的影响。此外，我们还利用靶捞、细胞热移法（CETSA）、核糖核酸干扰和Western blot （WB）等方法鉴定了肝细胞癌细胞中丙酮酸的蛋白靶点。我们的研究结果表明，丙酮酸通过线粒体途径显著抑制HCC细胞增殖，诱导G0/G1期细胞周期阻滞，促进细胞凋亡。采用炔-鲁丙酮酸探针结合质谱法进行靶结合研究，确定烯醇化酶1 （ENO1）为直接结合靶，CETSA证实了其不稳定性。鲁派通酸抑制磷酸肌醇3-激酶(PI3K)/蛋白激酶B (Akt)/叉头盒蛋白O （FOXO）信号通路，鲁派通酸与紫杉醇（PTX）具有协同细胞毒作用。这些发现表明鲁丙酮酸是一种很有希望的HCC治疗候选药物。他们还强调了丙酮酸在HCC治疗先导化合物的设计和开发中的潜力，并确定了ENO1作为可行的治疗靶点。

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引用次数: 0

Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis 曲美他嗪通过mir -211/CHOP调节和SIRT1/AMPK/ pgc1 α-介导的线粒体生物发生对膀胱缺血-再灌注损伤的保护机制

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-11 DOI: 10.1016/j.taap.2025.117687

Sultan Alrashdi , Shimaa K. Mohamed , Mohamad Elbaz , Elsayed K. El-Sayed

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.

膀胱缺血常伴有血管功能不全，可通过氧化应激、炎症、内质网应激、线粒体缺陷和细胞凋亡等途径引起下尿路症状。缺血再灌注（I/R）损伤通过产生过多的活性氧而加剧了这些影响。曲美他嗪（TMZ）是一种抗缺血性药物，在几种I/R模型中显示出保护作用；然而，其在膀胱损伤中的作用尚未得到充分的研究。本研究主要从氧化应激、炎症、内质网应激、线粒体生物发生、microRNA调控和细胞凋亡等方面探讨TMZ对大鼠膀胱I/R损伤的保护作用。将40只大鼠分为4组：假对照组、I/R组和2个tmz预处理组（10或20 mg/kg/d， p.o，连续14 d）。控制室收到80辆车。收集膀胱组织进行生化、分子和组织病理学分析。TMZ通过降低MDA（~ 43.5 - 60.8%）、提高GSH（~ 2-2.6倍）和SOD活性（~ 2-3.2倍）显示出保护作用。内质网应激减弱，p-PERK（~ 29.4 - 63%）和CHOP（~ 29.1 - 60%）降低，同时mir -211上调（~ 1.4-1.9倍）。TMZ通过增加SIRT1（~ 1.9-2.4倍）、PGC1α（~ 2.1-4.3倍）、p-AMPK（~ 3-6.3倍）和ATP（~ 2-2.8倍）来恢复线粒体的生物发生。它还下调促凋亡（Bax, Caspase 3）和促炎症（TNF-α, IL-1β）介质。组织病理学显示膀胱结构明显保留，特别是在20mg /kg剂量下。TMZ通过调节氧化应激、内质网应激、线粒体通路和mir -211/CHOP轴，在膀胱I/R损伤中发挥强大的抗氧化、抗炎、抗凋亡和细胞保护作用。这些发现表明TMZ可能是一种有希望的治疗缺血性相关性膀胱功能障碍的候选药物，为未来的转化和临床研究提供了机制基础。

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