Toxicology and applied pharmacology最新文献_第6页

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

Integrated assessment of the effects of PFOA exposure on hepatic transcriptome and lipid profiles in mice expressing human PPARα PFOA暴露对表达人PPARα的小鼠肝脏转录组和脂质谱影响的综合评估

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-24 DOI: 10.1016/j.taap.2025.117658

G. Nielsen , E. Reed , B. Lara , D.H. Sherr , W.J. Heiger-Bernays , T. Hyötyläinen , T.F. Webster , J.J. Schlezinger

Per- and polyfluoroalkyl substances (PFAS) are a family of persistent chemicals that continue to be released pervasively into the environment, leading to widespread human exposure. Emerging epidemiological evidence shows adverse effects on liver lipids; however, past toxicological studies have been limited by a focus on peroxisome proliferator activated receptor α (PPARα) driven effects on triglycerides in rodent systems. Here, we use a more agonostic approach incorporating lipidomics and transcriptomics to test the hypothesis that activation of human PPARα by perfluorooctanoic acid (PFOA), disrupts liver lipid homeostasis, broadly, similar to that seen in human liver diseases. Female and male mice expressing human PPARα or that were PPARα null were fed a What We Eat In America diet and exposed to PFOA via drinking water for 6 weeks. Serum PFOA concentrations averaged 48 ± 9 μg/mL. PFOA changed the expression of ∼2000 hepatic genes with changes in expression of a larger number of genes in hPPARα versus PPARα null mice. In this occupational level PFOA exposure scenario, less than 60 % of transcriptional changes induced by PFOA depended on hPPARα expression. CAR was another major molecular initiating event, with other transcription factors pathways more likely to be modulated downstream of hPPARα activation. In hPPARα mice of both sexes, PFOA increased total liver lipids. In addition to triacylglycerides, lipid classes strongly altered by PFOA exposure predominantly belong to the phosphatidylcholine and sphingolipid classes. PFOA significantly decreased sphingomyelin abundance and increased ceramide abundance regardless of genotype, which coincided with an increase in expression of SMase, the enzyme that converts sphingomyelin to ceramide. These results highlight the ability of PFOA to modulate liver lipids beyond triacylglycerides in both an hPPARα-dependent and -independent manner.

全氟烷基和多氟烷基物质（PFAS）是一类持久性化学品，它们继续普遍释放到环境中，导致人类广泛接触。新出现的流行病学证据显示对血脂有不利影响；然而，过去的毒理学研究受到过氧化物酶体增殖物激活受体α (PPARα)对啮齿动物系统甘油三酯的影响的限制。在这里，我们使用一种更激动的方法，结合脂质组学和转录组学来测试全氟辛酸（PFOA）激活人类PPARα，破坏肝脏脂质稳态的假设，大致类似于人类肝脏疾病。表达人类ppara α或ppara α缺失的雌性和雄性小鼠喂食我们在美国吃的食物，并通过饮用水暴露于PFOA 6周。血清PFOA平均浓度为48±9 μg/mL。PFOA改变了约2000个肝脏基因的表达，在hPPARα小鼠中与PPARα缺失小鼠相比，更多基因的表达发生了变化。在这种职业水平的PFOA暴露情景中，PFOA诱导的转录变化中只有不到60%依赖于hPPARα的表达。CAR是另一个主要的分子启动事件，其他转录因子途径更有可能在hPPARα激活的下游被调节。在两性hPPARα小鼠中，PFOA增加了总肝脂。除了甘油三酯外，受PFOA影响而发生强烈改变的脂类主要是磷脂酰胆碱类和鞘脂类。与基因型无关，PFOA显著降低了鞘磷脂丰度，增加了神经酰胺丰度，这与将鞘磷脂转化为神经酰胺的酶SMase的表达增加相一致。这些结果强调了PFOA以hppar α依赖和不依赖的方式调节肝脏脂质的能力，而不是甘油三酯。

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引用次数: 0

Nitazoxanide reverses pulmonary vascular remodeling in pulmonary hypertension by targeting the IMPA1-RAGE signaling axis Nitazoxanide通过靶向IMPA1-RAGE信号轴逆转肺动脉高压的肺血管重构。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-24 DOI: 10.1016/j.taap.2025.117657

Di Wang , Ning Huang , Mingyuan Cai , Ruihua Huang , Xiaoyun Zhu , Changping Hu

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.

肺动脉高压（Pulmonary hypertension， PH）是一种危及生命的疾病，其特征是肺动脉平滑肌细胞（PASMCs）过度增殖和迁移，导致肺血管重构、肺血管阻力（PVR）升高和肺动脉压（PAP）升高。这些病理改变最终导致右心室肥厚、右心衰和死亡。目前的治疗方法不足以解决ph重塑方面的问题。因此，迫切需要针对PASMCs增殖和血管重塑的新治疗策略。Nitazoxanide是一种fda批准的抗寄生虫药，具有良好的安全性和生物利用度，在PH实验模型中，包括SU5416/缺氧和单碱大鼠模型，可显著降低PAP并缓解肺血管重构。利用药物亲和反应靶稳定性（DARTS）、细胞热移测定（CETSA）、共免疫沉淀和Western blot分析，我们确定了肌醇单磷酸酶1 （IMPA1）是nitazoxanide的一个新的直接分子靶点。从机制上讲，nitazoxanide治疗抑制了IMPA1-RAGE相互作用，从而抑制了PI3K/Akt/mTOR信号级联的下游激活，并减弱了PASMCs在ph下增强的糖酵解特性。总的来说，我们的研究结果突出了nitazoxanide作为肺血管重构和肺动脉高压的有希望的治疗候选药物。

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引用次数: 0

Activated autophagy drives the adaptive response to LPS-evoked lung pyroptosis in adolescent mice 激活的自噬驱动对lps诱发的青春期小鼠肺焦亡的适应性反应。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-22 DOI: 10.1016/j.taap.2025.117650

Hao Li , Hua Wang , Ye-Xin Luo , Tian-Tian Wang , Kong-Wen Ouyang , Xin-Mei Zheng , Xin-Xin Zhang , Qing Ling , Yong-Wei Xiong , De-Xiang Xu , Hua-Long Zhu , Hua Wang

The disease of lipopolysaccharide (LPS)-induced acute lung injury (ALI) is prevalent among clinical respiratory patients. The LPS adaptive response is a phenomenon whereby prior exposure to a low dose of LPS results in insensitivity to a subsequent high-dose challenge. However, the LPS adaptive response and its mechanism in mice with LPS-induced ALI remains limited. In this study, CD-1 male mice received a low-dose LPS (0.1 mg/kg) pretreatment for 24 h before high-dose LPS (5 mg/kg) challenge. Pretreatment with low-dose LPS mitigates the effects of high-dose LPS-induced lung pyroptosis and ALI. Low-dose LPS pretreatment also blocked high-dose LPS-induced activation of NLRC4 inflammasome in the lung. Interestingly, low-dose LPS pretreatment further increased the level of autophagy-related proteins in the lung with high-dose LPS treatment, suggesting that autophagy was further activated after low-dose LPS pretreatment. It is also important to note that 3-methyladenine is a specific inhibitor of autophagy, blocks the adaptive response to LPS-evoked pyroptosis and ALI. Inversely, rapamycin, an autophagy inducer, promotes adaptive response to LPS-evoked pyroptosis and ALI. Mechanistically, activated autophagy drives the adaptive response to LPS-evoked lung pyroptosis in mice via promoting p62-dependent degradation of NLRC4. Collectively, our results indicate that low-dose LPS pretreatment activates autophagy to degrade NLRC4 by p62 dependent manner, thereby protecting against pyroptosis and ALI induced by high-dose of LPS.

脂多糖（LPS）引起的急性肺损伤（ALI）在临床呼吸系统患者中很常见。LPS适应性反应是一种现象，即先前暴露于低剂量LPS导致对随后的高剂量挑战不敏感。然而，LPS诱导ALI小鼠的适应性反应及其机制尚不清楚。在本研究中，CD-1雄性小鼠在高剂量LPS（5 mg/kg）刺激前接受低剂量LPS（0.1 mg/kg）预处理24 h。低剂量LPS预处理可减轻高剂量LPS诱导的肺焦亡和ALI的影响。低剂量LPS预处理也阻断了高剂量LPS诱导的NLRC4炎性体在肺中的活化。有趣的是，低剂量LPS预处理进一步增加了高剂量LPS处理的肺中自噬相关蛋白的水平，表明低剂量LPS预处理进一步激活了自噬。同样值得注意的是，3-甲基腺嘌呤是一种特异性的自噬抑制剂，可以阻断对lps诱发的焦亡和ALI的适应性反应。相反，自噬诱导剂雷帕霉素可促进对lps诱发的焦亡和ALI的适应性反应。在机制上，激活的自噬通过促进NLRC4的p62依赖性降解来驱动lps诱发的小鼠肺焦亡的适应性反应。综上所述，我们的研究结果表明，低剂量LPS预处理激活自噬，以p62依赖的方式降解NLRC4，从而保护高剂量LPS诱导的焦亡和ALI。

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引用次数: 0

circSHOC1-SLC25A3 promotes 2-naphthylamine-induced DNA damage in bronchial epithelial cells via activation of oxidative stress circSHOC1-SLC25A3通过激活氧化应激促进2-萘胺诱导的支气管上皮细胞DNA损伤。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-22 DOI: 10.1016/j.taap.2025.117652

Yan Jiang , Jiayu Zhou , Shusen Fang , Yufei Liu, Yueting Shao, Yiguo Jiang

Smoking, a pivotal environmental risk factor, drives diseases including lung cancer through genetic and epigenetic alterations. While 2-Naphthylamine (2-NA), a tobacco-derived carcinogen, is established as a bladder carcinogen via DNA damage, its role in lung carcinogenesis remains mechanistically uncharacterized despite epidemiological associations. This study identifies bronchial epithelium as a direct target of 2-NA, demonstrating dose-dependent DNA damage in 16HBE cells (peak at 250 μM, 12 h; P < 0.05), accompanied by S-phase arrest, apoptosis, reduced proliferation, and reactive oxygen species (ROS) generation. 2-NA exposure upregulated the expression of circSHOC1, which is a circular RNA derived from the SHOC1 gene, in a dose-dependent manner. Functional assays revealed that circSHOC1 overexpression exacerbated 2-NA-induced DNA damage by enhancing ROS production and 8-hydroxy-2′-deoxyguanosine (8-OHdG) accumulation, whereas knockdown attenuated these effects. Mechanistically, circSHOC1 interacted with mitochondrial protein SLC25A3 (Solute Carrier Family 25 Member 3), a key oxidative stress regulator; SLC25A3 knockdown mitigated DNA damage (P < 0.01), and co-transfection experiments confirmed SLC25A3 as a critical mediator of circSHOC1-driven genotoxicity. Collectively, this work provides the first experimental evidence that 2-NA induces bronchial epithelial DNA damage via a circSHOC1-SLC25A3-ROS axis, supporting a novel mechanism for tobacco-associated lung carcinogenesis and highlighting 2-NA as a potential pulmonary carcinogen.

吸烟是一个关键的环境风险因素，通过遗传和表观遗传改变导致肺癌等疾病。虽然2-萘胺（2-NA）是一种烟草衍生的致癌物，已通过DNA损伤被确定为膀胱癌，但其在肺癌发生中的作用机制尚未确定，尽管与流行病学有关。本研究确定支气管上皮是2-NA的直接靶点，在16HBE细胞中显示出剂量依赖性DNA损伤(峰值在250 μM， 12 h

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引用次数: 0

Capsaicin alleviates DEHP-induced testicular dysfunction by suppressing oxidative stress in mice 辣椒素通过抑制小鼠氧化应激减轻dehp诱导的睾丸功能障碍。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-21 DOI: 10.1016/j.taap.2025.117655

Yi Liu , Xu Yan , Yinwei Chen , Longjie Gu , Lei Jin

Di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental endocrine disruptor known to impair testicular function. Capsaicin, the bioactive compound in chili peppers, has not been thoroughly explored for its protective effects against DEHP-induced testicular damage. In this study, male C57BL/6 mice were divided into control, DEHP-exposed (200 mg/kg/day orally for 6 weeks), and DEHP-exposed with varying doses of capsaicin (5, 10, and 20 mg/kg/day orally for 6 weeks). Leydig and Sertoli cells were cultured in vitro with DEHP or capsaicin (0, 25, 50, and 100 μM). Chronic DEHP exposure impaired testicular development, leading to morphological abnormalities and reduced sperm quality, which were largely restored by capsaicin treatment. Both in vivo and in vitro assays revealed that capsaicin modulated the BAX/BCL2 ratio and inhibited testicular apoptosis. Additionally, capsaicin restored DEHP-induced suppression of testosterone biosynthesis in Leydig cells and maintained the integrity of the blood-testis barrier in Sertoli cells. Mechanistically, these protective effects were likely due to the antioxidant properties of capsaicin. In conclusion, our findings suggest that capsaicin may serve as a promising therapeutic agent for mitigating DEHP-induced testicular dysfunction, offering valuable insights for potential clinical applications.

邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种广泛存在的环境内分泌干扰物，已知会损害睾丸功能。辣椒素是辣椒中的一种生物活性化合物，其对dehp引起的睾丸损伤的保护作用尚未得到充分的研究。在这项研究中，雄性C57BL/6小鼠被分为对照组，dehp暴露组（200 mg/kg/天口服，持续6 周）和dehp暴露组（5、10和20 mg/kg/天口服，持续6 周）。分别用DEHP和辣椒素（0、25、50和100 μM）体外培养Leydig和Sertoli细胞。慢性DEHP暴露会损害睾丸发育，导致形态异常和精子质量下降，而辣椒素治疗在很大程度上恢复了这些功能。体内和体外实验均显示辣椒素可调节BAX/BCL2比值，抑制睾丸细胞凋亡。此外，辣椒素恢复了dehp诱导的Leydig细胞中睾酮生物合成的抑制，并维持了Sertoli细胞血睾丸屏障的完整性。从机制上讲，这些保护作用可能是由于辣椒素的抗氧化特性。综上所述，我们的研究结果表明辣椒素可能作为一种有前景的治疗药物来缓解dehp诱导的睾丸功能障碍，为潜在的临床应用提供了有价值的见解。

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引用次数: 0

Matrine triggers cardiotoxicity via apoptosis induced by reduction of GSH synthesis through the ATF4/CTH pathway 苦参碱通过ATF4/CTH通路减少GSH合成诱导细胞凋亡，从而触发心脏毒性。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-21 DOI: 10.1016/j.taap.2025.117654

Xin Zheng, Wei Wu, Yurou Li, Wupei Pan, Yinan Xu, Lianwei Zhong, Yinjie Jiang, Jie Zhou

Matrine (MT), an alkaloid extracted from Sophora flavescens, is widely used in traditional Chinese medicine. However, its clinical application is limited by its toxic effects. In this study, we explored the function of the activating transcription factor 4 /cystathionine γ-lyase (ATF4/CTH) pathway in MT-induced cardiac injury. Our results indicated that MT significantly decreased cysteine (Cys) and glutathione (GSH) levels, leading to mitochondrial dysfunction and apoptosis characterised by ROS accumulation, mPTP opening, ΔΨm disruption, and caspase-9/3 activation. However, caspase-3 inhibition and GSH supplementation alleviated these toxic effects. NAC similarly protected against MT-induced apoptosis by providing Cys as a substrate for GSH synthesis, whereas BSO abolished this protection by inhibiting GSH biosynthesis. Additionally, MT suppressed both ATF4 expression and its transcriptional activity, leading to reduced mRNA and protein levels of the downstream target gene CTH, and consequently diminished CTH-dependent Cys production. Overexpression of either ATF4 or CTH attenuated MT-induced apoptosis by restoring intracellular Cys and GSH levels. CTH knock-down completely abrogated the protective effects of ATF4 overexpression, whereas CTH overexpression retained its efficacy, even in the absence of ATF4. These results indicated that MT-induced suppression of the ATF4/CTH pathway causes GSH deficiency, leading to mitochondria-dependent apoptosis and cardiotoxicity.

苦参碱是一种从苦参中提取的生物碱，在中药中有着广泛的应用。但其毒性作用限制了其临床应用。在本研究中，我们探讨了激活转录因子4/胱硫氨酸γ-裂解酶（ATF4/CTH）通路在mt诱导的心脏损伤中的作用。我们的研究结果表明，MT显著降低了半胱氨酸（Cys）和谷胱甘肽（GSH）水平，导致线粒体功能障碍和凋亡，其特征是ROS积累、mPTP打开、ΔΨm破坏和caspase-9/3激活。然而，抑制caspase-3和补充谷胱甘肽可减轻这些毒性作用。NAC同样通过提供Cys作为GSH合成的底物来防止mt诱导的细胞凋亡，而BSO通过抑制GSH的生物合成来消除这种保护作用。此外，MT抑制ATF4的表达及其转录活性，导致下游靶基因CTH的mRNA和蛋白水平降低，从而减少CTH依赖性Cys的产生。过表达ATF4或CTH均可通过恢复细胞内Cys和GSH水平来减弱mt诱导的细胞凋亡。CTH敲除完全消除了ATF4过表达的保护作用，而CTH过表达即使在没有ATF4的情况下仍保持其保护作用。这些结果表明，mt诱导的ATF4/CTH通路的抑制导致GSH缺乏，导致线粒体依赖性细胞凋亡和心脏毒性。

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引用次数: 0

Aurocyanide, an active metabolite of auranofin, exerts cytoprotective effects via ROS-mediated Nrf2 activation in HepG2 cells 金嘌呤是金嘌呤的活性代谢物，通过ros介导的Nrf2激活在HepG2细胞中发挥细胞保护作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-21 DOI: 10.1016/j.taap.2025.117656

Undarmaa Otgontenger, Seokwon Yang, Eun Kyung Kim, Young-Mi Kim

Auranofin, an FDA-approved oral gold(I) compound for rheumatoid arthritis, is being repurposed due to its established clinical safety and emerging therapeutic potential. Given its extensive in vivo metabolism, identifying active metabolites and characterizing their biological activities are critical for understanding its therapeutic mechanisms. Here, we evaluated the cytoprotective effects of seven potential auranofin metabolites against tert-butylhydroperoxide-induced oxidative injury in HepG2 cells. Among them, only aurocyanide markedly improved cell viability, as demonstrated by MTT and live-cell imaging assays. This study is the first to elucidate the molecular mechanisms underlying the cytoprotective effects of aurocyanide, with a focus on Nrf2 signaling. Aurocyanide suppressed tert-butylhydroperoxide-induced intracellular and mitochondrial ROS production and significantly increased antioxidant responsive element (ARE)-luciferase activity, comparable to that of sulforaphane. It also promoted nuclear accumulation of Nrf2, leading to upregulation of Nrf2-regulated antioxidant enzymes (GCL, HO-1, NQO1). Induction of Nrf2 target genes was confirmed in both HepG2 cells and primary mouse hepatocytes. Aurocyanide elevated intracellular GSH levels and alleviated tert-butylhydroperoxide-induced GSH depletion. Importantly, the cytoprotective effect of aurocyanide was significantly reduced in Nrf2-knockdown cells, highlighting the essential role of Nrf2. Pretreatment with N-acetyl-L-cysteine (NAC) abolished aurocyanide-induced Nrf2 activation and HO-1 upregulation, indicating the involvement of ROS in Nrf2/ARE pathway activation. Aurocyanide induced mild ROS production, which was reduced by NAC, and NAC also diminished the protective effects of aurocyanide against oxidative injury. In conclusion, aurocyanide, an active metabolite of auranofin, exerts antioxidant and hepatoprotective effects via ROS-mediated activation of the Nrf2 signaling pathway, broadening our understanding of its pharmacological actions in liver pathology.

Auranofin是一种fda批准的用于治疗类风湿性关节炎的口服金(I)化合物，由于其已建立的临床安全性和新兴的治疗潜力，正在重新定位。鉴于其广泛的体内代谢，识别活性代谢物并描述其生物活性对于了解其治疗机制至关重要。在这里，我们评估了七种潜在的金糠磷脂代谢物对叔丁基过氧化氢诱导的HepG2细胞氧化损伤的细胞保护作用。其中，MTT和活细胞成像实验表明，只有金氰化物能显著提高细胞活力。本研究首次阐明了氰化物细胞保护作用的分子机制，重点关注Nrf2信号传导。金氰化物抑制叔丁基过氧化氢诱导的细胞内和线粒体ROS的产生，并显著提高抗氧化反应元素(ARE)-荧光素酶的活性，与萝卜硫素相当。它还促进Nrf2的核积累，导致Nrf2调控的抗氧化酶（GCL, HO-1, NQO1）的上调。Nrf2靶基因在HepG2细胞和小鼠原代肝细胞中均有诱导作用。金氰提高细胞内谷胱甘肽水平，减轻叔丁基过氧化氢诱导的谷胱甘肽耗竭。重要的是，在Nrf2敲低的细胞中，金氰化物的细胞保护作用显著降低，突出了Nrf2的重要作用。n -乙酰- l-半胱氨酸（NAC）预处理可消除金氰化物诱导的Nrf2激活和HO-1上调，表明ROS参与Nrf2/ARE通路激活。金氰化物诱导了轻度活性氧的产生，NAC降低了ROS的产生，NAC也降低了金氰化物对氧化损伤的保护作用。综上所述，金糠蛋白的活性代谢物金糠氰通过ros介导的Nrf2信号通路激活发挥抗氧化和肝脏保护作用，拓宽了我们对其在肝脏病理中的药理作用的认识。

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引用次数: 0

Exploring the role of metformin in high fluoride ingestion-induced bone lesions 探讨二甲双胍在高氟摄入致骨损伤中的作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-20 DOI: 10.1016/j.taap.2025.117653

Wenshu Xu, Ningning Jiang, Zhongyuan Zhang, Hui Xu

This study was to investigate the potential mechanisms of metformin administration against skeletal fluorosis by mitigating bone turnover. Rats were treated with fluoride via intragastric gavage to develop a model of skeletal fluorosis, and half of them were concurrently treated with metformin for 12 weeks. The cells involved in the process of bone turnover, including osteoclasts, osteoblast, and osteocyte were exposed to varying concentrations of fluoride with or without metformin. Results showed that excessive fluoride treatment increased levels of bone turnover markers in the serum and the expression of bone turnover-related factors in the femur. Additionally, fluoride treatment damaged the trabecular microstructure and mechanical function in long bone. Concurrent treatment of metformin reduced the serum levels of bone turnover markers and protein expression of bone turnover-related factors in the femurs of fluorotic rats. Furthermore, metformin cotreatment restored the trabecular microstructure of and mechanical function of the long bones of fluorotic rats. In vitro studies demonstrated that low-dose fluoride stimulated osteoclastic viability and upregulated osteoclastic differentiation proteins, but metformin inhibited the stimulatory effect of fluoride on them. Though fluoride exposure increased the apoptosis rate of osteoclasts and osteoblasts, and metformin aggravated fluoride-induced osteoclastic apoptosis but alleviated osteoblastic apoptosis. Additional, metformin stimulated SOST expression and inhibited RANKL expression in osteocytes exposed to fluoride. This is consistent with the KEGG enriched pathway in metformin-treated osteocytes, such as the osteoclast differentiation and Wnt signaling pathways. These results suggested that metformin counteracted high bone turnover that occurred in skeletal fluorosis by inhibiting osteoclastogenesis and regulating osteocytes to delay osteogenesis.

本研究旨在探讨二甲双胍通过减轻骨转换来治疗氟骨症的潜在机制。采用氟灌胃法建立氟骨症大鼠模型，半数大鼠同时给予二甲双胍治疗12 周。参与骨转换过程的细胞，包括破骨细胞、成骨细胞和骨细胞，暴露于含或不含二甲双胍的不同浓度氟化物中。结果表明，过量氟化物处理增加了血清中骨转换标志物的水平和股骨中骨转换相关因子的表达。此外，氟化物处理对长骨小梁的微观结构和力学功能也有损害。二甲双胍同时治疗降低氟中毒大鼠股骨骨转换标志物的血清水平和骨转换相关因子的蛋白表达。二甲双胍联合治疗可恢复氟中毒大鼠长骨小梁结构和力学功能。体外研究表明，低剂量氟化物刺激破骨细胞活力，上调破骨细胞分化蛋白，但二甲双胍抑制了氟化物的刺激作用。虽然氟暴露增加了破骨细胞和成骨细胞的凋亡率，二甲双胍加重了氟诱导的破骨细胞凋亡，但减轻了成骨细胞的凋亡。此外，二甲双胍刺激暴露于氟化物的骨细胞中SOST的表达并抑制RANKL的表达。这与二甲双胍处理的骨细胞中KEGG富集通路一致，如破骨细胞分化和Wnt信号通路。这些结果表明，二甲双胍通过抑制破骨细胞生成和调节骨细胞延迟成骨来抵消氟骨症中发生的高骨转换。

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引用次数: 0

The potential amelioration of oxaliplatin-induced peripheral neuropathy in Sprague Dawley rats by sodium butyrate via targeting neuro-immuno-inflammatory axis 丁酸钠靶向神经-免疫-炎症轴对奥沙利铂诱导大鼠周围神经病变的潜在改善作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-11-19 DOI: 10.1016/j.taap.2025.117651

Alaa R. AlKady, Maaly A. Abd Elmaaboud, Asmaa Fawzy Eltantawy, Amany A. Abdin

Oxaliplatin is widely used as one of the first-line treatments for colorectal carcinoma. Oxaliplatin-induced peripheral neuropathy (OIPN) is the most common dose-limiting adverse effect leading to discontinuation of treatment. This work aimed to investigate the potential ameliorative effect of sodium Butyrate (NaB) on OIPN via assessment of neurotrophic factors and the immune-inflammatory axis, either before induction (PRE) or WITH the induction of OIPN in Sprague Dawley rats. In this study, OIPN was induced by oxaliplatin in a dose of 2.4 mg/kg once daily for 5 consecutive days/ week for 3 weeks by i.p. injection. Behavioral tests were performed, and the sciatic nerves were dissected and processed for further assessment of biochemical parameters and the histopathological picture. NaB has a marked neurotrophic, anti-inflammatory and immunomodulatory effect represented by a significant decrease in mechanical and cold allodynia scores and tissue levels of TNF-α and a significant increase in tissue levels of nerve growth factor (NGF) and IL-10 with a significant improvement in the histopathological changes by H&E and Toluidine blue as well as a significant increase in the IHC expression of FOXP-3 and PPAR-γ. NaB-PRE OIPN showed more improvement in the neurotrophic, anti-inflammatory, and immunomodulatory properties than NaB WITH OIPN. These elaborated data indicated that NaB is a potential neuroprotective candidate for OIPN treatment due to its immunomodulatory, anti-inflammatory, and neurotrophic effects, particularly when used before the initiation of chemotherapeutic cycles to improve the clinical aspects of OIPN.

奥沙利铂作为结直肠癌的一线治疗药物之一被广泛应用。奥沙利铂诱导的周围神经病变（OIPN）是最常见的剂量限制性不良反应，导致停止治疗。本研究旨在探讨丁酸钠（NaB）在诱导前（PRE）或诱导后对大鼠OIPN的潜在改善作用，通过评估神经营养因子和免疫-炎症轴。在本研究中，奥沙利铂以2.4 mg/kg的剂量诱导OIPN，每日1次，连续5天/周，连续3 周。进行行为学测试，解剖并处理坐骨神经以进一步评估生化参数和组织病理学图像。NaB具有显著的神经营养、抗炎和免疫调节作用，其表现为显著降低机械和冷性异常痛评分和组织TNF-α水平，显著升高组织神经生长因子（NGF）和IL-10水平，显著改善H&E和甲苯胺蓝的组织病理改变，显著增加IHC中FOXP-3和PPAR-γ的表达。与NaB WITH OIPN相比，NaB- pre OIPN在神经营养、抗炎和免疫调节特性方面表现出更大的改善。这些详细的数据表明，由于NaB具有免疫调节、抗炎和神经营养作用，特别是在化疗周期开始前使用NaB以改善OIPN的临床方面，NaB是OIPN治疗的潜在神经保护候选者。

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引用次数: 0