Toxicology and applied pharmacology最新文献_第8页

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

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