Toxicology and applied pharmacology最新文献_第2页

Nicotinamide N-oxide alleviates sepsis-induced hepatic inflammation, oxidative stress, and mitochondrial damage depends on SIRT3/AKT signaling pathway 烟酰胺n -氧化物缓解脓毒症诱导的肝脏炎症、氧化应激和线粒体损伤依赖于SIRT3/AKT信号通路

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.taap.2026.117709

Shujuan Liu , Pan Shi , Yichen Jin , Liwen Fan , Qingyan Ni , Jinyi Mao , Zhaoxue Shao , Xinyi Du , Huizhen Chen , Mian Fu

Sepsis frequently gives rise to acute hepatic injury, representing a prevalent and critical pathological manifestation associated with high morbidity and mortality, yet effective therapeutic strategies remain limited. In this study, sepsis-induced acute liver injury was modeled in mice using cecum ligation and puncture (CLP) surgery. The therapeutic potential and underlying mechanisms of Nicotinamide nitrogen oxide (NAMO) were evaluated via intraperitoneal injection at doses of 40, 80, and 160 mg/kg. Histological analysis revealed that increasing doses of NAMO led to more orderly hepatocyte arrangement and significantly reduced vacuolar degeneration and inflammatory cell infiltration. NAMO treatment significantly downregulated the mRNA expression of pro-inflammatory cytokines (iNOS, IL-1β, TNF-α, and IL-6) and upregulated the anti-inflammatory cytokine IL-10. Additionally, NAMO enhanced the activity of antioxidant enzymes (CAT, GSH, and T-AOC), while reducing levels of lipid peroxidation markers (MDA) and reactive oxygen species (ROS) in both liver tissues and hepatocytes. Furthermore, NAMO restored the protein expression of mitochondrial regulatory factors NRF1 and PGC-1α and preserved intracellular ATP levels, indicating improved mitochondrial function. Mechanistic investigations showed that NAMO exerted its protective effects by modulating mitochondrial homeostasis and oxidative stress through the SIRT3/AKT signaling pathway being blocked. In conclusion, by minimizing oxidative stress and inflammation, keeping mitochondrial integrity, and managing the SIRT3/AKT pathway, NAMO shields with sepsis-induced acute liver injury. The results indicate that NAMO holds significant potential as a therapeutic agent for managing hepatic impairment associated with sepsis.

脓毒症经常引起急性肝损伤，是一种普遍和关键的病理表现，与高发病率和死亡率相关，但有效的治疗策略仍然有限。在本研究中，采用盲肠结扎穿刺（CLP）手术建立脓毒症诱导的小鼠急性肝损伤模型。通过腹腔注射40、80和160 mg/kg剂量的烟酰胺氮氧化物（Nicotinamide nitrogen oxide， NAMO）来评估其治疗潜力和潜在机制。组织学分析显示，增加NAMO剂量可使肝细胞排列更有序，显著减少空泡变性和炎症细胞浸润。NAMO处理显著下调促炎细胞因子（iNOS、IL-1β、TNF-α和IL-6） mRNA表达，上调抗炎细胞因子IL-10。此外，NAMO增强了抗氧化酶（CAT、GSH和T-AOC）的活性，同时降低了肝组织和肝细胞中脂质过氧化标志物（MDA）和活性氧（ROS）的水平。此外，NAMO恢复了线粒体调节因子NRF1和PGC-1α的蛋白表达，并保持了细胞内ATP水平，表明线粒体功能得到改善。机制研究表明，NAMO通过阻断SIRT3/AKT信号通路，调节线粒体稳态和氧化应激发挥其保护作用。综上所述，NAMO通过减少氧化应激和炎症、保持线粒体完整性和调控SIRT3/AKT通路，可以保护脓毒症诱导的急性肝损伤。结果表明，NAMO具有显著的潜力，作为治疗与败血症相关的肝功能损害的治疗剂。

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引用次数: 0

Effects of prenatal DINP exposure induced hepatic steatosis and underlying mechanism 产前暴露于DINP诱导肝脂肪变性的影响及其机制。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-03 DOI: 10.1016/j.taap.2026.117707

Yahui Jin , Junli Zhao , Xinjing Wang , Dan Li , Meiqiong Wu , Ben Li

Prenatal exposure to diisononyl phthalate (DINP) exerts sex-specific effects on offspring liver lipid metabolism, yet the underlying mechanisms remain insufficiently defined. In this study, pregnant mice were administered DINP throughout gestation, and offspring were evaluated through growth assessment, liver histopathology, lipid profiling, hepatic gene expression, and fecal metabolomics to investigate potential gut–liver axis involvement. Maternal weight and food intake were unaffected, whereas offspring exhibited growth retardation and developmental delay. Male offspring showed elevated serum and hepatic triglycerides and total cholesterol, accompanied by marked hepatic steatosis, while females displayed milder lipid deposition.

Mechanistic analyses indicated that males exhibited impaired fatty acid oxidation, with upregulation of fatty acid binding protein (FABP) and perilipin 2 (PLIN2) and downregulation of peroxisome proliferator-activated receptor alpha (PPARα). In contrast, females maintained fatty acid β-oxidation through increased carnitine palmitoyltransferase-1a (CPT-1A) expression and lipid regulation mediated by peroxisome proliferator-activated receptor gamma (PPARγ). Fecal metabolomics revealed alterations in α-linolenic acid metabolism and ubiquinone biosynthesis in males, suggesting disrupted fatty acid utilization and mitochondrial function contributing to hepatic lipid accumulation. Female offspring primarily showed alterations in glycerophospholipid metabolism, which may facilitate membrane remodeling and lipid redistribution, thereby mitigating steatosis.

In summary, prenatal DINPexposure induces hepatic steatosis through sex-specific disruptions of the gut–liver metabolic axis. Males are more susceptible to lipid accumulation, whereas females exhibit compensatory adaptations that preserve metabolic balance. These findings provide mechanistic insight into the sex-dependent metabolic consequences of early-life DINP exposure and support a more comprehensive evaluation of its safety profile.

产前暴露于邻苯二甲酸二异壬酯（DINP）会对后代肝脏脂质代谢产生性别特异性影响，但潜在的机制尚未明确。在这项研究中，怀孕小鼠在整个妊娠期都给予DINP，并通过生长评估、肝脏组织病理学、脂质谱、肝脏基因表达和粪便代谢组学来评估后代，以研究潜在的肠-肝轴损害。母亲的体重和食物摄入未受影响，而后代则表现出生长迟缓和发育迟缓。雄性后代表现出血清、肝脏甘油三酯和总胆固醇升高，并伴有明显的肝脏脂肪变性，而雌性后代表现出较轻微的脂质沉积。机制分析表明，雄性小鼠表现出脂肪酸氧化受损，脂肪酸结合蛋白（FABP）和perilippin 2 （PLIN2）上调，过氧化物酶体增殖物激活受体α (PPARα)下调。相比之下，雌性通过增加肉碱棕榈酰基转移酶1a （CPT-1A）的表达和过氧化物酶体增殖物激活受体γ (PPARγ)介导的脂质调节来维持脂肪酸β-氧化。粪便代谢组学显示，男性α-亚麻酸代谢和泛素生物合成发生改变，表明脂肪酸利用和线粒体功能的破坏导致肝脏脂质积累。雌性后代主要表现为甘油磷脂代谢的改变，这可能促进膜重塑和脂质再分配，从而减轻脂肪变性。总之，产前暴露于邻苯二甲酸二异戊二酯（DINP）可通过肠-肝代谢轴的性别特异性破坏诱导肝脏脂肪变性。雄性更容易受到脂质积累的影响，而雌性则表现出维持代谢平衡的代偿性适应。这些发现为早期接触邻苯二甲酸二异戊二酯的性别依赖性代谢后果提供了机制见解，并支持对其安全性进行更全面的评估。

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引用次数: 0

Pre-treatment with sevoflurane alleviates hypoxia-reoxygenation-induced cardiomyocyte damage through PAX8-AS1-targeted miR-145-5p. 七氟醚预处理可通过pax8 - as1靶向miR-145-5p减轻缺氧再氧诱导的心肌细胞损伤。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-02 DOI: 10.1016/j.taap.2026.117705

Yan Xu, Xianglong Di, Ye Cai, Shilin Hu

Objective: To explore the regulatory role of the lncRNA PAX8-AS1/miR-145-5p axis in the mitigation of hypoxia-induced damage to oxygenated (HR) myocardial cells by sevoflurane (Sev).

Methods: A hypoxic-reoxygenation (HR) in vitro model was established by subjecting cells to 4 h of hypoxia followed by 24 h of aeration. An in vivo MI/RI model was established via ischemia-reperfusion. Gene expression was detected using RT-qPCR. Cell proliferation and apoptosis was assessed using CCK8 and flow cytometry. Expression of myocardial injury markers, inflammatory factors, and oxidative stress markers was measured via ELISA. The targeted relationship between genes was validated using dual luciferase reporter assays and RNA immunoprecipitation.

Results: Sev can resist the upregulation of PAX8-AS1 and downregulation of miR-145-5p in HR cardiomyocytes or MI/RI myocardial tissue. PAX8-AS1 overexpression attenuates Sev-induced suppression of cardiomyocyte proliferation and apoptosis inhibition following injury Sev pre-treatment reduced the expression of myocardial cell damage markers, inflammatory factors, and oxidative stress markers, but these markers increased after PAX8-AS1 overexpression and decreased after miR-145-5p analogue transfection.

Conclusion: Sev can alleviate HR-induced myocardial cell injury by inhibiting PAX8-AS1 and promoting miR-145-5p expression.

目的：探讨lncRNA PAX8-AS1/miR-145-5p轴在减轻七氟醚（Sev）对缺氧诱导的氧合（HR）心肌细胞损伤中的调控作用。方法：将细胞缺氧4 h后再通气24 h，建立体外缺氧复氧（HR）模型。采用缺血再灌注法建立心肌梗死/心肌缺血再灌注模型。RT-qPCR检测基因表达。CCK8和流式细胞术检测细胞增殖和凋亡。采用ELISA法检测心肌损伤标志物、炎症因子和氧化应激标志物的表达。通过双荧光素酶报告基因测定和RNA免疫沉淀验证了基因间的靶向关系。结果：Sev可抑制HR心肌细胞或MI/RI心肌组织中PAX8-AS1的上调和miR-145-5p的下调。Sev预处理降低了心肌细胞损伤标志物、炎症因子和氧化应激标志物的表达，但这些标志物在PAX8-AS1过表达后升高，在转染miR-145-5p类似物后降低。结论：Sev可通过抑制PAX8-AS1、促进miR-145-5p表达来减轻hr诱导的心肌细胞损伤。

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引用次数: 0

Histone deacetylase SIRT2 regulates the development and metastasis of tongue cancer via FZD1-mediated Wnt/β-catenin pathway. 组蛋白去乙酰化酶SIRT2通过fzd1介导的Wnt/β-catenin通路调控舌癌的发生转移。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-02 DOI: 10.1016/j.taap.2026.117706

Zizheng Lu, Minxiao Lin

In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using in vitro and in vivo experiments. Human tongue cancer cells SCC-25, SCC-9, CAL-27, CAL-33 and human oral epithelial cells were cultured for cell line selection. In vitro, SCC-25 cells were manipulated with pcDNA3.1-SIRT2, pcDNA3.1-FZD1, pcDNA3.1-NC, or/and Wnt/β-catenin pathway inhibitor (MSAB) or activator (SKL2001), while CAL-33 cells were treated with siRNA-SIRT2, siRNA-NC or MSAB. The levels of H3K27ac, β-catenin (nuclear, cytoplasmic and total protein), and Wnt1/3a/7a were detected using WB. Based on data from the ENCODE database, the enrichment level of H3K27ac in the FZD1 promoter region was examined by ChIP experiment. Finally, an orthotopic xenograft tumor model in nude mice was constructed for in vivo validation. Re-expression of SIRT2 impaired the proliferative, invasive, and migratory behaviors of tongue cancer cells, while strengthening their apoptosis. Furthermore, SIRT2 decreased H3K27 acetylation, resulting in increased cytoplasmic β-catenin and decreased expression of FZD1, Wnt1/3a/7a, and nuclear β-catenin. FZD1 overexpression or the Wnt/β-catenin pathway activation partially compromised the inhibitory impacts of SIRT2 on the aforementioned behaviors of human tongue cancer cells. The in vivo validation suggested that SIRT2 played a regulatory role in FZD1 expression and Wnt/β-catenin pathway, thereby hindering the growth and metastasis of the orthotopic tongue cancer xenograft model. SIRT2 inhibits the transcriptional expression of FZD1 through H3K27 deacetylation to block the Wnt/β-catenin pathway, consequently suppressing the growth and metastasis of tongue cancer.

本研究主要通过体外和体内实验研究组蛋白去乙酰化酶sirtuin 2 （SIRT2）影响舌癌生长和转移的机制。培养人舌癌细胞SCC-25、SCC-9、CAL-27、CAL-33和人口腔上皮细胞进行细胞系筛选。体外，SCC-25细胞分别用pcDNA3.1-SIRT2、pcDNA3.1-FZD1、pcDNA3.1-NC或/和Wnt/β-catenin通路抑制剂（MSAB）或激活剂（SKL2001）处理，CAL-33细胞分别用siRNA-SIRT2、siRNA-NC或MSAB处理。WB法检测H3K27ac、β-catenin（核蛋白、胞质蛋白和总蛋白）和Wnt1/3a/7a水平。基于ENCODE数据库的数据，通过ChIP实验检测了H3K27ac在FZD1启动子区域的富集水平。最后，建立了裸鼠原位异种移植瘤模型进行体内验证。重新表达SIRT2会损害舌癌细胞的增殖、侵袭和迁移行为，同时加强舌癌细胞的凋亡。此外，SIRT2降低H3K27乙酰化，导致细胞质β-catenin升高，FZD1、Wnt1/3a/7a和细胞核β-catenin表达降低。FZD1过表达或Wnt/β-catenin通路激活部分削弱了SIRT2对人舌癌细胞上述行为的抑制作用。体内验证提示SIRT2在FZD1表达和Wnt/β-catenin通路中发挥调控作用，从而阻碍原位舌癌异种移植模型的生长和转移。SIRT2通过H3K27去乙酰化抑制FZD1的转录表达，阻断Wnt/β-catenin通路，从而抑制舌癌的生长和转移。

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引用次数: 0

Aloperine mitigates cigarette smoke-induced inflammation and pyroptosis by inhibiting the BRD4/NLRP3/GSDMD pathway in chronic obstructive pulmonary disease Aloperine通过抑制BRD4/NLRP3/GSDMD通路在慢性阻塞性肺疾病中减轻香烟烟雾诱导的炎症和焦亡。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-02 DOI: 10.1016/j.taap.2025.117704

Xiaofeng Li , Zhe Wang , Tingting Zhang , Xiaoli Zeng , Xin Li , Kai Liu , Ping Huang , Xiaoju Liu

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and progressive airflow limitation, primarily caused by cigarette smoke (CS) exposure. Current pharmacological interventions for COPD merely slow disease progression, which further underscores the urgent need for innovative therapeutics. Aloperine has demonstrated potent anti-inflammatory properties, yet its therapeutic potential in COPD remains unclear. In this study, we investigated the effects and mechanisms of aloperine using a CS-induced COPD mouse model and a cigarette smoke extract (CSE)-stimulated alveolar macrophage (AM; MH-S cell) model. Aloperine treatment significantly improved pulmonary function and alleviated emphysema in COPD mice. Furthermore, it suppressed CSE-induced alveolar macrophage pyroptosis and inflammatory responses both in vivo and in vitro. Mechanistically, the bromodomain-containing protein 4 (BRD4) inhibitor—JQ1—attenuated CSE-induced pyroptosis; however, this effect was partially reversed by the NLRP3 activator— nigericin. Comprehensive analyses, including results from molecular docking, molecular dynamics simulations, surface plasmon resonance, and in vivo and in vitro experiments, supported that aloperine interacts with BRD4 and attenuates NLRP3-mediated pyroptosis. Collectively, our findings indicate that aloperine alleviates CS-induced airway inflammation and pyroptosis potentially by modulating the BRD4/NLRP3/GSDMD signaling, positioning it as a promising therapeutic candidate for COPD.

慢性阻塞性肺疾病（COPD）的特征是持续气道炎症和进行性气流限制，主要由香烟烟雾（CS）暴露引起。目前COPD的药物干预仅仅是减缓疾病进展，这进一步强调了创新治疗方法的迫切需要。Aloperine已被证明具有有效的抗炎特性，但其治疗COPD的潜力仍不清楚。在这项研究中，我们通过cs诱导的COPD小鼠模型和香烟烟雾提取物（CSE）刺激的肺泡巨噬细胞（AM； hh -s细胞）模型研究了aloperine的作用和机制。Aloperine治疗可显著改善COPD小鼠肺功能，减轻肺气肿。此外，在体内和体外均能抑制cse诱导的肺泡巨噬细胞焦亡和炎症反应。机制上，含溴结构域蛋白4 （BRD4）抑制剂- jq1可减弱cse诱导的焦亡；然而，这种作用被NLRP3激活剂尼日利亚菌素部分逆转。综合分析，包括分子对接、分子动力学模拟、表面等离子体共振和体内外实验的结果，支持aloperine与BRD4相互作用并减弱nlrp3介导的焦亡。总的来说，我们的研究结果表明，aloperine可能通过调节BRD4/NLRP3/GSDMD信号通路来缓解cs诱导的气道炎症和焦亡，将其定位为有希望的COPD治疗候选药物。

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引用次数: 0

Salidroside derivative SHPL-49 accelerates cutaneous wound healing in diabetic mice by modulating macrophage-mediated TGF-β1/Smad2/3 signaling pathway 红景天苷衍生物SHPL-49通过调节巨噬细胞介导的TGF-β1/Smad2/3信号通路促进糖尿病小鼠皮肤创面愈合。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-02 DOI: 10.1016/j.taap.2025.117699

Feiyun Wang , Zhouyun Ma , Anam Latif , Changsen Zhan , Chunxiao Cui , Pei Zhang , Qianfei Cui , Jiange Zhang

Impaired wound healing represents a major complication of diabetes, yet effective therapeutic options remain limited. Our research group has developed a salidroside derivative, SHPL-49, which exhibits antioxidant, anti-inflammatory, and pro-angiogenic properties. We hypothesized that SHPL-49 may promote diabetic wound healing through the modulation of macrophage-mediated immune responses and fibroblast activity. In vivo studies revealed that SHPL-49 significantly accelerated wound closure in diabetic mice, with enhanced granulation tissue formation and extracellular matrix (ECM) deposition. Mechanistically, SHPL-49 induced M2 polarization of wound-associated macrophages, which subsequently secreted TGF-β1 to activate the TGF-β1/Smad2/3 pathway in fibroblasts. In vitro experiments further confirmed that SHPL-49 directly promoted M2 polarization in RAW 264.7 macrophages, as evidenced by increased CD206 expression and TGF-β1 secretion. The conditioned medium from SHPL-49-activated macrophages promoted Smad2/3 phosphorylation in L929 fibroblasts, thereby stimulating their proliferation, migration, and upregulating the expression of collagen I/III, α-SMA, and TGFβRI. Collectively, our findings suggest that SHPL-49 is a promising therapeutic candidate for diabetic wound healing, functioning through a macrophage-to-fibroblast signaling axis: it polarizes macrophages toward an M2 phenotype, which subsequently release TGF-β1 to enhance fibroblast function via the Smad2/3 signaling pathway. This study establishes a theoretical foundation for the future exploration and development of novel therapeutic indications for SHPL-49.

伤口愈合受损是糖尿病的主要并发症，但有效的治疗选择仍然有限。我们的研究小组开发了一种红景天苷衍生物SHPL-49，它具有抗氧化、抗炎和促血管生成的特性。我们假设SHPL-49可能通过调节巨噬细胞介导的免疫反应和成纤维细胞活性来促进糖尿病伤口愈合。体内研究显示，SHPL-49显著加速糖尿病小鼠伤口愈合，增强肉芽组织形成和细胞外基质（ECM）沉积。机制上，SHPL-49诱导创伤相关巨噬细胞M2极化，巨噬细胞随后分泌TGF-β1，激活成纤维细胞中TGF-β1/Smad2/3通路。体外实验进一步证实SHPL-49直接促进RAW 264.7巨噬细胞M2极化，表现为CD206表达增加，TGF-β1分泌增加。shpl -49激活巨噬细胞的条件培养基促进L929成纤维细胞Smad2/3磷酸化，从而刺激其增殖、迁移，上调胶原I/III、α-SMA和tgf - β ri的表达。总之，我们的研究结果表明，SHPL-49是糖尿病伤口愈合的有希望的治疗候选药物，通过巨噬细胞到成纤维细胞的信号轴起作用：它使巨噬细胞向M2表型极化，随后通过Smad2/3信号通路释放TGF-β1以增强成纤维细胞功能。本研究为今后探索和发展SHPL-49的新适应症奠定了理论基础。

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引用次数: 0

Repurposing of bithionol as a potential anxiolytic agent through NF-κB suppression: Insights from behavioural, biochemical, and molecular modelling studies 通过抑制NF-κB将双硫醇作为一种潜在的抗焦虑剂：来自行为、生化和分子模型研究的见解。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.taap.2025.117700

Kiran Satao , Maheshkumar Borkar , Angel Godad , Gaurav Doshi

Chronic stress activates neuroinflammatory responses through the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, rendering anxiety disorders the leading psychological disease. For the current investigation, an anxiety-related mouse model of restraint stress was adopted to analyse the potential anxiolytic activities of bithionol, a Food and Drug Administration (FDA) an approved anthelmintic drug. It is expected that bithionol should act through inhibiting the process of NF-κB activation, which reduces pro-inflammatory cytokines production. Three dosages of bithionol (25, 50, 100 mg/kg) were administered in male Swiss albino mice subjected to chronic restraint stress, of which diazepam served as the comparator anxiolytic. The behavioural tests, like the Marble Burying Test, Open Field Test (OFT), Elevated Plus Maze (EPM), Light and Dark Transition Screening test, were used for determining anxiety-like behaviours. Therapy with bithionol significantly reduced NF-κB, Tumor necrosis factor- alpha (TNF-α), as well as (Interleukin-1beta) IL-1β, while enhancing serotonin levels primarily at the highest dose of 100 mg/kg, as revealed through biochemical analysis of brain homogenates. These observations suggest that bithionol exhibits dose-dependent anxiolytic activity, possibly through suppression of the NF-κB pathway as well as neuroinflammatory reductions. Molecular modelling study has been performed to gain the insights of molecular level interactions between bithionol and NF-κB, TNF-α and IL-1β. Thus, the repurposing of bithionol for anxiety disorders is investigated.

慢性应激通过活化B细胞的核因子κB轻链增强子（NF-κB）信号通路激活神经炎症反应，使焦虑症成为主要的心理疾病。本研究采用约束应激小鼠焦虑相关模型，分析了美国食品和药物管理局（FDA）批准的驱虫药比硫醇的潜在抗焦虑活性。预计双硫醇可能通过抑制NF-κB活化过程起作用，从而减少促炎细胞因子的产生。以地西泮为对照剂，给药25、50、100 mg/kg三种剂量的双硫醇。行为测试，如大理石掩埋测试，开放场地测试（OFT），高架加迷宫（EPM），明暗过渡筛选测试，用于确定焦虑样行为。脑匀浆生化分析显示，双硫醇治疗可显著降低NF-κ b、肿瘤坏死因子-α (TNF-α)和白细胞介素-1β (IL-1β)，同时主要在最高剂量100 mg/kg时提高血清素水平。这些观察结果表明，双硫醇表现出剂量依赖性的抗焦虑活性，可能是通过抑制NF-κB途径以及神经炎症的减少。通过分子模拟研究，深入了解双硫醇与NF-κB、TNF-α和IL-1β的分子水平相互作用。因此，研究了双硫酚治疗焦虑症的重新用途。

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引用次数: 0

Unveiling the therapeutic potential and leukemia risk of PD-166866 in sepsis via an integrated computational-experimental strategy 通过综合计算-实验策略揭示PD-166866在败血症中的治疗潜力和白血病风险。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.taap.2025.117702

Mingkai Chang , Ye Shang , Jianing Zheng , Wenfei Wang , Tingting Zhao

Objective: This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology.Methods: In terms of druggability, network pharmacology was used to screen drug-disease common targets and conduct enrichment analysis. Meanwhile, transcriptome sequencing was performed on the LPS-induced Raw264.7 cell model for target validation. In terms of toxicology, network toxicology was applied to predict the potential toxicity of small molecules, which was further verified by gene expression and survival analysis using the TCGA and Kaplan-Meier Plotter databases.Results: A total of 39 common targets between PD-166866 and sepsis were identified. The core pathways include the Rap1 signaling pathway, and the core targets are SRC, EGFR, and CCND1; molecular docking showed stable binding between PD-166866 and these targets. Transcriptomic analysis confirmed that PD-166866 can significantly regulate the expression of inflammation-related genes and inhibit the Rap1 pathway. Network toxicology indicated a significant risk of hematological toxicity associated with this drug. Transcriptome sequencing revealed that PD-166866 treatment led to the downregulation of IRAK3 and IKBKE, and the low expression of these two genes was significantly associated with poor prognosis in leukemia patients, confirming the potential hematological toxicity of PD-166866.Conclusion: This study confirms that PD-166866 exerts anti-sepsis effects by regulating pathways such as Rap1, but it also has the potential risk of inducing leukemia. More importantly, this study successfully established a comprehensive evaluation framework integrating in silico and in vitro experiments. It provides a feasible methodological reference for systematically evaluating the dual attributes of “efficacy-risk” in the early stage of drug development and reducing the initial reliance on traditional animal models.

目的：本研究通过网络药理学、转录组测序、网络毒理学等综合手段，评价FGFR1抑制剂PD-166866的抗脓毒症疗效及潜在风险。方法：在可用药性方面，采用网络药理学方法筛选药物-疾病共同靶点并进行富集分析。同时，对lps诱导的Raw264.7细胞模型进行转录组测序，进行靶标验证。在毒理学方面，应用网络毒理学预测小分子的潜在毒性，并通过TCGA和Kaplan-Meier Plotter数据库的基因表达和生存分析进一步验证。结果：PD-166866与脓毒症共发现39个共同靶点。核心通路包括Rap1信号通路，核心靶点为SRC、EGFR、CCND1；分子对接显示PD-166866与这些靶点的结合稳定。转录组学分析证实，PD-166866可以显著调节炎症相关基因的表达，抑制Rap1通路。网络毒理学表明与该药物相关的血液学毒性的显著风险。转录组测序结果显示，PD-166866治疗导致IRAK3和IKBKE下调，这两个基因的低表达与白血病患者预后不良显著相关，证实了PD-166866的潜在血液学毒性。结论：本研究证实PD-166866通过调控Rap1等通路发挥抗脓毒症作用，但也存在诱导白血病的潜在风险。更重要的是，本研究成功建立了一个集成了计算机和体外实验的综合评价框架。为药物研发初期系统评价“疗效-风险”双重属性，减少初期对传统动物模型的依赖提供了可行的方法学参考。

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引用次数: 0

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