Toxicology and applied pharmacology最新文献_第4页

Norcantharidin inhibits the EZH2-mediated JAK2/STAT3 signaling pathway to inhibit the proliferation of non-small cell lung cancer 去甲斑蝥素抑制ezh2介导的JAK2/STAT3信号通路抑制非小细胞肺癌的增殖。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-09 DOI: 10.1016/j.taap.2026.117714

Shuang Wu , Wei Zhang

Objective

The purpose of this study was firstly to investigate the anti-tumor effects of NCTD on NSCLC cell proliferation, apoptosis, migration, and invasion. Secondly, it aimed to explore whether these effects were associated with the modulation of the EZH2/JAK2/STAT3 signaling axis.

Methods

This study employed a series of in vitro experiments, including CCK-8, Edu staining, colony formation, flow cytometry, and Transwell assays, to evaluate the effects of NCTD on the proliferation, apoptosis, migration, and invasion of NSCLC cells. The in vivo anti-tumor efficacy was evaluated using an A549 xenograft mouse model. Underlying mechanisms were explored via western blot and genetic perturbation (knockdown and overexpression) of EZH2.

Results

The results of the in vitro experiments demonstrated that NCTD significantly inhibited NSCLC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Furthermore, NCTD effectively suppressed tumor growth in the xenograft mouse model. The molecular mechanism study revealed that NCTD treatment was associated with downregulation of EZH2 and concomitant suppression of JAK2/STAT3 phosphorylation and activation of the JAK2/STAT3 signaling pathway. Genetic knockdown of EZH2 mimicked the anti-tumor effects of NCTD, whereas overexpression of EZH2 partially reversed its efficacy.

Conclusion

The anti-tumor activity of NCTD is associated with the downregulation of EZH2 protein expression and concomitant inhibition of the JAK2/STAT3 signaling pathway. These findings provide novel insights into the molecular mechanisms underlying NCTD's anti-tumor activity.

目的：本研究首先探讨NCTD对非小细胞肺癌细胞增殖、凋亡、迁移和侵袭的抗肿瘤作用。其次，旨在探讨这些影响是否与EZH2/JAK2/STAT3信号轴的调制有关。方法：本研究采用CCK-8、Edu染色、集落形成、流式细胞术、Transwell等一系列体外实验，评价NCTD对NSCLC细胞增殖、凋亡、迁移和侵袭的影响。采用A549异种移植小鼠模型评价其体内抗肿瘤效果。通过western blot和基因扰动（敲低和过表达）探讨EZH2的潜在机制。结果：体外实验结果表明，NCTD显著抑制NSCLC细胞增殖、集落形成、迁移和侵袭，促进细胞凋亡。此外，NCTD在异种移植小鼠模型中有效抑制肿瘤生长。分子机制研究表明，NCTD治疗与EZH2下调，同时抑制JAK2/STAT3磷酸化和激活JAK2/STAT3信号通路有关。基因敲低EZH2可模拟NCTD的抗肿瘤作用，而过表达EZH2可部分逆转其抗肿瘤作用。结论：NCTD的抗肿瘤活性可能与下调EZH2蛋白表达并同时抑制JAK2/STAT3信号通路有关。这些发现为NCTD抗肿瘤活性的分子机制提供了新的见解。

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引用次数: 0

Akkermansia muciniphila enhances the antitumour efficacy of αPD-1 therapy in gastric cancer by remodelling the tumour immune microenvironment 嗜mucinimansia通过重塑肿瘤免疫微环境，增强αPD-1治疗胃癌的抗肿瘤效果。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.taap.2026.117711

Ziyi Yang , Lanfan Liang , Xin Li , Xizhen Peng , Xinyi Qian , Zehua Huang , Xi Wang , Qing Hu , Xiangsheng Fu

There is growing advocacy for employing probiotics as adjuncts to potentiate immune checkpoint blockade (ICB) in cancer therapy. In this study, we investigated whether the probiotic Akkermansia muciniphila (A. muciniphila) could enhance the antitumour responses to anti-PD-1 (αPD-1) in gastric cancer (GC) by reshaping the tumour microenvironment (TME). A subcutaneous GC model was established in male strain 615 mice by inoculating 1 × 10⁶ Mouse Forestomach Carcinoma (MFC) cells on Day 10. A. muciniphila was given by daily oral gavage (1 × 10⁹ CFU per mouse) from Day 0 to Day 31, and the αPD-1 antibody was administered intraperitoneally (100 μg per mouse) every 3 days from Day 16 to Day 31. Tumour volume was recorded every 3 days, and tumours were collected on Day 31 for histology, flow cytometry, enzyme-linked immunosorbent assay (ELISA), 16S rRNA sequencing and statistical analyses. Combined treatment with A. muciniphila and αPD-1 significantly inhibited subcutaneous tumour growth (P < 0.0001) and promoted tumour cell apoptosis (P < 0.0001). A. muciniphila increased the therapeutic effectiveness of αPD-1 treatment by driving CD8⁺ T-cell accumulation within the TME (P < 0.0001). Supplementation with A. muciniphila reshaped the leading constituents of the gut microbiota and was associated with a significant fall in the relative abundance of Escherichia coli (E. coli) (P = 0.0170). By driving CD8⁺ T-cell infiltration and activation and reshaping the intestinal microbiota, A. muciniphila augmented the efficacy of αPD-1 therapy against gastric tumours.

越来越多的人提倡在癌症治疗中使用益生菌作为辅助剂来增强免疫检查点阻断（ICB）。在这项研究中，我们研究了益生菌Akkermansia muciniphila （A. muciniphila）是否通过重塑肿瘤微环境（TME）来增强胃癌（GC）对抗pd -1 （αPD-1）的抗肿瘤反应。在第10天接种1 × 106小鼠前胃癌细胞，建立615雄性小鼠皮下胃癌模型。第0 ~ 31天每天灌胃（1 × 109 CFU /只小鼠）给药，第16 ~ 31天每3 天腹腔注射αPD-1抗体（100 μg /只小鼠）。每3 d记录肿瘤体积，第31天采集肿瘤进行组织学、流式细胞术、酶联免疫吸附试验（ELISA）、16S rRNA测序及统计学分析。与αPD-1联合治疗可显著抑制皮下肿瘤生长(P + TME内t细胞聚集（P + t细胞浸润、激活和重塑肠道微生物群），增强αPD-1治疗胃肿瘤的疗效。

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引用次数: 0

Synergistic assault of DEHP and MPs: Unmasking the ER stress-triggered autophagic injury male fertility DEHP和MPs的协同攻击：揭示内质网应激引发的自噬损伤男性生育能力。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.taap.2026.117710

Jiajun Guo , Xiaoyan Feng , Yuankun Zhou , Tao You , Hengyi Xu

As an emerging category of environmental pollutants, microplastics (MPs) garner significant attention due to their exceptionally high exposure risk. Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in the plastics industry, shares a similar trajectory of escalating risk as plastic pollution intensifies. MPs and DEHP are widely present in environments accessible to humans, exerting significant adverse effects on human health. The reproductive toxicity of both MPs and DEHP has been reported. However, their combined toxicity, particularly the damage to the male reproductive system, remains unclear. Here, we employed the C57BL/6 J mouse model for our experiments. The mice were continuously exposed to 10 mg/L MPs and 500 μg/L DEHP through free drinking water for two months to investigate the effects of these two pollutants on mouse testes. Our study found that mice co-exposed to MPs and DEHP experienced severe impairment of male reproductive system, manifested as disruption of testicular structure, decline in sperm quality, and dysregulation of sex hormone synthesis. Furthermore, the co-exposure to DEHP and MPs activated endoplasmic reticulum stress via the PERK-eIF2α-ATF4 pathway, and also induced excessive autophagy, contributing to reproductive damage. In summary, our findings highlight the significant risks of co-exposure to DEHP and MPs and provide new insights into their combined reproductive toxicity in male mammals.

微塑料作为一种新兴的环境污染物，因其极高的暴露风险而备受关注。邻苯二甲酸二（2-乙基己基）酯（DEHP）是塑料工业中普遍存在的增塑剂，随着塑料污染的加剧，其风险也在不断上升。MPs和DEHP广泛存在于人类可接近的环境中，对人类健康产生重大不利影响。MPs和DEHP的生殖毒性都有报道。然而，它们的综合毒性，特别是对男性生殖系统的损害，仍不清楚。本文采用C57BL/6 J小鼠模型进行实验。将10 mg/L的MPs和500 μg/L的DEHP通过免费饮用水连续暴露于小鼠两个月，研究这两种污染物对小鼠睾丸的影响。我们的研究发现，同时暴露于MPs和DEHP的小鼠雄性生殖系统出现了严重的损害，表现为睾丸结构破坏，精子质量下降，性激素合成失调。此外，DEHP和MPs共同暴露通过PERK-eIF2α-ATF4途径激活内质网应激，诱导过度自噬，导致生殖损伤。总之，我们的研究结果强调了DEHP和MPs共同暴露的重大风险，并为雄性哺乳动物的综合生殖毒性提供了新的见解。

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引用次数: 0

Sinapic acid attenuates colistin-driven nephrotoxicity by targeting the miRNA-21/SIRT1/NF-κB pathway and facilitating tubular repair and inflammation in a rat model 在大鼠模型中，辛酸通过靶向miRNA-21/SIRT1/NF-κB通路，促进小管修复和炎症，减轻粘菌素驱动的肾毒性。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.taap.2026.117708

Medine Akkan Öz , Hasan Şimşek , Selçuk Özdemir , Özge Kandemir , Sefa Küçükler , Hüseyin Mutlu , Ramiz Yazıcı , Fatih Mehmet Kandemir

The present study aimed to investigate the nephrotoxic effects of colistin (CS) in a rat model and to elucidate the potential renoprotective mechanisms of sinapic acid (SA) at biochemical, molecular, and metabolic levels. Colistin administration induced pronounced renal dysfunction, as evidenced by significant elevations in serum creatinine (Scr) and blood urea nitrogen (BUN), along with marked increases in kidney injury biomarkers, including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Metabolic disruption was further confirmed by reduced ATP levels and increased lactate dehydrogenase (LDH) and triacylglycerol (TAG) concentrations, indicating mitochondrial dysfunction and cytotoxicity. Serum proteomic profiling using proximity extension assay identified significant alterations in 22 of 43 proteins, with IL-1β, IL-2, CXCL2, CSF-1, CCL22, and IFN-α2 showing marked upregulation following CS exposure. These inflammatory and immune-related proteins were significantly attenuated by SA co-treatment. Molecular analyses revealed that CS activated the miR-21/NF-κB/CD68 axis while suppressing SIRT1 expression, reflecting enhanced inflammation and macrophage infiltration. Sinapic acid effectively normalized these molecular disturbances. Furthermore, CS significantly upregulated renal mRNA expression of Cst3, Timp2, Igfbp7, Hgf, IL9, and Dkk3—genes associated with renal stress, fibrosis, and inflammation—whereas SA treatment markedly reduced their expression. Collectively, these findings demonstrate that sinapic acid exerts renoprotective effects primarily through modulation of inflammatory signaling pathways, suppression of miR-21/NF-κB-mediated responses, restoration of SIRT1 activity, and improvement of metabolic homeostasis. The study confirms the therapeutic potential of SA against colistin-induced nephrotoxicity.

本研究旨在探讨粘菌素（CS）在大鼠模型中的肾毒性作用，并从生化、分子和代谢水平阐明辛酸（SA）的潜在肾保护机制。粘菌素引起了明显的肾功能障碍，血清肌酐（Scr）和血尿素氮（BUN）显著升高，同时肾损伤生物标志物（包括KIM-1、NGAL、FABP、IL-18、MCP-1和YKL-40）显著增加。ATP水平降低、乳酸脱氢酶（LDH）和三酰甘油（TAG）浓度升高进一步证实了代谢紊乱，表明线粒体功能障碍和细胞毒性。使用接近扩展法的血清蛋白质组学分析发现43种蛋白中的22种发生了显著变化，其中IL-1β、IL-2、CXCL2、CSF-1、CCL22和IFN-α2在CS暴露后显着上调。这些炎症和免疫相关蛋白被SA共同处理显著减弱。分子分析显示，CS激活miR-21/NF-κB/CD68轴，同时抑制SIRT1表达，反映炎症和巨噬细胞浸润增强。辛酸有效地使这些分子干扰正常化。此外，CS显著上调了与肾应激、纤维化和炎症相关的Cst3、Timp2、Igfbp7、Hgf、IL9和dkk3基因的肾脏mRNA表达，而SA治疗显著降低了它们的表达。综上所述，这些发现表明辛酸主要通过调节炎症信号通路、抑制miR-21/NF-κ b介导的反应、恢复SIRT1活性和改善代谢稳态来发挥肾保护作用。该研究证实了SA对粘菌素引起的肾毒性的治疗潜力。

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引用次数: 0

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 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