Toxicology and applied pharmacology最新文献_第4页

Pharmacological inhibition of USP7 attenuates deltamethrin-induced neuronal ferroptosis via GPX4 stabilization 药理抑制USP7通过GPX4稳定减轻溴氰菊酯诱导的神经元铁下垂。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-13 DOI: 10.1016/j.taap.2026.117716

Minjia Wu , Yang Chen , Peixuan Ma , Wen Pan , Yaqin Deng , Lexing Wei , Guodong Lu , Michael Aschner , Yueming Jiang , Jing Zhou , Xiaowei Huang

Recent studies suggest a significant association between deltamethrin (DM) exposure and an elevated risk of neurodegenerative diseases, yet the underlying molecular mechanisms remain poorly understood. The role of Ubiquitin-specific protease 7 (USP7), a key deubiquitinating enzyme regulating protein homeostasis, in DM-induced neurotoxicity is particularly elusive. Here, we combined in vitro HT22 mouse hippocampal neuronal cells and in vivo male C57BL/6 J mice, which received daily oral gavage of DM at 4.5, 9.0, and 18.0 mg/kg for 30 consecutive days, to investigate the molecular mechanisms underlying DM-induced neurotoxicity. DM exposure significantly induced ferroptosis which was characterized by lipid peroxidation, disruption of iron homeostasis, mitochondrial damage and GPX4 degradation in HT22 cells and in the hippocampus, and was accompanied by impaired spatial learning and memory and neuronal hyperexcitability in mice. Consistently, DM decreased GSH and SOD levels, increased MDA and Fe²⁺, and reduced GPX4, supporting ferroptosis-associated oxidative injury in both models. Mechanistically, DM treatment markedly increased USP7 expression and enhanced GPX4 ubiquitination, thereby promoting its degradation. Increased USP7 levels subsequently induced the ubiquitination of GPX4. Critically, inhibition of USP7 reversed DM-induced GPX4 degradation, lipid peroxidation, iron dysregulation, and mitochondrial damage, thereby stabilizing GPX4 and mitigating neuronal ferroptosis. In conclusion, our findings identify that the upregulation of USP7 is a key mechanism in DM-induced neurotoxicity. USP7 promotes GPX4 degradation via ubiquitination, and inhibition of USP7 preserves GPX4 stability, thereby protecting neurons from ferroptosis and highlighting USP7 as a promising therapeutic target for preventing and treating DM-induced neurotoxicity.

最近的研究表明，溴氰菊酯（DM）暴露与神经退行性疾病风险升高之间存在显著关联，但其潜在的分子机制尚不清楚。泛素特异性蛋白酶7 （USP7）是一种调节蛋白质稳态的关键去泛素化酶，在dm诱导的神经毒性中的作用尤其难以捉摸。本研究将体外HT22小鼠海马神经元细胞与体内雄性C57BL/6 J小鼠相结合，连续30天每天口服4.5、9.0和18.0 mg/kg的DM，研究DM诱导神经毒性的分子机制。DM暴露显著诱导小鼠铁下沉，表现为HT22细胞和海马的脂质过氧化、铁稳态破坏、线粒体损伤和GPX4降解，并伴有空间学习记忆和神经元高兴奋性受损。DM降低GSH和SOD水平，增加MDA和Fe2+，降低GPX4，支持两种模型中与铁中毒相关的氧化损伤。机制上，DM处理显著增加USP7表达，增强GPX4泛素化，从而促进其降解。增加的USP7水平随后诱导GPX4泛素化。关键的是，抑制USP7逆转dm诱导的GPX4降解、脂质过氧化、铁失调和线粒体损伤，从而稳定GPX4并减轻神经元铁下垂。总之，我们的研究结果表明，USP7的上调是dm诱导的神经毒性的关键机制。USP7通过泛素化促进GPX4降解，抑制USP7可保持GPX4的稳定性，从而保护神经元免于铁凋亡，并突出显示USP7是预防和治疗dm诱导的神经毒性的有希望的治疗靶点。

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引用次数: 0

GKB7I-53: A novel anti-metastatic agent for colorectal cancer GKB7I-53：一种新型结直肠癌抗转移药物

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.taap.2026.117712

Min Hee Yang , Ducdat Le , Thinhulinh Dang , Vinhquang Truong , In Jin Ha , Mina Lee , Kwang Seok Ahn

Metastasis driven by epithelial-mesenchymal transition (EMT) remains a critical challenge in colorectal cancer treatment. This study investigated GKB7I-53, a saponin compound isolated through feature-based molecular networking, as a potential therapeutic agent targeting EMT pathways. GKB7I-53 demonstrated minimal cytotoxicity (>90% cell viability at 50 μM) while effectively inhibiting metastatic processes. The compound downregulated mesenchymal markers (CXCR4, CXCR7) and upregulated epithelial markers (E-cadherin, occludin), suppressing EMT progression. In CXCL12-stimulated cells, GKB7I-53 significantly reduced cell migration and invasion while decreasing MMP-2/9 activity, key enzymes facilitating metastatic spread. Mechanistically, GKB7I-53 suppressed MnSOD-induced STAT3 activation, thereby blocking the JAK/STAT3 signaling pathway crucial for metastasis. Molecular docking studies confirmed strong binding affinity to target proteins involved in EMT and cancer progression. These findings suggest that GKB7I-53 may serve as a potential lead compound with anti-metastatic properties in colorectal cancer. Rather than inducing general cytotoxicity, GKB7I-53 selectively modulates EMT-related pathways, indicating a mechanistic basis for its anti-metastatic effects. However, further in vivo validation and preclinical studies are required to determine its therapeutic relevance.

上皮-间质转化（EMT）驱动的转移仍然是结直肠癌治疗的一个关键挑战。GKB7I-53是一种通过基于特征的分子网络分离的皂苷化合物，该化合物有望作为一种靶向EMT通路的潜在治疗剂。GKB7I-53表现出最小的细胞毒性（50 μM时细胞存活率为90%），同时有效抑制转移过程。该化合物下调间充质标志物（CXCR4, CXCR7）和上调上皮标志物（E-cadherin, occludin），抑制EMT进展。在cxcl12刺激的细胞中，GKB7I-53显著减少了细胞迁移和侵袭，同时降低了促进转移扩散的关键酶MMP-2/9的活性。在机制上，GKB7I-53抑制了mnsod诱导的STAT3激活，从而阻断了对转移至关重要的JAK/STAT3信号通路。分子对接研究证实了与EMT和癌症进展相关的靶蛋白有很强的结合亲和力。这些发现提示GKB7I-53可能作为结直肠癌抗转移特性的潜在先导化合物。GKB7I-53不是诱导一般的细胞毒性，而是选择性地调节emt相关途径，这表明其抗转移作用的机制基础。然而，需要进一步的体内验证和临床前研究来确定其治疗相关性。

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引用次数: 0

Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells 紫杉醇损害人感觉样神经元细胞的线粒体动力学

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.taap.2026.117715

Mariana Caprio Schiess , Gessica Sabrina de Assis Silva , Natália Gabriele Hösch , Vitória Carvalho Troitiño , Marcelo Medina de Souza , Carlos DeOcesano-Pereira , Talita Glaser , Henning Ulrich , Ana Marisa Chudzinski-Tavassi , Michelle Cristiane Bufalo , Vanessa Olzon Zambelli

Taxanes are considered first-line chemotherapeutic agents to treat solid cancer. Paclitaxel (PTX) is a commonly used taxane and although effective, it induces peripheral chronic neuropathy in around 60–70% of patients. Studies have demonstrated a correlation between impairment in bioenergetic metabolism and the development of neuropathies. However, the correlation between mitochondrial fusion-fission processes in sensory neurons and the development of neurodegeneration and pain remains poorly understood. Considering that neurons have a high metabolic demand and numerous mitochondria, and that chemotherapy-induced neuropathy is often accompanied by mitochondrial dysfunction, we investigated the role of mitochondrial plasticity in sensory-like neuron cells incubated with paclitaxel. Our findings indicate that neurotoxic concentrations of paclitaxel induce mitochondrial fragmentation by downregulating fusion proteins, such as mitofusin-1 and − 2 (MFN1 and MFN2), and upregulating fission proteins, such as dynamin-related protein 1 (Drp1). Also, paclitaxel increases superoxide release, impairs neuritogenesis, and activates pro-nociceptive signaling, measured by activating transcription factor 3 (ATF-3) expression, substance P release, and prostaglandin E2 (PGE2) - induced calcium influx. Of note, blocking excessive fission with P110, a pharmacological inhibitor of Drp1, PTX-induced cytotoxicity was prevented in sensory neuron-like cells. Together, our data suggest that impairment in mitochondrial dynamics of sensory neurons contributes to paclitaxel neurotoxicity and, consequently, to nociception. Therefore, preventing mitochondrial fission may be a strategy to prevent PTX-induced neurotoxicity, opening a new perspective to understanding the mechanisms involved in the development of PTX-induced neuropathy.

紫杉烷被认为是治疗实体癌的一线化疗药物。紫杉醇（PTX）是一种常用的紫杉烷，虽然有效，但在约60-70%的患者中引起周围慢性神经病变。研究表明，生物能量代谢障碍与神经病变的发展之间存在相关性。然而，感觉神经元中线粒体融合-裂变过程与神经变性和疼痛的发展之间的相关性仍然知之甚少。考虑到神经元具有高代谢需求和大量线粒体，并且化疗诱导的神经病变通常伴有线粒体功能障碍，我们研究了线粒体可塑性在紫杉醇培养的感觉样神经元细胞中的作用。我们的研究结果表明，紫杉醇的神经毒性浓度通过下调融合蛋白（如mitofusin-1和- 2 (MFN1和MFN2)）和上调裂变蛋白（如动力蛋白相关蛋白1 (Drp1)）诱导线粒体断裂。此外，通过激活转录因子3 （ATF-3）表达、P物质释放和前列腺素E2 （PGE2）诱导的钙内流来测量，紫杉醇增加超氧化物释放，损害神经生成，并激活促伤害信号。值得注意的是，用P110 （Drp1的药理抑制剂）阻断过度裂变，ptx诱导的感觉神经元样细胞毒性被阻止。总之，我们的数据表明，感觉神经元线粒体动力学的损伤有助于紫杉醇神经毒性，从而导致伤害感觉。因此，防止线粒体分裂可能是预防ptx诱导的神经毒性的一种策略，为理解ptx诱导的神经病变的发生机制开辟了新的视角。

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引用次数: 0

GSDMD inhibitor GI-Y1 alleviates doxorubicin-induced cardiotoxicity via the inhibition of mitochondrial dysfunction GSDMD抑制剂GI-Y1通过抑制线粒体功能障碍减轻阿霉素诱导的心脏毒性。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-10 DOI: 10.1016/j.taap.2026.117713

Yucong Zhang , Ruihan Zheng , Minne Xie , Yunxuan Chen , Binbin Xia , Zexin Yang , Zhuoning Li , Yuzheng Li , Li Luo , Weijian Huang , Shanshan Dai , Bozhi Ye , Wenli Zhang

Objective

This study aimed to explore GI-Y1's (a GSDMD inhibitor) protective effect against doxorubicin (Dox)-induced cardiotoxicity (DIC) and clarify its molecular mechanisms.

Methods

In vivo, wild-type and Gsdmd⁻/⁻ mice received Dox (5 mg/kg/week for 4 weeks) and GI-Y1 (10 or 20 mg/kg/day). AAV9-mediated GSDMD overexpression verified target specificity. Cardiac function was assessed by echocardiography; myocardial injury via H&E staining, TUNEL assay, and serum biomarkers (CK-MB, LDH, cTnT). In vitro, HL-1 cardiomyocytes were treated with Dox (0.5 μg/mL) and GI-Y1 (10 or 20 μM). Pyroptosis markers (GSDMD cleavage, IL-1β secretion, LDH release) and mitochondrial function were measured using Western blot, ELISA, JC-1 staining, and TEM.

Results

GI-Y1 improved survival and cardiac function in Dox-treated mice. It reduced serum cardiac injury biomarkers and alleviated myocardial histological damage. In vivo and in vitro, GI-Y1 inhibited Dox-induced cardiomyocyte pyroptosis, shown by reduced GSDMD cleavage, less IL-1β secretion, and decreased cell death. Mechanistically, GI-Y1 bound GSDMD, impairing its lipid-binding and pore-forming abilities. It also relieved Dox-induced mitochondrial dysfunction by reducing mitochondrial GSDMD-N, restoring MMP, boosting ATP, and inhibiting mtDNA release.

Conclusion

GI-Y1 alleviates DIC by directly targeting GSDMD, inhibiting pyroptosis and mitochondrial damage. This study highlights GI-Y1 as a promising therapy for chemotherapy-related cardiac injury and a valuable tool to study pyroptosis in cardiovascular diseases.

目的：探讨GI-Y1 （GSDMD抑制剂）对多柔比星（Dox）诱导的心脏毒性（DIC）的保护作用，并阐明其分子机制。方法：在体内，野生型和Gsdmd-/-小鼠分别给予Dox（5 mg/kg/周，持续4 周）和GI-Y1（10或20 mg/kg/天）。aav9介导的GSDMD过表达证实了目标特异性。超声心动图评估心功能；通过H&E染色、TUNEL试验和血清生物标志物（CK-MB、LDH、cTnT）检测心肌损伤。在体外，用Dox（0.5 μg/mL）和GI-Y1（10或20 μM）处理HL-1心肌细胞。采用Western blot、ELISA、JC-1染色和TEM检测焦亡标志物（GSDMD裂解、IL-1β分泌、LDH释放）和线粒体功能。结果：GI-Y1改善了dox处理小鼠的存活率和心功能。降低血清心肌损伤生物标志物，减轻心肌组织学损伤。在体内和体外，GI-Y1抑制dox诱导的心肌细胞焦亡，表现为GSDMD切割减少，IL-1β分泌减少，细胞死亡减少。在机制上，GI-Y1结合GSDMD，损害其脂质结合和成孔能力。它还通过降低线粒体GSDMD-N、恢复MMP、促进ATP和抑制mtDNA释放来缓解dox诱导的线粒体功能障碍。结论：GI-Y1通过直接靶向GSDMD减轻DIC，抑制热亡和线粒体损伤。本研究强调GI-Y1是化疗相关心脏损伤的一种有前景的治疗方法，也是研究心血管疾病焦亡的一种有价值的工具。

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引用次数: 0

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。

{"title":"Norcantharidin inhibits the EZH2-mediated JAK2/STAT3 signaling pathway to inhibit the proliferation of non-small cell lung cancer","authors":"Shuang Wu , Wei Zhang","doi":"10.1016/j.taap.2026.117714","DOIUrl":"10.1016/j.taap.2026.117714","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117714"},"PeriodicalIF":3.4,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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