Toxicology最新文献_第4页

Effective analysis of thyroid toxicity and mechanisms of acetyltributyl citrate using network toxicology, molecular docking, and machine learning strategies 应用网络毒理学、分子对接和机器学习策略对枸橼酸乙酰三丁酯甲状腺毒性及机制进行有效分析。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2024.154029

Yujian Lan , Qingping Peng , Bowen Fu , Huan Liu

The growing prevalence of environmental pollutants has raised concerns about their potential role in thyroid dysfunction and related disorders. Previous research suggests that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect thyroid health, yet the precise mechanisms remain poorly understood. The objective of this study was to elucidate the complex effects of acetyl tributyl citrate (ATBC) on the thyroid gland and to clarify the potential molecular mechanisms by which environmental pollutants influence the disease process. Through an exhaustive exploration of databases such as ChEMBL, STITCH, and GEO, we identified a comprehensive list of 19 potential targets closely associated with ATBC and the thyroid gland. After rigorous screening using the STRING platform and Cytoscape software, we narrowed this list to 15 candidate targets, ultimately identifying five core targets: CBX5, HADHB, TRIM33, TP53, and CUL4A, utilizing three well-established machine learning methods. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses conducted in the DAVID database revealed that the primary pathways through which ATBC affects the thyroid gland involve key signaling cascades, including the FoxO signaling pathway and metabolic pathways such as fatty acid metabolism. Furthermore, molecular docking simulations using Molecular Operating Environment software confirmed strong binding interactions between ATBC and these core targets, enhancing our understanding of their interactions. Overall, our findings provide a theoretical framework for comprehending the intricate molecular mechanisms underlying ATBC's effects on thyroid damage and pave the way for the development of preventive and therapeutic strategies against thyroid disorders caused by exposure to ATBC-containing plastics or overexposure to ATBC.

日益普遍的环境污染物引起了人们对其在甲状腺功能障碍和相关疾病中的潜在作用的关注。先前的研究表明，各种化学物质，包括增塑剂，如乙酰柠檬酸三丁酯（ATBC），可能会对甲状腺健康产生不利影响，但确切的机制仍然知之甚少。本研究的目的是阐明乙酰柠檬酸三丁酯（ATBC）对甲状腺的复杂作用，并阐明环境污染物影响疾病过程的潜在分子机制。通过对ChEMBL、STITCH和GEO等数据库的详尽研究，我们确定了19个与ATBC和甲状腺密切相关的潜在靶点。在使用STRING平台和Cytoscape软件进行严格筛选后，我们将该列表缩小到15个候选靶点，最终确定了五个核心靶点：CBX5， HADHB, TRIM33， TP53和CUL4A，利用三种成熟的机器学习方法。在DAVID数据库中进行的深度基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析显示，ATBC影响甲状腺的主要通路涉及关键信号级联，包括FoxO信号通路和脂肪酸代谢等代谢通路。此外，利用molecular Operating Environment软件进行分子对接模拟，证实了ATBC与这些核心靶点之间存在强结合相互作用，增强了我们对它们相互作用的理解。总之，我们的研究结果为理解ATBC对甲状腺损伤影响的复杂分子机制提供了理论框架，并为针对暴露于含ATBC的塑料或过度暴露于ATBC引起的甲状腺疾病的预防和治疗策略的发展铺平了道路。

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引用次数: 0

Pulmonary inflammatory responses and retention dynamics of cellulose nanofibrils 肺炎症反应和纤维素纳米原纤维的保留动力学。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2024.154038

Katsuhide Fujita, Sawae Obara, Junko Maru, Yuka Kawai, Shigehisa Endoh

Cellulose nanofibrils (CNFs) are advanced biomaterials valued for their strength, lightweight nature, and low thermal expansion, making them suitable for diverse industrial applications. However, their potential inhalation risks necessitate thorough safety evaluations. This study investigates the pulmonary inflammatory effects and retention of CNFs following intratracheal instillation in rats. TEMPO-oxidized CNF (CNF1; 11.5 nm × 1.8 μm), mechanically fibrillated CNF (CNF2; 23.9 nm × 2.4 μm), and shorter-fibrillated CNF (CNF3; 21.6 nm × 1.2 μm) were administered at 2.0 mg/kg body weight. Endotoxin contamination was assessed using lipopolysaccharide (LPS) controls. Pulmonary inflammation was evaluated 28 days post-instillation, and lung retention of chemically stained CNFs was tracked for 90 days. Results indicated: (1) CNFs were taken up by alveolar macrophages, but no significant acute inflammation was observed; (2) CNF characteristics, particularly fiber diameter and length, play a key role in influencing lung inflammation responses and determining inflammation sites; (3) endotoxin levels in the CNF dispersions may have limited effects on inflammatory responses; and (4) CNFs persist in lung tissue for extended periods, indicating slow clearance. While immediate inflammatory responses were minimal, the prolonged retention of CNFs in the lungs could contribute to chronic low-grade inflammation. Given the variability in CNF properties influenced by raw materials and manufacturing processes, it is essential to test each CNF type individually, including toxicological endpoints beyond inflammation, to accurately assess their potential health risks.

纤维素纳米原纤维（CNFs）是一种先进的生物材料，其强度大、重量轻、热膨胀小，适用于各种工业应用。然而，它们潜在的吸入风险需要进行彻底的安全评估。本研究探讨气管内灌注CNFs对大鼠肺部炎症的影响和保留。tempo -氧化CNF (CNF1；11.5nm × 1.8 μm)，机械纤原化CNF (CNF2；23.9nm × 2.4 μm)和短纤化CNF (CNF3；21.6nm × 1.2 μm)，剂量为2.0mg/kg体重。内毒素污染评价采用脂多糖（LPS）对照。在注射后28天评估肺部炎症，并对化学染色的cnf进行90天的肺保留追踪。结果表明：(1)CNFs被肺泡巨噬细胞吞噬，但未见明显的急性炎症反应；(2) CNF特征，特别是纤维直径和长度，在影响肺部炎症反应和确定炎症部位方面起关键作用；(3) CNF分散体中的内毒素水平可能对炎症反应的影响有限；(4) CNFs在肺组织中持续存在较长时间，表明清除缓慢。虽然立即的炎症反应很小，但CNFs在肺部的长期滞留可能导致慢性低度炎症。考虑到CNF特性受原材料和制造工艺影响的可变性，必须单独测试每种CNF类型，包括炎症以外的毒理学终点，以准确评估其潜在的健康风险。

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引用次数: 0

Preclinical liver toxicity models: Advantages, limitations and recommendations 临床前肝毒性模型：优点、局限性和建议。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2024.154020

Devaraj Ezhilarasan , Sivanesan Karthikeyan , Mustapha Najimi , Paramasivan Vijayalakshmi , Ganapathy Bhavani , Muthukrishnan Jansi Rani

Experimental animal models are crucial for elucidating the pathophysiology of liver injuries and for assessing new hepatoprotective agents. Drugs and chemicals such as acetaminophen, isoniazid, valproic acid, ethanol, carbon tetrachloride (CCl₄), dimethylnitrosamine (DMN), and thioacetamide (TAA) are metabolized by the CYP2E1 enzyme, producing hepatotoxic metabolites that lead to both acute and chronic liver injuries. In experimental settings, acetaminophen (centrilobular necrosis), carbamazepine (centrilobular necrosis and inflammation), sodium valproate (necrosis, hydropic degeneration and mild inflammation), methotrexate (sinusoidal congestion and inflammation), and TAA (centrilobular necrosis and inflammation) are commonly used to induce various types of acute liver injuries. Repeated and intermittent low-dose administration of CCl₄, TAA, and DMN activates quiescent hepatic stellate cells, transdifferentiating them into myofibroblasts, which results in abnormal extracellular matrix production and fibrosis induction, more rapidly with DMN and CCL₄ than TAA (DMN > CCl₄ > TAA). Regarding toxicity and mortality, CCl₄ is more toxic than DMN and TAA (CCl₄ > DMN > TAA). Models used to induce metabolic dysfunction-associated liver disease (MAFLD) vary, but MAFLD’s multifactorial nature driven by factors like obesity, fatty liver, dyslipidaemia, type II diabetes, hypertension, and cardiovascular disease makes it challenging to replicate human metabolic dysfunction-associated steatohepatitis accurately. From an experimental point of view, the degree and pattern of liver injury are influenced by various factors, including the type of hepatotoxic agent, exposure duration, route of exposure, dosage, frequency of administration, and the animal model utilized. Therefore, there is a pressing need for standardized protocols and regulatory guidelines to streamline the selection of animal models in preclinical studies.

实验动物模型对于阐明肝损伤的病理生理和评估新的肝保护药物至关重要。对乙酰氨基酚、异烟肼、丙戊酸、乙醇、四氯化碳（CCl4）、二甲基亚硝胺（DMN）和硫代乙酰胺（TAA）等药物和化学品通过CYP2E1酶代谢，产生肝毒性代谢物，导致急性和慢性肝损伤。在实验环境中，对乙酰氨基酚（小叶中心坏死）、卡马西平（小叶中心坏死和炎症）、丙戊酸钠（坏死、积水变性和轻度炎症）、甲氨蝶呤（窦性充血和炎症）和TAA（小叶中心坏死和炎症）常用于诱导各种类型的急性肝损伤。反复和间歇性的低剂量给药CCl4、TAA和DMN激活静止的肝星状细胞，将其转分化为肌成纤维细胞，导致细胞外基质产生异常和纤维化诱导，DMN和CCl4比TAA更快（DMN > CCl4 > TAA）。在毒性和死亡率方面，CCl4毒性大于DMN和TAA （CCl4 > DMN > TAA）。用于诱导代谢功能障碍相关肝病（MAFLD）的模型各不相同，但MAFLD由肥胖、脂肪肝、血脂异常、II型糖尿病、高血压和心血管疾病等因素驱动的多因素性质使得准确复制人类代谢功能障碍相关脂肪性肝炎具有挑战性。肝损伤的程度和模式受多种因素的影响，包括肝毒性物质的类型、暴露时间、暴露途径、剂量、给药频率和所采用的动物模型。因此，迫切需要标准化的方案和监管指南来简化临床前研究中动物模型的选择。

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引用次数: 0

Cadmium exposure induces inflammation, oxidative stress and DNA damage in HUVEC and promotes THP-1 adhesion: A possible mechanism on the formation of atherosclerotic plaque 镉暴露诱导HUVEC炎症、氧化应激和DNA损伤，促进THP-1粘附：这是动脉粥样硬化斑块形成的可能机制。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2025.154046

Haotian Liu , Mingyang Fu , Ziqi Ren, Zhaoshuo Liu, Xiangyu Cao, Jiahe Chen, Yulin Pang, Jianli Liu

Observational studies have shown that cadmium exposure increases the risk of cardiovascular disease, but the underlying mechanism is still unclear. Atherosclerotic plaque can cause vascular obstruction, which is important for the death from cardiovascular disease. Cell damage and monocyte adhesion are two early events in atherosclerotic plaque formation that can be induced by cadmium exposure, but the mechanism remains to be determined. This study was carried out to investigate the toxicity of cadmium in HUVECs and the effect of cadmium on the adhesion of THP-1 cells, and further explored the possible mechanisms. Rhodamine staining, DCFH-DA staining, Hoechst33258 staining, morphological observation and western blot were used to detect mitochondrial membrane potential, ROS, apoptosis, cell adhesion, signaling pathways and cell adhesion factors respectively. The results indicated that cadmium exposure increased the level of ROS, activated MAPK signaling pathway and resulted in cellular oxidative stress in HUVECs. Exposure to cadmium made nuclear shrinkage, activated DNA damage response pathways and mitochondria-mediated intrinsic apoptosis pathway in HUVECs. Cadmium exposure activated the NLRP3 inflammasome and NF-κB signaling pathway, led to the upregulation of inflammatory cytokines in HUVECs. In addition, cadmium exposure also upregulated the adhesion factors including ICAM-1, VCAM-1 and E-Selectin via NF-κB signaling pathway and resulted in the adhesion of THP-1 cells. The present study elucidated that cadmium could damage the HUVECs and promote the adhesion of THP-1 cells, which clarified the toxicity of cadmium in HUVECs and revealed the possible mechanism for the occurrence of cardiovascular disease induced by cadmium.

观察性研究表明，镉暴露会增加心血管疾病的风险，但其潜在机制尚不清楚。动脉粥样硬化斑块可引起血管阻塞，这是心血管疾病死亡的重要原因。细胞损伤和单核细胞粘附是镉暴露诱导动脉粥样硬化斑块形成的两个早期事件，但其机制仍有待确定。本研究旨在探讨镉对HUVECs的毒性及镉对THP-1细胞粘附的影响，并进一步探讨其可能的机制。采用罗丹明染色、DCFH-DA染色、Hoechst33258染色、形态观察和western blot分别检测线粒体膜电位、ROS、凋亡、细胞粘附、信号通路和细胞粘附因子。结果表明，镉暴露增加了huvec中ROS水平，激活了MAPK信号通路，导致细胞氧化应激。镉暴露使HUVECs细胞核收缩，激活DNA损伤反应途径和线粒体介导的内在凋亡途径。镉暴露激活NLRP3炎性体和NF-κB信号通路，导致HUVECs炎症细胞因子上调。此外，镉暴露还通过NF-κB信号通路上调了粘附因子ICAM-1、VCAM-1和E-Selectin，导致THP-1细胞的粘附。本研究阐明了镉可损伤HUVECs，促进THP-1细胞的粘附，阐明了镉对HUVECs的毒性作用，揭示了镉致心血管疾病发生的可能机制。

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引用次数: 0

Methamphetamine inhibits huntingtin-associated protein 1-mediated tyrosine receptor kinase B endocytosis resulting the neuroprotective dysfunction of brain-derived neurotrophic factor 甲基苯丙胺抑制亨廷顿蛋白相关蛋白1介导的酪氨酸受体激酶B内吞导致脑源性神经营养因子的神经保护功能障碍。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2025.154047

Baoyu Shen , Zhenling Wu , Mengran Lv , Genmeng Yang, Yuanyuan Cao, Yuan Zhang, Junjie Shu, Wenjuan Dong, Zhenping Hou, Di Jing, Xinjie Zhang, Yuhan Hou, Jing Xu, Shijun Hong, Lihua Li

Methamphetamine (METH), a synthetic stimulant, has seen an escalating abuse situation globally over the past decade. Although the molecular mechanism underlying METH-induced neurotoxicity has been explored, the dysfunction of brain-derived neurotrophic factor (BDNF) neuroprotection in the context of METH neurotoxicity remains insufficiently understood. Our previous studies have found that METH induced neurotoxicity and BDNF expression in rat primary neurons, necessitating further research into this paradox. Specifically, BDNF-dependent tyrosine receptor kinase B (TrkB) endocytosis was crucial for BDNF to confer neuroprotection in neurons. Therefore, we investigated the effect and molecular mechanism of METH on TrkB endocytosis. This work attempted to explain the potential reasons why BDNF did not exert neuroprotection in the context of METH exposure. In the current study, excessive apoptosis, elevated BDNF and reduced huntingtin-associated protein 1 (HAP1) expression were observed in the hippocampus of METH users. METH also induced cell degeneration, cytotoxicity, and BDNF expression and release in HT-22 cells in both a concentration- (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Furthermore, following 24 h of exposure to METH (2 mM), apoptosis, impaired TrkB endocytosis, and reduced HAP1 expression were evident in HT-22 cells and organotypic hippocampal slices from mice. Notably, overexpression of HAP1 attenuated METH-induced cell degeneration, cytotoxicity, apoptosis, and TrkB endocytosis disruption in HT-22 cells. These findings suggest that HAP1 is a key molecule in the disruption of BDNF-mediated neuroprotective signaling by METH, and that targeting HAP1-mediated TrkB endocytosis may represent a promising therapeutic avenue for METH-induced neurotoxicity.

甲基苯丙胺（冰毒）是一种合成兴奋剂，在过去十年中，全球滥用情况不断升级。虽然甲基安非他明诱导神经毒性的分子机制已经被探索，但脑源性神经营养因子（BDNF）在甲基安非他明神经毒性背景下的神经保护功能障碍仍未得到充分的了解。我们之前的研究已经发现甲基安非他明诱导大鼠原代神经元的神经毒性和BDNF的表达，需要进一步研究这一悖论。具体来说，BDNF依赖性酪氨酸受体激酶B （TrkB）内吞作用对于BDNF在神经元中赋予神经保护作用至关重要。因此，我们研究了甲基安非他明对TrkB内吞作用的影响及其分子机制。这项工作试图解释BDNF在甲基安非他明暴露的情况下没有发挥神经保护作用的潜在原因。在目前的研究中，在冰毒使用者的海马中观察到过度的细胞凋亡，BDNF升高和亨廷顿蛋白相关蛋白1 （HAP1）表达降低。在HT-22细胞中，甲基安非他明还能诱导细胞变性、细胞毒性以及BDNF的表达和释放，其浓度依赖于（0.25、0.5、1、2和4mM）和时间依赖于（3、6、12、24和48小时）。此外，暴露于甲基苯丙胺（2mM） 24h后，小鼠HT-22细胞和器官型海马切片中明显出现细胞凋亡、TrkB内吞作用受损和HAP1表达降低。值得注意的是，HAP1的过表达减轻了meth诱导的HT-22细胞变性、细胞毒性、细胞凋亡和TrkB内吞作用的破坏。这些发现表明，HAP1是甲基苯丙胺破坏bdnf介导的神经保护信号的关键分子，靶向HAP1介导的TrkB内吞可能是甲基苯丙胺诱导的神经毒性的一种有希望的治疗途径。

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引用次数: 0

Loss of Urat1 exacerbates APAP-induced liver injury in mice

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2025.154070

Kunlu Zhao , Shuaishuai Zhang , Jinhong Tian , Siyan Wu , Yongjun Chen , Zhenkun Wu , Jiacheng Liang , Huicong Wu , Jianxin Pang , Ting Wu

Acetaminophen (APAP) overdose stands as the paramount contributor to drug-elicited liver damage in clinical settings. Despite this, the intricate interplay between uric acid (UA) levels, its metabolism-linked regulatory genes, and their effects on APAP metabolism and hepatic functions remains elusive. Our study sheds light on this nexus, uncovering that uric acid concentrations and urate transporter-1 (URAT1) expression are intricately intertwined in APAP-induced hepatotoxicity. Notably, elevated serum uric acid levels concomitant with a marked downregulation of hepatic URAT1 expression were discernible in APAP-mediated liver injury models. We also found that high UA exacerbated APAP-induced liver injury in vitro and in vivo. To delve deeper, we devised genetic knockout mice models, specifically targeting URAT1, to unravel its pivotal role in this pathological process. Strikingly, Urat1 knockout (Urat1^-/-) mice exhibited exacerbated APAP-triggered hepatotoxicity when juxtaposed against their genetically intact wild-type (Urat1^+/+) counterparts, accompanied by increased serum and hepatic UA contents. However, the changes in UA levels might not be the only factor exacerbating APAP liver injury in Urat1^-/- mice, as Urat1 knockout has also been proved to affect many other metabolites associated with the redox homeostasis. Mechanistically, we found that the ablation of Urat1 not only intensified triglyceride accumulation instigated by APAP via inhibiting PPAR-α pathway but also ignited the NLRP3/NF-κB and JNK/ERK signaling cascades, and disrupted oxidative stress homeostasis via downregulating KEAP1/NRF2 pathway. Collectively, our findings underscore that URAT1 acts as a multifaceted facilitator of APAP-induced liver injury in mice, thereby positioning it as a genetic vulnerability factor in APAP overdose scenarios.

{"title":"Loss of Urat1 exacerbates APAP-induced liver injury in mice","authors":"Kunlu Zhao , Shuaishuai Zhang , Jinhong Tian , Siyan Wu , Yongjun Chen , Zhenkun Wu , Jiacheng Liang , Huicong Wu , Jianxin Pang , Ting Wu","doi":"10.1016/j.tox.2025.154070","DOIUrl":"10.1016/j.tox.2025.154070","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose stands as the paramount contributor to drug-elicited liver damage in clinical settings. Despite this, the intricate interplay between uric acid (UA) levels, its metabolism-linked regulatory genes, and their effects on APAP metabolism and hepatic functions remains elusive. Our study sheds light on this nexus, uncovering that uric acid concentrations and urate transporter-1 (URAT1) expression are intricately intertwined in APAP-induced hepatotoxicity. Notably, elevated serum uric acid levels concomitant with a marked downregulation of hepatic URAT1 expression were discernible in APAP-mediated liver injury models. We also found that high UA exacerbated APAP-induced liver injury <em>in vitro</em> and <em>in vivo</em>. To delve deeper, we devised genetic knockout mice models, specifically targeting URAT1, to unravel its pivotal role in this pathological process. Strikingly, <em>Urat1</em> knockout (<em>Urat1</em><sup>-/-</sup>) mice exhibited exacerbated APAP-triggered hepatotoxicity when juxtaposed against their genetically intact wild-type (<em>Urat1</em><sup>+/+</sup>) counterparts, accompanied by increased serum and hepatic UA contents. However, the changes in UA levels might not be the only factor exacerbating APAP liver injury in <em>Urat1</em><sup>-/-</sup> mice, as <em>Urat1</em> knockout has also been proved to affect many other metabolites associated with the redox homeostasis. Mechanistically, we found that the ablation of <em>Urat1</em> not only intensified triglyceride accumulation instigated by APAP via inhibiting PPAR-α pathway but also ignited the NLRP3/NF-κB and JNK/ERK signaling cascades, and disrupted oxidative stress homeostasis via downregulating KEAP1/NRF2 pathway. Collectively, our findings underscore that URAT1 acts as a multifaceted facilitator of APAP-induced liver injury in mice, thereby positioning it as a genetic vulnerability factor in APAP overdose scenarios.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154070"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075591","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

KCNJ15 inhibits chemical-induced lung carcinogenesis and progression through GNB1 mediated Hippo pathway KCNJ15通过GNB1介导的Hippo通路抑制化学诱导的肺癌的发生和进展。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2024.154034

Hong-qiang Chen , Na Wang , Yong Zeng , Yu Shi , Zhe Zhang , Jiang-ying Li , Ya-wen Li , Shuang-wu Deng , Zi-yuan Zhou , Wen-bin Liu

Polycyclic aromatic hydrocarbons (PAHs) are important environmental carcinogens that can cause lung cancer. However, the underlying epigenetic mechanism during PAHs-induced lung carcinogenesis has remained largely unknown. Previously, we screened some novel epigenetic regulatory genes during 3-methylcholanthrene (3-MCA)-induced lung carcinogenesis, including the potassium inwardly rectifying channel subfamily J member 15 (KCNJ15) gene. This study aimed to investigate the expression regulation, function, and mechanism of KCNJ15 through database analysis, malignant transformed cell model, and xenograft tumor models. We found that KCNJ15 was remarkably under-expressed during lung carcinogenesis and progression. High levels of DNA methylation led to low KCNJ15 expression in 3-MCA-induced malignantly transformed HBE cells. High expression of KCNJ15 was positively correlated with good survival prognosis in lung cancer patients. KCNJ15 overexpression significantly inhibited the growth, invasion, and migration of lung cancer cells both in vitro and in vivo. Knockdown of KCNJ15 resulted in an opposite phenotype. KCNJ15 regulated the Hippo pathway by activating YAP phosphorylation and inhibiting YAP expression. There was a significant protein-protein interaction between KCNJ15 and the G protein subunit beta 1 (GNB1). GNB1 overexpression effectively reduced the effect of KCNJ15 on Hippo pathway. Our data demonstrated that KCNJ15, as a novel epigenetic silencing tumor suppressor, regulates cell growth, invasion, and migration by interaction with GNB1 protein mediating the Hippo-YAP signaling pathway during chemical-induced lung carcinogenesis and progression. It provides novel insights into epigenetic regulation mechanism during carcinogenesis induced by environmental pollutants.

多环芳烃（PAHs）是一种重要的环境致癌物，可引起肺癌。然而，在多环芳烃诱导的肺癌发生过程中，潜在的表观遗传机制在很大程度上仍然未知。此前，我们在3-甲基胆蒽（3-MCA）诱导的肺癌发生过程中筛选了一些新的表观遗传调控基因，包括钾向内纠偏通道亚家族J成员15 （KCNJ15）基因。本研究旨在通过数据库分析、恶性转化细胞模型和异种移植肿瘤模型研究KCNJ15的表达调控、功能及机制。我们发现KCNJ15在肺癌发生和发展过程中显著低表达。在3- mca诱导的恶性转化的HBE细胞中，DNA甲基化水平升高与KCNJ15表达的逐渐降低有关。KCNJ15的高表达与肺癌患者良好的生存预后密切相关。KCNJ15过表达在体外和体内均能显著抑制肺癌细胞的生长、侵袭和迁移。相反，敲低KCNJ15导致相反的表型。此外，KCNJ15通过激活YAP磷酸化和抑制YAP表达来抑制Hippo通路。在机制上，KCNJ15与G蛋白亚基β 1 （GNB1）之间存在显著的蛋白-蛋白相互作用。GNB1过表达部分恢复了KCNJ15调控的Hippo通路的抑制作用。综上所述，我们的数据表明，KCNJ15作为一种新型的表观遗传沉默肿瘤抑制因子，在化学诱导的肺癌发生和进展过程中，通过结合介导希波- yap信号通路的GNB1蛋白，调节细胞的生长、侵袭和迁移。为研究环境污染物致癌过程中的表观遗传调控机制提供了新的思路。

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引用次数: 0

EGFR-TKIs induce acneiform rash and xerosis via Caspase-3/GSDME-mediated pyroptosis of keratinocytes and sebocytes EGFR-TKIs通过Caspase-3/ gsdme介导的角质形成细胞和皮脂细胞的焦亡诱导痤疮样皮疹和干燥。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2024.154018

Huiling Zhu , Qiuyun She , Hongmei Li , Ning Zhang , Weining Huang , Yingping Xu , Zhongrong Liu , Yunsheng Liang

Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.

皮肤毒性是表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）最常见的不良反应。虽然EGFR-TKIs通过激活Gasdermin E （GSDME）诱导肺癌细胞焦亡，但它们是否能类似地影响皮肤细胞尚不清楚。在本研究中，我们使用免疫组织化学方法证明，在痘样皮疹中，GSDME的n端（GSDME- n）主要在滤泡上皮和皮脂细胞的基底层表达，而在滤泡间表皮中不存在。相反，在干燥或继发性湿疹皮疹的病例中，GSDME-N在滤泡间表皮的基底层显著表达，在滤泡上皮中弱或部分阳性。经阿法替尼处理的HaCaT和SZ95细胞在亮场显微镜下显示细胞肿胀和大泡形成，扫描电镜显示微绒毛和膜孔形成减少。透射电镜进一步显示多个膜孔和降低的细胞质密度。重要的是，我们发现GSDME在阿法替尼诱导的焦亡过程中通过caspase-3激活被切割。ELISA分析进一步证实，阿法替尼处理的细胞释放的HMGB1和IL-1α水平升高。同时，抑制caspase-3活性或敲低GSDME均能抑制阿法替尼诱导的焦亡，而消除GSDME不影响caspase-3的激活。这些结果表明，阿法替尼诱导的角质形成细胞和皮脂细胞的焦亡是通过caspase-3/GSDME途径介导的。我们的研究结果表明，HaCaT和SZ95细胞中gsdme依赖性的焦亡有助于痤疮样皮疹和干燥的发展，强调需要进一步研究其潜在机制。

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引用次数: 0

Dynamic analysis of intrahepatic T cells reveals a unique group of restorative Cxcr3+ tissue-resident CD4 T cells in acute liver injury 肝内T细胞的动态分析揭示了急性肝损伤中一组独特的恢复性Cxcr3+组织驻留CD4 T细胞

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2025.154058

Shen-Xi Ouyang , Yong-Gang Xu , Peng Ding , Yue Long , Zhen Zhang , Si-Jia Sun , Yan Zhang , Hang Yin , Jia-Bao Zhang , Qi Cao , Fu-Ming Shen , Pei Wang , Jian Liu , Dong-Jie Li

Acetaminophen (APAP) stands as one of the most prevalent triggers of drug-induced acute liver injury (ALI). The intricate modulation of immune system activation and inflammatory cascades by hepatic immune cells is paramount in managing liver injury and subsequent restoration. In this study, we employed an integrative approach that fused our proprietary flow cytometry analyses across various time points post-APAP injury with publicly available single-cell RNA sequencing (scRNA-seq) datasets, encompassing time-series data from liver tissue of mice subjected to APAP intoxication. This allowed us to delve into the dynamics of T cell profiles during APAP-induced ALI. Our comprehensive analyses unveiled the intricate temporal shifts in intrahepatic T cell populations across different phases following APAP-induced ALI. Notably, we observed a persistent augmentation of intrahepatic CD4⁺ T cells post-APAP injury. Amongst these, a distinct population of restorative Cxcr3⁺ tissue-resident CD4⁺ T cells emerged. Inhibition of CXCR3 using a neutralizing antibody exacerbated APAP-induced liver function impairment and hepatocyte death. Furthermore, we identified that the Cxcr3⁺ tissue-resident CD4⁺ T cells were tightly regulated by intrahepatic ‘'Lgals9-Cd45'’ and ‘CXCL13-Cxcr3’ signaling pathways. These discoveries underscore the novel protective function of CXCR3, a vital biological macromolecule, in mitigating APAP-induced ALI, and may shed lights on new therapeutic strategies targeting this condition.

对乙酰氨基酚（APAP）是药物性急性肝损伤（ALI）最常见的诱发因素之一。肝脏免疫细胞对免疫系统激活和炎症级联反应的复杂调节在处理肝损伤和随后的恢复中至关重要。在这项研究中，我们采用了一种综合方法，将我们专有的流式细胞术分析与公开可用的单细胞RNA测序（scRNA-seq）数据集融合在APAP损伤后的各个时间点上，包括APAP中毒小鼠肝组织的时间序列数据。这使我们能够深入研究apap诱导ALI期间T细胞谱的动态。我们的综合分析揭示了apap诱导ALI后不同时期肝内T细胞群的复杂时间变化。值得注意的是，我们观察到apap损伤后肝内CD4+ T细胞持续增加。其中，出现了一种独特的恢复性Cxcr3+组织常驻CD4+ T细胞群。使用中和抗体抑制CXCR3加重apap诱导的肝功能损害和肝细胞死亡。此外，我们发现Cxcr3+组织常驻CD4+ T细胞受到肝内“Lgals9-Cd45”和“CXCL13-Cxcr3”信号通路的严格调控。这些发现强调了CXCR3（一种重要的生物大分子）在减轻apap诱导的ALI中的新保护功能，并可能为针对这种疾病的新治疗策略提供线索。

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引用次数: 0

Integrative assessment of mixture toxicity of household chemicals using the toxic unit approach and mode of action 用毒性单位法和作用方式综合评价生活化学品的混合毒性。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2025.154060

Hye-Jin Jeong , Yeon-Ho Kang , Ah-Yoon Song , Hye-In Park , Myungwon Seo , Yong Joo Park

Household chemicals used daily are often combined, leading to inhalation exposure to mixtures. However, methods for assessing their toxic effects are limited. This study proposes an in vitro assay strategy for evaluating household chemical mixtures using benzalkonium chloride (BKC) and didecyldimethylammonium chloride (DDAC), a common disinfectant. Our approach utilizes the mode of action (MOA) of chemicals by applying toxicity units (TU) to assess the key events related to lung disease, such as reactive oxygen species (ROS) production and cell death. The TU (EC₅₀) values for BKC and DDAC were 3.97 µg/mL and 1.89 µg/mL, respectively, from cytotoxicity results. The TU value of the mixture (5:5 ratio of BKC to DDAC) was calculated as 2.56 µg/mL. Using the OpenMRA platform, the TU values were predicted as 2.37 µg/mL with the concentration addition (CA) model and 11.26 µg/mL with the independent action (IA) model, indicating that the mixture effects were additive and closer to that predicted using the CA model. Both BKC and DDAC induced apoptosis and ROS production in human epithelial cells in a dose-dependent manner, suggesting similar modes of action in promoting cell death. Our results suggested that BKC and DDAC exhibited additive toxicity when combined. Our results demonstrate the utility of the TU-based approach, which combines cytotoxicity, ROS induction, and apoptosis measurements to evaluate mixture toxicity. This approach may be beneficial for assessing early key events relevant to lung diseases and offers a practical strategy for evaluating the inhalation toxicity of household chemical mixtures.

日常使用的家用化学品通常是混合使用的，导致吸入暴露于混合物中。然而，评估其毒性作用的方法有限。本研究提出了一种使用苯扎氯铵（BKC）和二烷基二甲基氯化铵（DDAC）（一种常见的消毒剂）评估家用化学混合物的体外测定策略。我们的方法利用化学物质的作用模式（MOA），通过应用毒性单位（TU）来评估与肺部疾病相关的关键事件，如活性氧（ROS）的产生和细胞死亡。BKC和DDAC的TU （EC50）值分别为3.97µg/mL和1.89µg/mL。计算BKC与DDAC比例为5:5的混合物TU值为2.56µg/mL。使用OpenMRA平台，浓度添加（CA）模型预测TU值为2.37µg/mL，独立作用（IA）模型预测TU值为11.26µg/mL，表明混合效应是可加性的，更接近于使用CA模型预测的结果。BKC和DDAC均以剂量依赖的方式诱导人上皮细胞凋亡和ROS产生，表明它们在促进细胞死亡方面的作用模式相似。我们的结果表明，BKC和DDAC在联合使用时表现出加性毒性。我们的研究结果证明了基于tu的方法的实用性，该方法结合了细胞毒性，ROS诱导和凋亡测量来评估混合物的毒性。这种方法可能有利于评估与肺部疾病有关的早期关键事件，并为评估家用化学混合物的吸入毒性提供了一种实用的策略。

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引用次数: 0