Toxicology最新文献_第2页

Could cannabigerol protect against neuroinflammation? Insights from an in vitro microglial study 大麻酚能预防神经炎症吗？来自体外小胶质细胞研究的见解

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-16 DOI: 10.1016/j.tox.2026.154406

Júlia Maiara dos Santos , Amanda Kolinski Machado , Djenifer Leticia Ulrich Bick , Michele Rorato Sagrillo , Elaine Aparecida Del Bel , Alencar Kolinski Machado , Antonio Cardozo dos Santos

Cannabigerol (CBG), a non-psychotropic cannabinoid from Cannabis sativa, has been investigated for its anti-inflammatory potential. However, its toxicological profile and the mechanisms underlying its effects are still poorly understood. This experimental study evaluated the safety and anti-inflammatory efficacy of CBG in BV-2 microglial cells, in a model of neuroinflammation. BV-2 cells were exposed to CBG concentrations ranging from 0.01 to 100 μM for 24 h to investigate non-cytotoxic doses. Colorimetric and fluorometric assays were performed in triplicate to assess cellular viability (MTT), the production of reactive oxygen species (ROS) and nitric oxide (NO), genotoxicity (GEMO and Alkaline Comet assay), and Caspase-1 gene expression. Cell morphology was also monitored microscopically. The results revealed that CBG 100 μM was highly cytotoxic, reducing cell viability by about 80 % and significantly increasing NO (approximately 400 %) and ROS (approximately 900 %) levels. Additionally, CBG was shown to be genotoxic in the GEMO assay at various concentrations, with 10 μM and 100 μM inducing DNA damage of approximately 200 % and 300 %, respectively. However, no genotoxicity was identified in the Comet assay. At higher concentrations, CBG also promoted the activation of microglia, altering their morphology. In a neuroinflammation model, CBG was unable to attenuate the increase in ROS levels induced by NLRP3 activation and promoted an increase in Caspase-1 gene expression. Despite a favorable safety profile at low doses, CBG exhibits inconsistent anti-inflammatory effects and can be genotoxic depending on the dose and exposure conditions.

大麻酚（Cannabigerol， CBG）是一种来自大麻的非精神类大麻素，因其抗炎潜力而被研究。然而，其毒理学特征和潜在的作用机制仍然知之甚少。本实验研究在神经炎症模型中评估CBG对BV-2小胶质细胞的安全性和抗炎功效。将BV-2细胞暴露于浓度为0.01至100 μM的CBG中24 h，以观察其无细胞毒性。采用三次比色法和荧光法测定细胞活力（MTT）、活性氧（ROS）和一氧化氮（NO）的产生、遗传毒性（GEMO和碱性彗星法）和Caspase-1基因表达。显微镜下观察细胞形态。结果显示，CBG 100 μM具有高度的细胞毒性，使细胞活力降低约80% %，并显著增加NO（约400 %）和ROS（约900 %）水平。此外，在GEMO实验中，CBG在不同浓度下显示出遗传毒性，10 μM和100 μM分别诱导约200 %和300 %的DNA损伤。然而，在Comet试验中未发现遗传毒性。在较高浓度下，CBG还能促进小胶质细胞的活化，改变其形态。在神经炎症模型中，CBG不能减弱NLRP3激活引起的ROS水平的增加，并促进Caspase-1基因表达的增加。尽管在低剂量下具有良好的安全性，但CBG表现出不一致的抗炎作用，并且根据剂量和暴露条件可能具有遗传毒性。

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引用次数: 0

The regulatory roles of BMAL1 in TDCIPP-induced autophagy and apoptosis in HT22 cells BMAL1在tdcipp诱导HT22细胞自噬和凋亡中的调控作用

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-15 DOI: 10.1016/j.tox.2026.154405

Yu Liu , Ruoxuan Liang , Benhong Xu

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), a common organophosphate flame retardant, is extensively used in various consumer products and has emerged as an environmental pollutant. Recent studies have documented the neurotoxic effects of TDCIPP, highlighting its ability to promote neuronal apoptosis and induce autophagy. Nonetheless, the underlying regulatory mechanisms remain poorly understood. The present study observed an upregulation of Brain and Muscle ARNT-Like 1 (BMAL1) in TDCIPP-treated mouse HT22 cells, indicating that BMAL1 may play a critical role in TDCIPP-induced neuronal autophagy and apoptosis. Furthermore, the impact of BMAL1 knockdown on TDCIPP-induced autophagy and apoptosis in HT22 cells was explored using Western blot (WB) and flow cytometry (FACS) analysis. The results demonstrated that TDCIPP exposure modulated the expression levels of BMAL1 and autophagy-related proteins and increased the phosphorylation of mTOR. The suppression of BMAL1 expression resulted in decreased AMPK expression, thereby blocking cell autophagy. Collectively, the results highlight the role of BMAL1 in the cell death mechanism induced by TDCIPP through the AMPK signaling pathway in HT22 cells. Therefore, the present study provides a new perspective and evidence on the mechanism of TDCIPP-induced neurotoxicity in HT22 cells.

三（1,3-二氯-2-丙基）磷酸盐（TDCIPP）是一种常见的有机磷阻燃剂，广泛应用于各种消费品中，已成为一种环境污染物。最近的研究证明了TDCIPP的神经毒性作用，强调了其促进神经元凋亡和诱导自噬的能力。尽管如此，人们对潜在的监管机制仍然知之甚少。本研究在tdcipp处理的小鼠HT22细胞中观察到脑和肌肉ARNT-Like 1 （BMAL1）的上调，表明BMAL1可能在tdcipp诱导的神经元自噬和凋亡中起关键作用。此外，采用Western blot （WB）和流式细胞术（FACS）分析BMAL1敲低对tdcipp诱导的HT22细胞自噬和凋亡的影响。结果表明，TDCIPP暴露可调节BMAL1和自噬相关蛋白的表达水平，并增加mTOR的磷酸化。抑制BMAL1表达导致AMPK表达降低，从而阻断细胞自噬。综上所述，这些结果突出了BMAL1在TDCIPP通过AMPK信号通路诱导HT22细胞死亡机制中的作用。因此，本研究为tdcipp诱导HT22细胞神经毒性的机制提供了新的视角和证据。

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引用次数: 0

PM2.5 induces cardiac defects by triggering endoplasmic reticulum stress mediated through the impairment of SIRT6 deacetylase activity PM2.5通过SIRT6去乙酰化酶活性受损介导内质网应激，诱发心脏缺陷

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-14 DOI: 10.1016/j.tox.2026.154404

Jianhui Liu , Yuan Wang , Shaofei Su , Ruixia Liu , Jiajia Wang , Shuanghua Xie , Chenghong Yin , Enjie Zhang

A growing body of research suggests that maternal exposure to fine particulate matter (PM2.5) is linked to congenital heart disease in the offspring. Endoplasmic reticulum stress (ERS) has been established as a cause of the cardiac developmental toxicity of PM2.5. Silent information regulator 6 (SIRT6) which serves as a protective element against environmental pollutants, was closely associated with cardiovascular conditions. However, the precise underlying molecular mechanisms remain unclear. Pregnant mice were exposed to PM2.5 or sterile saline through oropharyngeal aspiration, proteomic analysis of fetal cardiac tissue was performed. Co-immunoprecipitation analysis was used to examine the interaction of SIRT6 and PERK. We observed that maternal exposure to PM2.5 caused abnormal cardiac development in offspring, accompanied by a marked reduction in the expression of NKX2.5. In the AC16 cardiomyocyte model, exposure to PM2.5, contributed to a marked increase in cardiomyocyte apoptosis. Moreover, proteomic analysis revealed a significant disruption in protein processing in the endoplasmic reticulum. We further demonstrated that the expression of PERK and activity of the PERK/eIF2α/CHOP signaling pathway were significantly upregulated, along with a notable increase in PERK acetylation levels. More importantly, we confirmed the interaction between SIRT6 and PERK. Concurrently, a significant reduction in SIRT6 expression was detected alongside elevated H3K9 acetylation after exposure to PM2.5. The treatment of AC16 cells with the SIRT6 activator UBCS039 significantly attenuated PM2.5-induced PERK activation and cardiomyocyte apoptosis. Our results reveal that PM2.5 induces the downregulation of SIRT6, which promotes PERK hyperacetylation and activates the PERK/eIF2α/CHOP pathway, triggering ERS, ultimately resulting in abnormal cardiac development in offspring.

越来越多的研究表明，母亲接触细颗粒物（PM2.5）与后代的先天性心脏病有关。内质网应激（ERS）已被确定为PM2.5心脏发育毒性的一个原因。SIRT6 （Silent information regulator 6, Silent information regulator）是一种具有抗环境污染物保护作用的基因，与心血管疾病密切相关。然而，确切的潜在分子机制仍不清楚。将妊娠小鼠经口咽吸入PM2.5或无菌生理盐水，对胎儿心脏组织进行蛋白质组学分析。采用免疫共沉淀法检测SIRT6与PERK的相互作用。我们观察到，母亲暴露在PM2.5中会导致后代心脏发育异常，并伴有NKX2.5表达的显著降低。在AC16心肌细胞模型中，PM2.5暴露导致心肌细胞凋亡显著增加。此外，蛋白质组学分析揭示了内质网中蛋白质加工的显著中断。我们进一步证明，PERK的表达和PERK/eIF2α/CHOP信号通路的活性显著上调，同时PERK乙酰化水平显著升高。更重要的是，我们确认了SIRT6和PERK之间的相互作用。同时，暴露于PM2.5后，SIRT6表达显著降低，H3K9乙酰化水平升高。用SIRT6激活剂UBCS039处理AC16细胞可显著减弱pm2.5诱导的PERK激活和心肌细胞凋亡。我们的研究结果表明，PM2.5诱导SIRT6下调，从而促进PERK超乙酰化，激活PERK/eIF2α/CHOP通路，触发ERS，最终导致后代心脏发育异常。

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引用次数: 0

Corrigendum to “Titanium nanoparticles provoke ferritinophagy-mediated ferroptosis via inhibition of the Nrf2-HO-1 signaling pathway in osteocytes’’ [Toxicology 519 (January) (2026) 154324, doi:10.1016/j.tox.2025.154324] “钛纳米颗粒通过抑制骨细胞中Nrf2-HO-1信号通路引发铁蛋白吞噬介导的铁凋亡”的更正[毒理学]519（1月）（2026）154324,doi:10.1016/ j.x x.2025.154324]。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-13 DOI: 10.1016/j.tox.2026.154399

Ruirong Zhu, Yun Zhang, Yuting Wang, Xinyi Bao, Lubing Zhang, Jian Fang, Hongjiao Mao

引用次数: 0

PFHxS exposure causes osteoarthritis through the innate immune signaling pathway mediated by lipid peroxidation PFHxS暴露通过脂质过氧化介导的先天免疫信号通路引起骨关节炎。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-10 DOI: 10.1016/j.tox.2026.154403

Xicong Chen , Huiliang Zeng , Guocai Chen , Haiyun Yang

PFHxS have been widely used and detected in the environment. The toxicological effects of PFHxS exposure on cartilage tissues and cells are not fully clear. The objective of this work was to study the toxicological effects of PFHxS on cartilage. We investigated these effects using both in-vitro and in-vivo models. In the in-vitro model, we exposed chondrocytes to environmentally relevant concentrations of PFHxS. In the in-vivo model, we assessed cartilage damage using various staining methods, including toluidine blue, alcian blue, and safranin-fast green staining. In chondrocytes, PFHxS exposure decreased cell viability and induced inflammatory and oxidative stress responses.Further experiments showed that PFHxS induced lipid peroxidation, increased Fe²⁺ levels, and significantly decreased the expression of GPX4 and xCT, indicating the induction of ferroptosis. Oxidative stress also led to large-scale production of ds-DNA and activation of the cGAS-STING signaling pathway.In the in-vivo model, PFHxS exposure caused damage to cartilage tissues, as evidenced by the tissue staining.Similarly, in vivo findings showed that PFHxS induced ferroptosis-like characteristics in cartilage tissues, including decreased GPX4 and xCT and increased iron ion levels. This study is the first to reveal that the environmental pollutant PFHxS causes extracellular matrix degradation and functional damage to chondrocytes by inducing ferroptosis and activating the cGAS-STING inflammatory pathway. These findings establish a theoretical basis for a potential association between PFHxS environmental exposure and cartilage-degenerative diseases.

PFHxS在环境中得到了广泛的应用和检测。PFHxS暴露对软骨组织和细胞的毒理学影响尚不完全清楚。本研究旨在研究PFHxS对软骨的毒理学作用。我们使用体外和体内模型研究了这些影响。在体外模型中，我们将软骨细胞暴露于环境相关浓度的PFHxS中。在体内模型中，我们使用各种染色方法评估软骨损伤，包括甲苯胺蓝、阿利新蓝和红花素耐绿染色。在软骨细胞中，PFHxS暴露降低细胞活力并诱导炎症和氧化应激反应。进一步实验表明，PFHxS诱导脂质过氧化，Fe 2 +水平升高，GPX4和xCT表达显著降低，提示诱导铁下垂。氧化应激还导致ds-DNA的大规模产生和cGAS-STING信号通路的激活。在体内模型中，PFHxS暴露对软骨组织造成损伤，组织染色证实了这一点。同样，体内研究结果显示PFHxS在软骨组织中诱导了类似铁中毒的特征，包括GPX4和xCT的降低以及铁离子水平的升高。本研究首次揭示了环境污染物PFHxS通过诱导铁凋亡和激活cGAS-STING炎症通路导致细胞外基质降解和软骨细胞功能损伤。这些发现为PFHxS环境暴露与软骨退行性疾病之间的潜在关联奠定了理论基础。

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引用次数: 0

Impact of PM2.5 on cardiorespiratory mortality: A study in the capitals of Brazilian amazon rainforest pm2.5对心肺疾病死亡率的影响：巴西亚马逊雨林首府的一项研究。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-09 DOI: 10.1016/j.tox.2026.154401

Gustavo de Oliveira Silveira , Rodrigo de Lima Brum , Ronan Adler Tavella , Alicia da Silva Bonifácio , Ronabson Cardoso Fernandes , Flavio Manoel Rodrigues da Silva Júnior

Wildfire-related air pollution represents an escalating health threat in the Brazilian Amazon, where fine particulate matter (PM_2.5) concentrations frequently exceed safe levels (5 µg/m⁻³). This study quantified long-term PM_2.5 exposure and its impact on cardiorespiratory mortality across the seven Amazonian capitals, Belém, Boa Vista, Macapá, Manaus, Palmas, Porto Velho, and Rio Branco, between 2018 and 2023. In addition, disease-specific outcomes including chronic obstructive pulmonary disease (COPD), lung cancer (LC), and ischemic heart disease (IHD) were assessed. Daily PM_2.5 data were obtained from the CAMS reanalysis, and mortality records from the Brazilian Health Data Platform. Health impacts were estimated using the WHO AirQ+ log-linear model. Annual mean PM_2.5 ranged from 10.47 µg.m³ (Palmas, 2020) to 49.69 µg.m³ (Porto Velho, 2021), exceeding the WHO guideline of 5 µg.m³ in all cities. Most capitals experienced over 100 days per year above the 15 µg.m³ daily guideline, and significant correlations were observed between wildfire counts and PM_2.5 in Porto Velho (r = 0.24) and Rio Branco (r = 0.21). Between 2018 and 2023, approximately 5472 (95 % CI: 4595–6711) deaths from circulatory diseases and 2621 (95 % CI: 864–4278) from respiratory diseases were attributable to PM_2.5 exposure. COPD accounted for 627 (95 % CI: 462–781) deaths, LC for 427 (95 % CI: 314–534), and IHD for 304 (95 % CI: 150–467). The highest burdens occurred in Belém, Manaus, and Porto Velho. These findings demonstrate that persistent smoke from seasonal fires has become a critical environmental health crisis in the Amazon, demanding urgent action to prevent deforestation, reduce emissions, and protect population health.

在巴西亚马逊地区，与野火有关的空气污染对健康的威胁不断升级，细颗粒物（PM2.5）浓度经常超过安全水平（5微克/立方米）。这项研究量化了2018年至2023年期间，亚马逊地区七个首都贝尔萨姆、博阿维斯塔、马卡帕、玛瑙斯、帕尔马斯、韦洛港和布兰科的PM2.5长期暴露及其对心肺疾病死亡率的影响。此外，还评估了特定疾病的结局，包括慢性阻塞性肺疾病（COPD）、肺癌（LC）和缺血性心脏病（IHD）。每日PM2.5数据来自CAMS再分析，死亡率记录来自巴西健康数据平台。使用世卫组织AirQ+对数线性模型估计健康影响。年平均PM2.5为10.47µg。m3（帕尔马斯，2020年）至49.69µg。m3（波尔图韦柳，2021年），超过了世卫组织5微克的指导标准。所有城市的M3。大部分首都每年有超过100天的pm2.5浓度超过15µg。韦柳港（r=0.24）和布兰科（r=0.21）野火数量与PM2.5之间存在显著相关性。2018年至2023年期间，约有5472人（95% CI: 4595 - 6711）死于循环系统疾病，2621人（95% CI: 864- 4278）死于呼吸系统疾病。COPD死亡627例（95% CI: 462-781）， LC死亡427例（95% CI: 314-534）， IHD死亡304例（95% CI: 150-467）。最重的负担发生在贝尔萨姆、玛瑙斯和韦柳港。这些发现表明，季节性火灾产生的持续烟雾已成为亚马逊地区严重的环境健康危机，需要采取紧急行动，防止森林砍伐，减少排放，保护人口健康。

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引用次数: 0

Hepatotoxicity: Mechanisms and animal-free prediction models 肝毒性：机制和无动物预测模型。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-08 DOI: 10.1016/j.tox.2026.154400

Julen Sanz-Serrano, Laura Suter-Dick

引用次数: 0

In vivo and in vitro toxicokinetics including metabolism, isozyme mapping, and monoamine oxidase inhibition of three (2-aminopropyl)benzo[b]thiophene (APBT) psychedelics 三（2-氨基丙基）苯并[b]噻吩（APBT）致幻剂的体内和体外毒性动力学，包括代谢、同工酶定位和单胺氧化酶抑制

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-08 DOI: 10.1016/j.tox.2026.154402

Lea Wagmann , Simon D. Brandt , Pierce V. Kavanagh , Markus R. Meyer

3-(2-Aminopropyl)benzo[b]thiophene (3-APBT), 5-APBT, and 6-APBT are recently identified psychedelics and entactogens that activate serotonin 2 receptor subtypes and lead to a head-twitch response in mice. The present study characterized their toxicokinetics, metabolism, and monoamine oxidase (MAO) inhibition using liquid chromatography-high-resolution tandem mass spectrometry. Metabolites were tentatively identified in urine from male Wistar rats collected over 24 h after oral administration (2 mg/kg body weight) and in incubations with pooled human liver S9 fraction (25 µM after 1 and 6 h). Phase I isoenzyme mapping and MAO inhibition were assessed using individual incubations with 11 human monooxygenases or recombinant human MAO-A and MAO-B. Hydroxylation was the predominant phase I biotransformation, primarily catalyzed by cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A4, and CYP3A5, while N-acetylation, glucuronidation, and sulfation were observed as phase II reactions. The metabolic patterns were similar to those of related 5- and 6-(2-aminopropyl)benzofuran analogues, and the involvement of multiple CYP isozymes suggested a reduced toxicity risk e.g., by CYP-mediated drug-drug interactions. However, all three APBT isomers strongly inhibited MAO-A (IC₅₀ of 5-APBT 0.4 µM, 6-APBT 0.6 µM, and 3-APBT 4 µM) but only weakly MAO-B (IC₅₀ 23–49 µM). Given that the MAO-A inhibition strengths of 5-APBT and 6-APBT were in the range of model inhibitors, clinically relevant MAO-A inhibition and associated interaction risks and toxic effects cannot be excluded. These data provide a toxicokinetic basis to support the clinical and forensic interpretation of exposures to APBT and related sulfur-based psychedelics.

3-（2-氨基丙基）苯并[b]噻吩（3- apbt）， 5-APBT和6-APBT是最近发现的致幻剂和致幻剂，可激活5-羟色胺2受体亚型并导致小鼠头抽搐反应。本研究采用液相色谱-高分辨率串联质谱法对其毒性动力学、代谢和单胺氧化酶（MAO）抑制进行了表征。在口服给药（2 mg/kg体重）24 h后收集的雄性Wistar大鼠尿液和与人肝脏S9混合孵育（1和6 h后25 µM）的尿液中初步鉴定了代谢物。通过11种人单加氧酶或重组人MAO- a和MAO- b单独孵育，评估I期同工酶定位和MAO抑制作用。羟基化是主要的I期生物转化，主要由细胞色素P450 (CYP) 1A2、CYP2D6、CYP3A4和CYP3A5催化，而n -乙酰化、葡萄糖醛酸化和硫酸化是II期反应。代谢模式与相关的5-和6-（2-氨基丙基）苯并呋喃类似物相似，并且多种CYP同工酶的参与表明毒性风险降低，例如通过CYP介导的药物-药物相互作用。然而，这三种APBT异构体都强烈抑制MAO-A (5-APBT 0.4 µM、6-APBT 0.6 µM和3-APBT 4 µM的IC50)，但仅弱抑制MAO-B （IC50 23-49 µM）。鉴于5-APBT和6-APBT对MAO-A的抑制强度在模型抑制剂范围内，不能排除临床相关的MAO-A抑制及其相互作用风险和毒性作用。这些数据为支持APBT和相关硫基致幻剂暴露的临床和法医解释提供了毒物动力学基础。

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引用次数: 0

In vitro hepatic metabolism and associated binding of enniatin B 叶莲素B的体外肝脏代谢及相关结合。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-06 DOI: 10.1016/j.tox.2025.154379

Ludovic Le Hegarat , Estelle Dubreil , Nicolas Le Yondre , Solenne Martin , Francoise Bree , Jérôme Henri

Enniatin B (ENNB), a secondary metabolite produced by various Fusarium species, frequently contaminates cereals, which constitutes the main dietary source of human exposure. Critical toxicodynamic and toxicokinetic data gaps currently impede a robust and accurate risk assessment. The primary objective of this study was to characterize the in vitro toxicokinetic profile of ENNB. We investigated its clearance using human and mouse liver microsomes (HLM and MLM), as well as 2D and 3D HepaRG cell models. To facilitate reliable in vitro-in vivo extrapolation (IVIVE), we also determined key parameters: plasma protein binding, binding to microsomes and HepaRG cells, CYP450 inhibition, and the identification of HepaRG metabolites. Binding studies revealed a very high binding of ENNB to human plasma proteins and a high binding to inactivated human liver microsomes and HepaRG cells. The predicted in vivo hepatic clearance (cl_H,blood) of ENNB, calculated using the in vitro results from MLM, HLM, and HepaRG 2D indicated a low hepatic first pass effect. Interestingly, no observable disappearance of ENNB was found in the HepaRG 3D model. Our findings on ENNB-mediated CYP inhibition in HLM, in combination with literature results, suggest a potential for CYP3A4/5-related auto-inhibition. Finally, we successfully performed a putative identification of 13 Phase I metabolites using the human HepaRG cell line. In conclusion, the low hepatic first pass effect could imply a high oral bioavailability in vivo if intestinal barrier passage is significant, as predicted elsewhere. However, this could be counteracted by transport limited hepatic clearance that should be further investigated and a pre-systemic first-pass effect already demonstrated in vitro.

镰刀菌素B （Enniatin B，简称ENNB）是由各种镰刀菌产生的次级代谢物，经常污染谷物，这是人类接触镰刀菌的主要膳食来源。目前，毒物动力学和毒物动力学的关键数据缺口阻碍了可靠和准确的风险评估。本研究的主要目的是表征ENNB的体外毒性动力学特征。我们使用人和小鼠肝微粒体（HLM和MLM）以及2D和3D HepaRG细胞模型来研究其清除情况。为了促进可靠的体内外推断（IVIVE），我们还确定了关键参数：血浆蛋白结合、与微粒体和HepaRG细胞的结合、CYP450抑制和HepaRG代谢物的鉴定。结合研究表明，enb与人血浆蛋白高度结合，与灭活的人肝微粒体和HepaRG细胞高度结合。利用MLM、HLM和HepaRG 2D的体外结果计算的预测的ENNB的体内肝脏清除率（clH，血液）显示肝脏首过效应低。有趣的是，在HepaRG 3D模型中未发现可观察到的ENNB消失。我们的研究结果表明，在HLM中，enb介导的CYP抑制，结合文献结果，表明cyp3a4 /5相关的自身抑制可能存在。最后，我们成功地使用人类HepaRG细胞系进行了13个I期代谢物的推定鉴定。综上所述，如果肠道屏障通过显著，低肝脏首过效应可能意味着高体内口服生物利用度。然而，这可能会被运输限制的肝脏清除所抵消，这应该进一步研究，并且在体外已经证明了系统性前的首过效应。

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引用次数: 0

Toxic effects and mechanism of silver nanoparticles with different particle sizes and surface coatings in lung epithelial cells 不同粒径和表面包覆银纳米颗粒对肺上皮细胞的毒性作用及其机制。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-06 DOI: 10.1016/j.tox.2026.154398

Zige Jiang , Yue Chen , Xiaoyu Guo , Ke Li , Liqun Chen

With nanotechnology's advancement and popularity, nanosafety assessment has attracted public attention, nanosafety assessment has attracted public attention. Silver nanoparticles (AgNPs) have been extensively applied in people’s work and life, but there is still limited knowledge of their potential toxicity to humans. Although many studies have shown that AgNPs causes physiological changes in the lung, the effects and molecular mechanisms of AgNPs on the lung are not fully understood at low-dose exposures and assessed with different physicochemical properties. To comprehensively compare the potential effects and molecular mechanisms of AgNPs with different particle sizes and surface modifications on A549 cells, three PVP-coated AgNPs with particle sizes of 20, 40, and 75 nm and Lipoic Acid (LA), mPEG, and BPEI-coated AgNPs with a particle size of 40 nm, which are referred to as PVP₂₀, PVP₄₀, PVP₇₅, LA₄₀, mPEG₄₀ and BPEI₄₀ were selected in this study. The methods used in this study included characterization of AgNP using transmission electron microscopy (TEM) and zeta potential, the study of cytotoxicity, oxidative stress, and subsequent damage to cell membrane integrity, apoptosis, and RNA-seq. Our findings indicated that AgNPs with different particle sizes and modifications had different toxicological effects, and the smaller size of AgNPs exerts the stronger cytotoxicity. In addition, transcriptome sequencing and qRT-PCR analyses confirmed that the mechanisms of action of these AgNPs varied, but PVP₂₀, PVP₄₀, PVP₇₅, LA₄₀, and BPEI₄₀ AgNPs could all affect A549 cells via IL-17 signaling pathway. Our research findings demonstrate the deleterious effects of different nanosilvers on lung epithelial cells and reveal related possible pathways of influence.

随着纳米技术的进步和普及，纳米安全评价引起了人们的广泛关注。纳米银在人们的工作和生活中得到了广泛的应用，但对其潜在毒性的认识仍然有限。尽管许多研究表明AgNPs会引起肺部的生理变化，但在低剂量暴露下，AgNPs对肺部的影响和分子机制尚未完全了解，并以不同的物理化学性质进行评估。为了综合比较不同粒径和表面修饰的AgNPs对A549细胞的潜在作用和分子机制，本研究选择了3种粒径分别为20、40和75nm的pvp包被AgNPs，以及硫辛酸（LA）、mPEG和bpei包被粒径为40nm的AgNPs，分别为PVP20、PVP40、PVP75、LA40、mPEG40和BPEI40。本研究中使用的方法包括使用透射电子显微镜（TEM）和zeta电位表征AgNP，研究细胞毒性，氧化应激以及随后对细胞膜完整性的损伤，凋亡和RNA-seq。结果表明，不同粒径和修饰的AgNPs具有不同的毒理学效应，粒径越小的AgNPs具有越强的细胞毒性。此外，转录组测序和qRT-PCR分析证实了这些AgNPs的作用机制不同，但PVP20、PVP40、PVP75、LA40和BPEI40 AgNPs都可以通过IL-17信号通路影响A549细胞。我们的研究结果证明了不同纳米银对肺上皮细胞的有害作用，并揭示了相关的可能影响途径。

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引用次数: 0