Toxicology letters最新文献_第5页

Diverse impacts of cadmium exposure on adolescent liver health: Suppression of steatosis and promotion of fibrosis 镉暴露对青少年肝脏健康的多种影响：抑制脂肪变性和促进纤维化。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-16 DOI: 10.1016/j.toxlet.2025.111806

Si-Jie Hong , Li-Wei Hong , Xiao-Qin He , Xiao-Qing Yang , Xiao-Hong Zhong , Jin-Zhun Wu

Objectives

Cadmium exposure's impact on adolescent liver health is of concern. This study aimed to explore the association between cadmium exposure and liver health in adolescents.

Methods

A cross-sectional study was conducted using data from NHANES 2017–2020.3. Urinary cadmium concentration was used as an indicator of exposure. Liver ultrasound parameters, controlled attenuation parameter (CAP) and stiffness (E) (STF), were employed to assess the degree of liver steatosis and fibrosis in adolescents. Multivariate linear and logistic regression analyses were performed to examine the correlations between cadmium exposure and liver health. Mediation analysis was utilized to explore the roles of alkaline phosphatase, creatine phosphokinase, cholesterol, triglycerides, C-reactive protein, and creatinine. Additionally, a restricted cubic spline (RCS) analysis was conducted to evaluate the impact of nutritional intake on liver health in high-cadmium exposure groups.

Results

Cadmium exposure levels were associated with ethnicity and family income. Regression analysis showed a negative correlation with CAP and a positive correlation with STF. Mediation analysis demonstrated that creatinine and triglycerides partially mediated cadmium's effect on CAP, while only creatinine mediated the effect on STF. Dietary intake, including eicosadienoic acid and theobromine, significantly impacts liver health in adolescents with high cadmium exposure.

Conclusions

Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes.

目的：镉暴露对青少年肝脏健康的影响值得关注。本研究旨在探讨镉暴露与青少年肝脏健康之间的关系。方法：采用NHANES 2017 - 2020.3的数据进行横断面研究。尿镉浓度被用作暴露的指标。采用肝脏超声参数，控制衰减参数（CAP）和刚度(E) （STF）评估青少年肝脏脂肪变性和纤维化程度。进行多变量线性和逻辑回归分析以检验镉暴露与肝脏健康之间的相关性。采用中介分析探讨碱性磷酸酶、肌酸磷酸激酶、胆固醇、甘油三酯、c反应蛋白和肌酐的作用。此外，进行了限制性三次样条（RCS）分析，以评估营养摄入对高镉暴露组肝脏健康的影响。结果：镉暴露水平与种族和家庭收入有关。回归分析显示与CAP负相关，与STF正相关。中介分析表明，肌酐和甘油三酯部分介导了镉对CAP的影响，而只有肌酐介导了对STF的影响。饮食摄入，包括二十碳二烯酸和可可碱，显著影响高镉暴露青少年的肝脏健康。结论：镉暴露通过抑制脂肪变性和促进纤维化影响肝脏健康，其中肾脏和脂质代谢因子起中介作用，饮食影响结果。

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引用次数: 0

Advances in understanding the neurotoxicity of lead, cadmium, arsenic, and therapeutic strategies 铅、镉、砷的神经毒性及其治疗策略研究进展。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-24 DOI: 10.1016/j.toxlet.2025.111810

Yi-Ling Li , Zhi-Xin Huang , Jian-chao Peng , Thanh-Tung Ho , Hai Huang , Michael Aschner , Yue-Ming Jiang

The rapid progression of industrialization and urbanization has intensified the public health threat posed by heavy metal pollution. Among these, lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects. Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases. This review aims to summarize the neurotoxicity mechanisms of Pb, Cd, and As. Additionally, it focuses on the latest advancements in therapeutic strategies for their neurotoxicity. Particular emphasis is placed on evaluating research progress of nanoparticle-assisted therapeutic approaches. It is expected that this review will offer theoretical and empirical support and research insights for the development of more efficient therapeutic methods in the future.

工业化和城市化的快速发展加剧了重金属污染对公众健康的威胁。其中，铅（Pb）、镉（Cd）和砷（As）是普遍存在的环境毒物，能够通过多种暴露途径进入人体，导致严重的神经毒性作用。常规螯合治疗长期使用可导致肾脏和胃肠道疾病。本文就铅、镉、砷的神经毒性机制作一综述。此外，它侧重于其神经毒性治疗策略的最新进展。特别强调了评价纳米粒子辅助治疗方法的研究进展。希望本文能为今后开发更有效的治疗方法提供理论和实证支持及研究见解。

引用次数: 0

Subtotal removal of the stratum corneum by brushing as a decontamination strategy after hydrofluoric-acid exposure of human skin 在氢氟酸暴露于人体皮肤后，通过刷牙去除角质层作为一种去污策略

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-02 DOI: 10.1016/j.toxlet.2025.111788

Suvarna Mini Vijayan , Thomas Göen , Andrea Kaifie , Franklin Kiesewetter , Raymund E. Horch , Wibke Müller-Seubert , Hans Drexler , Sonja Kilo , Anna Wolfschmidt

Accidents with hydrofluoric acid (HF) can cause systemic poisoning by transdermal penetration of fluoride ions. Abrasive techniques, like mechanical brushing, are occasionally used as a method of decontamination, but their efficacy in reducing systemic fluoride absorption remains unclear. In a modified Franz diffusion-cell model, human skin samples (0.9 mm thickness, n = 6 per group) were exposed to 30 % HF. After one minute of exposure, the supernatant fluid was removed with cotton swabs. With the exception of untreated controls, the skin was then decontaminated either with a water jet alone or combined with brushing, using an electric toothbrush. Samples were collected from the receptor solution at different timepoints during the 72 h post-exposure timeframe. Both strategies were effective when compared to a lack of decontamination. There was no significant difference in cumulative fluoride absorption between the combination of water jet plus brushing and the water jet alone. However, approximately 4–48 h after exposure, the fluoride flux (absorption per hour) was lower in the skin samples treated with the combination of water jet and brushing. This difference was significant at 12 h and 24 h post-exposure. Overall, our results suggest an additional efficacy of mechanical decontamination during the prolonged follow-up period after hydrofluoric-acid exposure. This might be especially relevant in exposure scenarios with a larger skin depot of fluoride, like exposure to higher HF-concentrations. However, future research is needed to place these findings on a broader data basis and to evaluate the safety and efficacy of mechanical decontamination in practice.

氢氟酸（HF）事故可通过氟离子经皮渗透引起全身中毒。磨料技术，如机械刷，偶尔被用作去污方法，但它们在减少全身氟化物吸收方面的功效尚不清楚。在改进的Franz扩散细胞模型中，人体皮肤样品（0.9 mm厚度，每组 = 6）暴露于30 % HF。暴露1分钟后，用棉签除去上清液。除未经处理的对照组外，研究人员分别用喷水或用电动牙刷对皮肤进行消毒。在暴露后72 h的不同时间点从受体溶液中收集样品。与缺乏净化相比，这两种策略都是有效的。水射流联合刷牙与单独使用水射流刷牙的累积氟化物吸收量无显著差异。然而，在接触后约4-48 h，使用水射流和刷牙组合处理的皮肤样品的氟化物通量（每小时吸收量）较低。这种差异在暴露后12 h和24 h显著。总的来说，我们的研究结果表明，在氢氟酸暴露后的长时间随访期间，机械去污具有额外的功效。这可能与皮肤氟化物储存量较大的暴露情况特别相关，例如暴露于较高的hf浓度。然而，未来的研究需要将这些发现建立在更广泛的数据基础上，并评估机械去污在实践中的安全性和有效性。

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引用次数: 0

Multi-omics analysis reveals the mechanism of indirect hepatotoxicity of triptolide upon LPS stimulation 多组学分析揭示了雷公藤甲素在LPS刺激下的间接肝毒性机制。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-09 DOI: 10.1016/j.toxlet.2025.111802

Tao Shen , Linrui Fan , Huayu Luo , Yulong Zha , Yu Zhang , Hongzheng Ren

Purpose

Triptolide (TP), an active compound derived from the traditional Chinese herb Tripterygium wilfordii Hook F, is notable for its therapeutic properties. However, hepatotoxicity remains its primary adverse effect. There is a new perspective about TP hepatotoxicity: hepatic hypersensitivity triggered by lipopolysaccharide (LPS) stimulation. However, the global molecular alterations underlying this synergistic effect remain poorly defined.

Methods

We employed an integrated proteomics and metabolomics approach to systematically characterize the molecular landscape in the livers of mice treated with TP and LPS. Liver injury was assessed by serum biochemistry and histopathology.

Results

The TP+LPS combination induced severe liver damage, based upon histopathological and biochemical analyses, which was not observed with either agent alone. Proteomic analysis revealed that TP+LPS co-treatment induced aberrant expression of fatty acid/cholesterol metabolizing enzymes and dysregulation of cytoskeletal proteins, which collectively contributed to hepatocyte steatosis, structural disruption, and impaired regeneration. Metabolomics results showed that TP+LPS co-treatment significantly inhibited glucose metabolic pathways compared to LPS treatment alone, leading to a reduction of critical metabolic intermediates. This inhibition significantly impaired ATP production and triggered energy depletion. Integrated analysis showed that the suppression of these enzymes in the TP+LPS group impaired mitochondria integrity and the electron transport chain, contributing to ROS-mediated oxidative stress and consequent aggravation of inflammatory response. The inflammatory environment further inhibits mitochondrial function, worsening metabolic disorders and promoting ROS accumulation, thereby forming a self-perpetuating cycle of "metabolism-oxidation-inflammation".

Conclusion

Our multi-omics data provide a comprehensive resource and novel insights into the mechanism of TP-potentiated, LPS-induced hepatotoxicity. TP might amplify hepatotoxicity by influencing energy metabolism, activating oxidative stress and inflammation in the context of LPS-induced inflammation.

目的：雷公藤甲素（Triptolide， TP）是一种从中药雷公藤中提取的活性化合物，具有显著的治疗作用。然而，肝毒性仍然是其主要的副作用。TP肝毒性有一个新的观点：脂多糖刺激引起的肝脏超敏反应。然而，这种协同效应背后的全局分子改变仍然不明确。方法：采用综合蛋白质组学和代谢组学方法，系统表征TP和LPS处理小鼠肝脏的分子景观。采用血清生化及组织病理学检测肝损伤程度。结果：经组织病理学和生化分析，TP+LPS联合用药可引起严重的肝损伤，单独使用两种药物均未观察到肝损伤。蛋白质组学分析显示，TP+LPS共处理诱导脂肪酸/胆固醇代谢酶的异常表达和细胞骨架蛋白的失调，这些共同导致肝细胞脂肪变性、结构破坏和再生受损。代谢组学结果显示，与单独LPS处理相比，TP+LPS共处理显著抑制了葡萄糖代谢途径，导致关键代谢中间体减少。这种抑制显著损害ATP的产生并引发能量消耗。综合分析表明，TP+LPS组对这些酶的抑制破坏了线粒体完整性和电子传递链，导致ros介导的氧化应激，从而加重炎症反应。炎症环境进一步抑制线粒体功能，加重代谢紊乱，促进ROS积累，从而形成“代谢-氧化-炎症”的自我延续循环。结论：我们的多组学数据为tp增强、lps诱导的肝毒性机制提供了全面的资源和新的见解。在lps诱导炎症的情况下，TP可能通过影响能量代谢、激活氧化应激和炎症来增强肝毒性。

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引用次数: 0

Lopinavir/ritonavir induces hepatotoxicity in HepG2 cells through inhibition of the Nrf2 pathway, resulting in oxidative stress, endoplasmic reticulum stress, and cell cycle arrest 洛匹那韦/利托那韦通过抑制Nrf2通路诱导HepG2细胞肝毒性，导致氧化应激、内质网应激和细胞周期阻滞。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-05 DOI: 10.1016/j.toxlet.2025.111798

Wenhong Zhou , Dan Wang , Jundou Tu , Jun Li , Jiayu Xu , Wenjing Tan , Diwei Mo , Pengying Liang , Yinglin Guo , Ming Hu , Linhu Ye

Lopinavir/ritonavir (LPV/r), a clinically used protease inhibitor for treating human immunodeficiency virus, is associated with liver injury. In this study, we demonstrated that LPV/r significantly suppressed HepG2 cell viability and increased the secretion of ALT, AST and LDH in the cell supernatant. Flow cytometry analysis revealed that LPV/r induced cell cycle arrest at the G0/G1 phase and triggered apoptosis in HepG2 cells. Furthermore, LPV/r significantly induced oxidative stress and endoplasmic reticulum (ER) stress, evidenced by elevated intracellular reactive oxygen species (ROS) levels, ER vesicular dilation, and alterations in the expression of related proteins. Additionally, LPV/r markedly increased the expression of apoptosis-related proteins. Mechanistically, activation of Nrf2 with tBHQ or overexpression of Nrf2 protein can effectively reverse the suppression of Nrf2/HO-1 expression by LPV/r, thereby reducing ROS accumulation and alleviating LPV/r-induced hepatocyte injury. Collectively, our findings demonstrate that LPV/r suppresses Nrf2 and HO-1 protein, promotes ROS accumulation, which induces oxidative stress and ER stress, ultimately leading to cell apoptosis and G0/G1 phase cell cycle arrest. This research provides novel mechanistic insights into the hepatotoxic effects of LPV/r.

洛匹那韦/利托那韦（LPV/r）是临床用于治疗人类免疫缺陷病毒的蛋白酶抑制剂，与肝损伤有关。在本研究中，我们发现LPV/r显著抑制HepG2细胞活力，增加细胞上清中ALT、AST和LDH的分泌。流式细胞术分析显示，LPV/r诱导HepG2细胞周期阻滞于G0/G1期，并引发细胞凋亡。此外，LPV/r显著诱导氧化应激和内质网（ER）应激，表现为细胞内活性氧（ROS）水平升高、内质网囊泡扩张和相关蛋白表达改变。此外，LPV/r显著增加凋亡相关蛋白的表达。机制上，通过tBHQ激活Nrf2或Nrf2蛋白过表达可有效逆转LPV/r对Nrf2/HO-1表达的抑制，从而减少ROS的积累，减轻LPV/r诱导的肝细胞损伤。综上所述，我们的研究结果表明，LPV/r抑制Nrf2和HO-1蛋白，促进ROS积累，诱导氧化应激和内质网应激，最终导致细胞凋亡和G0/G1期细胞周期阻滞。这项研究为LPV/r的肝毒性作用提供了新的机制见解。

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引用次数: 0

Developing a novel in vitro toxicity assay for predicting inhalation toxicity in rats 建立一种预测大鼠吸入毒性的新型体外毒性试验。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-10 DOI: 10.1016/j.toxlet.2025.111803

Arpamas Vachiraarunwong , Masaki Fujioka , David B. Alexander , Shugo Suzuki , Runjie Guo , Guiyu Qiu , Yurina Kawamura , Kana Shibano , Ikue Noura , Kwanchanok Praseatsook , Hirotoshi Akane , Shinji Takasu , Hiroyuki Tsuda , Kumiko Ogawa , Hideki Wanibuchi , Min Gi

The development of alternative in vitro methods for assessing acute inhalation toxicity is essential to reduce animal testing and aligns with the 3Rs principles (replacement, reduction, refinement). In this study, we developed a neutral red uptake (NRU) assay using human lung adenocarcinoma cells (A549) as a predictive model (A549-NRU) for acute inhalation toxicity. The assay incorporates two key features: a 15-minute incubation time to simulate the transient contact of inhaled chemicals with the airway surface under acute inhalation conditions, and the use of both polystyrene plates and glass plates for chemicals reactive with polystyrene. LC₅₀ values were determined for 49 chemicals and compared with reported LC₅₀ values from 4-hour rat inhalation studies. A significant positive correlation was observed between A549-NRU-derived LC₅₀ values and in vivo LC₅₀ values for water-soluble compounds (r = 0.4632, p = 0.0197) as well as chemicals containing aldehyde and ketone (r = 0.9339, p = 0.0007), and alcohol, ether, and epoxide (r = 0.7668, p = 0.0159) functional groups, suggesting that in vivo LC₅₀ values may be predictable using the A549-NRU assay. Importantly, the A549-NRU assay (r = 0.8879, p = 0.1121) demonstrated a stronger correlation with in vivo LC₅₀ values than the conventional NRU assay using mouse 3T3 fibroblast cells (r = 0.4524, p = 0.5476). These findings support the A549-NRU assay as an alternative for predicting acute inhalation toxicity and for estimating starting doses for confirmatory in vivo studies.

开发用于评估急性吸入毒性的替代体外方法对于减少动物试验和符合3Rs原则（替代、减少、改进）至关重要。在这项研究中，我们开发了一种中性红色摄取（NRU）试验，使用人肺腺癌细胞（A549）作为急性吸入毒性的预测模型（A549-NRU）。该试验具有两个关键特征：15分钟的潜伏期，以模拟吸入的化学物质在急性吸入条件下与气道表面的短暂接触，以及使用聚苯乙烯板和玻璃板用于与聚苯乙烯反应的化学物质。测定了49种化学物质的LC50值，并与4小时大鼠吸入研究报告的LC50值进行了比较。A549-NRU衍生的LC50值与体内水溶性化合物（r = 0.4632, p = 0.0197）、含有醛和酮的化学物质（r = 0.9339, p = 0.0007）、醇、醚和环氧化物（r = 0.7668, p = 0.0159）的LC50值呈显著正相关，表明体内LC50值可以通过A549-NRU检测预测。重要的是，A549-NRU实验（r = 0.8879, p = 0.1121）与使用小鼠3T3成纤维细胞的传统NRU实验（r = 0.4524, p = 0.5476）相比，与体内LC50值的相关性更强。这些发现支持A549-NRU测定作为预测急性吸入毒性和估计体内验证性研究起始剂量的替代方法。

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引用次数: 0

Rotenone-induced cellular dysfunction in human blood platelets: Unraveling calcium dysregulation, mitochondrial impairment, oxidative stress, and apoptosis 鱼藤酮诱导的人血小板细胞功能障碍：揭示钙失调、线粒体损伤、氧化应激和细胞凋亡。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-09 DOI: 10.1016/j.toxlet.2025.111804

Samir Kumar Beura, Nisha Yadav, Abhishek Kumar Maurya, Nikki Kumari, Sunil Kumar Singh

Rotenone, a naturally occurring pesticide and a well-established mitochondrial complex I inhibitor, disrupts electron transport chain activity, resulting in impaired energy metabolism, oxidative stress, and apoptosis. Our recent findings revealed that rotenone suppresses agonist-induced platelet functional activity; however, the molecular mechanisms underlying this effect remain largely unclear. In this study, we demonstrate that rotenone exposure induces pronounced cytotoxic effects in human platelets, evident from decreased cell viability and phosphatidylserine externalization, a hallmark of apoptosis-like processes. At the mitochondrial level, rotenone markedly compromises organelle integrity by inducing mitochondrial membrane potential depolarization, excessive reactive oxygen species generation, and calcium dysregulation. These mitochondrial perturbations act as key upstream signals that trigger caspase activation and drive apoptosis-like cascades in platelets. Collectively, our findings identify mitochondrial dysfunction, oxidative stress, and calcium imbalance as central mediators of rotenone-induced, caspase-dependent platelet apoptosis. This study demonstrates that rotenone induces cytotoxicity and organelle dysfunction in human blood platelets, thereby providing mechanistic insight into altered platelet functions.

鱼藤酮是一种天然存在的杀虫剂，也是一种公认的线粒体复合物I抑制剂，它会破坏电子传递链活性，导致能量代谢受损、氧化应激和细胞凋亡。我们最近的发现表明鱼藤酮抑制激动剂诱导的血小板功能活性；然而，这种作用背后的分子机制仍不清楚。在这项研究中，我们证明鱼藤酮暴露在人血小板中诱导明显的细胞毒性作用，从细胞活力降低和磷脂酰丝氨酸外化（细胞凋亡样过程的标志）可见。在线粒体水平上，鱼藤酮通过诱导线粒体膜电位去极化、活性氧生成过多和钙失调而显著损害细胞器完整性。这些线粒体扰动作为关键的上游信号，触发半胱天冬酶激活，驱动血小板细胞凋亡样级联反应。总的来说，我们的研究结果确定了线粒体功能障碍、氧化应激和钙失衡是鱼藤酮诱导的caspase依赖性血小板凋亡的中心介质。本研究表明鱼藤酮诱导人血小板细胞毒性和细胞器功能障碍，从而为血小板功能改变提供了机制见解。

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引用次数: 0

Evaluation of interspecies differences in DS-2087b-induced gastrointestinal toxicity using mouse and monkey intestinal organoids ds -2087b致小鼠和猴肠道类器官胃肠道毒性的种间差异评价

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2026-01-01 Epub Date: 2025-12-17 DOI: 10.1016/j.toxlet.2025.111805

Yuji Shirai, Takuma Iguchi, Kazunori Fujimoto, Masako Imaoka, Yuko Hasegawa, Katsuyoshi Chiba

Gastrointestinal (GI) toxicity is a common adverse event induced by anti-cancer drugs; however, the information of the correlations in vitro to in vivo regarding GI toxicity is limited. The objective of this study was elucidating the usefulness of animal small intestinal organoids using DS-2087b, a novel epidermal growth factor receptor/human epidermal growth factor receptor 2 exon 20 insertion inhibitor. Mice showed no DS-2087b-related GI toxicities up to 100 mg/kg in 28-day repeated oral toxicity studies, while monkeys exhibited diarrhea at 10 mg/kg, along with histopathological changes including intestinal atrophy/erosion at 30 and 100 mg/kg. To clarify the mechanisms involved in interspecies differences, cell viability and transcriptomic analysis were performed using mouse and monkey small intestinal organoids generated from adult stem cells treated with DS-2087b at 0–10,000 nM for 3 days. Cell viability in monkey small intestinal organoids treated with DS-2087b at 1000 and 10,000 nM was significantly decreased compared to that of mice. In the transcriptomic analysis, expression of stem- and Paneth-cell marker genes was markedly decreased in the monkey small intestinal organoids. In conclusion, the intestinal organoids are valuable in vivo–in vitro translation of drug-induced GI toxicity and the changes in specific cell-type composition induced by DS-2087b may be important factors for contributing the interspecies differences.

胃肠道毒性是抗癌药物引起的常见不良事件；然而，关于胃肠道毒性的体内外相关性的信息有限。本研究的目的是阐明DS-2087b（一种新型表皮生长因子受体/人表皮生长因子受体2外显子20插入抑制剂）对动物小肠类器官的作用。在28天的重复口服毒性研究中，当ds -2087b达到100mg/kg时，小鼠未显示出ds -2087b相关的胃肠道毒性，而猴子在10mg/kg时表现出腹泻，同时在30mg /kg和100mg/kg时出现组织病理变化，包括肠道萎缩/侵蚀。为了阐明物种间差异的机制，用DS-2087b在0-10,000nM处理3天的小鼠和猴子成体干细胞产生的小肠类器官进行了细胞活力和转录组学分析。与小鼠相比，DS-2087b在1000和10000 nm下处理的猴小肠类器官细胞活力显著降低。在转录组学分析中，猴小肠类器官中干细胞和泛细胞标记基因的表达明显降低。综上所述，肠道类器官在药物诱导的胃肠道毒性的体内外翻译中具有重要价值，DS-2087b诱导的特定细胞类型组成的变化可能是造成种间差异的重要因素。

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引用次数: 0

The single nucleotide polymorphism rs155787 on the autophagy gene of SQSTM1 is associated with silicosis susceptibility: A multi-stage study SQSTM1自噬基因rs155787单核苷酸多态性与矽肺易感性相关：一项多阶段研究

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-10-17 DOI: 10.1016/j.toxlet.2025.111744

Lijing Jiang , Fan Wang , Mingwei Huai , Wendi Zhang , Xiaofeng Chen , Chunping Li , Xinsheng Zhang , Bingchen Liu , Yao Su , Minjie Chu , Na Sun , Jiandong Jiao , Wei Wang

Objective

To investigate the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (ATGs) and susceptibility to silicosis.

Methods

Used silicosis genome-wide association study (GWAS) data and multiple publicly available databases to identify autophagy-associated positive expression quantitative trait locus (eQTL)-SNPs. Candidate positive SNPs were subsequently validated for their association with silicosis susceptibility in an independent population. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to explore the expression of target genes. Finally, gene enrichment analysis was performed to preliminary explore the biological functions and potential pathways associated with the identified susceptibility genes.

Results

A total of 15 SNPs in 10 ATGs were finally obtained after screening. Validation phase results indicated a significant association between the mutant G allele of rs155787 on the Sequestosome 1 (SQSTM1) and an increased risk of silicosis (additive model: odds ratio (OR)= 1.55, 95 % confidence interval (95 % CI): 1.05–2.28, P = 0.027). Combining GWAS and validation phase data, the mutant G allele was correlated with heightened silicosis susceptibility (additive model: OR=1.70, 95 % CI: 1.22–2.36, P = 0.002). The eQTL results indicated that significantly higher SQSTM1 expression in AG and GG genotypes than in AA genotypes (P < 0.05). Bioinformatics analysis revealed that SQSTM1 may bind to a range of autophagy proteins and immunoproteins to activate the biological process of macroautophagy, which influences the development of silicosis.

Conclusion

The rs155787 locus on the SQSTM1 may be associated with silicosis susceptibility, and the mutant G allele may serve as a potential risk factor. Furthermore, the A>G variation at this locus was observed to upregulate SQSTM1 gene expression. Additional large-scale studies are necessary to further validate our findings.

目的：探讨自噬相关基因（ATGs）单核苷酸多态性（snp）与矽肺易感性的关系。方法：利用矽肺全基因组关联研究（GWAS）数据和多个公开数据库，鉴定自噬相关阳性表达数量性状位点(eQTL)- snp。候选阳性snp随后在独立人群中验证了它们与矽肺易感性的关联。采用实时荧光定量聚合酶链反应（qRT-PCR）检测靶基因的表达情况。最后，进行基因富集分析，初步探索与鉴定的易感基因相关的生物学功能和潜在途径。结果：筛选10个atg，最终获得15个snp。验证阶段结果显示，Sequestosome 1 （SQSTM1）上rs155787突变基因G等位基因与矽肺病风险增加之间存在显著关联(加性模型：优势比（OR)=1.55, 95%可信区间（95% CI）： 1.05-2.28, P = 0.027）。结合GWAS和验证期数据，突变G等位基因与矽肺易感性增高相关（加性模型：OR=1.70, 95% CI: 1.22-2.36, P = 0.002）。eQTL结果显示，SQSTM1在AG和GG基因型中的表达量显著高于AA基因型（P < 0.05）。生物信息学分析表明，SQSTM1可能与一系列自噬蛋白和免疫蛋白结合，激活巨噬的生物学过程，影响矽肺的发展。结论：SQSTM1上rs155787位点可能与矽肺易感性相关，突变的G等位基因可能是一个潜在的危险因素。此外，该位点的A>G变异被观察到上调SQSTM1基因的表达。需要更多的大规模研究来进一步验证我们的发现。

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引用次数: 0

Integrated transcriptomic and metabolomic analyses reveal the pathogenesis of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced liver injury in mice 综合转录组学和代谢组学分析揭示了3,5-二氧羰基-1,4-二氢碰撞碱诱导小鼠肝损伤的发病机制。

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters

Pub Date : 2025-12-01 Epub Date: 2025-12-02 DOI: 10.1016/j.toxlet.2025.111786

Zijun Zhang, Rong Ji, Ahua Ku, Ruhan A, Binbin Song

The hepatotoxic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) has been widely utilized to establish various liver disease models. However, the molecular networks and metabolic regulatory mechanisms underlying DDC-induced liver injury remain to be fully elucidated. In this study, an integrated transcriptomic and metabolomic approach was employed to investigate the mechanisms of DDC-induced hepatotoxicity. C57BL/6 J mice were administered a 0.1 % DDC-supplemented diet for two weeks to induce liver injury, followed by collection of serum and liver tissue samples for analysis. The results demonstrated that DDC treatment significantly elevated markers of liver injury, cholestasis, and fibrosis. Histopathological examination revealed hepatocyte damage, inflammatory cell infiltration, and increased collagen deposition in DDC-treated mice. Liver transcriptomic analysis identified 814 differentially expressed genes, while serum metabolomic profiling detected 958 differentially expressed metabolites. Integrated pathway analysis revealed co-enrichment of 14 pathways in both transcriptomic and metabolomic datasets, including steroid hormone biosynthesis, glycerophospholipid metabolism, retrograde endocannabinoid signaling, and primary bile acid biosynthesis. Validation experiments using qRT-PCR and UPLC-MS/MS demonstrated that DDC treatment upregulated hepatic mRNA levels of Cyp27a1, Mrp2, and Mrp3, while downregulating Cyp8b1, Hsd3b7, Scp2, and Hsd17b4. Serum analysis showed significant increases in the concentrations of CA, TCA, GCA, TCDCA, α-MCA, β-MCA, Tβ-MCA, TUDCA, CDCA, UDCA, ω-MCA, and HDCA, along with decreased LCA levels. These findings indicate that DDC-induced liver injury involves multiple pathways and mechanisms, with disruption of bile acid homeostasis representing a central pathological feature.

肝毒性化合物3,5-二氧羰基-1,4-二氢碰撞碱（DDC）已被广泛用于建立各种肝脏疾病模型。然而，ddc诱导的肝损伤的分子网络和代谢调控机制仍未完全阐明。本研究采用综合转录组学和代谢组学方法研究ddc诱导肝毒性的机制。C57BL/6 J小鼠给予添加0.1% % ddc的日粮诱导肝损伤2周，然后采集血清和肝组织样本进行分析。结果表明，DDC治疗显著提高肝损伤、胆汁淤积和纤维化指标。组织病理学检查显示ddc处理小鼠肝细胞损伤，炎症细胞浸润，胶原沉积增加。肝脏转录组学分析鉴定出814个差异表达基因，而血清代谢组学分析检测到958个差异表达代谢物。综合通路分析显示，转录组学和代谢组学数据集中共有14条通路富集，包括类固醇激素生物合成、甘油磷脂代谢、逆行内源性大麻素信号传导和初级胆油酸生物合成。qRT-PCR和UPLC-MS/MS验证实验表明，DDC处理上调了肝脏Cyp27a1、Mrp2和Mrp3 mRNA水平，下调了Cyp8b1、Hsd3b7、Scp2和Hsd17b4 mRNA水平。血清分析显示CA、TCA、GCA、TCDCA、α-MCA、β-MCA、t - mca、TUDCA、CDCA、UDCA、ω-MCA、HDCA浓度显著升高，LCA水平降低。这些发现表明，ddc诱导的肝损伤涉及多种途径和机制，胆汁酸稳态的破坏是一个主要的病理特征。

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