Toxicology Reports最新文献_第7页

Benzene exposure and health risk assessment among workers in informal footwear workshops: A cross-sectional study in Medan, Indonesia 非正式制鞋车间工人的苯暴露和健康风险评估：印度尼西亚棉兰的一项横断面研究

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-10-11 DOI: 10.1016/j.toxrep.2025.102140

Taufik Ashar, Devi Nuraini Santi, Evi Naria

Benzene is widely used in small-scale industries, particularly in informal footwear manufacturing, due to its adhesive properties. However, its volatility and carcinogenicity pose serious health risks to workers in poorly regulated environments. This study hypothesized that informal footwear workers in Medan are exposed to benzene concentrations exceeding international safety standards, resulting in measurable biological effects and increased health risks. Environmental monitoring was conducted in seven workshops, revealing ambient benzene levels ranging from 0.101 to 0.5147 mg/m³ . Five locations exceeded the NIOSH Recommended Exposure Limit (0.32 mg/m³), and all surpassed the WHO air quality guideline (0.005 mg/m³). Biomarker analysis showed elevated trans,trans-muconic acid (tt-MA) and malondialdehyde (MDA) levels, particularly in workshops with poor ventilation and high worker density. A moderate correlation between tt-MA and MDA (r = 0.462, p = 0.003) confirmed the link between benzene exposure and oxidative stress. Clinical symptoms such as headache and appetite loss were significantly associated with MDA and tt-MA levels, respectively, suggesting early biological effects. Carcinogenic risk assessment indicated that four locations exceeded acceptable lifetime cancer risk thresholds, with Location VI presenting a 65-fold exceedance. These findings underscore the urgent need for low-cost interventions, such as improved ventilation and safer chemical substitutes, to reduce exposure in informal industrial settings. Longitudinal studies are recommended to clarify causal pathways and inform occupational health policy.

苯因其粘连性被广泛应用于小型工业，特别是非正式的制鞋业。然而，它的挥发性和致癌性对管理不善的环境中的工人构成严重的健康风险。本研究假设棉兰的非正式制鞋工人接触到的苯浓度超过国际安全标准，导致可测量的生物效应和增加的健康风险。在7个车间进行了环境监测，发现环境苯含量为0.101至0.5147 mg/m³ 。5个地点超过了NIOSH建议暴露限值（0.32 mg/m³），所有地点都超过了WHO空气质量指南（0.005 mg/m³）。生物标志物分析显示反式、反式mucic酸（tt-MA）和丙二醛（MDA）水平升高，特别是在通风不良和工人密度高的车间。tt-MA和MDA之间的中度相关性（r = 0.462,p = 0.003）证实了苯暴露与氧化应激之间的联系。临床症状如头痛和食欲减退分别与MDA和tt-MA水平显著相关，提示早期生物学效应。致癌风险评估表明，有四个地点超过了可接受的终身癌症风险阈值，其中VI地点超过了65倍。这些发现强调迫切需要低成本的干预措施，如改善通风和更安全的化学替代品，以减少在非正式工业环境中的暴露。建议进行纵向研究，以澄清因果关系，并为职业健康政策提供信息。

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引用次数: 0

Targeting ferroptosis as a therapeutic strategy for hepatotoxicity 靶向铁下垂作为肝毒性的治疗策略

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-10-10 DOI: 10.1016/j.toxrep.2025.102137

Negar Hemmati , Mahdieh Anoush , Bahman Abedi Kiasari , Alireza Torkamani

Hepatotoxicity is a global health problem with a scarcity of treatment modalities that can reverse extensive liver injury. The liver’s central role in detoxification, iron regulation, and redox balance makes it highly vulnerable to toxic, metabolic, and inflammatory insults. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key mechanism linking oxidative stress, disrupted iron homeostasis, and hepatocellular injury Ferroptosis differs from apoptosis or necroptosis since it entails metabolic frailties of the glutathione–GPX4 system, the FSP1–CoQ10 system, and the BH4/DHFR system with peroxidation failure-prone lipid remodeling processes. Notably, growing evidence implicate ferroptosis in a number of hepatic disorders, including drug-induced liver injury, alcoholic and non-alcoholic liver disease, ischemia–reperfusion injury, and non-alcoholic steatohepatitis. Beyond acute death of hepatocytes, chronic ferroptotic signaling also enhances fibrogenesis and accelerates cirrhosis and hepatocellular carcinoma, and viral hepatitis exploits ferroptotic mechanisms via iron imbalances and oxidative stress. Acting both sides of this coin, pathogenic catalyst of parenchymal disease and therapeutic target of malignancy, puts ferroptosis both as a liability and a target. New therapeutic modalities, including natural products, synthetic small molecules, mesenchymal stem cell derivatives, and nanoparticle systems, modulate ferroptotic signaling to enhance antioxidant defenses, restore iron balance, or selectively induce tumor cell death. Collectively, these strategies underscore the translational promise of ferroptosis-based interventions. This review integrates mechanistic insights with emerging therapies, positioning ferroptosis as a context-dependent driver of hepatotoxicity and a compelling target for precision liver medicine.

肝毒性是一个全球性的健康问题，缺乏能够逆转广泛肝损伤的治疗方式。肝脏在解毒、铁调节和氧化还原平衡中的核心作用使其极易受到毒性、代谢性和炎症性损害。铁衰亡是一种铁依赖性的细胞死亡调控形式，已成为连接氧化应激、铁稳态破坏和肝细胞损伤的关键机制。铁衰亡不同于细胞凋亡或坏死衰亡，因为它涉及谷胱甘肽- gpx4系统、FSP1-CoQ10系统和BH4/DHFR系统的代谢脆弱性，以及容易发生过氧化衰竭的脂质重塑过程。值得注意的是，越来越多的证据表明，铁下垂与许多肝脏疾病有关，包括药物性肝损伤、酒精性和非酒精性肝病、缺血再灌注损伤和非酒精性脂肪性肝炎。除了肝细胞的急性死亡外，慢性铁沉信号还能增强纤维化，加速肝硬化和肝细胞癌，病毒性肝炎通过铁失衡和氧化应激利用铁沉机制。作为实质疾病的致病催化剂和恶性肿瘤的治疗靶点，铁下垂既是一种累赘，也是一种目标。新的治疗方式，包括天然产物、合成小分子、间充质干细胞衍生物和纳米颗粒系统，可调节铁致凋亡信号以增强抗氧化防御，恢复铁平衡，或选择性诱导肿瘤细胞死亡。总的来说，这些策略强调了基于铁枯病的干预措施的转化前景。这篇综述将机制见解与新兴疗法结合起来，将铁下垂定位为肝毒性的环境依赖性驱动因素和精确肝脏医学的引人注目的靶点。

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引用次数: 0

Aminoguanidine attenuates arsenic-induced hepatic oxidative stress: Dose-dependent effects in a mouse model 氨基胍减轻砷诱导的肝脏氧化应激：小鼠模型中的剂量依赖效应

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-10-09 DOI: 10.1016/j.toxrep.2025.102136

Behnam Ghorbani-Nejad , Matin Baghani , Nastaran Allahdini Hasaruyieh , Mahshid Jamshidi , Leila Poudineh , Somayyeh Karami-Mohajeri , Milad Rahimzadegan , Jafar Ahmadi

Background

Arsenic exposure through environmental contamination poses significant public health concerns via oxidative stress-mediated toxicity. While aminoguanidine (AG) demonstrates antioxidant properties, its protective effects against arsenic-induced hepatotoxicity remain unexplored.

Methods

Male mice (n = 32) were randomized into four groups (n = 8 per group): control (distilled water), arsenic (50 ppm sodium arsenite in drinking water), and two treatment groups receiving arsenic plus aminoguanidine (50 or 100 mg/kg/day, i.p.) for 28 days. Hepatic oxidative stress markers, plasma antioxidant capacity, and liver histopathology were evaluated.

Results

Arsenic exposure induced significant liver histopathological changes (grade +2) and oxidative damage. AG treatment at 50 mg/kg/day showed optimal protective effects, with some samples displaying normal hepatic structure (grade 0) and others showing minimal changes (grade +1). This dose effectively reduced lipid peroxidation and protein carbonylation in liver tissue. The higher AG dose (100 mg/kg/day) demonstrated less protective effect, though it significantly improved plasma antioxidant capacity compared to the arsenic group.

Conclusions

Aminoguanidine demonstrates dose-dependent hepatoprotective effects against arsenic-induced oxidative damage, with 50 mg/kg/day showing optimal efficacy. Further investigation of lower doses over extended periods is warranted to establish its therapeutic potential in arsenic toxicity.

背景：环境污染导致的砷暴露通过氧化应激介导的毒性引起重大的公共健康问题。虽然氨基胍（AG）具有抗氧化特性，但其对砷诱导的肝毒性的保护作用仍未被研究。方法将32只小白鼠（n = 32）随机分为4组（n = 8只/组）：对照组（蒸馏水）、砷组（饮用水中亚砷酸钠含量为50 ppm）和砷加氨基胍组（50或100 mg/kg/d， i.p），治疗28 d。评估肝脏氧化应激标志物、血浆抗氧化能力和肝脏组织病理学。结果砷暴露引起肝组织病理改变（+2级）和氧化损伤。50 mg/kg/天的AG处理显示出最佳的保护效果，一些样品显示出正常的肝脏结构（0级），而其他样品显示出最小的变化（+1级）。这一剂量有效地减少了肝组织中的脂质过氧化和蛋白质羰基化。与砷组相比，较高的AG剂量（100 mg/kg/天）显示出较低的保护作用，尽管它显著提高了血浆抗氧化能力。结论氨基胍具有剂量依赖性的抗砷性氧化损伤肝保护作用，以50 mg/kg/d为最佳。有必要在较长时间内对较低剂量进行进一步研究，以确定其在砷毒性方面的治疗潜力。

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引用次数: 0

Pre- and post-treatment effects of date fruit phenolics in cisplatin-induced hepatotoxicity 枣果酚类物质对顺铂所致肝毒性的前后作用

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-10-08 DOI: 10.1016/j.toxrep.2025.102139

Omowumi O. Adewale , Roseline F. Oyelola , Adeola B. Adenmosun , Oluwaseun A. Adebisi , Isaac O. Babatunde , Adedayo D. Adekomi , Johnson O. Oladele

Cisplatin is a popular chemotherapy drug effective in treatment of many solid tumours, however, it is limited by its liver toxicity essentially induced by oxidative stress and inflammation. Meanwhile plant phenolics have a long history of antioxidative and anti-inflammatory capabilities, but, information on the ability of phenolics derived from Date (Phoenix dactylifera) Fruits to modulate this condition remains underexplored. This study investigates the effects of Date Fruit Phenolics (DFP) against cisplatin-induced hepatic damage in male Wistar rats. Wistar rats were administered DFP (200 mg/kg body weight) daily for 7 days, while treated with or without a single intraperitoneal dose of cisplatin (5 mg/kg body weight) either 2 hrs prior to DFP on day 1 (CisB+DFP) or 2 hrs prior to DFP on day 7 (CisE+DFP). All the animals were allowed to have access to water and feed ad-libitum. They were sacrificed 24 hrs after cisplatin administration for histological (Hematoxylin/Eosin, and Periodic Acid Schiff stains), biochemical, inflammatory and redox biomarker analyses. Chromatographic, spectroscopic, and in vitro antioxidative assays were performed to elucidate the phytochemical content, structural features, and antioxidative potentials of DFP. Cisplatin significantly increased hepatic injury markers, lipid peroxidation, and nitric oxide levels, while decreasing glutathione, glutathione peroxidase, catalase, and superoxide dismutase activities (p < 0.05). Meanwhile, DFP significantly modified these observations, with corroborative evidence from histological analysis. Additionally, the chemical constituents in DFP showed significant antioxidative and functional properties. The findings suggest that DFP could offer effective protection against cisplatin-induced hepatotoxicity which could be beneficial for combination therapy in cancer treatment.

顺铂是一种流行的化疗药物，在许多实体肿瘤的治疗中有效，然而，它的肝脏毒性主要是由氧化应激和炎症引起的。同时，植物酚类物质具有悠久的抗氧化和抗炎能力，但是，从枣子中提取的酚类物质调节这一状况的能力仍未得到充分的研究。本研究探讨了枣酚类物质（DFP）对顺铂诱导的雄性Wistar大鼠肝损伤的影响。Wistar大鼠每天给药DFP（200 mg/kg体重）7天，同时在第1天DFP前2小时（CisB+DFP）或在第7天DFP前2小时（CisE+DFP）给药或不给药单次腹腔注射顺铂（5 mg/kg体重）。所有的动物都可以随意取水和喂食。顺铂给药后24小时处死，进行组织学（苏木精/伊红和周期性酸希夫染色）、生化、炎症和氧化还原生物标志物分析。通过色谱、光谱和体外抗氧化实验来阐明DFP的植物化学成分、结构特征和抗氧化潜力。顺铂显著增加肝损伤标志物、脂质过氧化和一氧化氮水平，同时降低谷胱甘肽、谷胱甘肽过氧化物酶、过氧化氢酶和超氧化物歧化酶活性（p <； 0.05）。同时，DFP显著地修正了这些观察结果，有来自组织学分析的确凿证据。此外，DFP的化学成分显示出显著的抗氧化和功能特性。提示DFP对顺铂诱导的肝毒性具有有效的保护作用，可用于肿瘤联合治疗。

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引用次数: 0

Benzene in cosmetic products: Non cancer and cancer risk assessment 化妆品中的苯：非致癌和致癌风险评估

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-10-03 DOI: 10.1016/j.toxrep.2025.102135

Abhishek Gautam, Peter J Cressey

Cosmetics are widely used products that include luxury beauty items like makeup and perfumes as well as everyday hygiene products like toothpaste, shampoo, deodorant, and soap. Most cosmetics are used by adults, although there are some products, such as sunscreen and shampoo, which are also used by children. Although benzene is not intentionally added in cosmetics, it may potentially be present in trace amounts as a contaminant or leftover solvent in finished goods. IARC has classified benzene carcinogenic to humans (Group 1) based on sufficient evidence that it causes acute myeloid leukaemia in adults. A risk assessment was performed to evaluate non-cancer and cancer human health risks of benzene in leave-on cosmetic products (deodorant and sunscreen) through dermal and inhalation pathways. Quantitative risk assessment estimated potential systemic exposure doses. The non-cancer risk assessment of benzene in cosmetics resulted in a safety margin greater than 100. The probability of lifetime cancer risk resulting from dermal and inhalation exposure to benzene from cosmetics was 2.4 × 10⁻⁶ i.e. lower than an excess cancer risk of 10⁻⁵ used as a World Health Organization benchmark. Given that it is highly improbable that a consumer would use benzene-contaminated products on a daily basis for the rest of their life, the study's findings indicate that there is no evidence of an elevated risk of non-cancer effects and minimal cancer risks in humans from exposure to benzene in deodorant and sunscreen.

化妆品是一种广泛使用的产品，包括化妆品和香水等奢侈美容产品，以及牙膏、洗发水、除臭剂和肥皂等日常卫生用品。大多数化妆品都是成年人使用的，尽管也有一些产品，如防晒霜和洗发水，也被儿童使用。虽然苯不是故意添加到化妆品中，但它可能作为污染物或成品中残留的溶剂以微量存在。国际癌症研究机构将苯列为人类致癌物（第1组），因为有充分的证据表明它会导致成人急性髓性白血病。进行了一项风险评估，以评估免洗化妆品（除臭剂和防晒霜）中苯通过皮肤和吸入途径对非癌症和癌症人类健康的风险。定量风险评估估计了潜在的全身暴露剂量。化妆品中苯的非癌症风险评估结果的安全裕度大于100。皮肤和吸入接触化妆品中的苯导致终生癌症风险的概率为2.4 × 10−6，即低于世界卫生组织基准的过量癌症风险10−5。考虑到消费者在余生中每天都使用受苯污染的产品是极不可能的，研究结果表明，没有证据表明人类接触除臭剂和防晒霜中的苯会增加非癌症影响的风险，而癌症风险也很小。

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引用次数: 0

Acute recreational drug and ethanol poisoning among adolescents: An observational study from Oslo, Norway 2014–2023 青少年急性消毒药和乙醇中毒：挪威奥斯陆2014-2023年的一项观察性研究

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-09-30 DOI: 10.1016/j.toxrep.2025.102134

Ingrid M. Stenbeck , Lüsette A. Subi , Mette Brekke , Odd Martin Vallersnes

Aims

To keep track on trends and changes over time, we describe drugs taken, clinical course, and incidence of recreational drug and ethanol poisoning among adolescents in Oslo, Norway, from 2014 to 2023.

Methods

We included all patients ≤ 20 years presenting to the city’s main emergency primary care clinic with recreational drug poisoning in 2014–2023, from 2018 also including sole ethanol poisoning. Data were retrospectively collected from local patient records. Incidences were estimated per 1000 inhabitants in Oslo aged 10–20 years per year.

Results

There were 1209 recreational drug poisonings, 51.1 % among girls. Cannabis was taken in 37.1 % of the cases, benzodiazepines in 22.2 %, heroin in 17.1 %, cocaine in 14.6 %, amphetamine in 13.1 %, and methylenedioxymethamphetamine (MDMA) in 12.2 %. More than one drug was taken in 406 (33.6 %) cases. There were 1675 sole ethanol poisonings, 59.9 % among girls. During the pandemic years 2020 and 2021 there was a temporary decrease in the incidence of sole ethanol poisoning, accompanied by an increase in recreational drug poisoning. Otherwise, the incidences were stable, except a marked increase for recreational drugs in 2023: recreational drug poisoning 1.20 (95 % CI 0.97–1.50) in 2014 and 3.55 (3.16–3.99) in 2023; sole ethanol poisoning 3.94 (3.50–4.42) in 2018 and 3.96 (3.54–4.42) in 2023. The incidence of recreational drug poisoning among girls were lower than among boys early in the study period, but higher from 2021.

Conclusions

Recreational drug poisoning in Oslo among adolescents was dominated by ethanol, cannabis, benzodiazepines, and heroin.

为了跟踪趋势和随时间的变化，我们描述了2014年至2023年挪威奥斯陆青少年的药物服用、临床过程以及娱乐性药物和乙醇中毒的发生率。方法纳入2014-2023年（2018年起）在该市主要急诊初级保健诊所就诊的所有≤ 20岁的娱乐性药物中毒患者，其中也包括单纯的乙醇中毒。资料回顾性地从当地患者记录中收集。据估计，奥斯陆每年每1000名10-20岁居民中就有发病率。结果娱乐性药物中毒1209例，其中女生占51.1% 。吸食大麻的占37.1% %，吸食苯二氮卓类药物的占22.2% %，吸食海洛因的占17.1% %，吸食可卡因的占14.6% %，吸食安非他命的占13.1 %，吸食亚甲二氧基甲基安非他命（MDMA）的占12.2 %。406例（33.6% %）患者同时服用一种以上药物。单纯乙醇中毒1675例，女生59.9 %。在2020年和2021年大流行期间，单纯乙醇中毒发生率暂时下降，同时娱乐性药物中毒发生率上升。其他方面，除2023年娱乐性药物中毒发生率明显上升外，其余年份均保持稳定：2014年娱乐性药物中毒发生率为1.20(95 % CI 0.97-1.50)， 2023年为3.55 (3.16-3.99)；单独乙醇中毒2018年3.94(3.50-4.42)，2023年3.96（3.54-4.42）。在研究初期，女孩的娱乐性药物中毒发生率低于男孩，但从2021年开始上升。结论奥斯陆青少年娱乐性药物中毒以乙醇、大麻、苯二氮卓类药物和海洛因为主。

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引用次数: 0

Building a predictive model for polycyclic aromatic hydrocarbon dosimetry in organotypically cultured human bronchial epithelial cells using benzo[a]pyrene 用苯并[a]芘建立人支气管上皮细胞多环芳烃剂量学预测模型

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-09-28 DOI: 10.1016/j.toxrep.2025.102133

Victoria C. Colvin , Kelley M. Bastin , Lisbeth K. Siddens , Monica L. Vermillion Maier , David E. Williams , Jordan N. Smith , Susan C. Tilton

The airway epithelium is a primary route of exposure for inhaled toxicants, and organotypic culture models represent an important advancement for toxicity testing compared to simple in vitro models that may lack metabolic capability and multicellular structure/communication associated with the bronchial epithelium in vivo. A quantitative understanding of chemical dosimetry is key for interpreting and extrapolating study results; however, dosimetry is understudied in organotypic models limiting ability to predict toxicity. We developed a dosimetry model for primary human bronchial epithelial cells (HBECs) cultured at the air-liquid interface (ALI) using benzo[a]pyrene (BAP), a representative polycyclic aromatic hydrocarbon. Dose and time course evaluation of metabolite formation and enzyme activity and expression were utilized to parameterize a cellular dosimetry model to improve the utility of ALI-HBECs for assessing chemical risk. Dosimetry analysis demonstrated absorption of BAP into cells and an increase in Phase 1 and 2 metabolites over time that correlated with regulation of metabolizing enzymes. BAP was cleared from cells by 48 h after exposure, and the primary metabolites generated in ALI-HBECs were BAP-3-phenol, BAP-4,5-dihydrodiol, BAP-7,8-dihydrodiol, BAP-9,10-dihydrodiol, BAP-7,8,9,10-tetrol, BAP-3-phenol-glucuronide, BAP-4,5-dihydrodiol-glucuronide, and BAP-9,10-dihydrodiol-glucuronide. The resulting dosimetry model described BAP and 7,8-dihydrodiol toxicokinetics in ALI-HBECs and suggested active excretion of 7,8-dihydrodiol. Overall, this study demonstrates metabolic competency of ALI-HBECs for BAP metabolism, demonstrates the usefulness of complex in vitro systems for human-relevant toxicity data, and exhibits how in silico models can be utilized for understanding the dosimetry of test compounds to aid in in vitro to human extrapolation of toxicity data for risk assessments.

气道上皮是吸入有毒物质的主要暴露途径，与简单的体外模型相比，器官型培养模型在毒性测试方面取得了重要进展，体外模型在体内可能缺乏与支气管上皮相关的代谢能力和多细胞结构/通讯。对化学剂量学的定量理解是解释和推断研究结果的关键；然而，剂量学在器官型模型中的研究不足，限制了预测毒性的能力。我们利用代表性的多环芳烃苯并[a]芘（BAP）建立了在气液界面（ALI）培养的原代人支气管上皮细胞（HBECs）的剂量学模型。利用代谢物形成的剂量和时间过程评估以及酶活性和表达来参数化细胞剂量学模型，以提高ALI-HBECs评估化学风险的效用。剂量学分析表明BAP被细胞吸收，随着时间的推移，1期和2期代谢产物增加，这与代谢酶的调节有关。暴露后48 h， BAP被细胞清除，ALI-HBECs产生的主要代谢产物为BAP-3-苯酚、BAP-4,5-二氢二醇、BAP-7,8-二氢二醇、BAP-9,10-二氢二醇、BAP-7,8,9,10-四醇、BAP-3-苯酚-葡萄糖醛酸盐、BAP-4,5-二氢二醇-葡萄糖醛酸盐和BAP-9,10-二氢二醇-葡萄糖醛酸盐。由此建立的剂量学模型描述了BAP和7,8-二氢二醇在ALI-HBECs中的毒性动力学，并表明7,8-二氢二醇有活性排泄。总的来说，本研究证明了ALI-HBECs对BAP代谢的代谢能力，证明了复杂的体外系统对人类相关毒性数据的有用性，并展示了如何利用计算机模型来理解测试化合物的剂量学，以帮助在体外推断人类毒性数据以进行风险评估。

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引用次数: 0

Prolonged intermittent hemodialysis using a standard dialysate flow rate for severe overdose of sustained-release valproic acid: A case report 使用标准透析液流速延长间歇血液透析治疗重度过量丙戊酸缓释：1例报告

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-09-26 DOI: 10.1016/j.toxrep.2025.102132

Hiroki Inoue , Satoshi Yoshikawa , Nobuyasu Matsukawa, Atsushi Shima , Takuya Nishizawa , Takeshi Ueda

Background

Valproic acid poisoning can be life threatening and may require urgent extracorporeal elimination. In particular, sustained-release formulations pose a challenge, as conventional short-duration intermittent hemodialysis may fail to remove the drug sufficiently because of delayed and prolonged drug absorption. While prolonged intermittent hemodialysis is a rational alternative, its clinical effectiveness and safety in cases of severe sustained-release sodium valproate overdose have not been reported.

Case

A woman in her 20 s developed coma after ingesting 45 g (approximately 1100 mg/kg) of sustained-release VPA. Prolonged IHD was delivered for 22 h using a blood flow rate (Qb) of 180 mL/min and a dialysate flow rate (Qd) of 500 mL/min. Her consciousness improved in parallel with a marked decline in serum VPA levels, and she was discharged without any neurological sequelae. A two-point, on-dialysis apparent elimination half-life was estimated to be approximately 2.35 h.

Conclusion

In this case, prolonged IHD appeared to have an effect in decreasing VPA concentrations and was safely implemented with monitoring.

丙戊酸中毒可危及生命，可能需要紧急体外清除。特别是，缓释制剂带来了挑战，因为传统的短时间间歇性血液透析可能无法充分去除药物，因为延迟和延长药物吸收。虽然长期间歇性血液透析是一种合理的选择，但其在重度丙戊酸钠缓释过量病例中的临床有效性和安全性尚未见报道。病例一名20岁 岁的妇女在摄入45 g（约1100 mg/kg）缓释VPA后出现昏迷。延长IHD为22 h，血流量（Qb）为180 mL/min，透析液流量（Qd）为500 mL/min。她的意识得到改善，同时血清VPA水平显著下降，出院时没有任何神经系统后遗症。两点透析时的表观消除半衰期估计约为2.35 h。结论在本病例中，延长IHD似乎对降低VPA浓度有效果，并且在监测下安全实施。

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引用次数: 0

Assessment of the main signaling pathways involved in the combined therapy of hepatocellular carcinoma using Sorafenib and NK cells in xenograft mice model 异种移植小鼠模型索拉非尼和NK细胞联合治疗肝癌的主要信号通路的评估

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-09-22 DOI: 10.1016/j.toxrep.2025.102131

Faezeh Hosseinzadeh , Tahereh Komeili movahhed , Masoumeh Dolati , Amir Hossein Kheirkhah , Nima Beheshtizadeh , Javad Verdi

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Sorafenib is the only FDA approved drug for HCC patients, affecting patient survival by just a few months with significant toxicities in approximately half of HCC patients and the poor prognosis of these patients. Thus, the combination therapy with Sorafenib and Natural killer (NK) cells has been suggested, due to NK cells' distinct effectiveness against HCC. This research examined the main signaling pathways in HCC progression affected by Sorafenib or NK cells in combination or individual treatment. The xenograft model of HCC was created by implanting human HepG2 cells subcutaneously into the flank of 12 nude mice and then divided into four groups: Control, Sorafenib, NK cells, and Sorafenib plus NK cells. Four weeks post tumor implantation, the mice were euthanized, and the levels of liver and kidney enzymes were analysed for safety purposes. Quantitative real-time PCR analysis was used to measure the expression of key effector genes related to Sorafenib and NK cell functions with focused on the signaling pathways involved in the development of HCC. The levels of Aspartate aminotransferase (AST), Alanine transaminase (ALT), Blood urea nitrogen (BUN), and creatinine (Cr) in all groups remained in normal ranges. The expression levels of certain proliferative, anti-apoptotic factors were reduced in groups treated with either Sorafenib or NK cells only, but in combinational treated group showed no significant differences compared to control group. Also, the NK cell effector function related genes were upregulated in NK cell treated group, but inhibited in co administration of both NK cell and Sorafenib. Therefore, combining Sorafenib and NK cells at the prescribed dosage led to a decrease in the anti-cancer efficiency of both and may not be a successful option for HCC treatment.

肝细胞癌（HCC）是全球癌症相关死亡的第三大原因。索拉非尼是FDA批准的唯一用于HCC患者的药物，仅影响患者生存几个月，约一半的HCC患者存在显著毒性，这些患者预后不良。因此，由于NK细胞对HCC具有明显的疗效，因此建议将索拉非尼和自然杀伤（NK）细胞联合治疗。本研究考察了索拉非尼或NK细胞联合或单独治疗影响HCC进展的主要信号通路。将人HepG2细胞皮下植入12只裸鼠腹部，建立肝癌异种移植模型，并将其分为对照组、索拉非尼组、NK细胞组和索拉非尼+ NK细胞组。肿瘤植入四周后，对小鼠实施安乐死，并对肝脏和肾脏酶水平进行安全分析。采用实时荧光定量PCR方法检测索拉非尼及NK细胞功能相关关键效应基因的表达，重点研究HCC发生发展的信号通路。各组血中谷草转氨酶（AST）、丙氨酸转氨酶（ALT）、尿素氮（BUN）、肌酐（Cr）水平均在正常范围内。单用索拉非尼或NK细胞治疗组细胞中某些增殖、抗凋亡因子的表达水平均降低，但联合治疗组与对照组相比差异无统计学意义。NK细胞处理组NK细胞效应功能相关基因表达上调，而NK细胞和索拉非尼联合给药组NK细胞效应功能相关基因表达受到抑制。因此，在规定剂量下联合索拉非尼和NK细胞导致两者的抗癌效率下降，可能不是HCC治疗的成功选择。

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引用次数: 0

Nucleophosmin 1 induction is an early event in a Phenobarbital induced proliferation response in rat but not human liver 3D microtissues 核蛋白1的诱导是大鼠苯巴比妥诱导的增殖反应的早期事件，而不是人类肝脏3D显微组织

Q1 Environmental Science

Toxicology Reports

Pub Date : 2025-09-19 DOI: 10.1016/j.toxrep.2025.102130

Matthew Elcombe, Stephanie Wallace, Simon Plummer

A key event in the process of rat but not human liver carcinogenesis caused by constitutive androstane receptor activators such as phenobarbital (PB) is hepatocyte proliferation, but the mechanism(s) underpinning this response is not fully understood. Previously we showed that rat liver microtissues (LiMTs) can recapitulate a PB-induced hepatocyte proliferation response (1). In this follow up study we used our microTMA technology coupled with transcriptomics and immunofluorescence (IF) staining to elucidate mechanisms of rat liver carcinogenesis in this model. We performed gene set enrichment analysis (GSEA) on transcriptomics data generated from laser microdissected liver microtissue microTMA FFPE sections from control and PB-treated LiMTs against custom liver cell proliferation and constitutive androstane receptor (CAR) activation signatures (2) and found that the former signature was significantly (q<0.25) enriched in rat but not human LiMT differentially expressed gene lists. This process also identified the cell proliferation gene nucleophosmin 1 (NPM1) as being significantly induced (p < 0.05) in rat but not human LiMTs. IF staining of parallel microTMA FFPE sections coupled with quantitative image analysis confirmed that the NPM1 protein was induced by PB treatment in rat but not human liver microtissues after 24 and 48 hrs PB treatment. In conclusion we have identified induction of nuclear NPM1 expression as an early event in PB-induced rat hepatocyte cell proliferation.

组成型雄甾受体激活剂如苯巴比妥（PB）引起的大鼠（而非人类）肝癌发生过程中的一个关键事件是肝细胞增殖，但支持这种反应的机制尚不完全清楚。先前我们发现，大鼠肝微组织（LiMTs）可以重现pb诱导的肝细胞增殖反应(1)。在这项后续研究中，我们利用我们的微tma技术结合转录组学和免疫荧光（IF）染色来阐明该模型中大鼠肝癌的发生机制。我们对对照和pb处理的LiMT的激光微解剖肝组织microTMA FFPE切片生成的转录组学数据进行了基因集富集分析（GSEA），发现前者在大鼠中显著（q<0.25）富集，而在人类LiMT差异表达的基因列表中不富集。该过程还发现细胞增殖基因核磷蛋白1 （NPM1）在大鼠中被显著诱导（p <； 0.05），而在人类LiMTs中没有。平行microTMA FFPE切片IF染色结合定量图像分析证实，PB处理24和48小时后，大鼠肝脏组织中诱导了NPM1蛋白，而人肝脏组织中没有诱导NPM1蛋白。总之，我们已经确定诱导核NPM1表达是pb诱导的大鼠肝细胞增殖的早期事件。

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引用次数: 0