Toxicology in Vitro最新文献_第9页

Development of a TK6-derived cell line expressing four human cytochrome P450s for genotoxicity testing 表达4种人类细胞色素p450的tk6衍生细胞系的建立及其遗传毒性试验

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-26 DOI: 10.1016/j.tiv.2025.106085

Xilin Li , Yuhan Wang , Hannah Xu , Xiaobo He , Si Chen , Xiaoqing Guo , Mugimane G. Manjanatha , Tong Zhou , Jessica Bonzo , Nan Mei

Metabolism is essential for in vitro genotoxicity testing. We previously developed a panel of TK6 cell lines, each expressing one of 14 human cytochrome P450 (CYP) enzymes, demonstrating their ability to effectively bioactivate indirect genotoxicants without relying on a rodent liver S9 fraction. In the present study, we extended this work by developing a TK6 cell line co-expressing four human CYP enzymes, including CYP2A6, CYP2E1, CYP2C19, and CYP3A4 (designated as TK6-4CYP), and subsequently assessed its capability to metabolize and activate pro-genotoxicants. Human lymphoblastoid TK6 cells were sequentially transduced with lentiviral vectors carrying CYP2A6/2E1 and CYP2C19/3A4, resulting in more than a 2¹⁰-fold increase in mRNA expression levels for each CYP compared to parental cells. RNA sequencing revealed selective upregulation of the four CYPs. Their protein expression and enzymatic activities were also confirmed. TK6-4CYP cells were subsequently tested with four CYP-metabolized pro-genotoxicants, including N-nitroso-diethylamine (NDEA) metabolized by CYP2A6, N-nitroso-dimethylamine (NDMA) by CYP2E1, N-nitroso-propranolol (NNP) by CYP2C19, and riddelliine by CYP3A4, in the micronucleus assay, cell cycle analysis, and comet assay. Significant increases were observed in the percentage (%) of micronuclei induction, G2/M phase arrest, and % DNA in tails with all compounds except riddelliine, which showed increases in % micronuclei induction and G2/M phase arrest but no positive response in the comet assay. This study establishes proof-of-concept for using a TK6 cell model co-expressing multiple drug-metabolizing enzymes for genotoxicity evaluation.

代谢是体外遗传毒性试验的必要条件。我们之前开发了一组TK6细胞系，每个细胞系表达14种人类细胞色素P450 （CYP）酶中的一种，证明它们能够有效地生物激活间接基因毒性物质，而不依赖于啮齿动物肝脏S9部分。在本研究中，我们扩展了这项工作，开发了一种TK6细胞系，共表达四种人类CYP酶，包括CYP2A6、CYP2E1、CYP2C19和CYP3A4（称为TK6- 4cyp），并随后评估了其代谢和激活前基因毒物的能力。人类淋巴母细胞TK6细胞依次被携带CYP2A6/2E1和CYP2C19/3A4的慢病毒载体转导，导致每个CYP的mRNA表达水平比亲本细胞增加210倍以上。RNA测序显示，这四种CYPs有选择性上调。它们的蛋白表达和酶活性也得到了证实。TK6-4CYP细胞随后用四种CYP2A6代谢的前基因毒性物质进行微核试验、细胞周期分析和彗星试验，包括由CYP2E1代谢的n -亚硝基二乙胺（NDEA）、n -亚硝基二甲胺（NDMA）、CYP2C19代谢的n -亚硝基普萘洛尔（NNP）和CYP3A4代谢的riddelliine。除riddelliine外，所有化合物的微核诱导百分比（%）、G2/M相阻滞和尾部% DNA均显著增加，而在彗星试验中，riddelliine显示微核诱导百分比和G2/M相阻滞增加，但没有阳性反应。本研究建立了使用TK6细胞模型共表达多种药物代谢酶进行遗传毒性评估的概念验证。

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引用次数: 0

Transcriptomic dose-response by UVC and heavy ion radiation reveal pathways to immune impairment UVC和重离子辐射的转录组剂量反应揭示了免疫损伤的途径

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-24 DOI: 10.1016/j.tiv.2025.106086

Mingming Tian , Xiaolin Ding , Yue Pang , Dan Xu , Yeqing Sun , Pu Xia

Irradiation-induced immune impairment has been linked to human immune diseases, such as myelodysplastic syndromes (MDS) and leukemia. Global molecular responses to genome instability in immune cells can be identified by using transcriptomics. However, it is hard to link the molecular mechanism to the disease outcomes in the previous mechanistic studies. Here, transcriptomic dose-responses in human CD4+ T lymphocytes exposed to ultraviolet and heavy ion radiation were revealed by identification of the gene expression patterns of differential expression genes (DEGs) and calculating the point of departure (POD) of each DEG and molecular pathway, which provided an opportunity for quantitively illustrating the biological process of irradiation-induced immune impairments. Two potential adverse outcome pathways (AOPs) to irradiation-related leukemia were identified by mapping the molecular pathways into the biological event cascades, which provided phenotypic anchoring for the toxicological mechanisms. In addition, this study also revealed that NOP14/ NOP14-AS1 could be potential biomarkers of irradiation-induced immune impairment. Our works strengthen the use of AOP network in the next-generation risk assessment of irradiation-related diseases.

辐照诱导的免疫损伤与人类免疫疾病有关，如骨髓增生异常综合征（MDS）和白血病。免疫细胞对基因组不稳定的全局分子反应可以通过转录组学来鉴定。然而，在以往的机制研究中，很难将分子机制与疾病结局联系起来。本研究通过鉴定差异表达基因（DEG）的基因表达模式，计算每个DEG的起点（POD）和分子通路，揭示了暴露于紫外线和重离子辐射下的人CD4+ T淋巴细胞的转录组剂量反应，为定量阐明辐照诱导免疫损伤的生物学过程提供了机会。通过将分子途径映射到生物事件级联中，确定了辐射相关白血病的两个潜在不良结局途径（AOPs），这为毒理学机制提供了表型锚定。此外，本研究还揭示了NOP14/ NOP14- as1可能是辐射诱导免疫损伤的潜在生物标志物。我们的工作加强了AOP网络在下一代辐射相关疾病风险评估中的应用。

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引用次数: 0

Molecular mechanistic approach to reveal decitabine's effect on DNMT gene modulation and its inhibitory role in heavy metal-induced proliferation in urinary bladder cancer cell line 地西他滨对重金属诱导的膀胱癌细胞DNMT基因调控及抑制作用的分子机制研究。

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-23 DOI: 10.1016/j.tiv.2025.106082

Deepika Saini , Pankaj Kumar Chaudhary , Ganesh Kumar Verma , Jitendra Kumar Chaudhary , Raman Kumar , Sarama Saha , Partha Roy , Bela Goyal , Ramasare Prasad , Anissa Atif Mirza-Shariff

Heavy metals are pervasive environmental and occupational carcinogens known to induce uncontrolled cell proliferation. They influence a number of cellular processes, including proliferation, metabolism, apoptosis, and carcinogenesis. Among the several underlying mechanisms of carcinogenesis, metal-induced aberrant modulation of DNA methyltransferase (DNMT) activity may play crucial role. In this context, our study explored the proliferative and/or cytotoxic effects of heavy metals on the T24 urinary bladder cancer cell line. Additionally, we evaluated the effects of heavy metals and the chemotherapeutic agent decitabine on DNMT expression and activity. For investigative purposes, T24 cells were exposed to different heavy metals; namely, lead (Pb), chromium (Cr), cadmium (Cd), nickel (Ni), and arsenic (As) at concentrations ranging from 0.5 to 32 μM for 24, 48, and 72 h, as well as to decitabine (1 to 64 μM) for 72 h. Post-incubation, cell proliferation and migration increased, and mitochondrial membrane potential decreased significantly in the presence of heavy metals, especially Cr and Cd. Moreover, in the presence of Cr and Cd, expression of DNMT1 and DNMT3b genes enhanced significantly. Furthermore, decitabine treatment effectively inhibited Cd- and Cr-induced proliferation and downregulated expression of DNMT genes. In conclusion, heavy metals such as Cd and Cr may contribute to urinary bladder carcinogenesis through DNMT upregulation, while decitabine showedprotective effects by suppressing DNMT expression and inhibiting cell proliferation.

重金属是普遍存在的环境和职业致癌物，已知可诱导细胞增殖。它们影响许多细胞过程，包括增殖、代谢、凋亡和癌变。在几种潜在的致癌机制中，金属诱导的DNA甲基转移酶（DNMT）活性的异常调节可能起着至关重要的作用。在此背景下，我们的研究探讨了重金属对T24膀胱癌细胞系的增殖和/或细胞毒性作用。此外，该研究还评估了重金属和化疗药物地西他滨对dnmt表达和活性的影响。为研究目的，将T24细胞暴露于重金属环境；分别为：铅（Pb）、铬（Cr）、镉（Cd）、镍（Ni）、砷（As），浓度为0.5 ~ 32 μM，作用时间为24、48、72 h；地西他斌（1 ~ 64 μM）作用时间为72 h。在重金属，尤其是Cr和Cd的存在下，孵育后细胞增殖和迁移增加，线粒体膜电位显著降低。在Cr和Cd的存在下，DNMT1和DNMT3b基因的表达显著增强。此外，地西他滨治疗可有效抑制Cd和cr诱导的细胞增殖，下调DNMT基因表达。综上所述，Cd、Cr等重金属可能通过上调DNMT参与膀胱癌的发生，而地西他滨通过抑制DNMT的表达、抑制细胞增殖发挥了显著的保护作用。

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引用次数: 0

Haemostasis-altering effects of Milos viper (Macrovipera schweizeri) venom 巨蟒毒液的止血作用

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-22 DOI: 10.1016/j.tiv.2025.106081

Ignazio Avella , Lennart Schulte , Maik Damm , Wolfgang Wüster , Andreas Vilcinskas , Tim Lüddecke

Haemotoxicity is one of the primary symptoms of viperid envenomation, manifesting in cardiovascular and haemostatic disturbances such as hypotension, haemorrhage, and coagulopathy. Bites by the Milos viper (Macrovipera schweizeri) have been reported to induce symptoms affecting the blood system, including fibrinogenolysis, erythrocytopenia, and venom-induced consumption coagulopathy. Consistent with these reports, its venom contains a variety of haemotoxic components and has been observed to exert strong procoagulant activity on human plasma. However, a more comprehensive analysis of the effects of Milos viper venom on haemostasis is currently lacking. Here, we present an in vitro evaluation of the haemostasis-altering properties of M. schweizeri venom. We conducted bioassays on key haematological targets to assess the thrombin-like, plasmin-like, coagulation Factor Xa-like, and haemolytic activities of Milos viper venom. A clear, positive concentration-dependent effect was observed in the thrombin-like and the plasmin-like activity assays, ranging from 1.6 % to 77.4 % and from 5.8 % to 82.5 %, respectively. The relatively comparable, pronounced activities detected at higher venom concentrations for these two haematological targets may align with the fibrinogenolysis and consumption coagulopathy described following M. schweizeri envenomation. Conversely, the assays revealed negligible Factor Xa-like and haemolytic activities. Our analysis provides a detailed overview of the haemostasis-altering potential of the toxin arsenal of M. schweizeri, shedding new light on its coagulotoxic effects.

血液毒性是毒蛇中毒的主要症状之一，表现为心血管和止血障碍，如低血压、出血和凝血功能障碍。据报道，被米洛斯毒蛇（Macrovipera schweizeri）咬伤会引起影响血液系统的症状，包括纤维蛋白原溶解、红细胞减少和毒液诱导的消耗性凝血功能障碍。与这些报道一致的是，它的毒液含有多种血液毒性成分，并被观察到对人血浆具有很强的促凝活性。然而，目前缺乏对米洛斯毒蛇毒液止血作用的更全面的分析。在这里，我们提出了一个体外评估的止血改变性质的瑞氏m.s weizeri毒液。我们对关键的血液学靶点进行了生物测定，以评估米氏蝰蛇毒液的凝血酶样、纤溶酶样、凝血因子xa样和溶血活性。在凝血酶样和纤溶酶样活性测定中观察到明显的阳性浓度依赖性效应，分别在1.6%至77.4%和5.8%至82.5%之间。在较高的毒液浓度下，这两种血液学目标检测到的相对可比的、明显的活性可能与施韦泽氏m.s heizeri毒液中毒后描述的纤维蛋白原溶解和消耗性凝血病一致。相反，检测显示可忽略的因子xa样和溶血活性。我们的分析提供了一个详细概述的止血改变潜力的毒素库的M. schweizeri，揭示新的光对其凝血毒性作用。

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引用次数: 0

Detection of skin sensitization hazards in medical device materials using a combination of three alternative in vitro testing methods 使用三种可选的体外测试方法组合检测医疗器械材料中的皮肤致敏危害。

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-21 DOI: 10.1016/j.tiv.2025.106084

Masayuki Okada, Harumi Tabata, Keiki Suzuki, Atsushi Kaneki

This study attempted to detect the skin sensitization hazards of medical device materials by combining multiple in vitro alternative testing methods. Nine materials were extracted using organic solvents, and the re-dissolved solutions were evaluated using the Amino acid Derivative Reactivity Assay (ADRA), Epidermal Sensitization Assay (EpiSensA), and human Cell Line Activation test (h-CLAT). The combined results of each test were compared with those of the Guinea Pig Maximization Test (GPMT) results. The findings of ADRA and h-CLAT were consistent with the GPMT results for seven of the nine materials, and EpiSensA was consistent with the GPMT results for eight of the nine materials. The findings of the “2 out of 3” and Sequential Testing Strategy (STS) approaches were compared with the GPMT results. The GMPT results for all nine materials were correctly predicted when the “2 out of 3” approach was used. When the STS was used, it correctly predicted the GMPT results for eight of the nine materials. Therefore, integrating the ADRA, EpiSensA, and h-CLAT may provide an effective testing method for detecting skin sensitization hazards of organic solvent extracts from medical device materials.

本研究试图结合多种体外替代测试方法检测医疗器械材料的皮肤致敏危害。采用有机溶剂提取9种材料，用氨基酸衍生物反应活性测定（ADRA）、表皮致敏试验（EpiSensA）和人细胞系激活试验（h-CLAT）对再溶解溶液进行评价。将各试验的综合结果与豚鼠最大化试验（GPMT）结果进行比较。ADRA和h-CLAT的结果与9种材料中的7种材料的GPMT结果一致，EpiSensA与9种材料中的8种材料的GPMT结果一致。将“2 / 3”和顺序测试策略（STS）方法的结果与GPMT结果进行比较。当使用“2 / 3”方法时，所有九种材料的GMPT结果都被正确预测。当使用STS时，它正确地预测了9种材料中的8种的GMPT结果。因此，将ADRA、EpiSensA和h-CLAT结合起来，可能为检测医疗器械材料有机溶剂提取物的皮肤致敏危害提供一种有效的检测方法。

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引用次数: 0

In vitro metabolic clearance of malathion in rats and humans 马拉硫磷在大鼠和人体内的体外代谢清除率。

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-17 DOI: 10.1016/j.tiv.2025.106080

Gopinath Nallani , Appavu Chandrasekaran , Kelem Kassahun , Li Shen , Rick Reiss , Paul Whatling

In vitro intrinsic clearance of malathion was determined in adult and juvenile rat and human liver microsomes. Due to rapid elimination with no detectable levels of the parent, clearance rates of malathion were calculated from formation kinetics of its metabolites: malathion monocarboxylic acid (MMCA) and malaoxon. To correlate in vitro data to in vivo exposure, pharmacokinetics (PK) study was performed in adult rats following a single i.v. (10 mg/kg bw) or oral dose (150 mg/kg bw). The in vitro kinetics data indicate that the metabolic clearance of malathion via formation of MMCA was at the same rate in adult and juvenile human liver microsomes (HLM), but in rat liver microsomes (RLM) the rate was about 10-fold higher in adults compared to juveniles. The rate of formation of malaoxon among the two species and age groups was within 3.5-fold difference. The formation kinetics of malaoxon represented <0.5 % of that observed for MMCA in both rats and humans. As seen in the in vitro results, following i.v. or oral dosing in rats, malathion was not detectable with MMCA being the major metabolite. The kinetics data from this study were useful for the development of a PBPK model for malathion.

测定了成年、幼年大鼠和人肝微粒体对马拉硫磷的体外内在清除率。由于消除速度快，没有检测到母体的水平，马拉硫磷的清除率是通过其代谢物：马拉硫磷单羧酸（MMCA）和马拉硫磷的形成动力学计算的。为了将体外数据与体内暴露相关联，对成年大鼠进行了单次静脉注射（10 mg/kg bw）或口服剂量（150 mg/kg bw）后的药代动力学（PK）研究。体外动力学数据表明，马拉硫磷在成人和幼年人肝微粒体（HLM）中通过MMCA形成的代谢清除率相同，但在成年大鼠肝微粒体（RLM）中，其清除率比幼年高约10倍。两种和年龄组间malaoxon的形成率差异在3.5倍以内。表征了丙二醇的形成动力学

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引用次数: 0

Selective JAK-1 inhibitor Upadacitinib and peptide PD29 modulate the JAK and TGF-β/Smad signaling pathways reducing experimental dermal fibrosis 选择性JAK-1抑制剂Upadacitinib和肽PD29调节JAK和TGF-β/Smad信号通路，减少实验性皮肤纤维化。

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-15 DOI: 10.1016/j.tiv.2025.106078

Ayşe Koçak , Cemre Ural , Zahide Cavdar , Sulen Sarioğlu , Gül Akdoğan , Merih Birlik

This study investigates the antifibrotic and anti-inflammatory effects of Janus kinase (JAK) inhibitors and the PD29 peptide in the context of systemic sclerosis (SSc), a condition characterized by dermal thickening, chronic inflammation, and excessive extracellular matrix deposition. Pulmonary arterial hypertension (PAH) and pulmonary fibrosis represent serious and often fatal complications associated with SSc. The pathogenesis of SSc involves dysregulation of immune responses and aberrant activation of signaling pathways, including TGF-β/Smad.

The antifibrotic properties of upadacitinib, a selective JAK1 inhibitor, and PD29 peptide were evaluated using a bleomycin-induced SSc mouse model and primary human lung fibroblasts. Both agents, administered individually or in combination, significantly attenuated dermal thickening, myofibroblast transdifferentiation, collagen deposition, and activation of the TGF-β1 signaling axis.

In vivo and in vitro analyses demonstrated that upadacitinib and PD29 downregulated key fibrotic markers, including α-SMA, JAK1, TGF-β1, Smad2, and collagen-1, at both the gene and protein levels. Furthermore, treatment significantly reduced systemic inflammatory cytokines, including IL-6 and TNF-α. Notably, combination therapy exhibited a more pronounced effect compared to monotherapy.

These findings suggest that upadacitinib and PD29 exert potent antifibrotic and anti-inflammatory effects through suppression of TGF-β1-mediated Smad2/3 signaling, predominantly via inhibition of JAK1 activation. Consequently, JAK inhibitors and PD29 represent promising therapeutic candidates for the management of fibrosis in systemic sclerosis.

本研究探讨了Janus激酶（JAK）抑制剂和PD29肽在系统性硬化症（SSc）中的抗纤维化和抗炎作用。系统性硬化症是一种以皮肤增厚、慢性炎症和过度的细胞外基质沉积为特征的疾病。肺动脉高压（PAH）和肺纤维化是与SSc相关的严重且往往致命的并发症。SSc的发病机制涉及免疫反应的失调和信号通路的异常激活，包括TGF-β/Smad。采用博来霉素诱导的SSc小鼠模型和原代人肺成纤维细胞，研究了JAK1选择性抑制剂upadacitinib和PD29肽的抗纤维化特性。这两种药物，单独或联合使用，显著减弱真皮增厚、肌成纤维细胞转分化、胶原沉积和TGF-β1信号轴的激活。体内和体外分析表明，upadacitinib和PD29在基因和蛋白水平上下调关键纤维化标志物，包括α-SMA、JAK1、TGF-β1、Smad2和胶原-1。此外，治疗显著降低了全身炎症细胞因子，包括IL-6和TNF-α。值得注意的是，与单一治疗相比，联合治疗表现出更明显的效果。这些发现表明upadacitinib和PD29通过抑制TGF-β1介导的Smad2/3信号通路（主要通过抑制JAK1激活）发挥有效的抗纤维化和抗炎作用。因此，JAK抑制剂和PD29是治疗系统性硬化症纤维化的有希望的治疗候选者。

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引用次数: 0

Cadmium sulfide nanoparticles (CdSNPs) modulate key oncogenic pathways in PA1 ovarian cancer cells: Insights from transcriptomic analysis 硫化镉纳米颗粒（CdSNPs）调节PA1卵巢癌细胞的关键致癌途径：来自转录组学分析的见解

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-13 DOI: 10.1016/j.tiv.2025.106079

Aditi Bhatnagar , Abhay Dev Tripathi , Sonali Kumari, Abha Mishra

Transcriptomics has become a useful tool for comparing the levels of gene expression in healthy and malignant cells, holding potential for the discovery of new cancer therapies. This study used RNA-sequencing and transcriptome analysis on the PA1 ovarian cancer cell line to examine the potential of Cadmium Sulfide Nanoparticles (CdSNPs) as a therapeutic agent. A total of 5.42 Gb of high-quality reads was estimated based on the findings of gene expression techniques, comprising 2.25 Gb of treated PA1 cells and 3.17 Gb of control cells. Of these, 1641 genes with padj<0.001 and log2 foldchange >2 were found to be significantly regulated DEGs (differentially expressed genes). Analysis of gene ontology (GO) assays demonstrates the molecular mechanism behind CdSNPs anticancer effects. GO:0006915, GO:0012501, GO:1903561, and GO:0070588 are a few significant highlights of elevated GO (enriched DEGs) that are involved in apoptotic pathways, extracellular vesicles, programmed cell death, and Ca++ signaling. KEGG analysis elucidated that up and downregulated DEGs were enriched in a few pathways: calcium signaling pathway, Apoptosis, and TNF signaling pathway. Important pathways like MAP kinase, JAK/STAT, cAMP, and folate biosynthesis, showed inhibitory effects on ovarian cancer cell proliferation. The results of this work provide insight into possible therapeutic approaches employing CdSNPs and encourage additional research using a variety of cell lines and in vivo models to improve ovarian cancer treatment.

转录组学已经成为比较健康和恶性细胞中基因表达水平的有用工具，具有发现新的癌症治疗方法的潜力。本研究通过对PA1卵巢癌细胞系的rna测序和转录组分析来研究硫化镉纳米颗粒（CdSNPs）作为治疗剂的潜力。根据基因表达技术的结果，共估计出5.42 Gb的高质量reads，其中处理过的PA1细胞为2.25 Gb，对照细胞为3.17 Gb。其中，1641个padj<；0.001和log2fold change >；2的基因被发现显著调节deg（差异表达基因）。基因本体论（GO）分析表明CdSNPs抗癌作用背后的分子机制。GO:0006915、GO:0012501、GO:1903561和GO:0070588是氧化石墨烯（富集的DEGs）升高的几个重要亮点，这些氧化石墨烯（富集的DEGs）参与凋亡途径、细胞外囊泡、程序性细胞死亡和钙离子信号传导。KEGG分析表明，上调和下调的DEGs富集于钙信号通路、凋亡信号通路和TNF信号通路。MAP激酶、JAK/STAT、cAMP、叶酸生物合成等重要通路对卵巢癌细胞增殖有抑制作用。这项工作的结果为利用CdSNPs的可能治疗方法提供了见解，并鼓励使用各种细胞系和体内模型进行进一步的研究，以改善卵巢癌的治疗。

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引用次数: 0

Zinc finger transcription factor ZNF384 mitigates LPS-induced ferroptosis and inflammation in lung epithelial cells by activating SESN2-mediated autophagy 锌指转录因子ZNF384通过激活sesn2介导的自噬，减轻lps诱导的肺上皮细胞铁凋亡和炎症

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-13 DOI: 10.1016/j.tiv.2025.106073

Lu Shi , Hongxue Fu , Yingting Hao , Chang Liu , Fachun Zhou

Background

Ferroptosis, a type of programmed cell death distinct from apoptosis, is potentially associated with sepsis-triggered acute respiratory distress syndrome (ARDS). ZNF384 is a transcription factor, but its role in ARDS remain unclear.

Methods

Blood samples were collected from sepsis-induced ARDS patients and healthy controls. BEAS-2B cells were stimulated with lipopolysaccharide (LPS) to mimic sepsis-induced damaged lung epithelial cell model. Gene and protein expression were elevated utilizing RT-qPCR, western blot, and immunofluorescent staining, respectively. Cell viability and death were evaluated by CCK-8 and flow cytometry. Inflammatory cytokines and oxidative stress markers were measured using ELISA. Intracellular ROS was determined using DCFH-DA staining. Iron concentration was measured using an iron detection kit. Target relationships were confirmed through ChIP and luciferase reporter assays.

Results

ZNF384 and SESN2 levels were downregulated in sepsis-induced ARDS patients. Overexpression of ZNF384 reduced inflammatory injury, ferroptosis and enhanced autophagy in LPS-stimulated BEAS-2B cells. Mechanistically, ZNF384 served as transcriptional activator of SESN2 to boost autophagy activation. Rescue experiments validated that depletion of SESN2 strikingly reversed the regulatory function of ZNF384 in LPS-induced inflammation, autophagy and ferroptosis.

Conclusion

ZNF384 alleviated LPS-triggered ferroptosis and inflammation in BEAS-2B cells via activating SESN2-mediated autophagy, indicating ZNF384 was a novel target for ARDS treatment.

背景：铁凋亡是一种不同于细胞凋亡的程序性细胞死亡，可能与败血症引发的急性呼吸窘迫综合征（ARDS）有关。ZNF384是一种转录因子，但其在ARDS中的作用尚不清楚。方法采集脓毒症致ARDS患者和健康对照者的血液样本。用脂多糖（LPS）刺激BEAS-2B细胞模拟脓毒症诱导的肺上皮细胞损伤模型。利用RT-qPCR、western blot和免疫荧光染色分别检测基因和蛋白的表达。采用CCK-8和流式细胞术检测细胞活力和死亡情况。采用ELISA法检测炎症因子和氧化应激标志物。DCFH-DA染色测定细胞内ROS。用铁检测试剂盒测定铁浓度。通过ChIP和荧光素酶报告基因检测确认靶关系。结果znf384和SESN2水平在脓毒症诱导的ARDS患者中下调。过表达ZNF384可减轻lps刺激的BEAS-2B细胞的炎症损伤、铁凋亡和自噬增强。从机制上讲，ZNF384作为SESN2的转录激活因子促进自噬激活。救援实验证实，SESN2的缺失显著逆转了ZNF384在lps诱导的炎症、自噬和铁凋亡中的调节功能。结论ZNF384通过激活sesn2介导的自噬，减轻了lps引发的BEAS-2B细胞铁凋亡和炎症，提示ZNF384是治疗ARDS的新靶点。

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引用次数: 0

The Alarming Consequences of Workforce Reductions at the FDA, EPA, NIH and CDC in the United States 美国FDA、EPA、NIH和CDC裁员的惊人后果

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-05-03 DOI: 10.1016/j.tiv.2025.106077

引用次数: 0