Archives of Toxicology最新文献_第4页

Mitigation of depleted uranium-induced mitochondrial damage by ethylmalonic encephalopathy 1 protein via modulation of hydrogen sulfide and glutathione pathways. 通过硫化氢和谷胱甘肽途径调节乙基丙二酸脑病1蛋白减轻贫铀诱导的线粒体损伤

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-27 DOI: 10.1007/s00204-024-03949-2

Juan Li, Yong Li, Yazhen Zhao, Suiyi Liu, Wenrun Li, Huanhuan Tan, Li Shen, Yonghong Ran, Yuhui Hao

{"title":"Mitigation of depleted uranium-induced mitochondrial damage by ethylmalonic encephalopathy 1 protein via modulation of hydrogen sulfide and glutathione pathways.","authors":"Juan Li, Yong Li, Yazhen Zhao, Suiyi Liu, Wenrun Li, Huanhuan Tan, Li Shen, Yonghong Ran, Yuhui Hao","doi":"10.1007/s00204-024-03949-2","DOIUrl":"https://doi.org/10.1007/s00204-024-03949-2","url":null,"abstract":"Depleted uranium (DU) is a byproduct of uranium enrichment, which can cause heavy-metal toxicity and radiation toxicity as well as serious damage to the kidneys. However, the mechanism of renal injury induced by DU is still unclear. This study aimed to explore the role of ethylmalonic encephalopathy 1 (ETHE1) in DU-induced mitochondrial dysfunction and elucidate the underlying mechanisms. Using ETHE1 gene knockout C57BL/6 mice (10 mg/kg DU) and renal cell models (500 µM DU) exposed to DU, we observed significantly reduced levels of hydrogen sulfide (H2S) and glutathione (GSH), alongside decreased adenosine triphosphate (ATP) content and increased oxidative stress. Our results demonstrated that knocking out or silencing ETHE1 led to a significant reduction in H2S and GSH levels, whereas the opposite occurred when was ETHE1 overexpressed. When the H2S donor sodium hydrosulfide and GSH precursor N-acetylcysteine were used to treat animals or cells, cellular ATP levels were increased, oxidative stress markers were reduced, and kidney damage was mitigated. In addition, H2S and GSH interacted with each other after DU poisoning. These findings suggest that the ETHE1/H2S/GSH pathway plays a critical role in mediating DU-induced mitochondrial dysfunction in renal cells, highlighting potential therapeutic targets for mitigating the harmful effects of DU. Thus, this study expands our understanding of DU-induced renal damage pathways, providing avenues for further research and intervention strategies.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Accelerating antiviral drug discovery: early hazard detection with a dual zebrafish and cell culture screen of a 403 compound library. 加速抗病毒药物的发现：利用斑马鱼和细胞培养筛选403化合物文库的早期危险检测。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-27 DOI: 10.1007/s00204-024-03948-3

Lisa Truong, Andrew A Bieberich, Raymond O Fatig, Bartek Rajwa, Michael T Simonich, Robyn L Tanguay

{"title":"Accelerating antiviral drug discovery: early hazard detection with a dual zebrafish and cell culture screen of a 403 compound library.","authors":"Lisa Truong, Andrew A Bieberich, Raymond O Fatig, Bartek Rajwa, Michael T Simonich, Robyn L Tanguay","doi":"10.1007/s00204-024-03948-3","DOIUrl":"https://doi.org/10.1007/s00204-024-03948-3","url":null,"abstract":"The constant emergence of new viral pathogens underscores the need for continually evolving, effective antiviral drugs. A key challenge is identifying compounds that are both efficacious and safe, as many candidates fail during development due to unforeseen toxicity. To address this, the embryonic zebrafish morphology, mortality, and behavior (ZBE) screen and the SYSTEMETRIC® Cell Health Screen (CHS) were employed to evaluate the safety of 403 compounds from the Cayman Antiviral Screening Library. Of these compounds, 114 were FDA-approved, 17 were discontinued, and 97 remained on the market. CHS identified 25% (104 compounds) as toxic, with a Cell Health Index™ (CHI) > 0.5. The embryonic zebrafish model identified an additional 20% as toxic (79), bringing the total to 183. ZBEscreen flagged 19 toxic hits among compounds still on the market, seven of which were also identified by CHS. The combined use of CHS and zebrafish models enhanced hazard detection. Together, CHS and ZBEscreen identified 45.5% of the library as potentially hazardous. Notably, the zebrafish non-hazardous compounds correlated strongly with over-the-counter or prescribed antiviral drugs, confirming their known safety profile. Over 130 hazard-associated compounds warranted further investigation. Using self-organizing maps, six distinct neighborhoods of compound similarity were identified. This dual approach streamlined the early detection of hazards associated with promising leads and is expected to facilitate faster, safer antiviral discovery.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Drug protection against radiation-induced neurological injury: mechanisms and developments. 辐射性神经损伤的药物保护：机制和进展。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-26 DOI: 10.1007/s00204-024-03933-w

Qingyu Wang, Caimao Guo, Tiantian Wang, Peimeng Shuai, Wenyu Wu, Shuqi Huang, Yuanyuan Li, Pei Zhao, Chengkai Zeng, Lan Yi

{"title":"Drug protection against radiation-induced neurological injury: mechanisms and developments.","authors":"Qingyu Wang, Caimao Guo, Tiantian Wang, Peimeng Shuai, Wenyu Wu, Shuqi Huang, Yuanyuan Li, Pei Zhao, Chengkai Zeng, Lan Yi","doi":"10.1007/s00204-024-03933-w","DOIUrl":"https://doi.org/10.1007/s00204-024-03933-w","url":null,"abstract":"In daily life, individuals are frequently exposed to various forms of radiation, which, when adhering to safety standards, typically result in relatively minor health effects. However, accidental exposure to radiation levels that exceed these safety standards can lead to significant health consequences. This study focuses on the analysis of radiation-induced damage to the nervous system and the mechanisms of pharmacological protection. The findings indicate that radiation can adversely affect neural structures, memory, and neurobehaviour. A range of pharmacological agents, including traditional Chinese medicine, Western medicine, and other therapeutic drugs, can be employed to safeguard the nervous system from radiation damage. The primary protective mechanisms of these agents encompass antioxidant effects, attenuation of apoptosis, and reduction of neurogenesis. A comprehensive review of these topics will offer new insights for the development and investigation of drugs aimed at mitigating radiation-induced damage to the nervous system.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Drug-induced hepatic sinusoidal obstruction syndrome: current advances and future perspectives. 药物性肝窦阻塞综合征：目前进展和未来展望。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-24 DOI: 10.1007/s00204-024-03950-9

Zaoqin Yu, Wei Li, Cheng Tian, Yan Cao, Chengliang Zhang

引用次数: 0

The fungicide propiconazole induces hepatic steatosis and activates PXR in a mouse model of diet-induced obesity. 在饮食性肥胖小鼠模型中，杀菌剂丙环康唑诱导肝脂肪变性并激活PXR。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-24 DOI: 10.1007/s00204-024-03942-9

Brecht Attema, Outi Kummu, Mária Krutáková, Petr Pavek, Jukka Hakkola, Guido J E J Hooiveld, Sander Kersten

{"title":"The fungicide propiconazole induces hepatic steatosis and activates PXR in a mouse model of diet-induced obesity.","authors":"Brecht Attema, Outi Kummu, Mária Krutáková, Petr Pavek, Jukka Hakkola, Guido J E J Hooiveld, Sander Kersten","doi":"10.1007/s00204-024-03942-9","DOIUrl":"https://doi.org/10.1007/s00204-024-03942-9","url":null,"abstract":"Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of the cyto- and genotoxicity of two types of cellulose nanomaterials using human intestinal cells and in vitro digestion simulation 利用人体肠道细胞和体外消化模拟评估两种纤维素纳米材料的细胞毒性和遗传毒性。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-24 DOI: 10.1007/s00204-024-03911-2

Nádia Vital, Maria Cardoso, Michel Kranendonk, Maria João Silva, Henriqueta Louro

{"title":"Evaluation of the cyto- and genotoxicity of two types of cellulose nanomaterials using human intestinal cells and in vitro digestion simulation","authors":"Nádia Vital, Maria Cardoso, Michel Kranendonk, Maria João Silva, Henriqueta Louro","doi":"10.1007/s00204-024-03911-2","DOIUrl":"10.1007/s00204-024-03911-2","url":null,"abstract":"<div>Emerging cellulose nanomaterials (CNMs) may have commercial impacts in multiple sectors, being their application particularly explored in the food sector. Thus, their potential adverse effects in the gastrointestinal tract should be evaluated before marketing. This work aimed to assess the safety of two CNMs (CNF–TEMPO and CMF–ENZ) through the investigation of their cytotoxicity, genotoxicity (comet and micronucleus assays), and capacity to induce reactive oxygen species in human intestinal cells, and their mutagenic effect using the Hprt gene mutation assay. Each toxicity endpoint was analysed after cells exposure to a concentration-range of each CNM or to its digested product, obtained by the application of a standardized static in vitro digestion method. The results showed an absence of cytotoxic effects in intestinal cells, up to the highest concentration tested (200 µg/mL or 25 µg/mL, for non-digested and digested CNMs, respectively). Of note, the cytotoxicity of the digestion control limited the top concentration of digested samples (25 µg/mL) for subsequent assays. Application of a battery of in vitro assays showed that CNF–TEMPO and CMF–ENZ do not induce gene mutations or aneugenic/clastogenic effects. However, due to the observed DNA damage induction, a genotoxic potential cannot be excluded, even though in vitro digestion seems to attenuate the effect. The lowest digested CNF–TEMPO concentration induced chromosomal damage in Caco-2 cells, leading to an equivocal outcome. Ongoing research on epigenotoxic effects of these CNMs samples may strengthen the lines of evidence on their safety when ingested, paving the way for their innovative application in the food industry.</div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"575 - 596"},"PeriodicalIF":4.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dermal penetration of 2-phenoxyethanol in humans: in vivo metabolism and toxicokinetics. 2-苯氧乙醇在人体内的皮肤渗透：体内代谢和毒性动力学。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-24 DOI: 10.1007/s00204-024-03938-5

Elisabeth Eckert, Thomas Jäger, Edgar Leibold, Michael Bader, Thomas Göen, Julia Hiller

{"title":"Dermal penetration of 2-phenoxyethanol in humans: in vivo metabolism and toxicokinetics.","authors":"Elisabeth Eckert, Thomas Jäger, Edgar Leibold, Michael Bader, Thomas Göen, Julia Hiller","doi":"10.1007/s00204-024-03938-5","DOIUrl":"https://doi.org/10.1007/s00204-024-03938-5","url":null,"abstract":"2-Phenoxyethanol (PhE) is an amphiphilic organic compound frequently used as a broad-spectrum preservative in cosmetic products and other consumer goods. PhE is also used as a biocidal component in occupational settings. A previous volunteer study by our working group following oral exposure to PhE showed that PhE is almost completely taken up into the human body followed by an extensive metabolization and fast urinary elimination. However, with respect to the importance of transdermal uptake, we now conducted another volunteer study applying dermal PhE exposure: five volunteers were dermally exposed with 0.4 mg/kg body weight of PhE each on a specified 800 cm2 skin area using non-occlusive conditions. Subsequently, blood and urine samples were collected up to 48 h post-exposure. The present study illustrates the fast transdermal uptake of PhE. Following systemic resorption, PhE was extensively metabolized and rapidly eliminated in urine mainly in form of the metabolites PhAA (phenoxyacetic acid) and 4-OH-PhAA (4-hydroxyphenoxyacetic acid) accounting together for over 99% of the renally excreted PhE dose. The absolute urinary recovery rate of PhE was observed to be significantly lower following dermal exposure compared to oral uptake indicating a dermal resorption rate of PhE of about 45% in humans. The present study provides for the first time detailed insights into human biotransformation and toxicokinetics of PhE after dermal exposure, thus establishing a reliable strategy for human biomonitoring of PhE. The here presented results may thus be useful for further toxicokinetic modeling and forward dosimetry.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of Hedgehog modulators on signaling pathways in primary murine and human hepatocytes in vitro: insights into liver metabolism. Hedgehog调节剂对小鼠和人原代肝细胞信号通路的影响：对肝脏代谢的见解。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-23 DOI: 10.1007/s00204-024-03931-y

Fritzi Ott, Christiane Körner, Knut Krohn, Janett Fischer, Georg Damm, Daniel Seehofer, Thomas Berg, Madlen Matz-Soja

{"title":"Impact of Hedgehog modulators on signaling pathways in primary murine and human hepatocytes in vitro: insights into liver metabolism.","authors":"Fritzi Ott, Christiane Körner, Knut Krohn, Janett Fischer, Georg Damm, Daniel Seehofer, Thomas Berg, Madlen Matz-Soja","doi":"10.1007/s00204-024-03931-y","DOIUrl":"https://doi.org/10.1007/s00204-024-03931-y","url":null,"abstract":"The Hedgehog (Hh) signaling pathway is essential for maintaining homeostasis during embryogenesis and in adult tissues. In the liver, dysregulation of this pathway often leads to liver cancer development. Recent studies also suggest that disturbances in the Hh pathway can affect liver metabolism in healthy livers through interactions with other signaling pathways, such as the Wnt/β-catenin pathway. As a result, the Hh pathway has emerged as a promising target for therapeutic intervention. However, little is known about the effects of Hh modulators on healthy hepatocytes. In our study, we investigated the effects of the Hh agonists SAG (300 nM) and triamcinolone acetonide (40 µM), as well as the antagonists RU-SKI 43 (100 nM), cyclopamine (5 µM), budesonide (25 µM), GANT61 (0.5 µM), and vismodegib (1 µM) on healthy mouse and human primary hepatocytes in vitro. We employed toxicological, transcriptomic, proteomic, and functional assays, including proliferation and Seahorse assays. Our results show that these compounds significantly impact metabolic pathways such as lipid and glucose metabolism at both transcriptional and protein levels. Mechanistically, our data suggest the involvement of both canonical and non-canonical Hedgehog pathways, a phenomenon not previously described in hepatocytes. These findings highlight the diverse effects of these compounds on signaling and key metabolic functions in the liver, which emphasizes the need to investigate the hepatic Hh cascade and its metabolic control in depth. As the compounds regulate different aspects of metabolism, they need to be carefully studied in appropriate model systems for specific therapeutic use.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Involvement of gut microbiota in chlorpyrifos-induced subchronic toxicity in mice. 肠道菌群参与毒死蜱诱导的小鼠亚慢性毒性。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-23 DOI: 10.1007/s00204-024-03934-9

Xiaohua Song, Xinyi Li, Yuzhen Wang, Yi-Jun Wu

{"title":"Involvement of gut microbiota in chlorpyrifos-induced subchronic toxicity in mice.","authors":"Xiaohua Song, Xinyi Li, Yuzhen Wang, Yi-Jun Wu","doi":"10.1007/s00204-024-03934-9","DOIUrl":"https://doi.org/10.1007/s00204-024-03934-9","url":null,"abstract":"Chlorpyrifos (CPF) is one of the most widely used organophosphorus pesticides all over the world. Unfortunately, long-term exposure to CPF may cause considerable toxicity to organisms. Some evidence suggests that the intestinal microbial community may be involved in regulating the toxicity of CPF. In this study, we explored if the intestinal microbial community is involved in regulating the toxicity of CPF. Adult mice were continuously exposed to CPF (4 mg/kg body weight /day) for 10 weeks with or without a 2-week pretreatment of antibiotics to change the ecological structure of intestinal microorganisms in advance. Pathological changes in the liver and kidneys were examined and the biochemical parameters in serum for liver and kidney functions were detected, and changes in the intestinal microbial community of the mice were measured. The results showed that subchronic exposure to low-dose CPF caused an ecological imbalance in the intestinal flora and caused pathological damage to the liver and kidneys. Serum biochemical indicators for liver function such as alanine aminotransferase and total bile acids contents and renal biochemical indicators such as urea nitrogen and creatinine were disrupted. Changes in intestinal microbial community structure by using antibiotics in advance can effectively alleviate the pathological and functional damage to the liver and kidneys caused by CPF exposure. Further analysis showed that intestinal microorganisms such as Saccharibacteria (TM7), Odoribacter, Enterococcus and AF12 genera may be involved in managing the toxicity of CPF. Together, our results indicated that long-term low-dose CPF exposure could induce hepatotoxicity and nephrotoxicity, and liver and kidney damage may be mitigated by altering the ecology of intestinal microorganisms.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A new human autologous hepatocyte/macrophage co-culture system that mimics drug-induced liver injury-like inflammation. 一种新的人类自体肝细胞/巨噬细胞共培养系统，模拟药物诱导的肝损伤样炎症。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-12-22 DOI: 10.1007/s00204-024-03943-8

Andrea Zimmermann, Andrea Scheffschick, René Hänsel, Hannes Borchardt, Jia Li Liu, Sabrina Ehnert, Gerda Schicht, Lena Seidemann, Achim Aigner, Susanne Schiffmann, Andreas Nüssler, Daniel Seehofer, Georg Damm

{"title":"A new human autologous hepatocyte/macrophage co-culture system that mimics drug-induced liver injury-like inflammation.","authors":"Andrea Zimmermann, Andrea Scheffschick, René Hänsel, Hannes Borchardt, Jia Li Liu, Sabrina Ehnert, Gerda Schicht, Lena Seidemann, Achim Aigner, Susanne Schiffmann, Andreas Nüssler, Daniel Seehofer, Georg Damm","doi":"10.1007/s00204-024-03943-8","DOIUrl":"https://doi.org/10.1007/s00204-024-03943-8","url":null,"abstract":"The development of in vitro hepatocyte cell culture systems is crucial for investigating drug-induced liver injury (DILI). One prerequisite for monitoring DILI related immunologic reactions is the extension of primary human hepatocyte (PHH) cultures towards the inclusion of macrophages. Therefore, we developed and characterized an autologous co-culture system of PHH and primary human hepatic macrophages (hepM) (CoC1). We compared CoC1 with a co-culture of the same PHH batch + M0 macrophages derived from THP1 cells (CoC2) in order to represent a donor independent macrophage reaction. Then, we treated the mono- and co-cultures with drugs that cause DILI-menadione (MEN, 1 or 10 µM, 3 h), diclofenac (DIC, 0.5 or 5 mM, 6 h), or acetaminophen (APAP, 0.5 or 5 mM, 6 h)-and assessed culture stability, cell activity, macrophage differentiation, cytokine production and cell viability. Without drug treatment, CoC1 was the most stable over a culture time of up to 60 h. Cytokine array analysis revealed a proinflammatory profile of PHH mono-cultures due to isolation stress but showed different influences of hepM and M0 on the cytokine profile in the co-cultures. MEN, DIC and APAP treatment led to donor-dependent signs of cell stress and toxicity. HepM can either promote or reduce the DILI effects donor dependently in CoC1. CoC2 are slightly less sensitive than CoC1 in representing DILI. In summary, we present a new autologous co-culture system that can mimic DILI in a donor-dependent manner. This cellular system could be useful for new drug testing strategies and reducing animal testing.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0