Journal of Applied Toxicology最新文献

{"title":"Bifidobacterium longum subsp. infantis YLGB‐1496—Toxicological evaluation","authors":"Jian Zhao, Yueyi Guo, Qiuyue Jiang, Hanglian Lan, Wei‐Lian Hung, Barry Lynch","doi":"10.1002/jat.4688","DOIUrl":"https://doi.org/10.1002/jat.4688","url":null,"abstract":"<jats:styled-content style=\"fixed-case\"><jats:italic>Bifidobacterium infantis</jats:italic></jats:styled-content> YLGB‐1496, originally isolated from breast milk from a Taiwanese mother, is under study for use as a probiotic. As part of safety assessment, an Ames, in vivo mouse micronucleus, and in vivo mouse spermatocyte chromosome aberration assay were conducted along with a 13‐week oral rat toxicity study. <jats:styled-content style=\"fixed-case\"><jats:italic>B. infantis</jats:italic></jats:styled-content> YLGB‐1496 had no activity in any of the genotoxicity assays. Administration of the bacteria to Sprague–Dawley rats at doses ranging from 0 to 1.5 g/kg bw/day had no treatment‐related effects on any of the endpoints measured. There appear to be no concerns for translocation or pathogenicity of <jats:styled-content style=\"fixed-case\"><jats:italic>B. infantis</jats:italic></jats:styled-content> YLGB‐1496 based on extensive experience with the species in general. The results of the current investigations support potential use of <jats:styled-content style=\"fixed-case\"><jats:italic>B. infantis</jats:italic></jats:styled-content> YLGB‐1496 as a probiotic in infant formula.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"4 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concentration-dependent effects of the nerve agents cyclosarin and VX on cytochrome P450 in a HepaRG cell-based liver model.","authors":"Gabriele Horn, Franziska Frielingsdorf, Tobias Demel, Simone Rothmiller, Franz Worek, Niko Amend","doi":"10.1002/jat.4694","DOIUrl":"https://doi.org/10.1002/jat.4694","url":null,"abstract":"<p><p>The exposure to highly toxic organophosphorus (OP) compounds, including pesticides and nerve agents, is an ongoing medical challenge. OP can induce the uncontrolled overstimulation of the cholinergic system through inhibition of the enzyme acetylcholinesterase (AChE). The cytochrome P450 (CYP) enzymes in the liver play a predominant role in the metabolism of xenobiotics and are involved in the oxidative biotransformation of most clinical drugs. Previous research concerning the interactions between OP and CYP has usually focused on organothiophosphate pesticides that require CYP-mediated bioactivation to their active oxon metabolites to act as inhibitors of AChE. Since there has been little data available concerning the effect of nerve agents on CYP, we performed a study with cyclosarin (GF) and O-ethyl-S-[2-(diisopropylamino)-ethyl]-methylphosphonothioate (VX) by using a well-established, metabolically competent in vitro liver model (HepaRG cells). The inhibitory effect of the nerve agents GF and VX on the CYP3A4 enzyme was investigated showing a low CYP3A4 inhibitory potency. Changes on the transcription level of CYP and associated oxygenases were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using the two nerve agent concentrations 250 nM and 250 μM. In conclusion, the results demonstrated various effects on oxygenase-associated genes in dependence of the concentration and the structure of the nerve agent. Such information might be of relevance for potential interactions between nerve agents, antidotes or other clinically administered drugs, which are metabolized by the affected CYP, for example, for the therapy with benzodiazepines, that are used for the symptomatic treatment of OP poisoning and that require CYP-mediated biotransformation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of vehicle on the in vitro penetration and metabolism of genistein and daidzein in ex vivo skin explants and the Phenion full-thickness skin model.","authors":"Camille Géniès, Corinne Jeanjean, Abdulkarim Najjar, Andreas Schepky, Daniela Lange, Jochen Kühnl, Eric Fabian, Anne Zifle, Helene Duplan, Nicola J Hewitt, Carine Jacques","doi":"10.1002/jat.4693","DOIUrl":"https://doi.org/10.1002/jat.4693","url":null,"abstract":"<p><p>In a read-across assessment of the safety of genistein and daidzein in cosmetic products, additional information was required to account for differences in their systemic exposure after topical application in a typical body lotion formulation. Therefore, we measured the penetration and metabolism of two doses (3 and 30 nmoles/cm²) of genistein and daidzein applied in ethanol and in a body formulation to fresh pig skin, fresh and frozen human skin, and PhenionFT models. Both chemicals readily penetrated all skin models when applied in ethanol. The same sulfate and glucuronide metabolites were formed in fresh pig skin, fresh human skin, and PhenionFT models, which also all demonstrated that (a) these pathways could be saturated between 3 and 30 nmoles/cm² and (b) the extent of metabolism of daidzein was lower than genistein. Although the relative amounts of radiolabeled chemical in human skin and medium compartments were altered by freezing, their overall bioavailability was not affected. The greatest impact on the bioavailability and distribution of both chemicals was observed when they were applied in the formulation. Most of the dose applied in the formulation was retained on the skin surface, especially at 30 nmoles/cm² (60%-90%), resulting in much lower amounts in the medium and/or skin. In conclusion, all four skin models demonstrated first-pass metabolism of genistein and daidzein and a marked alteration in their disposition by applying them in a body lotion formulation. This supports the use of fresh pig skin and PhenionFT models as alternatives to human skin for investigating skin metabolism and formulation effects for these two chemicals. The results were used to develop the dermal module of a PBPK model and dose setting for organ-on-chip experiments. They could also be used to refine internal exposure estimates in regulatory safety assessments.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the in vitro penetration and first-pass metabolism of genistein and daidzein using human and pig skin explants and Phenion full-thickness skin models.","authors":"Camille Géniès, Corinne Jeanjean, Abdulkarim Najjar, Andreas Schepky, Daniela Lange, Jochen Kühnl, Eric Fabian, Anne Zifle, Hélène Duplan, NIcola J Hewitt, Carine Jacques","doi":"10.1002/jat.4689","DOIUrl":"https://doi.org/10.1002/jat.4689","url":null,"abstract":"<p><p>OECD test guideline compliant skin penetration studies, which also comply with the SCCS basic criteria, are lacking for genistein and daidzein. Therefore, we have measured their penetration and metabolism using ex vivo explants of fresh (i.e., metabolically viable) pig skin, fresh and frozen human skin, and Phenion full-thickness (FT) models. Preliminary studies using fresh pig skin helped to define the optimal experimental conditions. The dermal absorption of 10 nmoles/cm² genistein and daidzein in ethanol was comparable in all four models. A first-pass metabolism in skin to glucuronide and sulfate metabolites was demonstrated for both chemicals in all models except frozen human skin. The main difference between fresh skin models was the overall extent of metabolism and the relative ratio of each metabolite, for example, much lower sulfate conjugates were formed in pig skin incubations. The extent of parent chemical metabolized and the contribution of the glucuronide pathway were relatively lower in PhenionFT models than in fresh human skin, possibly due to a higher penetration rate in this model and differences in the expression of functional metabolizing enzymes. When metabolism in human skin was abolished by freezing, more radiolabelled chemical remained in the skin tissue but the overall dermal absorption was unchanged. In conclusion, this initial characterization study showed that all models tested indicated that genistein and daidzein extensively penetrated the skin when applied to skin in ethanol. All fresh skin models produced the same metabolites, with the known species difference in the sulfation pathway demonstrated in pig skin.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic alternations in the SYP and DLG4 genes due to low-level methylmercury exposure during neuronal differentiation in vitro","authors":"Hisaka Kurita,&nbsp;Haruka Masuda,&nbsp;Ayu Okuda,&nbsp;Suzuna Go,&nbsp;Kazuki Ohuchi,&nbsp;Hiroki Yoshioka,&nbsp;Masatake Fujimura,&nbsp;Isao Hozumi,&nbsp;Masatoshi Inden","doi":"10.1002/jat.4690","DOIUrl":"10.1002/jat.4690","url":null,"abstract":"<p>Methylmercury (MeHg) is an environmental toxin known to damage the central nervous system. When pregnant women ingest seafood, which may contain accumulated MeHg, fetal development may be affected. The embryonic period, a time of major epigenetic change, is susceptible to epigenetic disruptions due to chemical exposure. Therefore, understanding the molecular mechanism underlying MeHg's effects on neuronal development requires consideration of epigenetic factors. In this study, we investigated epigenetic modifications in the synaptophysin (<i>SYP</i>) and discs large MAGUK scaffold protein 4 (<i>DLG4</i>) genes. LUHMES cells were exposed to 1 nM MeHg for 6 days during days 2–8 of neural differentiation. MeHg exposure significantly reduced the number of spikes observed on day 16 of differentiation. Both mRNA and protein expression levels of SYP and DLG4 were significantly decreased by MeHg exposure. Additionally, MeHg treatment reduced acetyl histone H3 levels associated with transcriptional activity in the <i>SYP</i> gene while increasing histone H3 lysine 27 tri-methylation (H3K27me3) levels related to transcriptional repression. Conversely, regarding the <i>DLG4</i> gene, MeHg exposure increased H3K27me3 levels. Differential changes in DNA methylation (high and low methylation states) were observed in the <i>SYP</i> and <i>DLG4</i> genes due to MeHg exposure depending on CpG site position. In conclusion, this study suggests that epigenetic changes, particularly histone modifications, contribute to decreased MeHg exposure-induced SYP and DLG4 expression during neuronal differentiation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1986-1996"},"PeriodicalIF":2.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appearance of sex-determining region Y-box 9 (SOX9)- and glutathione S-transferase placental form (GST-P)-positive hepatocytes as possible carcinogenic events in the early stage of furan-induced hepatocarcinogenesis","authors":"Daisuke Hibi,&nbsp;Meili Soma,&nbsp;Yuta Suzuki,&nbsp;Shinji Takasu,&nbsp;Yuji Ishii,&nbsp;Takashi Umemura","doi":"10.1002/jat.4691","DOIUrl":"10.1002/jat.4691","url":null,"abstract":"<p>Furan, the basic skeleton of various flavoring agents, induces cholangiocellular tumors with higher incidences in the caudate lobe and hepatocellular tumors without the lobe specificity in rats, but the mechanism is unclear. We investigated the lobe distribution of possible carcinogenic events. Furan caused proliferation/infiltration of oval and inflammatory cells prominently in the caudate lobe as early as 4 weeks and cholangiofibrosis in this lobe at 8 weeks. In vivo mutagenicity assays using DNA extracted from the caudate or left lateral lobe of male <i>gpt</i> delta rats, the reporter gene-transgenic rats, treated with 8 mg/kg furan for 4 or 8 weeks showed negative outcomes. The distribution of glutathione <i>S</i>-transferase placental form (GST-P)-positive or sex-determining region Y-box 9 (SOX9)-positive hepatocytes was examined. Significant increases in the number of GST-P-positive hepatocytes were observed in all lobes of furan-treated rats at 8 weeks. By contrast, SOX9-positive hepatocytes, liver injury-inducible progenitor cells, were also found in all lobes of treated rats, the incidences of which were by far the highest in the caudate lobe. In addition, some of these hepatocytes also co-expressed delta like 1 homolog (DLK1), a hepatoblast marker, particularly in areas with a predominant presence of inflammatory cells. Overall, furan induced liver injury, leading to the appearance of SOX9-positive hepatocytes, some of which were subjected to dedifferentiation in the inflammatory microenvironment of a cholangiocarcinoma-prone lobe. Thus, the appearance of SOX9-positive hepatocytes together with GST-P-positive hepatocytes could be initial events in furan-induced hepatocarcinogenesis via non-genotoxic mechanisms.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1976-1985"},"PeriodicalIF":2.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacillus subtilis ZB423: 90-Day repeat dose oral (gavage) toxicity study in Wistar rats","authors":"Vijayakumar K. N.,&nbsp;Swati S. Bamne,&nbsp;Johnson Crasta,&nbsp;Satish Kumar C.,&nbsp;Ramakrishna M. Bhat,&nbsp;Bentley M. Shuster,&nbsp;John W. K. Oliver,&nbsp;Zachary D. Abbott","doi":"10.1002/jat.4677","DOIUrl":"10.1002/jat.4677","url":null,"abstract":"<p>The novel genetically modified probiotic <i>Bacillus subtilis</i> ZB423 was assessed in a 90-day repeated-dose oral toxicity study adhering to Good Laboratory Practice (GLP) and Organization for Economic Cooperation and Development (OECD) guidelines. Spray-dried spores at a concentration of 1.1E12 CFU/g were administered at doses of 130, 260, and 519 mg/kg body weight/day correlating to 1.43 × 10¹¹, 2.86 × 10¹¹, and 5.71 × 10¹¹ CFU/kg/day, respectively, by oral gavage to Wistar rats for a period of 90 consecutive days. Results showed no toxicologically relevant findings for <i>B. subtilis</i> ZB423 from measured parameters. The no observed adverse effect level (NOAEL) of <i>B. subtilis</i> ZB423 is 519 mg/kg body weight/day corresponding to 5.71 × 10¹¹ CFU/kg/day for lyophilized <i>B. subtilis</i> ZB423 spores under the test conditions employed.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1874-1885"},"PeriodicalIF":2.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicity of soil leaching liquor from coking plant in developmental zebrafish embryos/larvae model","authors":"Guangchao Yang,&nbsp;Jining Liu,&nbsp;Qian Yang,&nbsp;Wen Gu","doi":"10.1002/jat.4692","DOIUrl":"10.1002/jat.4692","url":null,"abstract":"<p>The coking industry in China is the largest coke supplier in the world. Contaminated soil in industrial areas poses a serious threat to human and ecosystems. Most of the studies investigated the toxicity of soil from coking plant on soil microorganisms, while the toxic effects of soil leaching liquor on aquatics are limited. In this study, the composition of soil leaching liquor from a coking plant in Taiyuan (TY) was analyzed, and the developmental toxicity on zebrafish was evaluated. The results showed that a total of 91 polycyclic aromatic hydrocarbons were detected in the leaching liquor, followed by phenols and benzene series. The leaching liquor induced developmental impairment in zebrafish larvae, including delayed incubation, deficits in locomotor behavior, vascular and cardiac dysplasia, and impaired neurodevelopment. The results of metabolomics analysis showed that TY soil leaching liquor induced significant metabolic profile disturbances in zebrafish embryos/larvae. The developmental toxicity of the leaching liquor metabolic disorders may be associated with the leaching liquor-induced abnormalities in zebrafish embryonic development. Metabolic pathways were identified by arginine and proline metabolism, phosphotransferase system, starch and sucrose metabolism, steroid biosynthesis, beta-alanine metabolism, and nucleotide metabolism pathways.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1962-1975"},"PeriodicalIF":2.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composition of e-cigarette aerosols: A review and risk assessment of selected compounds.","authors":"Jonathan Heywood, Grayson Abele, Blake Langenbach, Sydney Litvin, Sarah Smallets, Dennis Paustenbach","doi":"10.1002/jat.4683","DOIUrl":"https://doi.org/10.1002/jat.4683","url":null,"abstract":"<p><p>The potential harms and benefits of e-cigarettes, or electronic nicotine delivery systems (ENDS), have received significant attention from public health and regulatory communities. Such products may provide a reduced risk means of nicotine delivery for combustible cigarette smokers while being inappropriately appealing to nicotine naive youth. Numerous authors have examined the chemical complexity of aerosols from various open- and closed-system ENDS. This body of literature is reviewed here, with the risks of ENDS aerosol exposure among users evaluated with a margin of exposure (MoE) approach for two non-carcinogens (methylglyoxal, butyraldehyde) and a cancer risk analysis for the carcinogen N-nitrosonornicotine (NNN). We identified 96 relevant papers, including 17, 13, and 5 reporting data for methylglyoxal, butyraldehyde, and NNN, respectively. Using low-end (minimum aerosol concentration, low ENDS use) and high-end (maximum aerosol concentration, high ENDS use) assumptions, estimated doses for methylglyoxal (1.78 × 10^-3-135 μg/kg-bw/day) and butyraldehyde (1.9 × 10^-4-66.54 μg/kg-bw/day) corresponded to MoEs of 227-17,200,000 and 271-280,000,000, respectively, using identified points of departure (PoDs). Doses of 9.90 × 10^-6-1.99 × 10^-4 μg/kg-bw/day NNN corresponded to 1.4-28 surplus cancers per 100,000 ENDS users, relative to a NNN-attributable surplus of 7440 per 100,000 cigarette smokers. It was concluded that methylglyoxal and butyraldehyde in ENDS aerosols, while not innocuous, did not present a significant risk of irritant effects among ENDS users. The carcinogenic risks of NNN in ENDS aerosols were reduced, but not eliminated, relative to concentrations reported in combustible cigarette smoke.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esculin alleviates lipopolysaccharide (LPS)–induced pneumonia by regulating the USP7/MAPK14 axis","authors":"Lijuan Wang,&nbsp;Na Li,&nbsp;Yanan Wang,&nbsp;Xu Chen","doi":"10.1002/jat.4686","DOIUrl":"10.1002/jat.4686","url":null,"abstract":"<p>Pneumonia is a serious and life-threatening lung inflammation with high morbidity and mortality. Accumulating evidence has suggested that esculin, a derivative of coumarin, possesses potent anti-inflammatory effects. This study is designed to explore the pharma role and underlying mechanism of esculin against lipopolysaccharides (LPS)-induced pneumonia. TC-1 cells were stimulated by LPS to mimic the inflammatory injury model <i>in vitro</i>. Cell viability, proliferation, and apoptosis were determined using MTT assay, 5-ethynyl-2′-deoxyuridine assay, and flow cytometry. Interleukin-1β and tumor necrosis factor α levels were analyzed using an enzyme-linked immunosorbent assay. Reactive oxygen species and superoxide dismutase were examined using special assay kits. Macrophage polarization was detected using flow cytometry. Mitogen-activated protein kinase 14 (MAPK14) level was detected by real-time quantitative polymerase chain reaction. MAPK14 and ubiquitin-specific protease 7 (USP7) protein levels were determined using western blot assay. After Ubibrowser database prediction, the interaction between USP7 and MAPK14 was verified using a Co-immunoprecipitation assay. The biological role of esculin was verified in LPS-challenged ALI mice <i>in vivo</i>. Here, we found that esculin significantly relieved LPS-induced TC-1 cell proliferation inhibition, and apoptosis, inflammatory response, oxidative stress, and M1-type macrophage polarization promotion. MAPK14 and USP7 expressions were enhanced in LPS-treated TC-1 cells, which was partly abolished by esculin treatment. Overexpressing MAPK14 attenuated the repression of esculin on LPS-triggered TC-1 cell injury. At the molecular level, USP7 interacted with MAPK14 and maintained its stability by removing ubiquitin. Moreover, esculin repressed the progression of pneumonia <i>in vivo</i> by regulating MAPK14. Taken together, esculin exposure could mitigate LPS-induced TC-1 cell injury partly by targeting the USP7/MAPK14 axis, providing a better understanding of the role of esculin in the anti-inflammatory therapeutics for pneumonia.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1949-1961"},"PeriodicalIF":2.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}