Toxicological Research最新文献

{"title":"<i>Pelargonium sidoides</i> extract mediates nephrotoxicity through mitochondrial malfunction and cytoskeleton destabilization.","authors":"Ju Young Lee, JuKyung Lee, Sung Ho Lee, Jeong Ho Hwang, Han Na Suh","doi":"10.1007/s43188-023-00186-0","DOIUrl":"10.1007/s43188-023-00186-0","url":null,"abstract":"<p><p>We investigated the cytotoxic effect of <i>Pelargonium sidoides</i> extract on Madin-Darby canine kidney (MDCK) cells. <i>P. sidoides</i> extract decreased the cell viability in a dose dependent manner (> 0.2%). The extract of <i>P. sidoides</i> decreased the mitochondrial action potential, increased the number of reactive oxygen species (ROS) inside the cell, and caused nicotinamide adenine dinucleotide hydride (NADH) to be released, all of which are signs of mitochondrial dysfunction. The results of unbiased mRNA sequencing showed that 0.3% <i>P. sidoides</i> extract upregulates the apoptosis-related gene (<i>BBC3</i>). This finding was supported by immunoblot analysis of apoptosis signal pathways, which included Bcl-2, Bax, cytochrome C (CytC), cleaved caspase 3 (CC3), cleaved caspase 7 (CC7), cleaved caspase 9 (CC9) and cleaved PARP (CP). It is interesting to note that the elevated levels of Bax, CytC, CC3, CC7, and CC9, as well as CP, were suppressed by N-acetyl-L-cysteine (NAC) pretreatment, which points to ROS-mediated apoptosis. The small GTPases, RhoA, and Rac1/cdc42-GTP-bound active form were all lowered when <i>P. sidoide</i>s extract was used. Also, RhoA-related cytoskeleton signals (ROCK, p-LIMK1/2, p-cofilin) and Rac1/cdc42-related signals (N-WASP, WAVE-2) were inhibited by <i>P. sidoides</i> extract. NAC or RhoA/Rac1/cdc42 activator pretreatment reduced <i>P. sidoides</i> extract-induced actin destabilization. In this work, <i>P. sidoides</i> extract promotes apoptosis by causing mitochondrial dysfunction and cytoskeleton disassembly.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 4","pages":"601-609"},"PeriodicalIF":1.6,"publicationDate":"2023-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41152228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterisation of changes in global genes expression in the lung of ICR mice in response to the inflammation and fibrosis induced by polystyrene nanoplastics inhalation.","authors":"You Jeong Jin,&nbsp;Ji Eun Kim,&nbsp;Yu Jeong Roh,&nbsp;Hee Jin Song,&nbsp;Ayun Seol,&nbsp;Jumin Park,&nbsp;Yong Lim,&nbsp;Sungbaek Seo,&nbsp;Dae Youn Hwang","doi":"10.1007/s43188-023-00188-y","DOIUrl":"10.1007/s43188-023-00188-y","url":null,"abstract":"<p><p>This study characterised the changes in global gene expression in the lung of ICR mice in response to the inflammation and fibrosis induced by the inhalation of 0.5 μm polystyrene (PS)-nanoplastics (NPs) at various concentrations (4, 8, and 16 μg/mL) for 2 weeks. The total RNA extracted from the lung tissue of NPs-inhaled mice was hybridised into oligonucleotide microarrays. Significant upregulation was detected in several inflammatory responses, including the number of immune cells in bronchoalveolar lavage fluid (BALF), the expression level of inflammatory cytokines, mucin secretion, and histopathological changes, while they accumulated average of 13.38 ± 1.0 μg/g in the lungs of the inhaled ICR mice. Similar responses were observed regarding the levels of fibrosis-related factors in the NPs-inhaled lung of ICR mice, such as pulmonary parenchymal area, expression of pro-fibrotic marker genes, and TGF-β1 downstream signalling without any significant hepatotoxicity and nephrotoxicity. In microarray analyses, 60 genes were upregulated, and 55 genes were downregulated in the lung of ICR mice during inflammation and fibrosis induced by NPs inhalation compared to the Vehicle-inhaled mice. Among these genes, many were categorised into several ontology categories, including the anatomical structure, binding, membrane, and metabolic process. Furthermore, the major genes in the upregulated categories included Igkv14-126000, Egr1, Scel, Lamb3, and Upk3b. In contrast, the major genes in the down-regulated categories were Olfr417, Olfr519, Rps16, Rap2b, and Vmn1r193. These results suggest several gene functional groups and individual genes as specific biomarkers respond to inflammation and fibrosis induced by PS-NPs inhalation in ICR mice.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00188-y.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":" ","pages":"1-25"},"PeriodicalIF":2.3,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10201517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9714952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impacts of PAH accumulation on reproductive hormones, indices of oxidative stress and BPDE-albumin adduct in women with recurrent pregnancy loss.","authors":"Amany El-Sikaily,&nbsp;Mohamed Helal,&nbsp;Augusta Chinyere Nsonwu-Anyanwu,&nbsp;Hossam Azab,&nbsp;Neveen Abd ElMoneim,&nbsp;Eman Othman Salem Farahat,&nbsp;Aziza Saad","doi":"10.1007/s43188-023-00181-5","DOIUrl":"10.1007/s43188-023-00181-5","url":null,"abstract":"<p><p>Chronic exposure to Poly aromatic hydrocarbons (PAHs) may be associated with adverse pregnancy outcomes. Disruption of hormonal and redox balance by toxic PAH metabolites may interfere with successful pregnancy leading to miscarriage. The association of exposure to PAH contaminated mussel via the dietary route with perturbations in reproductive hormones, biomarkers of oxidative stress, and PAH metabolites were assessed in women with recurrent pregnancy loss (RPL). Furthermore, an analysis of the concentration of PAHs in environmentally relevant bivalve animals was performed to preliminary get insights into the levels of these pollutants in the environment. Seventy-six women (20-35 years) were categorized into 18 fertile women without RPL (control), and Groups I, II, and III comprising 24, 18, and 16 women with RPL (2, 3, and > 3 abortions respectively) were studied. Whole blood samples were collected for the estimation of malondialdehyde (MDA), catalase, reduced glutathione (GSH), glutathione-S-transferase (GST), progesterone (P4), follicle-stimulating hormone (FSH), benzo[a]pyren-7,8-dihydrodiol-9,10-epoxide-albumin adduct (BPDE-albumin) and urine for α-naphthol and β-naphthol. Two species of mussel <i>Donax trunculus</i> and <i>Andar aduloii</i> samples were collected for the estimation of 16 priority PAHs. The concentration of PAHs exceeding the maximum limits was observed in the two species of mussels studied. Higher levels of BPDE-albumin, MDA, GST, α and β-naphthol and lower GSH, catalase, FSH, and P4 were observed in women with RPL (Groups I-III) compared to controls (<i>p</i> =  < 0.001). Negative associations were observed between BPDE-albumin and catalase (r = - 0.276, <i>p</i> = 0.036), and GSH (r = - 0.331, <i>p</i> = - 0.011) only in women with RPL. Collectively, our findings indicate a possible association of chronic PAH accumulation with recurrent pregnancy loss in women.</p><p><strong>Graphical abstract: </strong>High PAH exposure in pregnant women is associated with 10-epoxide-albumin adduct formation and high MDA levels in their sera. On the other hand, PAH exposure in those women led to a decrease in their GSH, catalase, P4, and FSH sera levels. These findings indicate that PAH exposure can exert different physiological effects in pregnant women leading to a high level of abortion in those women.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"517-531"},"PeriodicalIF":2.3,"publicationDate":"2023-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9743939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent insights into autophagy and metals/nanoparticles exposure.","authors":"Qiong Li, Yajing Feng, Ruike Wang, Rundong Liu, Yue Ba, Hui Huang","doi":"10.1007/s43188-023-00184-2","DOIUrl":"10.1007/s43188-023-00184-2","url":null,"abstract":"<p><p>Some anthropogenic pollutants, such as heavy metals and nanoparticles (NPs), are widely distributed and a major threat to environmental safety and public health. In particular, lead (Pb), cadmium (Cd), chromium (Cr), arsenic (As), and mercury (Hg) have systemic toxicity even at extremely low concentrations, so they are listed as priority metals in relation to their significant public health burden. Aluminum (Al) is also toxic to multiple organs and is linked to Alzheimer's disease. As the utilization of many metal nanoparticles (MNPs) gradually gain traction in industrial and medical applications, they are increasingly being investigated to address potential toxicity by impairing certain biological barriers. The dominant toxic mechanism of these metals and MNPs is the induction of oxidative stress, which subsequently triggers lipid peroxidation, protein modification, and DNA damage. Notably, a growing body of research has revealed the linkage between dysregulated autophagy and some diseases, including neurodegenerative diseases and cancers. Among them, some metals or metal mixtures can act as environmental stimuli and disturb basal autophagic activity, which has an underlying adverse health effect. Some studies also revealed that specific autophagy inhibitors or activators could modify the abnormal autophagic flux attributed to continuous exposure to metals. In this review, we have gathered recent data about the contribution of the autophagy/mitophagy mediated toxic effects and focused on the involvement of some key regulatory factors of autophagic signaling during exposure to selected metals, metal mixtures, as well as MNPs in the real world. Besides this, we summarized the potential significance of interactions between autophagy and excessive reactive oxygen species (ROS)-mediated oxidative damage in the regulation of cell survival response to metals/NPs. A critical view is given on the application of autophagy activators/inhibitors to modulate the systematic toxicity of various metals/MNPs.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"355-372"},"PeriodicalIF":1.6,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9743941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc and selenium attenuate quaternary heavy metal mixture-induced testicular damage via amplification of the antioxidant system, reduction in metal accumulation, inflammatory and apoptotic biomarkers.","authors":"Harrison Ozoani, Anthonet N Ezejiofor, Kenneth O Okolo, Chinna N Orish, Ana Cirovic, Aleksandar Cirovic, Orish E Orisakwe","doi":"10.1007/s43188-023-00187-z","DOIUrl":"10.1007/s43188-023-00187-z","url":null,"abstract":"<p><p>Heavy metals (HMs) such as cadmium (Cd), lead (Pb), arsenic (As), and mercury (Hg) are highly toxic elements. They are often found together in nature as a heavy metal mixture (HMM) and are known to contribute to subfertility/infertility as environmental pollutants. This study aims to evaluate the potential benefits of treating HMM-induced testicular pathophysiology with zinc (Zn) and/or selenium (Se). Six-week-old male Sprague Dawley rats were grouped into 5 (n = 7). The control group received deionized water, while the other groups were treated with PbCl₂ (20 mg kg^-1), CdCl₂ (1.61 mg kg^-1), HgCl₂ (0.40 mg kg^-1), and Na₂AsO₃ (10 mg kg^-1) in deionized water for 60 days. Additionally, groups III to V received Zn, Se, and Zn/Se, respectively, for 60 days. The study evaluated testis weight, metal accumulation, sperm analysis, FSH, LH, testosterone, prolactin, oxidative stress, antioxidants, pro-inflammatory and apoptotic markers, and presented structural changes in the testis as micrographs. HMM caused a significant increase in testis weight, metal accumulation, prolactin, oxidative stress, and pro-inflammatory and apoptotic markers, while significantly decreasing semen analysis, FSH, LH, and testosterone. Histology showed decreased spermatogenesis and spermiogenesis, as evidenced by the structure of the germ cells and spermatids. However, Zn, Se, or both ameliorated and reversed some of the observed damages. This study provides further evidence for the mitigative potential of Zn, Se, or both in reversing the damage inflicted by HMM in the testis, and as a countermeasure towards improving HM-induced decrease in public health fecundity.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"497-515"},"PeriodicalIF":1.6,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9737594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining the reactivity of nanoparticles to peptides through direct peptide reactivity assay (DPRA) using a high pressure liquid chromatography system with a diode array detector.","authors":"Eun-Nam Kim, Jung-Ah Seo, Bae-Hwan Kim, Gil-Saeng Jeong","doi":"10.1007/s43188-022-00166-w","DOIUrl":"10.1007/s43188-022-00166-w","url":null,"abstract":"<p><p>The possibility of inducing skin sensitization reactions following exposure to various chemicals can lead to skin diseases, and the evaluation of skin sensitivity to such substances is very important. However, as animal tests for skin sensitization are prohibited, the OECD Test Guideline 442 C was designated as part of an alternative testing method. Therefore, in this study, the reactivity of cysteine and lysine peptides to nanoparticle substrates was identified through HPLC-DAD analysis according to the skin sensitization animal replacement test method specified in the OECD Test Guideline 442 C. In this study, all criteria for skin sensitization experiments specified in OECD Test Guideline 442 C were satisfied. As a result of analyzing the disappearance rates of cysteine and lysine peptides for the five types of nanoparticle substrates (TiO₂, CeO₂, Co₃O₄, NiO, and Fe₂O₃) using the established analytical method, all were identified as positive. Therefore, our findings suggest that basic data from this technique can contribute to skin sensitization studies by providing the depletion percentage of cysteine and lysine peptides for nanoparticle materials that have not yet been tested for skin sensitization.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"485-495"},"PeriodicalIF":1.6,"publicationDate":"2023-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9743937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of structural characteristics and molecular markers of rabbit skin, pig skin, and reconstructed human epidermis for an ex vivo human skin model.","authors":"Chanyang Uhm,&nbsp;Haengdueng Jeong,&nbsp;Su Hyon Lee,&nbsp;Jae Sung Hwang,&nbsp;Kyung-Min Lim,&nbsp;Ki Taek Nam","doi":"10.1007/s43188-023-00185-1","DOIUrl":"10.1007/s43188-023-00185-1","url":null,"abstract":"<p><p>The Organization for Economic Co-operation and Development approved a reconstructed human epidermis (RHE) model for <i>in vitro</i> skin irritation and corrosion tests as an alternative to animal testing for cosmetics, which has been banned in the European Union since 2013. However, RHE models have several limitations, such as high manufacturing costs, a loose skin barrier, and inability to simulate all cellular and non-cellular components of the human epidermis. Therefore, new alternative skin models are needed. Ex vivo skin models have been suggested as promising tools. Here, we investigated the structural similarities in the epidermis of pig and rabbit skin, a commercial RHE model (Keraskin), and human skin. To compare the structural similarity, the thickness of each epidermal layer was compared using molecular markers. Among the candidate human skin surrogates, the epidermal thickness of the pig skin was the most similar to that of human skin, followed by rabbit skin and Keraskin. Keraskin showed thicker cornified and granular layers than human skin, while rabbit skin displayed thinner layers. Moreover, the proliferation indices of Keraskin and rabbit skin were higher than those of human skin, whereas the proliferation index of the pig skin was similar to that of human skin. Some or none of the human skin barrier proteins FLG, CLDN1, and CDH1 were expressed in pig and rabbit skin, whereas all human proteins were expressed in Keraskin. Collectively, we propose ex vivo pig skin as the most suitable model for skin irritation testing because of its similarity to human skin.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00185-1.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"477-484"},"PeriodicalIF":2.3,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9749085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ruthenium biochanin-A complex ameliorates lung carcinoma through the downregulation of the TGF-β/PPARγ/PI3K/TNF-α pathway in association with caspase-3-mediated apoptosis.","authors":"Ming Cao, Bo Fan, Tianchang Zhen, Abhijit Das, Junling Wang","doi":"10.1007/s43188-023-00177-1","DOIUrl":"10.1007/s43188-023-00177-1","url":null,"abstract":"<p><p>Lung cancer is the most often reported cancer with a terrible prognosis worldwide. Flavonoid metal complexes have exhibited potential chemotherapeutic effects with substantially low adverse effects. This study investigated the chemotherapeutic effect of the ruthenium biochanin-A complex on lung carcinoma in both in vitro and in vivo model systems. The synthesized organometallic complex was characterized via UV‒visible spectroscopy, FTIR, mass spectrometry, and scanning electron microscopy. Moreover, the DNA binding activity of the complex was determined. The in vitro chemotherapeutic assessment was performed on the A549 cell line through MTT assay, flow cytometry, and western blot analysis. An in vivo toxicity study was performed to determine the chemotherapeutic dose of the complex, and subsequently, chemotherapeutic activity was assessed in benzo-α-pyrene-induced lung cancer mouse model by evaluating the histopathology, immunohistochemistry, and TUNEL assays. The IC₅₀ value of the complex in A549 cells was found to be 20 µM. The complex demonstrated significant apoptosis induction, enhanced caspase-3 expression and cell cycle arrest with downregulated PI3K, PPARγ, TGF-β, and TNF-α expression in A549 cells. The in vivo study suggested that ruthenium biochanin-A therapy restored the morphological architecture of lung tissue in a benzo-α-pyrene-induced lung cancer model and inhibited the expression of Bcl₂. Additionally, increased apoptotic events were identified with upregulation of caspase-3 and p53 expression. In conclusion, the ruthenium biochanin-A complex successfully amelioratedlung cancer incidence in both in vitro and in vivo models through the alteration of the TGF-β/PPARγ/PI3K/TNF-α axis with the induction of the p53/caspase-3-mediated apoptotic pathway.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"455-475"},"PeriodicalIF":1.6,"publicationDate":"2023-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9743938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring scavenger receptor class F member 2 and the importance of scavenger receptor family in prediagnostic diseases.","authors":"Thuy-Trang T Vo, Gyeyeong Kong, Chaeyeong Kim, Uijin Juang, Suhwan Gwon, Woohyeong Jung, Huonggiang Nguyen, Seon-Hwan Kim, Jongsun Park","doi":"10.1007/s43188-023-00176-2","DOIUrl":"10.1007/s43188-023-00176-2","url":null,"abstract":"<p><p>Scavenger Receptor Class F Member 2 (<i>SCARF2</i>), also known as the Type F Scavenger Receptor Family gene, encodes for Scavenger Receptor Expressed by Endothelial Cells 2 (SREC-II). This protein is a crucial component of the scavenger receptor family and is vital in protecting mammals from infectious diseases. Although research on SCARF2 is limited, mutations in this protein have been shown to cause skeletal abnormalities in both SCARF2-deficient mice and individuals with Van den Ende-Gupta syndrome (VDEGS), which is also associated with SCARF2 mutations. In contrast, other scavenger receptors have demonstrated versatile responses and have been found to aid in pathogen elimination, lipid transportation, intracellular cargo transportation, and work in tandem with various coreceptors. This review will concentrate on recent progress in comprehending SCARF2 and the functions played by members of the Scavenger Receptor Family in pre-diagnostic diseases.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"341-353"},"PeriodicalIF":1.6,"publicationDate":"2023-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9749088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Wnt/β-catenin signaling pathway plays a role in drug-induced liver injury by regulating cytochrome P450 2E1 expression.","authors":"Yoo-Sub Shin, Da-Bin Hwang, Dong-Hoon Won, Shin-Young Kim, Changuk Kim, Jun Won Park, Young Jeon, Jun-Won Yun","doi":"10.1007/s43188-023-00180-6","DOIUrl":"10.1007/s43188-023-00180-6","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is a major cause of acute liver failure and drug withdrawal. Cytochrome P450 (CYP) 2E1 is involved in the metabolism of several drugs, and can induce liver injury through the production of toxic metabolites and the generation of reactive oxygen species. This study aimed to elucidate the role of Wnt/β-catenin signaling in CYP2E1 regulation for drug-induced hepatotoxicity. To achieve this, mice were administered cisplatin or acetaminophen (APAP) 1 h after treatment with the CYP2E1 inhibitor dimethyl sulfoxide (DMSO), and histopathological and serum biochemical analyses were performed. APAP treatment induced hepatotoxicity, as evidenced by an increase in liver weight and serum ALT levels. Moreover, histological analysis indicated severe injury, including apoptosis, in the liver tissue of APAP-treated mice, which was confirmed by TUNEL assay. Additionally, APAP treatment suppressed the antioxidant capacity of the mice and increased the expression of the DNA damage markers γ-H2AX and p53. However, these effects of APAP on hepatotoxicity were significantly attenuated by DMSO treatment. Furthermore, the activation of Wnt/β-catenin signaling using the Wnt agonist CHIR99021 (CHIR) increased CYP2E1 expression in rat liver epithelial cells (WB-F344), whereas treatment with the Wnt/β-catenin antagonist IWP-2 inhibited nuclear β-catenin and CYP2E1 expression. Interestingly, APAP-induced cytotoxicity in WB-F344 cells was exacerbated by CHIR treatment and suppressed by IWP-2 treatment. Overall, these results showed that the Wnt/β-catenin signaling is involved in DILI through the upregulation of CYP2E1 expression by directly binding the transcription factor β-cat/TCF to the <i>Cyp2e1</i> promoter, thus exacerbating DILI.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-023-00180-6.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"39 3","pages":"443-453"},"PeriodicalIF":1.6,"publicationDate":"2023-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9743936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}