Toxicology and applied pharmacology最新文献

{"title":"Misrepresentation of mouse genotypes: A call for precision","authors":"Wei Li","doi":"10.1016/j.taap.2025.117276","DOIUrl":"10.1016/j.taap.2025.117276","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117276"},"PeriodicalIF":3.3,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of accumulation of DNA double-strand breaks in mouse tissues by pulsed-field gel electrophoresis","authors":"Takeshi Terabayashi ,&nbsp;Takako Sasaki ,&nbsp;Toshimasa Ishizaki ,&nbsp;Tadashi Tomo ,&nbsp;Yoshihiro Nishida ,&nbsp;Katsuhiro Hanada","doi":"10.1016/j.taap.2025.117278","DOIUrl":"10.1016/j.taap.2025.117278","url":null,"abstract":"<div><div>Double-strand DNA breaks (DSBs) are among the most cytotoxic DNA lesions, which can lead to chromosomal instability and eventually cell death. The substances that can potentially induce DSB formation are thus regarded as genotoxic. To date, many genotoxicity tests for detecting DNA breaks have been designed. However, there are limited options available for measuring the accumulation of DSBs in vivo. In this study, we aimed to evaluate a method of detecting the DSBs formed by the direct action of genotoxic substances using pulsed-field gel electrophoresis (PFGE). This approach has the advantage of making it easier to distinguish between DSBs and single-strand DNA breaks (SSBs) induced by the direct action of genotoxic substances. To confirm the detection of DSBs using PFGE, we investigated their accumulation after treatment with <em>cis</em>-diamminedichloroplatinum(II) (cisplatin) or γ-rays in mouse organs. The results revealed the successful detection of cisplatin-induced DSB formation in mouse kidney and thymus and γ-ray-induced DSB formation in all organs. We also discuss the advantages of PFGE-based detection of DSBs in vivo.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117278"},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatotoxicity from long-term administration of hepatoprotective low doses of oleanolic acid in mice","authors":"Yasha Xu ,&nbsp;Xi Yang ,&nbsp;Yuanfu Lu ,&nbsp;Jie Liu","doi":"10.1016/j.taap.2025.117277","DOIUrl":"10.1016/j.taap.2025.117277","url":null,"abstract":"<div><div>Oleanolic acid is a triterpenoid existed in many medicinal herbs/plants. Oleanolic acid at low doses are hepatoprotective but at high doses produce cholestasis. This study examined hepatotoxicity potential of low doses of oleanolic acid after log-term administration. Male Kunming mice were orally given oleanolic acid at 100, 200 and 300 μmol/kg daily for 14 weeks. Body weights were monitored, and liver injury was determined via blood biochemistry. Histopathology was examined via H&amp;E, Masson, and Sirius red stains. Oleanolic acid accumulation in plasma and liver was determined by LC-MS and hepatic gene expression by qPCR. Oleanolic acid at low doses did not affect animal body weights, but increased liver index. Serum alanine aminotransferase and alkaline phosphatase were increased, while total bilirubin was unchanged. Chronic oleanolic acid produced hepatocyte degeneration, spot necrosis, and fibrosis. Plasma oleanolic acid was increased more than that in the liver. Oleanolic acid increased hepatic expression of Nrf2, Nqo1, Gclc and Mgst1; Expression of bile acid synthesis genes (Cyp7a1, Cyp8b1, Cyp27a1, Cyp7b1, FXR, SHP) was also suppressed at higher doses. The expression of TGF-β1 and Smad3 was increased, while Smad7 decreased, suggesting the progression to liver fibrosis. High dose of oleanolic acid was less effective in producing these changes, probably due to increased liver injury. Overall, oral administration of low doses of oleanolic acid for 14 weeks produced liver injury and fibrosis. These harmful effects were associated with increased oleanolic acid in plasma and liver, and the disruptions of bile acid metabolism, the Nrf2 and TGF-β/Smad signaling pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117277"},"PeriodicalIF":3.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Afzelechin alleviates deltamethrin induced hepatic dysfunction via regulating TLR4/MyD88, HMGB1/RAGE and NF-κB pathway","authors":"Fuad M. Alzahrani ,&nbsp;Khalid J. Alzahrani ,&nbsp;Khalaf F. Alsharif ,&nbsp;Muhammad Faisal Hayat ,&nbsp;Ahmed Al-Emam","doi":"10.1016/j.taap.2025.117275","DOIUrl":"10.1016/j.taap.2025.117275","url":null,"abstract":"<div><div>Deltamethrin (DMN) is a type-II pyrethroid that has been documented to instigate numerous organ toxicities. Afzelechin (ALN) is a plant based polyphenolic compound that exhibits marvelous biological properties. The present research was conducted to assess the alleviative potential of ALN against DMN induced hepatic dysregulations. Thirty-six male albino (Sprague Dawley) rats were apportioned into four random groups including the control, DMN (5mgkg⁻¹), DMN (5mgkg⁻¹) + ALN (2mgkg⁻¹), and ALN (2mgkg⁻¹) alone administrated group. ALN protected hepatic tissues against DMN induced oxidative stress, inflammation and apoptosis. ALN supplementation donwregulated the gene expression of <em>receptor for advanced glycation end products (RAGE), high mobility group box1 (HMGB1), tumor necrosis factor- α (TNF-α), Myeloid differentiation primary response 88 (MyD88), nuclear factor- kappa B (NF-κB), interleukin-6 (IL-6), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX-2)</em>, and <em>interleukin-1β (IL-1β)</em>. Besides, ALN administration reduced the levels of reactive oxygen species (ROS) and malondialdehyde while increasing the activities of glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GSR), heme oxygenase-1 (HO-1), superoxide dismutase (SOD) and glutathione (GSH). The levels of hepatic function markers including GGT, ALT, ALP, and AST were lowered while the concentrations of albumin and total proteins were promoted following the ALN treatment. The levels of Bax, Caspase-9 and Caspase-3 were suppressed while the levels of Bcl-2 were escalated after ALN therapy. Moreover, ALN treatment remarkably mitigated DMN induced histological impairments. These findings highlight the hepatoprotective efficacy of ALN against DMN induced liver toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117275"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyanidin-3-O-glucoside inhibits the malignant progression of colorectal cancer by regulating Kruppel-like factor 4-mediated ERK/p38 signaling pathway","authors":"Jian Chang,&nbsp;Geqiong Xiao","doi":"10.1016/j.taap.2025.117268","DOIUrl":"10.1016/j.taap.2025.117268","url":null,"abstract":"<div><h3>Background</h3><div>Cyanidin-3-<em>O</em>-glucoside (Cy3g) is a natural anthocyanin, showing favorable anti-cancer efficacy in colorectal cancer (CRC). However, its specific mechanism in CRC remains largely unexplored.</div></div><div><h3>Objective</h3><div>This study aimed to investigate the underlying mechanisms of Cy3g on CRC.</div></div><div><h3>Methods</h3><div>Cell viability of human CRC cell lines (SW620, HT29, LS174T, and HCT116) and normal colon fibroblast cell line (CCD-18Co) treated with Cy3g was detected by CCK-8. Effects of Cy3g on malignant characteristics of SW620 cells were determined by CCK-8, EdU, colony formation, wound healing, Transwell, and flow cytometry assays. To further elucidate Cy3g's mechanism in CRC, KLF4 expression was detected by RT-qPCR, and expression of the extracellular signal-related kinase (ERK) and p38 was examined by western blotting. The effects and mechanisms of Cy3g on CRC progression were further validated in a xenograft mouse model.</div></div><div><h3>Results</h3><div>Cy3g significantly inhibited the cell viability of human CRC cell lines but rarely affected the cell viability of normal colon fibroblast. Cy3g dose-dependently inhibited proliferation, migration, and invasion and promoted apoptosis of SW620 cells. Moreover, Cy3g upregulated KLF4 expression and inactivated the ERK/p38 pathway in a concentration-dependent manner. KLF4 knockdown reversed the inhibitory effects of Cy3g on the malignant characteristics of SW620 and expression of ERK and p38. Animal experiments further validated that Cy3g inhibited tumor growth without altering body weight, activated KLF4, and suppressed the ERK/p38 pathway in CRC model mice.</div></div><div><h3>Conclusion</h3><div>Cy3g inhibits CRC progression by suppressing the KLF4-mediated ERK/p38 pathway, offering new insights into CRC prevention and treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117268"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isonardosinone attenuates osteoclastogenesis and OVX-induced bone loss via the MAPK/NF-κB pathway","authors":"Guangwei Wen ,&nbsp;Haishan Li ,&nbsp;Jiasheng Yang ,&nbsp;Bin Mai ,&nbsp;Tengpeng Zhou ,&nbsp;GuoYe Mo ,&nbsp;Yongxian Li ,&nbsp;Yiyi Lai","doi":"10.1016/j.taap.2025.117267","DOIUrl":"10.1016/j.taap.2025.117267","url":null,"abstract":"<div><div>Osteoporosis is a globally prevalent metabolic bone disease that manifests itself as a decrease in bone mineral density and deterioration of bone structure, which reduces overall bone strength and increases fracture risk. However, the effect of anti-inflammatory isonardosinone (the active ingredient in <em>Nardostachys chinensis</em>) on osteoclastogenesis is unknown. We first predicted the main pathways and targets of ISO action in osteoporosis by network pharmacology. CCK-8 was used to test whether ISO affects cell proliferation of BMMs (osteoclast precursor cells) and to determine the safe action concentration. TRAcP and F-actin staining were used to characterise the inhibitory effect on osteoclast differentiation. RT-PCR and WB were used to examine changes in the relative expression of genes and proteins generated by osteoclasts under isopinacolone treatment, and we examined its effects on the RANKL-activated MAPK and NF-κB signaling pathways. An ovariectomy-induced osteoporosis model was constructed to assess the <em>in vivo</em> therapeutic effects of ISO. CCK-8 results showed that ISO had no cytotoxic or proliferative effects on BMMs at concentrations below 30 μM; TRAcP staining showed that ISO suppressed osteoclastogenesis in a concentration- and time-gradient-dependent manner; and F-actin staining showed that ISO suppressed osteoblast skeleton formation and expansion; RT-PCR and Western Blot assays showed that ISO suppressed the expression of CTSK, NFATC1, MMP9, C-Fos, and ACP5, inhibited the phosphorylation of JNK, P38, and ERK, and reversed the degradation of IκB-α, especially within 15 min. The <em>in vivo</em> results indicated that ISO has therapeutic effects on osteoporosis by improving bone microstructure to rescue bone loss. Taken together, these results lead to the conclusion that ISO is an attractive drug development strategy for the treatment of osteoporosis by effectively suppressing osteoclastogenesis through the MAPK/NF-κB signaling pathway, thereby reversing the bone loss associated with ovariectomy <em>in vivo</em>.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117267"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnolin ameliorates acetaminophen-induced liver injury in mice via modulating the MAPK pathway and lipid metabolism","authors":"Ting Yao ,&nbsp;Youhe Wu ,&nbsp;Liyun Fu,&nbsp;Lanjun Li","doi":"10.1016/j.taap.2025.117264","DOIUrl":"10.1016/j.taap.2025.117264","url":null,"abstract":"<div><div>Acetaminophen (APAP)-induced liver injury (AILI) represents a common yet potentially severe type of drug-induced liver injury with limited available effective therapeutic methods. Magnolin possesses excellent anti-inflammatory and antioxidant properties for treating various diseases. However, its effects against AILI and the fundamental mechanisms still lack comprehensive exploration. This research endeavors to assess magnolin's hepatoprotective properties against AILI. The AILI model was established in male C57BL/6 mice via intraperitoneal injection of 300 mg/kg APAP and in the HepG2 cell line by treating it with 20 mM APAP. The levels of oxidation, liver damage and inflammation were assessed. Transcriptomics and metabolomics were utilized to explore the mechanism underlying magnolin treatment in AILI. We found that 5 mg/kg magnolin effectively mitigated the elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), along with inflammatory factor (IL-6, and TNF-α) levels in vivo. Meanwhile, magnolin relieved oxidative stress by increasing superoxide dismutase activity and reducing malondialdehyde along with oxidized glutathione/reduced glutathione (GSSG/GSH). 6 μM magnolin increased cell viability and reduced the lipid peroxidation in vitro. Furthermore, 5 mg/kg magnolin altered the expression of 413 genes and the levels of 70 metabolites compared with Control group, which were enriched in lipid metabolism, inflammatory responses, and the MAPK signaling pathway. However, 10 mg/kg magnolin tended to exacerbate liver damage. Overall, 5 mg/kg magnolin effectively protects against AILI by modulating inflammatory responses and the MAPK pathway, whereas 10 mg/kg worsens liver injury, underscoring the need for dose optimization. These findings offer a fresh perspective and novel therapy for AILI.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117264"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting high mobility group protein B2 exerts antiproliferative effects in hypoxic pulmonary hypertension by modulating miR-21","authors":"Pan Wang ,&nbsp;Xu Zhang ,&nbsp;Mengge Yao ,&nbsp;Jiakang Li ,&nbsp;Xiaozhen Wei ,&nbsp;Zhihuang Qiu ,&nbsp;Liangwan Chen ,&nbsp;Li Zhang","doi":"10.1016/j.taap.2025.117265","DOIUrl":"10.1016/j.taap.2025.117265","url":null,"abstract":"<div><h3>Objective</h3><div>Pulmonary hypertension (PH) is characterized by excessive vascular cell proliferation, leading to vascular remodeling. In this study, we aimed to investigate the molecular mechanisms underlying the regulation of vascular cell proliferation in the context of HMGB2 and its potential involvement in the pathogenesis of PH.</div></div><div><h3>Methods</h3><div>Animals and pulmonary vascular smooth muscle cells (PASMCs) were exposed to hypoxia. Pathological changes in pulmonary vessels were detected by HE and Masson staining. The effect of HMGB2 on cell proliferation was detected by siRNA transfections and recombinant protein treatment. miR-21 inhibitor and mimics were applied, and TPM1 expression was detected. HMGB2^−/− mice were applied to observe the possible preventive effect of HMGB2 in PH development.</div></div><div><h3>Results</h3><div>HMGB2 expression was increased in hypoxic rats and PASMCs. Silencing ZDHHC5 reduced HMGB2 expression and cell proliferation. Cell proliferation was inhibited by knocking down HMGB2 and promoted by its over-expression. Hypoxia-induced miR-21 upregulation and TPM1 downregulation were mediated by HMGB2. 8-Br-cGMP suppressed HMGB2-induced PASMC proliferation and increased SOX2 expression by activating the cGMP/PKG signaling pathway. HMGB2^−/− attenuated pulmonary vascular remodeling and fibrosis in hypoxia induced PH mice.</div></div><div><h3>Conclusions</h3><div>HMGB2 promotes PASMC proliferation through the cGMP/PKG-SOX2-miR-21-TPM1 pathway, which provides a new theoretical basis and possible targets for the pathogenesis and clinical prevention of PH.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117265"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium taurocholate co-transporting polypeptide deficiency attenuates acetaminophen-induced hepatotoxicity via regulating expression of drug metabolism enzymes in mice","authors":"Fangji Yang ,&nbsp;Lina Wu ,&nbsp;Wenxiong Xu ,&nbsp;Yuankai Wu ,&nbsp;Shu Zhu ,&nbsp;Yuzhen Zhang ,&nbsp;Yutian Chong ,&nbsp;Liang Peng","doi":"10.1016/j.taap.2025.117266","DOIUrl":"10.1016/j.taap.2025.117266","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose can induce liver injury and is generally accompanied by disruption of bile acid homeostasis. Physiologically, sodium taurocholate <em>co</em>-transporting polypeptide (NTCP) participates in the uptake of bile acids from portal blood into hepatocytes to maintain enterohepatic recirculation but its role in APAP-induced hepatotoxicity is unclear. Wild-type (WT) C57BL/6J and NTCP knockout (KO) mice were injected with 400<!--> <!-->mg/kg APAP and liver injury was evaluated by serum biochemical markers and histologic evaluation. RNA-seq analysis was performed to evaluate the liver gene expression profiles in APAP-treated mice. Compared with WT mice, the exposure to APAP overdose caused liver dysfunction, oxidative stress, inflammation and cell death, which were ameliorated by NTCP deficiency. APAP detoxification, metabolism, and elimination were significantly accelerated by the upregulation of UDP-glucuronosyltransferase (Ugt1a1, Ugt1a6 and Ugt1a9), sulfotransferase (Sult1a1 and Sult2a1) and bile acid efflux transporters (Abcc2/3/4) in NTCP KO mice compared with WT mice. Interestingly, APAP-induced hepatotoxicity was ameliorated using Irbesartan and Ezetimibe (NTCP inhibitors). In conclusion, NTCP deficiency attenuates APAP-induced hepatotoxicity by enhancing the metabolism and elimination of APAP. NTCP inhibitors protect against APAP-induced hepatotoxicity and thus are a potential therapeutic option.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117266"},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrf2 deficiency aggravates hepatic cadmium accumulation, inflammatory response and subsequent injury induced by chronic cadmium exposure in mice","authors":"Chengjie Chen ,&nbsp;Xue Han ,&nbsp;Ning Xu ,&nbsp;Wei Shen ,&nbsp;Gang Wang ,&nbsp;Junying Jiao ,&nbsp;Weiwei Kong ,&nbsp;Jiaxin Yu ,&nbsp;Jingqi Fu ,&nbsp;Jingbo Pi","doi":"10.1016/j.taap.2025.117263","DOIUrl":"10.1016/j.taap.2025.117263","url":null,"abstract":"<div><div>Prolonged cadmium (Cd) exposure leads to Cd accumulation and oxidative damage in the liver. Nuclear factor erythroid-derived 2-like 2 (NRF2) plays a vital role in preventing acute hepatic toxicity of Cd. However, the participation of NRF2 in chronic liver injury, especially in the context of chronic Cd exposure, has rarely been investigated. Here, we explored the involvement of NRF2 in Cd-induced liver injury using <em>Nrf2</em> knockout (<em>Nrf2</em>-KO) mice chronically exposed to Cd in drinking water (100 or 200 ppm) for up to 24 weeks. We found that absence of <em>Nrf2</em> exacerbated the Cd-induced liver fibrosis, as evaluated by Masson's trichrome staining and increased expression of fibrosis-associated proteins. Mechanistic investigations using the liver tissues from the animals with 100 ppm Cd exposure for 16 weeks, in which no obvious hepatic fibrosis was observed in both genotypes, revealed that there were diminished expressions of antioxidant and detoxification genes and elevated Cd levels in the blood and liver of <em>Nrf2</em>-KO mice compared with those in wild-type (<em>Nrf2</em>-WT) under basal and/or Cd-exposed conditions. Notably, a bulk RNA-seq of the liver tissues showed lowered mRNA levels of genes related to xenobiotic and glutathione metabolic processes, but elevated mRNA expression of leukocyte migration pathway and adaptive immune pathway in <em>Nrf2</em>-KO mice relative to <em>Nrf2</em>-WT controls, either under basal or Cd-exposed conditions. Our findings demonstrated that <em>Nrf2</em>-KO mice are vulnerable to chronic Cd exposure-induced liver fibrosis, which is partially attributed to a compromised NRF2-mediated antioxidant response, lowered metallothionein expression and subsequent Cd accumulation and inflammatory response in the tissues.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117263"},"PeriodicalIF":3.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}