Toxicology and applied pharmacology最新文献

{"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}

{"title":"ADAMTS13 attenuates renal fibrosis by suppressing thrombospondin 1 mediated TGF-β1/Smad3 activation","authors":"Jie Guo ,&nbsp;Suhan Zhou ,&nbsp;Honghong Wang ,&nbsp;Xingyu Qiu ,&nbsp;Fang Dong ,&nbsp;Shan Jiang ,&nbsp;Nan Xu ,&nbsp;Yu Cui ,&nbsp;Ruisheng Liu ,&nbsp;Pengyun Li ,&nbsp;Zufu Ma ,&nbsp;Liang Zhao ,&nbsp;En Yin Lai","doi":"10.1016/j.taap.2025.117260","DOIUrl":"10.1016/j.taap.2025.117260","url":null,"abstract":"<div><div>Renal fibrosis is a common pathologic pathway for the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). Its mechanisms are unclear and it lacks effective therapy. Thrombospondin 1 (TSP1) mediated transforming growth factor-β1 (TGF-β1) activation was confirmed to promote renal fibrosis. Recently, a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13), was reported to inhibit Thrombospondin 1 (TSP1) mediated Ca²⁺ signaling in the myocardial cell, besides its cleavage of von Willebrand factor (VWF). Therefore, we hypothesized that ADAMTS13 might protect against renal fibrosis by inhibiting TSP1-mediated TGF-β1 activation. In this study, clinical data on renal fibrosis and healthy controls were collected. Renal fibrosis models were established both in vivo and in vitro. In vivo, mice underwent unilateral ureteral obstruction (UUO) for 14 days. In vitro, human proximal tubular epithelial cells (HK−2) were exposed to TGF-β1. The results showed that the expression of ADAMTS13 was decreased accompanied by the increased expression of TSP1 in patients with renal fibrosis and renal fibrosis models in vivo and in vitro. The administration of rhADAMTS13 reduced proteinuria and renal fibrosis in UUO mice. rhADAMTS13 inhibited the expression of TSP1 and the activation of TGF-β1/Smad signaling pathway. The knockdown of ADAMTS13 exhibited a contrary result. The regulation of TSP1 directly affected the protective role of ADAMTS13 in renal fibrosis. Moreover, rhADAMTS13 attenuated inflammation induced by UUO. In conclusion, ADAMTS13 attenuates renal fibrosis induced by UUO. ADAMTS13 exerts its protective role by inhibiting TGF-β1 /Smad signaling via TSP1.</div></div><div><h3>New and noteworthy</h3><div>ADAMTS13 may be used as a novel molecular marker and a new therapeutic target for renal fibrosis. In this paper, ADAMTS13 was found to have an antifibrotic effect independent of its cleavage of VWF.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117260"},"PeriodicalIF":3.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379178","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":"Isolicoflavonol alleviates UVB-induced photodamage via protecting mitochondria and blocking the activation of NLRP3 inflammasome","authors":"Xing-Jie Zhang ,&nbsp;Peng-Yun Yang ,&nbsp;Ling Ding ,&nbsp;Jun Wang ,&nbsp;Xiao-Li Li ,&nbsp;Wei-Lie Xiao","doi":"10.1016/j.taap.2025.117262","DOIUrl":"10.1016/j.taap.2025.117262","url":null,"abstract":"<div><div>Photodamage, a type of skin inflammation caused by excessive exposure to solar radiation, leads to skin redness, inflammation, and even the development of skin cancer, posing a severe threat to individuals living at high altitudes. UVB radiation is considered the primary factor contributing to photodamage. It stimulates macrophages within the epidermis, triggers inflammasome activation, and increases the inflammatory cytokine interleukin-1β (IL-1β) production. This study examined the protective effects of the compound isolicoflavonol (ILF) and its mechanism against UVB-induced photodamage. We irradiated UVB to create a photodamage model in mice and macrophages. Next, we assessed ILF's ability to protect the skin and cells from UVB photodamage and its inhibitory effects on UVB-mediated NLRP3 inflammasome. Our findings indicated that ILF reduced UVB-induced skin injury and inflammation in mouse skin, decreased cell death, NLRP3 inflammasome activation, ROS production, and mitochondrial dysfunction. These results suggest that ILF may be a potent agent for protecting the skin against UVB-induced photodamage.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117262"},"PeriodicalIF":3.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391977","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":"Nilotinib impairs relaxation and temporal electro-mechanical integrity in human iPS-derived cardiomyocyte sheets","authors":"Hiroko Izumi-Nakaseko ,&nbsp;Yuko Sekino ,&nbsp;Ryuichi Kambayashi ,&nbsp;Ai Goto ,&nbsp;Yoshinori Takei ,&nbsp;Yukiko Himeno ,&nbsp;Ayako Okado-Matsumoto ,&nbsp;Yoshinobu Nagasawa ,&nbsp;Atsuhiko T. Naito ,&nbsp;Yasunari Kanda ,&nbsp;Atsushi Sugiyama","doi":"10.1016/j.taap.2025.117258","DOIUrl":"10.1016/j.taap.2025.117258","url":null,"abstract":"<div><h3>Introduction</h3><div>Nilotinib, an anti-tumor tyrosine kinase inhibitor against BCR-ABL1, has been clinically reported to cause QT prolongation, but currently lacks evidence for a risk of torsade de pointes. Indeed, it is poorly understood why nilotinib rarely induces torsade de pointes.</div></div><div><h3>Methods and results</h3><div>We adopted two-dimensional human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) sheets to examine effects of nilotinib on their electrophysiological and mechanical properties besides intracellular calcium (Ca²⁺) dynamics. Nilotinib prolonged repolarization in concentration- and reverse-frequency-dependent manners but shortened the contraction-relaxation duration (CRD), which made the electro-mechanical window negative in hiPSC-CM sheets. These effects would correspond to “trigger” of drug-induced torsade de pointes. The drug also suppressed mitochondrial maximum respiration and decreased the peak amplitude and the decay rate of Ca²⁺ transients, which shortened the CRD and impaired relaxation function of the cell sheets, partly explaining the onset mechanism of nilotinib-induced heart failure in patients. Additionally, nilotinib-induced early afterdepolarization (EAD) fluctuated the conduction speed and repolarization, and shifted the electro-mechanical window in a negative direction. These phenomena increased beat-to-beat variability of repolarization and electrical vulnerability of the heart. Meanwhile, nilotinib caused the conduction delay by Na channel blockade, thereby blocking “substrate” formation for the arrhythmia persistence.</div></div><div><h3>Conclusion</h3><div>Nilotinib could deteriorate relaxation ability and temporal electrical integrity of the heart through impairing Ca²⁺ dynamics as well as repolarization phase, which were exacerbated by nilotinib-induced EAD. However, the drug only formed “trigger”, which would explain the lower occurrence of nilotinib-induced torsade de pointes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117258"},"PeriodicalIF":3.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143351022","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":"Inhibition of GRK2 reduced doxorubicin-induced oxidative stress and apoptosis through upregulating ADH1","authors":"Zihao Jiang ,&nbsp;Junyan Kan ,&nbsp;Dongchen Wang ,&nbsp;Yifei Lv,&nbsp;Chaohua Kong,&nbsp;Lida Wu,&nbsp;Yunwei Chen,&nbsp;Meng Yang,&nbsp;Yue Gu,&nbsp;ShaoLiang Chen","doi":"10.1016/j.taap.2025.117261","DOIUrl":"10.1016/j.taap.2025.117261","url":null,"abstract":"<div><h3>Objective</h3><div>Patients undergoing anti-cancer therapy with doxorubicin (DOX) face the risk of cumulative, irreversible cardiotoxicity. In failing hearts, the overexpressed and activated G protein-coupled receptor kinase 2 (GRK2) initiates pathological signaling, leading to cardiomyocyte death. This study aimed to investigate the potential role of GRK2 in DOX-induced cardiotoxicity (DIC).</div></div><div><h3>Methods</h3><div>Mice were administered intraperitoneal injections of DOX (5 mg/kg) weekly for four weeks to induce DIC. Small interfering RNAs (siRNAs) targeting GRK2, ADH1, and PABPC1 were employed in H9c2 cells. Oxidative stress and cell apoptosis were assessed using Reactive Oxygen Species (ROS) staining and TUNEL staining, respectively. Co-immunoprecipitation (Co-IP) was utilized to detect the interaction between GRK2 and PABPC1. RNA immunoprecipitation (RIP) assay was employed to evaluate the binding between PABPC1 and ADH1 mRNA.</div></div><div><h3>Results</h3><div>GRK2 was found to be upregulated in DOX-treated mouse hearts and H9c2 cells. Cardiomyocyte-specific <em>GRK2</em> knockout partially mitigated oxidative stress, apoptosis, and cardiac dysfunction. Additionally, GRK2 knockdown attenuated DOX-induced oxidative damage and apoptosis both <em>in vivo</em> and in H9c2 cells. Furthermore, a reduction in ADH1 expression was observed in DOX-treated hearts and cardiomyocytes, with a pronounced increase following GRK2 knockdown. Notably, the beneficial effects of GRK2 knockdown in H9c2 cells were abolished after ADH1 knockdown. Mechanistically, GRK2 knockdown promoted the binding of PABPC1 to ADH1 mRNA, thereby inhibiting the degradation of ADH1 mRNA. Increased ADH1 expression alleviated DOX-induced oxidative stress and apoptosis in cardiomyocytes.</div></div><div><h3>Conclusion</h3><div>In conclusion, our study demonstrates that targeting GRK2 may represent a promising therapeutic strategy for mitigating DOX-associated cardiotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117261"},"PeriodicalIF":3.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365995","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":"Effects of hypoxia and iron on ascorbic acid-mediated cytotoxicity in prostate cancer cell lines","authors":"Samiksha Deme ,&nbsp;Ida Ramezani ,&nbsp;Jonathan Coulter ,&nbsp;Channing Paller ,&nbsp;Joseph Bressler","doi":"10.1016/j.taap.2025.117259","DOIUrl":"10.1016/j.taap.2025.117259","url":null,"abstract":"<div><div>Ascorbic acid (ASC) has long been proposed as a potential cancer co-treatment due to its specific toxicity towards cancer cells, but discrepancies between in vitro and in vivo studies suggest that external factors may modulate its cytotoxicity. Here, we investigate the impact of hypoxia and iron on the therapeutic effectiveness of ASC on prostate cancer cell lines. Hypoxia-induced increases in the EC₅₀ of ASC in the prostate cancer cell lines PC-3, DU 145, LNCaP, and CWR22Rv1 but not in the prostate non-cancer cell lines RWPE-1 and TERT-PrECs. The synthetic androgen dihydrotestosterone did not modify ASC's effectiveness in either normoxia or hypoxia, which was tested because both early and advanced prostate cancer maintain the androgen receptor pathway. The effects of hypoxia on cytotoxicity depend on the drug. Hypoxia did not affect the EC₅₀ for the DNA-damaging agent etoposide but decreased the sensitivity for the anti-microtubule agent paclitaxel in PC-3 and DU 145 cells. Although hypoxic cells were iron deficient, adding iron back to cells did not reverse the effects of the hypoxic atmosphere. Interestingly, the EC₅₀ for ASC was approximately two-fold higher in iron-treated cells than non‑iron-treated cells for the PC-3 line. The higher EC50 was not observed by knocking down ferritin heavy chain mRNA. In summary, both hypoxia and iron attenuate the effectiveness of high concentrations of ASC in prostate cancer cell lines, which may affect the therapeutic benefit of ASC for prostate cancer patients.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117259"},"PeriodicalIF":3.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365991","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":"Complanatoside A disrupts copper homeostasis and induces cuproptosis via directly targeting ATOX1 in prostate cancer","authors":"Yi Zhao ,&nbsp;Ruonan Wang ,&nbsp;Chaoyu Hu ,&nbsp;Yan Wang ,&nbsp;Zengrui Li ,&nbsp;Dengke Yin ,&nbsp;Song Tan","doi":"10.1016/j.taap.2025.117257","DOIUrl":"10.1016/j.taap.2025.117257","url":null,"abstract":"<div><div>Complanatoside A (CA), a flavonoid derived from the Chinese medicinal herb <em>Semen Astragali Complanati</em>, exhibits anticancer activity. However, its effects on prostate cancer (PCa) remain unclear. We aimed to elucidate the anti-PCa effects and underlying mechanisms of action of CA, both <em>in vitro</em> and <em>in vivo</em>. MTT, transwell, wound-healing, and flow cytometry assays were used to detect PCa cell growth, invasion, migration, and apoptosis and cell cycle progression after CA treatment, respectively. The target of CA was predicted to be antioxidant 1 copper chaperone (ATOX1), and its expression levels were determined using immunoblotting analysis. As ATOX1 acts as copper carrier to maintain copper homeostasis and disrupted copper homeostasis leads to oxidative stress in mitochondria and cuproptosis, the concentration of copper, ATP，pyruvate, α-ketoglutamic acid, malondialdehyde, and glutathione were determined and markers of cuproptosis were analyzed by immunoblotting analysis. The copper chelator tetrathiomolybdate was used to identify CA-induced cuproptosis of PCa cells. Finally, a subcutaneous mouse model was constructed, and tumor growth, oxidative stress, and carcinogenesis were analyzed <em>in vivo</em>. Our investigation revealed that CA inhibited PCa cell growth, invasion, migration, and cell cycle progression and induced apoptosis. ATOX1 was downregulated by CA and promoted Cu ion accumulation, which inhibited mitochondrial activity and induced cuproptosis in PCa cells. In addition, CA markedly suppressed tumor growth <em>in vivo</em> and induced cuproptosis in tumor tissues. In conclusion, CA exerts its anti-PCa effects by reducing ATOX1 protein levels and promoting Cu ion accumulation, which in turn, inhibits mitochondrial activity and induces cuproptosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117257"},"PeriodicalIF":3.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143193050","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}