Toxicology and applied pharmacology最新文献_第2页

Nrf2 deficiency aggravates hepatic cadmium accumulation, inflammatory response and subsequent injury induced by chronic cadmium exposure in mice

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-10 DOI: 10.1016/j.taap.2025.117263

Chengjie Chen , Xue Han , Ning Xu , Wei Shen , Gang Wang , Junying Jiao , Weiwei Kong , Jiaxin Yu , Jingqi Fu , Jingbo Pi

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 Nrf2 knockout (Nrf2-KO) mice chronically exposed to Cd in drinking water (100 or 200 ppm) for up to 24 weeks. We found that absence of Nrf2 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 Nrf2-KO mice compared with those in wild-type (Nrf2-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 Nrf2-KO mice relative to Nrf2-WT controls, either under basal or Cd-exposed conditions. Our findings demonstrated that Nrf2-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.

{"title":"Nrf2 deficiency aggravates hepatic cadmium accumulation, inflammatory response and subsequent injury induced by chronic cadmium exposure in mice","authors":"Chengjie Chen , Xue Han , Ning Xu , Wei Shen , Gang Wang , Junying Jiao , Weiwei Kong , Jiaxin Yu , Jingqi Fu , 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}

引用次数: 0

ADAMTS13 attenuates renal fibrosis by suppressing thrombospondin 1 mediated TGF-β1/Smad3 activation

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-08 DOI: 10.1016/j.taap.2025.117260

Jie Guo , Suhan Zhou , Honghong Wang , Xingyu Qiu , Fang Dong , Shan Jiang , Nan Xu , Yu Cui , Ruisheng Liu , Pengyun Li , Zufu Ma , Liang Zhao , En Yin Lai

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.

New and noteworthy

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.

{"title":"ADAMTS13 attenuates renal fibrosis by suppressing thrombospondin 1 mediated TGF-β1/Smad3 activation","authors":"Jie Guo , Suhan Zhou , Honghong Wang , Xingyu Qiu , Fang Dong , Shan Jiang , Nan Xu , Yu Cui , Ruisheng Liu , Pengyun Li , Zufu Ma , Liang Zhao , 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 Ca<sup>2+</sup> 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}

引用次数: 0

Isolicoflavonol alleviates UVB-induced photodamage via protecting mitochondria and blocking the activation of NLRP3 inflammasome

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-08 DOI: 10.1016/j.taap.2025.117262

Xing-Jie Zhang , Peng-Yun Yang , Ling Ding , Jun Wang , Xiao-Li Li , Wei-Lie Xiao

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.

{"title":"Isolicoflavonol alleviates UVB-induced photodamage via protecting mitochondria and blocking the activation of NLRP3 inflammasome","authors":"Xing-Jie Zhang , Peng-Yun Yang , Ling Ding , Jun Wang , Xiao-Li Li , 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}

引用次数: 0

Inhibition of GRK2 reduced doxorubicin-induced oxidative stress and apoptosis through upregulating ADH1

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-04 DOI: 10.1016/j.taap.2025.117261

Zihao Jiang , Junyan Kan , Dongchen Wang , Yifei Lv, Chaohua Kong, Lida Wu, Yunwei Chen, Meng Yang, Yue Gu, ShaoLiang Chen

Objective

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).

Methods

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.

Results

GRK2 was found to be upregulated in DOX-treated mouse hearts and H9c2 cells. Cardiomyocyte-specific GRK2 knockout partially mitigated oxidative stress, apoptosis, and cardiac dysfunction. Additionally, GRK2 knockdown attenuated DOX-induced oxidative damage and apoptosis both in vivo 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.

Conclusion

In conclusion, our study demonstrates that targeting GRK2 may represent a promising therapeutic strategy for mitigating DOX-associated cardiotoxicity.

{"title":"Inhibition of GRK2 reduced doxorubicin-induced oxidative stress and apoptosis through upregulating ADH1","authors":"Zihao Jiang , Junyan Kan , Dongchen Wang , Yifei Lv, Chaohua Kong, Lida Wu, Yunwei Chen, Meng Yang, Yue Gu, 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}

引用次数: 0

Nilotinib impairs relaxation and temporal electro-mechanical integrity in human iPS-derived cardiomyocyte sheets

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-04 DOI: 10.1016/j.taap.2025.117258

Hiroko Izumi-Nakaseko , Yuko Sekino , Ryuichi Kambayashi , Ai Goto , Yoshinori Takei , Yukiko Himeno , Ayako Okado-Matsumoto , Yoshinobu Nagasawa , Atsuhiko T. Naito , Yasunari Kanda , Atsushi Sugiyama

Introduction

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.

Methods and results

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.

Conclusion

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.

{"title":"Nilotinib impairs relaxation and temporal electro-mechanical integrity in human iPS-derived cardiomyocyte sheets","authors":"Hiroko Izumi-Nakaseko , Yuko Sekino , Ryuichi Kambayashi , Ai Goto , Yoshinori Takei , Yukiko Himeno , Ayako Okado-Matsumoto , Yoshinobu Nagasawa , Atsuhiko T. Naito , Yasunari Kanda , 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 (Ca<sup>2+</sup>) 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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}

引用次数: 0

Effects of hypoxia and iron on ascorbic acid-mediated cytotoxicity in prostate cancer cell lines

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-04 DOI: 10.1016/j.taap.2025.117259

Samiksha Deme , Ida Ramezani , Jonathan Coulter , Channing Paller , Joseph Bressler

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.

{"title":"Effects of hypoxia and iron on ascorbic acid-mediated cytotoxicity in prostate cancer cell lines","authors":"Samiksha Deme , Ida Ramezani , Jonathan Coulter , Channing Paller , 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 EC<sub>50</sub> 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 EC<sub>50</sub> 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 EC<sub>50</sub> 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}

引用次数: 0

Complanatoside A disrupts copper homeostasis and induces cuproptosis via directly targeting ATOX1 in prostate cancer

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-03 DOI: 10.1016/j.taap.2025.117257

Yi Zhao , Ruonan Wang , Chaoyu Hu , Yan Wang , Zengrui Li , Dengke Yin , Song Tan

Complanatoside A (CA), a flavonoid derived from the Chinese medicinal herb Semen Astragali Complanati, 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 in vitro and in vivo. 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 in vivo. 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 in vivo 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.

络石苷 A（CA）是从中草药 "络石黄芪 "中提取的一种黄酮类化合物，具有抗癌活性。然而，它对前列腺癌（PCa）的作用仍不明确。我们的目的是在体外和体内阐明 CA 的抗 PCa 作用及其作用机制。我们使用 MTT、transwell、伤口愈合和流式细胞术检测 PCa 细胞的生长、侵袭、迁移以及 CA 治疗后的细胞凋亡和细胞周期进展。CA的靶点被预测为抗氧化剂1铜伴侣（ATOX1），并通过免疫印迹分析确定了其表达水平。由于 ATOX1 是维持铜平衡的铜载体，而铜平衡的破坏会导致线粒体氧化应激和杯突症，因此测定了铜、ATP、丙酮酸、α-酮戊二酸、丙二醛和谷胱甘肽的浓度，并通过免疫印迹分析了杯突症的标志物。铜螯合剂四巯基钼酸盐被用来鉴定CA诱导的PCa细胞杯突。最后，我们构建了小鼠皮下模型，并在体内对肿瘤生长、氧化应激和癌变进行了分析。我们的研究发现，CA能抑制PCa细胞的生长、侵袭、迁移和细胞周期进展，并诱导细胞凋亡。CA下调了ATOX1，促进了Cu离子的积累，从而抑制了线粒体的活性，诱导了PCa细胞的杯突变。此外，CA 还能明显抑制肿瘤在体内的生长，并诱导肿瘤组织中的杯突变。总之，CA 通过降低 ATOX1 蛋白水平和促进 Cu 离子积累，进而抑制线粒体活性和诱导杯突症，发挥抗 PCa 作用。

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引用次数: 0

Network pharmacological mechanism and molecular experimental validation of artemisinin in the treatment of lung adenocarcinoma 青蒿素治疗肺腺癌的网络药理机制及分子实验验证。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117226

Zhimin Lu , Jialu Jiang , Xuming Yao , Guoxin Hou

Background

Lung cancer is a medical ailment with high mortality and prevalence rates. Artemisinin (ART) and its derivatives exhibit anti-cancer properties against various malignancies, including lung cancer. However, further research is required to determine the precise anti-cancer mechanisms of ART. Hence, this study aimed to utilize network pharmacology to preliminarily investigate the therapeutic effectiveness and mode of action of this medication.

Methods

Using a bioinformatics approach, five target proteins with the strongest connections were selected for docking. Gene enrichment analysis was performed, and the ART target proteins were predicted. Various methods, including methyl thiazolyl tetrazolium (MTT) assays, colony formation assays, microsphere formation assays, flow cytometry, and western blotting analysis, were employed to assess the impact of ART on the malignant characteristics of lung cancer cells.

Results

Bioinformatic analysis identified 51 ART target genes in lung adenocarcinoma for further analysis. Pathway enrichment analysis of target genes revealed 639 enriched Gene Ontology-Biological Process (GO BP) and 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These findings imply that ART may control the IL-6 signaling pathway by focusing on important molecules such as CDK4 and IL-6. The ART-treated group experienced apoptosis induction, cell cycle arrest, and inhibition of cell proliferation and microsphere formation compared with the control group (p < 0.05, p < 0.01). Additionally, ART reduced the protein expression of CDK4, COX2, ERBB2, CD44, and EpCAM while increasing that of caspase 3, IL-6, p53, and SRC (p < 0.01).

Conclusion

ART inhibited the growth and stemness of HCC827 cells.

背景：肺癌是一种死亡率和患病率都很高的内科疾病。青蒿素（ART）及其衍生物对包括肺癌在内的多种恶性肿瘤具有抗癌作用。然而，需要进一步的研究来确定抗逆转录病毒治疗的确切抗癌机制。因此，本研究旨在利用网络药理学对该药物的治疗效果和作用方式进行初步探讨。方法：采用生物信息学方法，选择连接最强的5个靶蛋白进行对接。进行基因富集分析，并预测ART靶蛋白。采用多种方法，包括甲基噻唑四氮唑（MTT）测定、菌落形成测定、微球形成测定、流式细胞术和western blotting分析，评估ART对肺癌细胞恶性特征的影响。结果：生物信息学分析鉴定出51个ART靶基因用于肺腺癌的进一步分析。通路富集分析发现639条富集的基因本体-生物过程（GO BP）通路和17条富集的京都基因与基因组百科全书（KEGG）通路。这些发现暗示ART可能通过聚焦CDK4和IL-6等重要分子来控制IL-6信号通路。与对照组相比，ART治疗组细胞凋亡诱导、细胞周期阻滞、细胞增殖和微球形成受到抑制（p ）。结论：ART可抑制HCC827细胞的生长和干性。

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引用次数: 0

Thymidine phosphorylase participates in platelet activation and promotes inflammation in rheumatoid arthritis 胸苷磷酸化酶参与血小板活化并促进类风湿关节炎的炎症。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117217

Bo Cai , Zelin He , Dandan Liu , Yuping Zhang , Zikang Yin , Weijia Bao , Qiaoyi Le , Ju Shao , Hongyan Du , Ligang Jie

The elevated risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) have a higher mortality rate compared to the general population due to abnormal platelet activation. Thymidine phosphorylase (TYMP) plays a crucial role in platelet activation and thrombosis, following bridging the link between RA and CVD. Data from Gene Expression Omnibus (GEO) database exhibited that TYMP levels were highly expressed in synovial tissues, immune cells, and whole blood of RA patients especially those with high levels of inflammation. Platelet count (PLT) and plateletcrit (PCT) were positively correlated with the severity of inflammation in rheumatoid arthritis while platelet distribution width (PDW) and mean platelet volume (MPV) were adverse. Levels of CD62P and TYMP in platelets of patients with active RA were significantly elevated compared to patients in the inactive phase. In vivo experiments showed that reducing TYMP expression levels of platelets could relieve inflammation in Adjuvant-Induced Arthritis (AIA) mice. Platelet activation was significantly elevated in AIA model mice, along with increased levels of intracellular calcium (Ca²⁺), reactive oxygen species (ROS), and decreased Mitochondrial Membrane Potential (ΔΨm). However, treatment with Tipiracil hydrochloride (TPI) or the utilization of Tymp^−/− mice reversed these effects. In vitro stimulation of wild type (WT) mouse platelets with tumor necrosis factor-alpha (TNF-α) promoted platelet activation, elevated levels of intracellular Ca²⁺as well as ROS while decreased ΔΨm. Platelets of WT mice treated with TPI or platelets of Tymp^−/− mice exhibited the adverse results. Our study illustrates the vital role of TYMP in promoting RA inflammation and platelet activation, suggesting that TYMP may be a potential therapeutic target for RA.

与炎症性风湿病相关的心血管疾病（CVD）风险升高早已得到公认。由于血小板活化异常，已确诊的类风湿性关节炎（RA）患者的死亡率高于普通人群。胸腺嘧啶磷酸化酶（TYMP）在血小板活化和血栓形成过程中起着至关重要的作用，是类风湿性关节炎与心血管疾病之间联系的桥梁。基因表达总库（GEO）的数据显示，TYMP水平在RA患者尤其是高炎症水平患者的滑膜组织、免疫细胞和全血中高度表达。血小板计数（PLT）和血小板比容（PCT）与类风湿性关节炎的炎症严重程度呈正相关，而血小板分布宽度（PDW）和平均血小板体积（MPV）则呈负相关。与非活动期患者相比，活动期类风湿关节炎患者血小板中的 CD62P 和 TYMP 水平明显升高。体内实验表明，降低血小板中 TYMP 的表达水平可缓解佐剂诱发的关节炎（AIA）小鼠的炎症。AIA 模型小鼠的血小板活化明显升高，同时细胞内钙（Ca2+）、活性氧（ROS）水平升高，线粒体膜电位（ΔΨm）降低。然而，用盐酸替吡西尔（TPI）治疗或利用 Tymp-/- 小鼠可逆转这些影响。用肿瘤坏死因子-α（TNF-α）体外刺激野生型（WT）小鼠血小板可促进血小板活化、细胞内 Ca2+ 和 ROS 水平升高，同时降低ΔΨm。用 TPI 处理的 WT 小鼠血小板或 Tymp-/- 小鼠血小板均表现出不良结果。我们的研究说明了TYMP在促进RA炎症和血小板活化中的重要作用，提示TYMP可能是RA的潜在治疗靶点。

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引用次数: 0

Hesperidin enhanced anti-breast cancer effect and alleviated cisplatin induced nephrotoxicity through silk fibroin delivery system 橙皮苷通过丝素传递系统增强抗乳腺癌作用，减轻顺铂所致肾毒性。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117234

Yonglong Jin , Nina Dong , Shosei Shimizu , Yinuo Li , Yuan Yao , Hong Qiao , Xiguang Liu , Shuai Liu , Chuanlong Guo , Lijie Wang

The incidence rate and mortality rate of breast cancer remain high, and there is an urgent need for safe and effective drugs. The excellent biological activity of hesperidin (HE) is a potential drug for the treatment of breast cancer. In this study, silk fibroin peptides (SFP) were used as delivery carriers and HE loaded SFP nanofibers (SFP/HE NFs) was prepared. The in vitro results showed that SFP/HE NFs significantly inhibited the proliferation and migration of breast cancer cell MDA-MB-231 compared with free HE. The mechanism results demonstrated that SFP/HE NFs induced apoptosis and DNA double stranded damage (DSBs) and further activated the cyclic monophosphate guanosine adenosine monophosphate synthase- stimulator of interferon gene (cGAS-STING) pathway. The in vivo studies showed that SFP/HE NFs treatment significantly inhibited the growth of breast cancer, with an inhibition rate of 65.9 % (100 mg/kg). In vivo mechanism studies also demonstrated that the anti-tumor activity of SFP/HE NFs was related to the activation of the cGAS-STING pathway. Interestingly, we found that the combination of SFP/HE NFs and cisplatin not only enhanced the anti-tumor activity of cisplatin, but also alleviated cisplatin induced nephrotoxicity. In conclusion, our results demonstrate the benefits of activating the cGAS-STING pathway in the treatment of breast cancer, which is expected to provide potential candidates for combined treatment of breast cancer.

乳腺癌的发病率和死亡率居高不下，迫切需要安全有效的药物。橙皮苷（HE）具有良好的生物活性，是治疗乳腺癌的潜在药物。本研究以丝素蛋白肽（SFP）为载体，制备了HE负载的SFP纳米纤维（SFP/HE NFs）。体外实验结果显示，与游离HE相比，SFP/HE NFs可显著抑制乳腺癌细胞MDA-MB-231的增殖和迁移。机制结果表明，SFP/HE NFs诱导细胞凋亡和DNA双链损伤（DSBs），并进一步激活环单磷酸鸟苷腺苷单磷酸合成酶-干扰素基因刺激因子（cGAS-STING）通路。体内研究表明，SFP/HE NFs治疗可显著抑制乳腺癌的生长，抑制率为65.9% （100 mg/kg）。体内机制研究也表明，SFP/HE NFs的抗肿瘤活性与cGAS-STING通路的激活有关。有趣的是，我们发现SFP/HE NFs与顺铂联合使用不仅可以增强顺铂的抗肿瘤活性，还可以减轻顺铂引起的肾毒性。总之，我们的研究结果证明了激活cGAS-STING通路在乳腺癌治疗中的益处，有望为乳腺癌联合治疗提供潜在的候选药物。

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引用次数: 0