Toxicology and applied pharmacology最新文献_第5页

Ginkgetin enhances breast cancer radiotherapy sensitization by suppressing NRF2-HO-1 axis activity. 银杏黄酮通过抑制 NRF2-HO-1 轴活性增强乳腺癌放疗的敏感性

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-07 DOI: 10.1016/j.taap.2024.117199

Qiong Duan, Zhenting Cui, Mingxiao Wang, Ruochen Li, Feng Han, Jianxin Ma

{"title":"Ginkgetin enhances breast cancer radiotherapy sensitization by suppressing NRF2-HO-1 axis activity.","authors":"Qiong Duan, Zhenting Cui, Mingxiao Wang, Ruochen Li, Feng Han, Jianxin Ma","doi":"10.1016/j.taap.2024.117199","DOIUrl":"10.1016/j.taap.2024.117199","url":null,"abstract":"Breast cancer (BC) is a critical threat to women's lives. Radiotherapy (RT) is a pivotal treatment modality for BC, but the failure of RT due to radioresistance is still not well facilitated. Ginkgetin (GK) has a potent anti-tumor activity intimately associated with ferroptosis. This study applied in vitro and in vivo experimental models to ascertain the GK mechanism of action on BC radioresistance. The outcomes reported that GK could inhibit BC cell growth and increase apoptosis. In addition, when BC cells generated radioresistance, GK promoted ferroptosis of radioresistant BC cells by mitigating NRF2 expression, suppressing HO-1 and NQO1 expression, increasing the intracellular content of reactive oxygen species (ROS) and ferrous ions, accelerating the glutathione (GSH) depletion, and decreasing GPX4 expression. Notably, GK can damage intracellular mitochondria and cause a substantial increase in ferrous ions in BC cells. Therefore, GK shows immense potential for enhancing breast cancer radiotherapy sensitivity, which may provide pivotal evidence for subsequent RT sensitization.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117199"},"PeriodicalIF":3.3,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802161","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

Toxic effects of dibutyl phthalate on trophoblast through mitochondria mediated cellular dysfunction. 邻苯二甲酸二丁酯通过线粒体介导的细胞功能障碍对滋养层细胞的毒性作用。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-06 DOI: 10.1016/j.taap.2024.117186

Hyewon Jang, Gwonhwa Song, Whasun Lim, Sunwoo Park

{"title":"Toxic effects of dibutyl phthalate on trophoblast through mitochondria mediated cellular dysfunction.","authors":"Hyewon Jang, Gwonhwa Song, Whasun Lim, Sunwoo Park","doi":"10.1016/j.taap.2024.117186","DOIUrl":"10.1016/j.taap.2024.117186","url":null,"abstract":"Dibutyl phthalate is a chemical commonly used as a plasticizer in the production of daily necessaries, such as cosmetics and toys. Although several toxic effects of dibutyl phthalate have been confirmed, those related to pregnancy are unknown. Trophoblasts are critical for fetal and placental development, and trophoblast damage may cause preeclampsia. This study aimed to confirm the toxic effect of dibutyl phthalate on trophoblasts. We used the human trophoblast cell line HTR-8/SVneo and human choriocarcinoma JEG-3 cells as a placental trophoblast model to investigate the toxic effects of dibutyl phthalate. Both cell lines were treated with dibutyl phthalate (0-20 μg/mL) to verify the mechanisms regulating trophoblast function. Dibutyl phthalate treatment significantly reduced trophoblast viability, reduced invasion ability, and induced mitochondrial depolarization. Ultimately, dibutyl phthalate regulated the PI3K and MAPK signaling pathways and the expression of autophagy-related proteins ATG5, LC3B, and SQSTM1/p62. We concluded that dibutyl phthalate induced autophagy and effectively weakened trophoblast function. Additionally, we conducted experiments to assess the potential effects of monobutyl phthalate, a metabolite of dibutyl phthalate, on cellular mobility, penetration, and autophagy induction. Our results demonstrated that monobutyl phthalate impaired these functions and weakened the trophoblast barrier, after dibutyl phthalate metabolized. Thus, exposure to dibutyl phthalate and its metabolite monobutyl phthalate can damage trophoblast function, highlighting their potential as hazardous substances that impair trophoblast barrier integrity.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117186"},"PeriodicalIF":3.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795144","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

Analysis of children's kidney stones and comparison to canine kidney stones: Both resulting from ingesting adulterated food products. 儿童肾结石的分析和与犬肾结石的比较：两者都是由摄入掺假食品引起的。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-06 DOI: 10.1016/j.taap.2024.117190

James A Campbell, Catherine E Petersen

{"title":"Analysis of children's kidney stones and comparison to canine kidney stones: Both resulting from ingesting adulterated food products.","authors":"James A Campbell, Catherine E Petersen","doi":"10.1016/j.taap.2024.117190","DOIUrl":"10.1016/j.taap.2024.117190","url":null,"abstract":"Kidney stones resulting from ingestion of melamine-tainted food products were originally detected in dogs and cats in 2004 and 2007. Nephroliths were removed at necropsy from dogs that had died from acute kidney injury in Asia in 2004. Samples of these were submitted to our laboratories for analysis. The presence of a mixed s-triazine matrix comprising melamine, cyanuric acid, and ammelide, but no detectable ammeline was found in the canine stone samples we analyzed. The unusual and unique green coloration of these stones was attributed to the presence of biliverdin. The techniques developed in the canine study were applied to the analysis of human kidney stones. In 2008, high levels of melamine were detected in some infant formula and other liquid and powdered milk products originating from China. Human kidney stones, resulting from this type of contamination, were obtained from children, and analyzed using mass spectral techniques. The results indicated the presence of melamine, ammeline, uric acid, but no ammelide. No green color was observed, thereby eliminating biliverdin. Careful monitoring of food additives is warranted to prevent future problems in both animals and humans.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117190"},"PeriodicalIF":3.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795135","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

Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys. 重组CR1药物CSL040在大鼠和食蟹猴中的临床前安全性和有效性。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-06 DOI: 10.1016/j.taap.2024.117191

Tanja Ruthsatz, Sandra Wymann, Elena Velkoska, Mariam Mansour, Daniel Schu, Marit Lichtfuss, Paolo Rossato, Meaghan FitzPatrick, Sarah Hosback, Allison Dyson, Eva Herzog, Kirstee Martin, Barbara Dietrich, Matthew P Hardy

{"title":"Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys.","authors":"Tanja Ruthsatz, Sandra Wymann, Elena Velkoska, Mariam Mansour, Daniel Schu, Marit Lichtfuss, Paolo Rossato, Meaghan FitzPatrick, Sarah Hosback, Allison Dyson, Eva Herzog, Kirstee Martin, Barbara Dietrich, Matthew P Hardy","doi":"10.1016/j.taap.2024.117191","DOIUrl":"10.1016/j.taap.2024.117191","url":null,"abstract":"CSL040 is a soluble, recombinant fragment of the complement receptor 1 (CR1) extracellular domain that acts as an inhibitor of all three pathways of the complement system. Systemic toxicity, toxicokinetics (TK), and pharmacodynamics (PD) of CSL040 were assessed in two-week intravenous (IV) bolus studies in Han Wistar rats and cynomolgus monkeys. Recovery from any effects was evaluated during a four-week recovery period. Daily repeat-dose administration for 2 weeks at doses of up to 500 mg/kg CSL040 IV was well tolerated in rats and cynomolgus monkeys, leading to a no observed adverse effect level (NOAEL) of 500 mg/kg for both species. Safety pharmacology parameters such as electrophysiology of the heart, blood pressure, heart rate, and respiratory rate measurements, and general toxicological readouts were considered unaffected by CSL040 treatment. Anti-drug antibodies (ADAs) were observed in all cynomolgus monkeys and in some rats at the highest dose of CSL040, but with no effect on pharmacokinetics (PK), supportive of adequate exposure levels as required for a safety assessment. All three complement pathways were inhibited dose-dependently by CSL040. Additionally, no effect on cytokine levels by CSL040 was detected in vitro using a cytokine release assay. These non-clinical studies with CSL040 demonstrated PD activity consistent with its mode of action, adequate PK properties, and a safety profile supporting a phase 1 clinical strategy. A small follow-up study comparing the PK/PD effects of CSL040 following IV and subcutaneous (SC) administration also suggested that the latter route of administration might be a viable alternative to IV administration.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117191"},"PeriodicalIF":3.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795138","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

An oat fiber intervention for reducing PFAS body burden: A pilot study in male C57Bl/6 J mice. 燕麦纤维干预减轻PFAS身体负担：雄性C57Bl/6 J小鼠的初步研究。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-06 DOI: 10.1016/j.taap.2024.117188

Jennifer J Schlezinger, Kushal Biswas, Audrey Garcia, Wendy J Heiger-Bernays, Dhimiter Bello

{"title":"An oat fiber intervention for reducing PFAS body burden: A pilot study in male C57Bl/6 J mice.","authors":"Jennifer J Schlezinger, Kushal Biswas, Audrey Garcia, Wendy J Heiger-Bernays, Dhimiter Bello","doi":"10.1016/j.taap.2024.117188","DOIUrl":"10.1016/j.taap.2024.117188","url":null,"abstract":"Perfluoroalkyl substances (PFAS) are a major public health concern, in part because several PFAS have elimination half-lives on the order of years and are associated with adverse health outcomes. While PFAS can be transported into bile, their efficient reuptake by intestinal transporter proteins results in minimal fecal elimination. Here, we tested the hypothesis that consumption of oat β-glucan, a dietary supplement known to disrupt the enterohepatic recirculation of bile acids, will reduce PFAS body burdens. Male C57Bl/6 J mice were fed diets based on the \"What we eat in America\" analysis that were supplemented with inulin or oat β-glucan and exposed via drinking water to a seven PFAS mixture (PFHpA, PFOA, PFNA, Nafion Byproduct-2, PFHxS and PFOS) for 6 weeks. One cohort of mice was euthanized at the end of the exposure, and one cohort continued on the experimental diets for 4 more weeks without additional PFAS exposure. The β-glucan fed mice drank significantly more water than the inulin fed mice, resulting in a significantly higher dose of PFAS. Relative to overall exposure, we observed lower serum concentration trends (p < 0.1) in β-glucan fed mice for PFHpA, PFOA and PFOS. Additionally, β-glucan fed mice had lower adipose:body weight ratios and liver and jejunum triglyceride concentrations. Hepatic mRNA expression of Cyp4a10, Cyp2b10 and Cyp3a11 were elevated in PFAS exposed mice, with only the expression of Cyp3a11 decreasing following depuration. This pilot study generates support for the hypothesis that oat β-glucan supplementation can reduce PFAS body burdens and stimulate healthful effects on lipid homeostasis.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117188"},"PeriodicalIF":3.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795133","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

Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity and the underlying mechanism. 百里醌对阿霉素诱导的心脏毒性的保护作用及其机制。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-05 DOI: 10.1016/j.taap.2024.117179

Yi Chen, Wei Luo, Yanqing Wu

{"title":"Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity and the underlying mechanism.","authors":"Yi Chen, Wei Luo, Yanqing Wu","doi":"10.1016/j.taap.2024.117179","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117179","url":null,"abstract":"Background: Ferroptosis is a key process in doxorubicin (DOX)-induced cardiotoxicity and is a potentially important therapeutic target. Thymoquinone (TQ) is a monoterpenoid compound isolated from black cumin extract that exhibits antitumor effects and acts as a powerful mitochondrial-targeted antioxidant. In this study, we investigated the effect of TQ on DOX-induced cardiotoxicity and the potential underlying mechanisms.Methods and results: Mice were randomly assigned to the control (CON) group, DOX (20 mg/kg) group, TQ10 (10 mg/kg/d) group, and TQ20 (20 mg/kg/d) group and intraperitoneally injected with DOX and different doses of TQ. The electrocardiogram, blood pressure, and cardiac ultrasound changes during the experiments showed that TQ exerted a protective effect against DOX-induced cardiotoxicity. The glutathione (GSH), malondialdehyde (MDA), and total antioxidant capacity (T-AOC) levels in the mouse heart tissue were significantly different from those in the CON group. Western blot analysis revealed that the expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in the DOX group was lower than that in the control group. TQ treatment decreased these changes, indicating that TQ alleviated DOX-induced cardiotoxicity and increased the antioxidant capacity of murine cardiomyocytes. The mechanism might involve activating the Nrf2/HO-1 signaling pathway and reducing iron-mediated death. Immunohistochemical staining revealed similar effects on the expression levels of NQO1, COX-2, and NOX4. Moreover, transmission electron microscopy indicated that TQ protected murine cardiomyocytes against DOX-induced mitochondrial damage.Conclusion: The results of this study suggested that TQ can decrease oxidative stress levels and DOX-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway to alleviate ferroptosis in murine cardiomyocytes.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117179"},"PeriodicalIF":3.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792339","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

Corrigendum to "Differentiation of sow and mouse ovarian granulosa cells exposed to zearalenone in vitro using RNA-seq gene expression" [Toxicology and Applied Pharmacology, 350 (2018) 78-90]. “使用RNA-seq基因表达暴露于玉米霉烯酮的母猪和小鼠卵巢颗粒细胞的体外分化”[毒理学与应用药理学，350(2018)78-90]。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-04 DOI: 10.1016/j.taap.2024.117189

Guo-Liang Zhang, Jun-Lin Song, Yi Zhou, Rui-Qian Zhang, Shun-Feng Cheng, Xiao-Feng Sun, Guo-Qing Qin, Wei Shen, Lan Li

引用次数: 0

Cadmium alters the cellular metabolome of human ovarian granulosa cells. 镉改变人卵巢颗粒细胞的细胞代谢组。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-03 DOI: 10.1016/j.taap.2024.117187

Jun Zhang, Guofeng Xu, Shuang Liu, Meng Yang

{"title":"Cadmium alters the cellular metabolome of human ovarian granulosa cells.","authors":"Jun Zhang, Guofeng Xu, Shuang Liu, Meng Yang","doi":"10.1016/j.taap.2024.117187","DOIUrl":"10.1016/j.taap.2024.117187","url":null,"abstract":"Cadmium (Cd) is a toxic heavy metal that has been extensively implicated in disordered folliculogenesis, but the mechanisms underlying the ovarian toxicity of Cd remain to be explored fully. Granulosa cells are key players in ovarian follicular development and are the primary cells affected by Cd exposure-induced damage and dysfunction. In this study, we investigated how various levels of exposure of Cd (3 and 10 μM) to human granulosa cells (KGN cells) impacted the metabolism of the KGN cells utilizing a non-targeted metabolomics methodology. In vitro cell experiments revealed that Cd exposure dose-dependently diminished the viability of KGN cells. Metabolomics analysis revealed the presence of 296 (182 elevated and 114 reduced) and 397 (244 elevated and 153 reduced) differentially expressed metabolites after exposure to 3 and 10 μM, respectively. Cd exposure was found to significantly enrich nucleotide metabolism, sphingolipid metabolism, and ABC transporters in both groups. Although amino acid metabolic pathways exhibited significant enrichment across all groups, only glutathione, cysteine, and methionine metabolism were notably enriched in KGN cells exposed to 3 μM Cd, while glutathione and tryptophan metabolism were significantly enriched in the 10 μM Cd exposure cohort. The outcomes of this study provide mechanistic clues for elucidating Cd's cytotoxic impact on granulosa cells, and deepen our understanding of the ovarian toxicity of Cd.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117187"},"PeriodicalIF":3.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786863","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

A computational model of the crosstalk between hepatocyte fatty acid metabolism and oxidative stress highlights the key enzymes, metabolites, and detoxification pathways in the context of MASLD. 肝细胞脂肪酸代谢和氧化应激之间的串扰计算模型突出了MASLD背景下的关键酶、代谢物和解毒途径。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-02 DOI: 10.1016/j.taap.2024.117185

Yuki Miura, Cosmin Voican, Yasuyuki Sakai, Masaki Nishikawa, Eric Leclerc

{"title":"A computational model of the crosstalk between hepatocyte fatty acid metabolism and oxidative stress highlights the key enzymes, metabolites, and detoxification pathways in the context of MASLD.","authors":"Yuki Miura, Cosmin Voican, Yasuyuki Sakai, Masaki Nishikawa, Eric Leclerc","doi":"10.1016/j.taap.2024.117185","DOIUrl":"10.1016/j.taap.2024.117185","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as NAFLD) is a common liver disease worldwide and carries the risk of progressing to severe liver conditions, such as fibrosis and liver cancer. In the context of MASLD, evaluating fat accumulation in the liver and the subsequent production of oxidative stress is essential to understand the disease propagation. However, clinical studies using human patients to investigate the fat accumulation and the onset of oxidative stress in MASLD face ethical and technical challenges, highlighting the importance of alternative methods. To understand the relationship between fatty acid metabolism, lipid accumulation, oxidative stress generation, and antioxidant mechanisms in hepatocytes, we proposed a new mathematical model. The importance of this model lies in its ability to track the time-dependent changes in oxidative stress and glutathione concentration in response to the input of fatty acids. Furthermore, the model allows for the evaluation of the effects of altering the activity of the key enzymes involved in those mechanisms. Our model is anticipated to provide new insights into MASLD therapy strategies by identifying key pathways and predicting the effects of drug-induced changes in enzyme activity.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117185"},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781126","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

Canagliflozin reverses doxorubicin-induced cardiotoxicity via restoration of autophagic homeostasis. 加格列净通过恢复自噬稳态逆转阿霉素诱导的心脏毒性。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-12-02 DOI: 10.1016/j.taap.2024.117183

Jianping Luo, Mingyuan He, Changzhu Liang, Xiaoxia Huang, Yingqi Zhu, Donghong Hu, Junyu Yan, Mingjue Li, Hairuo Lin, Wangjun Liao, Jianping Bin, Ziyun Guan, Cankun Zheng, Yulin Liao

{"title":"Canagliflozin reverses doxorubicin-induced cardiotoxicity via restoration of autophagic homeostasis.","authors":"Jianping Luo, Mingyuan He, Changzhu Liang, Xiaoxia Huang, Yingqi Zhu, Donghong Hu, Junyu Yan, Mingjue Li, Hairuo Lin, Wangjun Liao, Jianping Bin, Ziyun Guan, Cankun Zheng, Yulin Liao","doi":"10.1016/j.taap.2024.117183","DOIUrl":"10.1016/j.taap.2024.117183","url":null,"abstract":"Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been reported as successful for preventing doxorubicin (DOX) -induced cardiotoxicity (DIC), but the underlying mechanisms are elusive. This study aimed to determine whether canagliflozin, an SGLT2i, protects against DIC by regulation of autophagic flux in cardiomyocytes through a mechanism independent of SGLT2. The differentially expressed autophagy-related genes (ARGs) in DIC were analyzed. Neonatal rat cardiomyocytes (NRCMs), H9C2 rat cardiomyocytes or C57BL/6 mice were treated with canagliflozin or vehicle. The effects on cellular apoptosis and autophagy were investigated using qRT-PCR, western blotting and immunofluorescence. Additionally, cardiac function, myocardial fibrosis, and apoptosis of cardiomyocytes were also assessed in mice. The potential molecular targets of canagliflozin were identified through molecular docking analysis. A total of 26 differentially expressed ARGs were identified. Canagliflozin significantly activated autophagic flux and inhibited apoptosis of cardiomyocytes in both DOX-treated H9C2 rat cardiomyocytes and NRCMs. In a murine model of DIC, canagliflozin improved cardiac dysfunction by suppressing cardiac remodeling, fibrosis, and apoptosis. Moreover, canagliflozin promoted autophagy by enhancing SIRT1 levels and inhibiting the PI3K/Akt/mTOR signaling pathway. Immunofluorescence assays revealed that canagliflozin promoted the translocation of LC3 from the nucleus to the cytoplasm. Molecular docking analysis confirmed that canagliflozin has high affinity for targets associated with DIC. These findings suggest that canagliflozin protects cardiomyocytes from DOX-induced cell death by activating SIRT1, inhibiting the PI3K/Akt/mTOR pathway, and enhancing autophagic flux.","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117183"},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781128","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