Toxicology and applied pharmacology最新文献

{"title":"Shikonin modulates activated fibroblast apoptosis in silicosis fibrosis via the PI3K/Akt signaling pathway: A network pharmacology approach","authors":"Shengpeng Wen ,&nbsp;Sirong Chang ,&nbsp;Huning Zhang ,&nbsp;Wenyue Zhang ,&nbsp;Yi Guo ,&nbsp;Na Zhang ,&nbsp;Anning Yang ,&nbsp;Yue Sun ,&nbsp;Zhihong Liu","doi":"10.1016/j.taap.2025.117236","DOIUrl":"10.1016/j.taap.2025.117236","url":null,"abstract":"<div><h3>Background</h3><div>Silicosis is a lung disease caused by the inhalation of free crystalline silica and is characterized mainly by lung inflammation and progressive pulmonary fibrosis. Shikonin, a biologically active compound isolated from the traditional Chinese medicine Comfrey, has been shown to have significant antifibrotic effects. However, the molecular mechanisms underlying the antifibrotic effects of SHK in silicosis remain unclear.</div></div><div><h3>Methods</h3><div>This study used a combination of network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experimental validation to investigate the potential targets of SHK in silicosis.</div></div><div><h3>Results</h3><div>Network pharmacology analysis identified 208 cross genes associated with disease drugs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis show that these intersecting genes are significantly associated with the PI3K/Akt signaling pathway. Protein protein interaction (PPI) network analysis further revealed 10 core crossover genes, namely ALB, Akt1, STAT3, CASP3, EGFR, MMP9, Bcl-2, ESR1, HSP90AA1, and NF-κB1. Among them, Akt1 and Bcl-2 have the strongest binding ability to SHK. The in vitro experimental results showed that SHK can significantly inhibit the activation of fibroblasts and promote apoptosis of activated fibroblasts through the PI3K/Akt signaling pathway.</div></div><div><h3>Conclusion</h3><div>SHK alleviates silica induced silicosis fibrosis by inhibiting the transformation of fibroblasts into myofibroblasts through the PI3K/Akt signaling pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117236"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041987","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":"Peripheral inflammation enhances opioid-induced gastrointestinal motility inhibition via up-regulating spinal mu opioid receptor","authors":"Zhonghua Zhang ,&nbsp;Yaofeng Zhao ,&nbsp;Dingnian Gou ,&nbsp;Pengtao Li ,&nbsp;Hao Wang ,&nbsp;Yanfang Li ,&nbsp;Chenxi Li ,&nbsp;Zhanyu Niu ,&nbsp;Tong Yang ,&nbsp;Lanxia Zhou ,&nbsp;Shouliang Dong","doi":"10.1016/j.taap.2025.117225","DOIUrl":"10.1016/j.taap.2025.117225","url":null,"abstract":"<div><div>Opioids are potent analgesics in clinical pain management but exert variable analgesia in different pain types. Opioid-induced constipation is a common side effect of opioid therapy, and whether opioids induce different gastrointestinal motility inhibitions in different pain types is unknown. In this study, we evaluated the antinociceptive effects and inhibition of upper gastrointestinal transit and colonic bead expulsion of morphine, DAMGO, and Deltorphin in mouse CFA chronic inflammatory pain, SNI chronic neuropathic pain, and carrageenan chronic inflammatory pain models. Furthermore, quantitative PCR and immunofluorescence were used to investigate the mechanisms underlying the altered inhibition. Results showed that intrathecal administration of morphine, DAMGO, and Deltorphin produced higher antinociceptive effects in the CFA and carrageenan groups than in the SNI group. Upper gastrointestinal transit inhibition was significantly enhanced in the carrageenan group by morphine and DAMGO; colonic bead expulsion inhibition was also enhanced in the CFA and carrageenan groups by morphine and DAMGO, but not in Deltorphin treatment. Additionally, mu (MOR) opioid receptor mRNA and MOR-expressing cell density in the lumbar spinal cord of CFA and carrageenan mice were increased, whereas delta opioid receptor expression remained unchanged in these groups. Finally, the pharmacological blockade of MOR completely prevented the enhanced upper gastrointestinal transit inhibition in the carrageenan group by morphine and DAMGO. Altogether, our results indicate that gastrointestinal motility inhibition induced by MOR agonists can be enhanced with upregulated spinal MOR expression in chronic inflammatory pain.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117225"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955634","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":"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 ,&nbsp;Cosmin Voican ,&nbsp;Yasuyuki Sakai ,&nbsp;Masaki Nishikawa ,&nbsp;Eric Leclerc","doi":"10.1016/j.taap.2024.117185","DOIUrl":"10.1016/j.taap.2024.117185","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117185"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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}

{"title":"γ-Glutamylcysteine restores glucolipotoxicity-induced islet β-cell apoptosis and dysfunction via inhibiting endoplasmic reticulum stress","authors":"Jinyi Zhou ,&nbsp;Yingying Shi ,&nbsp;Lishuang Zhao ,&nbsp;Rong Wang ,&nbsp;Lan Luo ,&nbsp;Zhimin Yin","doi":"10.1016/j.taap.2024.117206","DOIUrl":"10.1016/j.taap.2024.117206","url":null,"abstract":"<div><h3>Purpose</h3><div>The impaired function of islet β-cell is associated with the pathogenesis of type 2 diabetes mellitus (T2DM). γ-glutamylcysteine (γ-GC), an immediate precursor of glutathione (GSH), has antioxidant and neuroprotective functions. Its level has been reported to be down-regulated in hyperglycemia. However, whether γ-GC has a protective effect on islet β-cell dysfunction remains elusive. Recently, we explore the molecular mechanism by which γ-GC protects islet β-cell from glucolipotoxicity-induced dysfunction.</div></div><div><h3>Methods</h3><div>In vivo mice models and in vitro cell models were established to examine the therapeutic effects and molecular mechanisms of γ-GC.</div></div><div><h3>Results</h3><div>db mice develop impaired glucose-stimulated insulin secretion (GSIS) due to reduced islet number and damaged islet microstructure. Serious oxidative damage, apoptosis and lipid accumulation are also observed in β-cell stimulated by glucolipotoxicity. Mechanistic studies suggest that glucolipotoxicity inhibits PDX-1 nuclear translocation by inducing endoplasmic reticulum (ER) stress, which leads to impaired insulin (INS) secretion in β-cell. Nevertheless, γ-GC as an inhibitor of ER stress can alleviate the damage of islet microstructure in db mice. Importantly, γ-GC promotes INS gene expression and GSIS through driving nuclear translocation of PDX-1, thereby enhancing intracellular INS content. Moreover, treatment with γ-GC can also mitigate oxidative damage, apoptosis and lipid accumulation of β-cell, resulting in ameliorating islet β-cell dysfunction induced by glucolipotoxicity.</div></div><div><h3>Conclusion</h3><div>Our results support the use of γ-GC as an inhibitor of ER stress for prevention and treatment of T2DM in the future.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117206"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865556","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":"Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity and the underlying mechanism","authors":"Yi Chen ,&nbsp;Wei Luo ,&nbsp;Yanqing Wu","doi":"10.1016/j.taap.2024.117179","DOIUrl":"10.1016/j.taap.2024.117179","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods and results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117179"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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}

{"title":"Betaine alleviates methomyl-triggered oxidative stress-mediated cardiopulmonary inflammation in rats through iNOS/Cox2 and Nrf2/HO1/Keap1 signaling pathway","authors":"Eman I. Hassanen ,&nbsp;Neven H. Hassan ,&nbsp;Ahmed M. Hussien ,&nbsp;Marwa A. Ibrahim ,&nbsp;Merhan E. Ali","doi":"10.1016/j.taap.2024.117223","DOIUrl":"10.1016/j.taap.2024.117223","url":null,"abstract":"<div><div>Methomyl (MET), a universally used insecticide, has many adverse effects on various organs in both humans and animals including the liver, kidneys, and heart. Betaine (BET), a natural antioxidant, has a protective role against many toxicants-induced cardiovascular disorders. The present study was designed to elucidate the molecular mechanistic way underlying the mitigating effect of BET against MET-induced cardiopulmonary injury and inflammation in rats. Four groups of rats were used and orally administered the consequent materials daily for 28 days: normal saline, BET (250 mg/kg bwt), MET (2 mg/kg bwt), MET + BET. Blood and tissue (heart &amp; lungs) samples were collected to assess the oxidative stress markers, lipid profile, biochemical markers, microscopic appearance, and inflammatory gene regulations. The results proved that MET induced oxidant/antioxidant imbalance, elevation of serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels, and deterioration in lipid profile. The histopathological inspection showed severe myocardial necrosis and interstitial pneumonia along with bronchitis and alveolar damage. There was a marked increase in the intensity of cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) immunostaining with marked upregulation of the transcriptase levels of <em>keap-1</em>gene and downregulation of nuclear factor erythroid 2-related factor-2 <em>(Nrf-2) and</em> heme oxygenase-1 <em>(HO-1)</em> genes in both heart and lung tissues of MET group. Otherwise, the coadministration of BET with MET markedly alleviated the abovementioned toxicological parameters. We can conclude that BET was able to reduce the MET-induced oxidative stress-mediated cardiovascular injury and pulmonary inflammation by modulating Keap-1/Nrf-2 signaling pathway and inactivating Cox-2 and iNOS expression which therefore reduced further cellular damage and inflammatory response.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117223"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915639","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 angiogenic and proliferative mediators by montelukast & trimetazidine Ameliorates thioacetamide-induced liver fibrosis in rats","authors":"Rehab S. Abdelrahman ,&nbsp;Ahmed A. Elnfarawy ,&nbsp;Asmaa E. Nashy ,&nbsp;Ramy A. Abdelsalam ,&nbsp;Marwa S. Zaghloul","doi":"10.1016/j.taap.2024.117208","DOIUrl":"10.1016/j.taap.2024.117208","url":null,"abstract":"<div><div>Liver fibrosis is a significant health complication with the potential to result in serious mortality and morbidity. However, there is no standard treatment due to its complex pathogenesis. The drug montelukast reversibly and selectively antagonizes the cysteinyl-leukotrienes-1 receptor and reduces inflammation; thus, it is used in the treatment of asthma. Trimetazidine, an anti-anginal agent, selectively inhibits the activity of mitochondrial long-chain 3-ketoacyl-CoA thiolase, inhibition of free fatty acid (FFA) oxidation. This study explores the efficacy of montelukast (5 and 10 mg/kg) and trimetazidine (10–20 mg/kg) against liver fibrosis induced by thioacetamide (TAA) in rats. Impaired liver function tests were significantly improved by montelukast and trimetazidine. The antioxidant and anti-inflammatory effects of montelukast and trimetazidine were proved by the inhibition of malondialdehyde (MDA) and nitric oxide (NO) accumulation, with elevation of glutathione (GSH) and superoxide dismutase activity, decreased heat shock protein (HSP-70) expression, and a decline in interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) levels in liver tissue. Also, the antifibrotic effects were explored by reducing levels of hydroxyproline and alpha-smooth muscle actin (α-SMA) expression in liver tissue and attenuating hepatic expression of hepatic expression of angiogenic mediator vascular endothelium growth factor (VEGF) and proliferative mediator Antigen Kiel 67 (Ki-67).</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117208"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883031","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":"Heritable dysregulation of DNA methylation may underlie the diabetogenic effects of paternal preconception exposure to inorganic arsenic in C57BL/6J mice","authors":"Hadley J. Hartwell ,&nbsp;Bingzhen Shang ,&nbsp;Christelle Douillet ,&nbsp;Audrey G. Bousquet ,&nbsp;Tianyi Liu ,&nbsp;Fei Zou ,&nbsp;Folami Ideraabdullah ,&nbsp;Miroslav Stýblo ,&nbsp;Rebecca C. Fry","doi":"10.1016/j.taap.2025.117242","DOIUrl":"10.1016/j.taap.2025.117242","url":null,"abstract":"<div><div>Chronic exposure to inorganic arsenic (iAs) has been linked with the development of diabetes mellitus (DM). We recently showed that parental exposure to iAs (200 ppb) prior to mating was associated with diabetic phenotypes in offspring and altered gene expression in parents and offspring. The goal of the present study was to determine if DNA methylation underlies the differential gene expression in the livers of offspring. DNA methylation was assessed in paternal (G0) sperm and livers of their offspring (G1) using a genome wide DNA methylation array. We found that iAs exposure significantly altered CpG methylation (<em>p</em> &lt; 0.05) in 54.3 %, 49.4 %, and 63.7 % of the differentially expressed genes in G0 sperm, G1 female livers, and G1 male livers, respectively. Importantly, a subset of differentially methylated CpG sites were shared across generations. Sensitivity analyses (FDR &lt; 0.1) of imprinted and DM-associated genes revealed differential methylation of 74 imprinted genes and 100 DM-associated genes in the livers of G1 males. These male-specific results are intriguing given the prior findings of diabetic phenotypes found exclusively in male offspring from parents exposed to iAs. In summary, these data demonstrate that heritable changes in DNA methylation through the paternal germline may underlie the diabetogenic effects of preconception iAs exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117242"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081141","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":"In vitro NIH3T3 mouse embryonic fibroblast cell model does not predict AAV2 or AAVdj-mediated cell transformation","authors":"Luping Qiu,&nbsp;Steven W. Kumpf,&nbsp;Elias M. Oziolor,&nbsp;Mark Sheehan,&nbsp;James E. Finley,&nbsp;David M. Rubitski,&nbsp;Jessie Qian,&nbsp;Mark M. Gosink ,&nbsp;Anna K. Kopec,&nbsp;Thomas A. Lanz,&nbsp;Andrew D. Burdick","doi":"10.1016/j.taap.2025.117229","DOIUrl":"10.1016/j.taap.2025.117229","url":null,"abstract":"<div><div>One of the potential risk factors of recombinant adeno-associated virus (rAAV)-based gene therapy is insertional mutagenesis, which has been associated with the development of hepatocellular carcinoma (HCC) in rAAV-treated neonatal mice. The objective of this study was to investigate if well-established <em>in vitro</em> cell transformation assays (CTA) in mouse cell lines can detect AAV2 or AAVdj-mediated cell transformation. Since AAV integration at the <em>Rian</em> locus in neonatal mice has been implicated in AAV-mediated HCC, an rAAV vector specifically targeting the mouse <em>Rian</em> locus and an additional rAAV vector previously shown to cause HCC in neonatal mice were both tested for the induction of cell transformation in NIH3T3 cells. To increase the frequency of AAV DNA integration at the <em>Rian</em> locus in the genome of NIH3T3 cells, double-strand breaks in <em>Rian</em> locus of NIH3T3 cells were created by CRISPR-Cas9 to increase the homologous crossover between viral DNA and the cell genome. When transduced cells were assayed in CTA, the transformation frequency observed in AAV-transduced NIH3T3 cells was not significantly different from that of untreated vehicle cells. The finding that rAAV is unable to transform the NIH3T3 <em>in vitro</em> indicates that either the transformation rate is less than the spontaneous rate of NIH3T3 cellular transformation, or <em>in vitro</em> CTA are not predictive of rAAV-induced HCC in mice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117229"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984881","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":"Canagliflozin reverses doxorubicin-induced cardiotoxicity via restoration of autophagic homeostasis","authors":"Jianping Luo ,&nbsp;Mingyuan He ,&nbsp;Changzhu Liang ,&nbsp;Xiaoxia Huang ,&nbsp;Yingqi Zhu ,&nbsp;Donghong Hu ,&nbsp;Junyu Yan ,&nbsp;Mingjue Li ,&nbsp;Hairuo Lin ,&nbsp;Wangjun Liao ,&nbsp;Jianping Bin ,&nbsp;Ziyun Guan ,&nbsp;Cankun Zheng ,&nbsp;Yulin Liao","doi":"10.1016/j.taap.2024.117183","DOIUrl":"10.1016/j.taap.2024.117183","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117183"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}