Toxicology and applied pharmacology最新文献

{"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":"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}

{"title":"Desloratadine mitigates hepatocellular carcinoma in rats: Possible contribution of TLR4/MYD88/NF-κB pathway","authors":"Heba A. Bahriz,&nbsp;Rania R. Abdelaziz,&nbsp;Dalia H. El-Kashef","doi":"10.1016/j.taap.2024.117202","DOIUrl":"10.1016/j.taap.2024.117202","url":null,"abstract":"<div><div>Chemotherapeutic medication-induced systemic toxicity makes cancer treatment less effective. Thus, the need for drug repurposing, which aids in the development of safe and efficient cancer therapies, is urgent. The primary goal of this research was to assess desloratadine hepatoprotective abilities and its capacity to attenuate TLR4/MyD88/NF-κB inflammatory pathway in hepatocellular carcinoma (HCC) induced by thioacetamide (TAA). Male Sprague Dawely rats received TAA injections (200 mg/kg, i.p., 2 times/week) for 16 weeks. To confirm the development of HCC, liver function biomarkers and histopathological analysis were evaluated. Desloratadine (5 mg/kg, p.o.) was administered to rats in 2 treatment groups; HCC + DES 1 group received desloratadine with TAA for 1 month from week 13–16, HCC + DES 2 group received desloratadine with TAA for 2 months from week 9–16. Chronic TAA administration resulted in considerable overexpression of the profibrogenic cytokine TGF-β and elevation in protein expression of NF-κB besides levels of TLR4, MyD88, TRAF6, TAK1 and IL-1β. Desloratadine administration showed a significant improvement in liver function tests, as well as an increase in tissue antioxidant enzymes and an improvement in the liver's histopathological features. Collectively, desloratadine through modulating TLR4/MyD88/TRAF6/TAK1/NF-κB and acting as an antioxidant, is a promising treatment for HCC induced by TAA.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117202"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822628","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":"Anabolic-androgen steroids: A possible independent risk factor to Cardiovascular, Kidney and Metabolic Syndrome","authors":"Antonio Ferreira de Melo Junior ,&nbsp;Leonardo Escouto ,&nbsp;António B. Pimpão ,&nbsp;Pollyana Peixoto ,&nbsp;Girlandia Brasil ,&nbsp;Silas Nascimento Ronchi ,&nbsp;Sofia Azeredo Pereira ,&nbsp;Nazaré Souza Bissoli","doi":"10.1016/j.taap.2025.117238","DOIUrl":"10.1016/j.taap.2025.117238","url":null,"abstract":"<div><div>Millions of individuals make illicit use of anabolic-androgenic steroids (AAS), remaining a public health issue. It often leads to detrimental effects, including cardiovascular and renal diseases, besides hormonal and metabolic imbalances. The objective of this review is to emphasize the contribution of oxidative stress and inflammation to these effects and connect the findings of experimental animal studies with the alterations found in clinical contexts, in AAS users. The study's results showed that AAS promotes a redox disruption and a pro-inflammatory state on organs that are involved in important physiologic processes. These drugs increase inflammatory high-sensitivity C-reactive protein (hs-CRP) and cytokines that contribute to the progression of atherosclerosis, cardiovascular disease risk or endpoints, including stroke, myocardial infarction and death. In the kidney, the AAS increase proteinuria and structural damage. Studies have linked AAS abuse with high BP, low HDL-C levels, high triglyceride levels and impaired fasting blood glucose that characterize Metabolic syndrome. Overall, the studies indicate that oxidative stress, apoptosis, and AAS-mediated inflammation play a significant role in tissue damage, regardless of the dose and duration of exposure, and we point it as a putative independent risk factor to Cardiovascular, Kidney and Metabolic syndrome.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117238"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041902","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}

{"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":"Cadmium alters the cellular metabolome of human ovarian granulosa cells","authors":"Jun Zhang ,&nbsp;Guofeng Xu ,&nbsp;Shuang Liu ,&nbsp;Meng Yang","doi":"10.1016/j.taap.2024.117187","DOIUrl":"10.1016/j.taap.2024.117187","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117187"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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}

{"title":"Knockdown of regulator of Calcineurin 2 promotes transcription factor EB-mediated lipophagy to prevent non-alcoholic fatty liver disease","authors":"Lei Shan,&nbsp;Pengzhan Guo,&nbsp;Mumeike Wen,&nbsp;Yue Sun,&nbsp;Fei Gao,&nbsp;Kai Zhang,&nbsp;Ning Zhang,&nbsp;Baoshan Yang","doi":"10.1016/j.taap.2024.117210","DOIUrl":"10.1016/j.taap.2024.117210","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117210"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877926","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}