Toxicology and applied pharmacology最新文献

{"title":"AnxA2-EGFR pro-inflammatory signaling potentiates EMT-induced fibrotic stress and its modulation by short-chain fatty acid butyrate in idiopathic pulmonary fibrosis","authors":"Vinay C. Sangamesh ,&nbsp;Pavan K. Jayaswamy ,&nbsp;M. Vijaykrishnaraj ,&nbsp;Nithin K. Kuriakose ,&nbsp;B.H. Giridhar ,&nbsp;K. Jayaprakash Shetty ,&nbsp;Prakash Patil ,&nbsp;Sukanya Shetty ,&nbsp;Roopa Bhandary ,&nbsp;Praveenkumar Shetty","doi":"10.1016/j.taap.2025.117342","DOIUrl":"10.1016/j.taap.2025.117342","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive extracellular matrix deposition, leading to irreversible lung scarring. This study explores the underlying molecular mechanisms of IPF and delves into membrane-anchored synergism between EGFR and AnxA2, which amplifies fibrotic stress and plays a pivotal role in promoting pulmonary fibroblast activation and fibrosis. Indeed, these interactions create a synergistic effect that promotes the loss of epithelial traits and the transition to a mesenchymal phenotype, thereby contributing to fibrotic stress and disease progression. In addition, this study also explores the potential of butyrate, a short-chain fatty acid, as a therapeutic agent in reducing fibrotic stress by modulating AnxA2-EGFR signaling. Pre-treatment with butyrate significantly dampens AnxA2-EGFR signaling and Galectin-3 expression, effectively curbing prolonged EGFR phosphorylation. The suppression of upstream signaling leads to a reduction in the angiogenic marker VEGF and a decrease in pro-inflammatory mediators such as TNF-α and IL-6. Collectively, our findings highlight the critical role of EGFR-AnxA2 signaling and Galectin 3 in the pathogenesis of IPF, and highlight butyrate as a potential therapeutic agent for alleviating fibrotic stress.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117342"},"PeriodicalIF":3.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838874","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 effects of melatonin against 5-fluorouracil-induced cardiotoxicity in rats: A comprehensive evaluation of oxidative, inflammatory, and apoptotic pathways","authors":"Razieh Mansoori ,&nbsp;Manoochehr Ashrafpour ,&nbsp;Mohammad Hossien Asghari ,&nbsp;Ravieh Golchoobian ,&nbsp;Seyed Mohammad Hosseini ,&nbsp;Russel J. Reiter ,&nbsp;Bardia Karim ,&nbsp;Ali Akbar Moghadamnia ,&nbsp;Sohrab Kazemi","doi":"10.1016/j.taap.2025.117343","DOIUrl":"10.1016/j.taap.2025.117343","url":null,"abstract":"<div><h3>Background</h3><div>Cardiotoxicity is a serious adverse effect of 5-fluorouracil (5-FU) a common chemotherapeutic agent. This study aimed to evaluate the protective effects of melatonin (MLT) against 5-fluorouracil (5-FU)-induced cardiotoxicity in rats, focusing on oxidative stress, inflammatory pathways, gene expression, electrocardiographic and histopathological changes.</div></div><div><h3>Materials and methods</h3><div>Twenty-five male Wistar rats were divided into five groups. The animals received either MLT at doses of 2.5, 5, or 10 mg/kg/day, 5-FU at 50 mg/kg (i.p.), or a combination of both treatments. Cardiotoxicity was assessed through electrocardiography, cardiac enzymes, oxidative stress markers, and histopathology.</div></div><div><h3>Results</h3><div>5-FU treatment significantly increased oxidative stress markers and inflammatory mediators while causing histopathological damage in heart tissues. Co-administration of MLT with 5-FU significantly mitigated these effects by reducing oxidative damage, as evidenced by lower levels of malondialdehyde (MDA), nitric oxide (NO), and myeloperoxidase (MPO). Additionally, MLT enhanced antioxidant activity, as reflected by increased levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in heart tissues. Gene expression analysis further confirmed that MLT treatment reduced the elevated levels of COX-2 and VEGF, which are critical players in the inflammatory process. Histopathological examination demonstrated that MLT preserved the structural integrity of myocardial tissues, reducing 5-FU-induced damage score in a dose-dependent manner. Furthermore, MLT co-administration significantly attenuated the rise in cardiac biomarkers, including LDH, AST, and CK-MB, associated with 5-FU-induced cardiotoxicity.</div></div><div><h3>Conclusion</h3><div>These findings highlight that MLT, through its antioxidant and anti-inflammatory properties, exerts a protective effect against 5-FU-induced toxicity, suggesting its therapeutic potential for improving cardiovascular health during chemotherapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117343"},"PeriodicalIF":3.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847676","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":"Quercetin-loaded PEGylated liposomes alleviate testicular dysfunction in alloxan-induced diabetic rats: The role of Kisspeptin/Neurokinin B/Dynorphin pathway","authors":"Mohamed Fouad Mansour ,&nbsp;Amany Behairy ,&nbsp;Mahmoud Mostafa ,&nbsp;Tarek Khamis ,&nbsp;Amira Ebrahim Alsemeh ,&nbsp;Noura Mohammed Qenawy Ahmed ,&nbsp;Mahran Mohamed Abd El-Emam","doi":"10.1016/j.taap.2025.117337","DOIUrl":"10.1016/j.taap.2025.117337","url":null,"abstract":"<div><div>Diabetes mellitus (DM) is a chronic metabolic disorder that can lead to serious complications, including testicular dysfunction. This dysfunction is considered a significant cause of male infertility. Quercetin (Que), a naturally existing flavonoid with versatile biological functions, has limited water solubility and low bioavailability. The current study was designed to develop a bioavailable formulation of Que. via encapsulating it in PEGylated liposomes (Que-PEG-Lip) and determine whether this formulation is effective in the treatment of alloxan-induced testicular injury via targeting Kisspeptin/Neurokinin B/Dynorphin/steroidogenesis signaling pathway. Thirty-two male Sprague Dawley rats were randomly divided into four groups: Control, alloxan-induced diabetes with testicular dysfunction (ALX), ALX + metformin (MET) and ALX + Que-PEG-Lip. The results showed that treatment of ALX group with Que-PEG-Lip significantly improved the alteration of glycemic index, serum reproductive hormones, testicular antioxidant status, testicular Kiss-1, androgen receptor (AR), and proliferation marker protein (ki67) immunoexpression in compared to ALX group. Moreover, the treatment of ALX group with Que-PEG-Lip regulated the Kisspeptin/Neurokinin B/Dynorphin/steroidogenesis pathway gene expression. Interestingly, the outcomes of the molecular docking analysis revealed a strong agonistic effect of Que. on the kisspeptin, neurokinin, and dynorphin receptors. In conclusion, Que-PEG-Lip mitigated the testicular dysfunction in alloxan-induced diabetic rats via regulation of hypothalamic-pituitary-gonadal axis signaling pathway and alleviation the testicular oxidative stress.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117337"},"PeriodicalIF":3.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843374","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":"Differences in chemotherapeutic drug sensitivity before and after patient-derived tumor organoid construction","authors":"Fang Shao ,&nbsp;Xin Huang ,&nbsp;Zhihong Ma ,&nbsp;Liqin Li ,&nbsp;Chunjian Qi","doi":"10.1016/j.taap.2025.117340","DOIUrl":"10.1016/j.taap.2025.117340","url":null,"abstract":"<div><h3>Background</h3><div>Patient-derived organoids (PDOs) have emerged as promising preclinical models for various tumor types. This study aimed to optimize the process of constructing 3D organoid models and facilitate the development of personalized therapies for gastric and colon cancers.</div></div><div><h3>Methods</h3><div>Tumor tissues were divided into two parts: one part was dissociated into a single-cell suspension, and the other part was used to culture tumor organoids. RNA sequencing (RNA-seq) was performed on both tumor cells and cultured organoids. Four chemotherapeutic agents-Oxaliplatin (L-OHP), Gemcitabine (GEM), 5-Fluorouracil (5-FU), and Paclitaxel (PTX)-were utilized to assess cytotoxicity and proliferation in both organoids and freshly isolated tumor cells, then the effects of these agents were evaluated.</div></div><div><h3>Results</h3><div>Organoids were successfully established from both surgically resected and biopsy-derived tumor tissues. Phenotypic analysis indicated that the organoids retained the histological features and expression profiles of the original tumors. Notably, the morphological characteristics of the organoids remained stable across passages, demonstrating robust growth over time. Differentially expressed genes were identified in both gastric and colon cancer PDOs. GO and KEGG pathway analyses revealed similar gene enrichment in gastric and colon PDOs. Both gastric and colon cancer PDOs exhibited increased significant sensitivity to PTX and 5-FU compared to freshly isolated cancer cells. Furthermore, the expression of most stemness-related genes was reduced after organoid culture.</div></div><div><h3>Conclusions</h3><div>We successfully established organoid models that demonstrated robust growth and heightened drug sensitivity compared to freshly isolated tumor cells. These findings suggest that caution should be exercised when interpreting drug sensitivity results from organoid-based assays.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117340"},"PeriodicalIF":3.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826462","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":"Estrogenic and androgenic activity of tert-butyl phenolic antioxidants assessed by in vitro receptor transcriptional activation and their association with in silico molecular docking analysis","authors":"Ngoc Minh-Hong Hoang,&nbsp;Kwangsik Park","doi":"10.1016/j.taap.2025.117344","DOIUrl":"10.1016/j.taap.2025.117344","url":null,"abstract":"<div><div>Tert-butyl phenolic antioxidants (TBP-AOs) are utilized in a variety of consumer products, including food packaging, daily use items, and industrial applications. Their widespread use raises significant concerns regarding potential health risks, particularly endocrine disruption. However, our understanding of many TBP-AOs concerning endocrine systems remains limited, underscoring the need for screening of their hormonal activities and better insight into their adverse outcome pathways (AOPs). Transcriptional activation (TA) assays are crucial experimental tools in the early stages of risk assessment. This study evaluated the estrogenic and androgenic characteristics of 30 TBP-AOs through TA assays in hERα-HeLa-9903 and 22Rv1/MMTV_GR-KO cell lines, respectively, augmented by docking simulation using CB-Dock2. Our findings identified 21 estrogen receptor (ER) agonists, one ER antagonist, and eight androgen receptor (AR) antagonists, with significant correlations between biological activity and docking scores for specific proteins: 1GWR_C4 and 7KBS_C2 for ERα, and 2AM9_C1 for AR. These results enhance our understanding of TBP-AOs' toxicity on the endocrine system and confirm that TA assays and docking are effective methods for evaluating their endocrine activities. This research lays the foundation for future studies on endocrine disruptors, aiming to elucidate the mechanisms underlying molecular initiating events and key events within AOPs for TBP-AOs and other chemicals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117344"},"PeriodicalIF":3.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834912","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":"Fudosteine attenuates lung inflammation in mice with PM2.5-induced asthma exacerbation by inhibiting pyroptosis via the NLRP3/caspase-1/GSDMD pathway","authors":"Jianling Liu ,&nbsp;Zhongpeng Li ,&nbsp;Zhangwen Li ,&nbsp;Aili Wang ,&nbsp;Xiaoyang Liao ,&nbsp;Zhangquan Liu ,&nbsp;Jian Wu","doi":"10.1016/j.taap.2025.117346","DOIUrl":"10.1016/j.taap.2025.117346","url":null,"abstract":"<div><div>This study aimed to explore the potential preventive effects of fudosteine (Fud) on PM2.5-induced asthma exacerbations in a murine model. BALB/c mice were randomly allocated into six groups: control, Fud, ovalbumin (OVA), OVA+Fud, OVA+PM2.5, and OVA+PM2.5 + Fud. An asthma model was established through OVA sensitization and challenge. Compared to the OVA group, PM2.5 exposure exacerbated allergic asthma, as evidenced by increased collagen fiber deposition, goblet cell metaplasia, mucus secretion, heightened airway inflammation, elevated total cell and eosinophil counts, and upregulated levels of interleukin (IL)-1β, IL-18, and NLRP3 expression in lung tissues. Notably, fudosteine treatment mitigated these pathological changes. Western blot analysis revealed that fudosteine significantly reduced the expression of NLRP3, caspase-1, gasdermin D (GSDMD), cleaved-caspase-1, and cleaved-GSDMD in lung tissues. In conclusion, fudosteine alleviated lung inflammation, collagen deposition, and mucus secretion in PM2.5-induced asthma exacerbation, potentially by inhibiting the NLRP3 inflammasome-mediated pyroptosis pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117346"},"PeriodicalIF":3.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838875","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":"Activation of steroid hormone receptors by metabolism-disrupting chemicals","authors":"Sini Pitkänen ,&nbsp;Jonna Niskanen ,&nbsp;Raghavendra Mysore ,&nbsp;Einari A. Niskanen ,&nbsp;Jorma J. Palvimo ,&nbsp;Dirk Pijnenburg ,&nbsp;Rinie van Beuningen ,&nbsp;Azam Rashidian ,&nbsp;Thales Kronenberger ,&nbsp;Antti Poso ,&nbsp;Anna-Liisa Levonen ,&nbsp;Jenni Küblbeck ,&nbsp;Paavo Honkakoski","doi":"10.1016/j.taap.2025.117335","DOIUrl":"10.1016/j.taap.2025.117335","url":null,"abstract":"<div><div>Exposure to metabolism-disrupting chemicals (MDCs), compounds largely belonging to the group of endocrine-disrupting chemicals (EDCs), is associated with metabolic dysfunctions such as dyslipidemia, insulin resistance and hepatic steatosis. Steroid hormone receptors (SHRs) are known targets for MDCs but their regulatory environment in the presence of environmental chemicals remains elusive. Here, we studied the activation and molecular interactions of SHRs exposed to 17 suspected MDCs including pesticides, plasticizers, pharmaceuticals, flame retardants, industrial chemicals and their metabolites by combining in vitro and in silico approaches. We first established and pre-validated reporter gene assays in HepG2 hepatoma cells to assess the activation of estrogen (ER), androgen (AR), glucocorticoid (GR) and progesterone (PR) receptors. Next, using RNA-seq and publicly available protein interaction data, we identified relevant SHR-interacting coregulators expressed in hepatic cells and measured their MDC-dependent interactions with SHRs using the Microarray Assay for Real-time Coregulator-Nuclear receptor Interaction (MARCoNI) technology. Finally, we examined MDC binding to ER and GR using molecular dynamics simulations. These combined approaches lead to identification of MDCs capable of SHR activation at picomolar-to-low micromolar concentrations and paralleled with their ability to induce recruitment of multiple coregulators. MDCs induced distinct SHR-coregulator binding patterns involving multiple coactivators, corepressors and other modulatory proteins. Our results have broadened the test battery to detect MDCs and indicate that the activation of SHRs by MDCs is driven by diverse molecular interactions.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117335"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821180","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":"The lipidome landscape of amiodarone toxicity: An in vivo lipid-centric multi-omics study","authors":"Nguyen Quang Thu ,&nbsp;Jung-Hwa Oh ,&nbsp;Nguyen Tran Nam Tien ,&nbsp;Se-Myo Park ,&nbsp;Nguyen Thi Hai Yen ,&nbsp;Nguyen Ky Phat ,&nbsp;Tran Minh Hung ,&nbsp;Huy Truong Nguyen ,&nbsp;Duc Ninh Nguyen ,&nbsp;Seokjoo Yoon ,&nbsp;Dong Hyun Kim ,&nbsp;Nguyen Phuoc Long","doi":"10.1016/j.taap.2025.117341","DOIUrl":"10.1016/j.taap.2025.117341","url":null,"abstract":"<div><div>Amiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatotoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates might be associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117341"},"PeriodicalIF":3.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826299","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":"Breaking the scar barrier: The anti-fibrotic and hemodynamic benefits of total salvianolic acid in hypertrophic scars","authors":"Qiaoju Zhang ,&nbsp;Xi Luo ,&nbsp;Yuwen Zheng ,&nbsp;Junqiao Zheng ,&nbsp;Xinying Wu ,&nbsp;Jun Shi","doi":"10.1016/j.taap.2025.117339","DOIUrl":"10.1016/j.taap.2025.117339","url":null,"abstract":"<div><h3>Abstract</h3><div>Hypertrophic scars (HS) affect up to 70 % of individuals following deep dermal injuries, burns, or surgical procedures, leading to significant functional impairments and psychological distress. Despite their high prevalence, effective therapeutic options remain limited, and the underlying pathophysiology is not fully elucidated. This study integrates network pharmacology, molecular docking, and in vivo experimentation to investigate the therapeutic potential of total salvianolic acid (TSA) from <em>Salvia miltiorrhiza</em> in HS treatment. A systematic pharmacology approach identified 186 target proteins, highlighting TGF-β1, Smad3, IL-2, and IL-4 as key modulators of fibrosis and inflammation. Molecular docking confirmed high-affinity interactions between TSA's active components and these targets. TSA significantly reduced scar elevation, fibrosis, and collagen deposition in a rabbit ear hypertrophic scar model, restoring tissue architecture and improving hemorheological parameters. Histological and immunohistochemical analyses confirmed TSA's ability to suppress TGF-β/Smad signaling, downregulate inflammatory cytokines and normalize collagen dynamics. These findings provide compelling evidence that TSA is a multi-targeted, pharmacologically active compound with promising anti-fibrotic and microcirculatory benefits, paving the way for novel therapeutic strategies in HS management. This study establishes a scientific foundation for TSA-based interventions, with potential clinical implications in regenerative medicine and scar therapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117339"},"PeriodicalIF":3.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847675","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":"Aminooxyacetic acid up-regulates the Cry1 and Bmal1 clock gene in a sirtuin 1 dependent manner. In vitro study","authors":"Maria Romerowicz-Misielak ,&nbsp;Katarzyna Kozioł ,&nbsp;Sławomir Nowak ,&nbsp;Renata Wojnarowska-Nowak ,&nbsp;Klaudia Łuc","doi":"10.1016/j.taap.2025.117338","DOIUrl":"10.1016/j.taap.2025.117338","url":null,"abstract":"<div><div>The regulation of the cyclic oscillation of the components of the circadian clock is complex in itself. Numerous clock interactions with processes and molecules present in cells further complicate this mechanism. Recently, the anti-aging protein Silencing Information Regulator Two family member, SIRT1, has been linked with the molecular circadian clock. In this study, we investigated the <em>in vitro</em> effect of aminooxyacetic acid on SIRT1 expression in relation to circadian dynamics of <em>Cry1</em> and <em>Bma11</em> expressions in serum shocked NIH-3 T3 and HaCaT cells. The study was carried out in the context of the inhibitory activity of aminooxyacetic acid against cystathionine-<em>β</em>-synthase and cystathionine-<em>γ</em>-lyase. We have shown that aminooxyacetic acid effectively inhibits SIRT1 transcription and synthesis, which, given the pleiotropic effects of sirtuin 1 on numerous metabolic pathways, may have other implications. We also found that AOAA contributes to up-regulation of the expression of the <em>Cry1</em> and <em>Bmal1</em> genes in cells. This effect does not appear to be related to inhibition of the activity of cystathionine-<em>β</em>-synthase and cystathionine-<em>γ</em>-lyase. At the same time, this does not deny the role of hydrogen sulphide, a product of the activity of these enzymes, in the regulation of the circadian clock.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117338"},"PeriodicalIF":3.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817719","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}