Toxicology and applied pharmacology最新文献

{"title":"Impact of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) exposure on reproductive development in adolescent offspring","authors":"Wei Tan ,&nbsp;Kusheng Wu ,&nbsp;Chenran Shao ,&nbsp;Yueting Zhou ,&nbsp;Shukai Zheng ,&nbsp;Yikai Ma ,&nbsp;Jiajun Peng ,&nbsp;Kexin Cao ,&nbsp;Xiaoling Shi ,&nbsp;Caixia Liu","doi":"10.1016/j.taap.2025.117535","DOIUrl":"10.1016/j.taap.2025.117535","url":null,"abstract":"<div><div>Polybrominated diphenyl ethers (PBDEs) are known to disrupt neuroendocrine functions and impaired perinatal growth and reproductive health. However, the long-term reproductive toxicity of PBDEs following perinatal exposure remains poorly understood. This study investigated the effects of perinatal exposure to 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) on reproductive development in adolescent offspring. Female C57BL/6 J mice were exposed to BDE-47 at doses of 0 (control), 10, and 50 mg/kg during the perinatal period (gestational day 13.5 to postnatal day 7). Subsequently, gonadal tissues and serum were collected from adolescent offspring mice for analysis. Histological examination of gonadal tissue sections using hematoxylin and eosin (H&amp;E) staining revealed structural alterations. ELISA was employed to evaluate the reproductive endocrine hormone levels (E₂, LH, FSH, AMH and T) in the serum of dams and offspring. Subsequently, multiplex immunohistochemical (mIHC) staining was employed to observe the protein expression in the testicular stroma of adolescent male pups. In maternal mice, perinatal exposure to BDE-47 led to an increased number of primary and secondary oocytes, accompanied by a decreased number of corpora luteum in the ovaries. Additionally, an increase in endometrial thickness and elevated serum E₂ levels was observed in the 10 mg/kg BDE-47 group. In adolescent female offspring, an increase in secondary oocytes and corpora lutea in ovaries were found, along with increased serum E₂ levels at both doses, while AMH levels decreased in 10 mg/kg BDE-47 group. In male offspring, testicular structural loosening, detachment of some spermatogenic cells, and cytoplasmic vacuolation were noted. The epididymal epithelial cells were shorter compared to the control group, with vacuolar structures and reduced sperm content. Testosterone secretion was decreased correspondingly with increasing dose. Consistent with the hormonal changes, a decrease in Cyp11a1-positive cells and StAR and Cyp11a1dual-positive cells was observed in the testicular stroma of adolescent male pups exposed to 50 mg/kg BDE-47, suggesting dysfunction of steroidogenic enzymes. In conclusion, perinatal exposure to BDE-47 disrupts the structure of gonadal tissues in both maternal and offspring mice, affects hormonal levels, and impairs the normal synthesis of steroid hormones, thereby exerting reproductive toxicity effects. These findings highlight the potential long-term reproductive health risks associated with perinatal exposure to BDE-47 and underscore the need for further research to elucidate the underlying mechanisms and develop preventive strategies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117535"},"PeriodicalIF":3.4,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932714","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":"Nrf2-mediated inhibition of ferroptosis contributes to the amelioration of atherosclerosis by polydatin","authors":"Yu Qiu Wu ,&nbsp;Ruo Man Wu ,&nbsp;Yi Zeng,&nbsp;Xiao Le Xu","doi":"10.1016/j.taap.2025.117538","DOIUrl":"10.1016/j.taap.2025.117538","url":null,"abstract":"<div><div>Polydatin is a bioactive compound extracted from the roots of Reynoutria japonica Houtt. It has demonstrated various protective effects on the cardiovascular system. However, the underlying molecular mechanisms through which polydatin exerts its effects in atherosclerosis (AS) remain largely unclear, particularly regarding the involvement of the ferroptosis pathway in its anti-atherosclerotic action. This study aims to investigate the anti-atherosclerotic effects of polydatin and its potential mechanisms, with a primary focus on the ferroptosis pathway. To this end, we employed an ApoE^−/− mouse model and endothelial cells exposed to oxidized low-density lipoprotein (ox-LDL). We analyzed atherosclerosis progression, endothelial function, and ferroptosis both in vitro and in vivo using various biological and biochemical techniques. To further explore the underlying mechanisms of polydatin's effects, Nrf2 expression was silenced using siRNA. Polydatin inhibited atherosclerosis in vivo and improved endothelial function in vitro. We evaluated ferroptosis-related markers, including ferrous iron, glutathione, malondialdehyde, lipid reactive oxygen species (ROS), GPX4, and SLC7A11, as well as overall ROS production, mitochondrial membrane potential, and mitochondrial ROS. The results indicated that polydatin suppressed ferroptosis both in vivo and in vitro. Moreover, the ferroptosis inducer erastin counteracted the endothelial cytoprotective effects of polydatin. Mechanistically, polydatin significantly enhanced Nrf2 nuclear translocation in both the aortic tissues of ApoE^−/− mice and ox-LDL-stimulated endothelial cells. Furthermore, silencing Nrf2 markedly abrogated the protective effects of polydatin on endothelial ferroptosis and impaired cellular function. Collectively, these findings demonstrate that modulating Nrf2-dependent ferroptosis contributes to the ability of polydatin to mitigate atherosclerosis and protect endothelial cells from injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117538"},"PeriodicalIF":3.4,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932715","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":"USF2 regulates the JAK2/STAT3 pathway through PEX3-mediated SLC25A17 upregulation to affect lipid metabolism and promote the progression of lung adenocarcinoma","authors":"Huifeng Wang ,&nbsp;Yanyan Sun ,&nbsp;Rui Zi ,&nbsp;Tingting Shi ,&nbsp;Hui Dong","doi":"10.1016/j.taap.2025.117534","DOIUrl":"10.1016/j.taap.2025.117534","url":null,"abstract":"<div><div>Upstream Stimulator Factor 2 (USF2) has been identified as an oncogenic factor in various types of cancer; however, its precise biological function and underlying molecular mechanisms in the pathogenesis of lung cancer remain to be fully elucidated. In this study, we found that USF2 was markedly upregulated in lung adenocarcinoma (LUAD) tissues and cells. Knockdown of <em>USF2</em> inhibits A549 cell proliferation and invasion and induces cell apoptosis. Overexpression of <em>USF2</em> promotes abnormal lipid metabolism in A549 cells, as evidenced by elevated levels of triglycerides, cholesterol, and free fatty acids, upregulated fatty acid synthase levels, and downregulated acyl-CoA oxidase 1 levels. Mechanistically, USF2 directly binds to the promoter of <em>Peroxisome biogenesis factor 3 (PEX3)</em> to drive its transcriptional activation. Upregulated PEX3 promotes abnormal lipid metabolism in LUAD cells by interacting with solute carrier family 25 member 17 (SLC25A17) to upregulate its protein levels. Knockdown of <em>PEX3</em> reverses the effects of USF2 overexpression on A549 cells. Additionally, <em>SLC25A17</em> overexpression exacerbates lipid accumulation in A549 cells by activating the janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, while AG490, a JAK2 inhibitor, eliminates this effect. Finally, a xenograft tumor model was established by subcutaneously injecting A549 cells transfected with sh-USF2 lentiviral vectors into nude mice. Results showed that <em>USF2</em> knockdown inhibits abnormal lipid metabolism and tumor growth in xenografted mice. In conclusion, our study demonstrates that <em>USF2</em> overexpression enhances SLC25A17-mediated JAK2/STAT3 signaling by promoting <em>PEX3</em> transcriptional activation, thereby exacerbating abnormal lipid metabolism in A549 cells and accelerating LUAD progression.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117534"},"PeriodicalIF":3.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926160","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":"NFE2L2 protects against Sorafenib-induced Ferroptosis and cardiotoxicity by activating the HO1/ferritin pathway","authors":"Hui Jiang ,&nbsp;Yan Su ,&nbsp;Yinglong Hou ,&nbsp;Cong Wang","doi":"10.1016/j.taap.2025.117537","DOIUrl":"10.1016/j.taap.2025.117537","url":null,"abstract":"<div><div>Sorafenib, a tyrosine kinase inhibitor, has demonstrated efficacy in the treatment of hepatocellular carcinoma and clear cell renal carcinoma. However, its clinical application is limited by cardiotoxicity. Here, we show that NFE2L2, a transcription factor that regulates oxidative stress and iron homeostasis, mitigates Sorafenib-induced cardiotoxicity. Sorafenib increases NFE2L2 expression in cardiomyocytes, while ferroptosis inhibitors such as ferrostatin-1 (Fer-1) and deferoxamine (DFO) attenuate this effect, indicating that ferroptosis is involved in NFE2L2 activation. Further studies revealed that NFE2L2 knockdown exacerbates Sorafenib-induced cardiomyocyte ferroptosis, which is characterized by increased lipid peroxidation and reactive oxygen species (ROS) production. Conversely, NFE2L2 agonist sulforaphane (SFN) mitigated Sorafenib-induced ferroptosis. Mechanistically, NFE2L2 activates the heme oxygenase-1 (HO-1)/ferritin axis, which alleviates oxidative stress and promotes iron homeostasis in cardiomyocytes, thereby mitigating Sorafenib-induced ferroptosis. Interestingly, Sorafenib activates NFE2L2 via the endoplasmic reticulum (ER) stress-related kinase EIF2AK3, rather than the SQSTM1-KEAP1 pathway. This finding reveals a novel role for ER stress-dependent pathways in counteracting Sorafenib-induced cardiotoxicity. Finally, we found that SFN alleviates Sorafenib-induced cardiotoxicity in vivo, providing a new therapeutic strategy for managing drug-induced cardiac injury. Taken together, these data suggest that NFE2L2 and its downstream pathways, including the HO-1/ferritin axis, may represent promising therapeutic targets for mitigating Sorafenib-induced cardiotoxicity. Further investigation of NFE2L2 agonists could enhance the safety of Sorafenib therapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117537"},"PeriodicalIF":3.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932722","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":"An integrative bioinformatics approach unveils fibrosis-driven prognostic signature and immunotherapeutic potential in kidney renal clear cell carcinoma","authors":"Junmei Lai ,&nbsp;Zhang Chen ,&nbsp;Wenjing Wu","doi":"10.1016/j.taap.2025.117533","DOIUrl":"10.1016/j.taap.2025.117533","url":null,"abstract":"<div><h3>Background</h3><div>Fibrosis plays a significant role in tumor progression and modifies the immune microenvironment; however, its prognostic implications in kidney renal clear cell carcinoma (KIRC) warrant further investigation. This study develops a robust prognostic model that predicts patient outcomes and responsiveness to immunotherapy in KIRC based on fibrosis-related gene signatures.</div></div><div><h3>Methods</h3><div>Fibrosis-associated genes were curated from three reputable databases (GeneCards, CTD, and OMIM). RNA-sequencing datasets for KIRC were acquired from TCGA, ICGC, and E-MTAB-1980 cohorts. Comprehensive analyses, including differential gene expression, univariate Cox regression, and LASSO Cox regression, were employed to establish and validate a fibrosis-related signature (FRS). Functional enrichment analyses, genomic instability profiling, and assessments of immune cell infiltration were performed to elucidate the biological features of FRS. <em>PDGFRA</em> was examined through single-cell and pan-cancer analyses, with subsequent <em>PDGFRA</em> knockdown created in OS-RC-2 and Caki-1 cell lines. Co-culture experiments with HDF were conducted to evaluate the expression of <em>MMP2</em> and <em>MMP9</em>. Cell proliferation, migration, and apoptosis were assessed using CCK8, Transwell assays, and Annexin V/PI staining, respectively, while an <em>in vivo</em> xenograft model was utilized to investigate <em>PDGFRA</em>'s role in KIRC.</div></div><div><h3>Results</h3><div>The FRS, incorporating four genes (<em>PDGFRA</em>, <em>SLC40A1</em>, <em>CXCL2</em>, <em>AGTR1</em>), demonstrated strong prognostic capabilities. High-FRS patients experienced significantly worse survival rates, heightened genomic instability, and distinctive immune profiles characterized by increased immune cell infiltration and immune dysfunction. <em>PDGFRA</em> emerged as a significant prognosticator, exhibiting substantial clinical relevance. <em>In vitro</em> silencing of <em>PDGFRA</em> impeded cell proliferation and migration while promoting apoptosis and inhibiting <em>MMP2</em> and <em>MMP9</em> expression in HDF. Additionally, <em>PDGFRA</em> knockdown markedly reduced fibrosis and tumorigenicity in KIRC models <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>The fibrosis-related signature effectively stratifies KIRC patients according to prognosis and potential immunotherapy responses, enhancing our understanding of fibrosis-mediated tumor biology and enabling personalized therapeutic approaches in kidney cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117533"},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893816","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":"Carnosol attenuates Ang II-induced renal injury by p62-KEAP1-NRF2 signaling pathway","authors":"Shijie Fan ,&nbsp;Ying Zhao ,&nbsp;Qingqing Zhao ,&nbsp;Diyun Xu ,&nbsp;Xi Chen ,&nbsp;Jibo Han ,&nbsp;Ziming Fang ,&nbsp;Guang Liang ,&nbsp;Yunjie Zhao","doi":"10.1016/j.taap.2025.117528","DOIUrl":"10.1016/j.taap.2025.117528","url":null,"abstract":"<div><div>Hypertension engenders numerous complications, including hypertensive renal disease (HRD). Recent studies have underscored the significance of redox homeostasis in hypertension-associated kidney disorders. Carnosol (Car) has been identified as a potent antioxidant in other diseases. Nevertheless, its role in HRD remains uncertain. This research evaluated the therapeutic impact of Car on HRD and explored its pharmacological mechanism. Car (40 mg/kg) effectively ameliorated kidney injury and oxidative stress (OS) induced by angiotensin II (Ang II) both in vitro and in vivo. Mechanistically, Car facilitates the phosphorylation of p62 through its interaction with mTOR, leading to the degradation of KEAP1, the release of NRF2, and the subsequent upregulation of antioxidant genes. Blocking mTORC1 eliminated Car-induced p62 activation and its antioxidant functions. In summary, our research has demonstrated that Car activates the p62-KEAP1-NRF2 pathway to alleviate the kidney injury and OS caused by Ang II. Consequently, Car may emerge as a promising candidate for the prevention and treatment of Ang II-induced kidney injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117528"},"PeriodicalIF":3.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902759","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":"Chrysin enhances sunitinib sensitivity in renal cell carcinoma by inducing ferroptosis via targeting PI3K/Akt/GPX4 pathway","authors":"Zixuan Chen ,&nbsp;Weiyuan Li ,&nbsp;Boshen Jia ,&nbsp;Guohuan Yin ,&nbsp;Zongrun Sun ,&nbsp;Yanjun Tong ,&nbsp;Sheng Cheng ,&nbsp;Min Liu","doi":"10.1016/j.taap.2025.117531","DOIUrl":"10.1016/j.taap.2025.117531","url":null,"abstract":"<div><div>Renal cell carcinoma (RCC) continues to pose a significant clinical challenge due to its high resistance to conventional therapies. Sunitinib, a first-line treatment for metastatic RCC, is often limited by acquired resistance, necessitating novel therapeutic strategies. Chrysin, a natural flavonoid with known anticancer properties, has shown potential in various malignancies; however, its role in RCC is still not well understood. This research employed network pharmacology and molecular docking techniques to identify the primary targets of Chrysin in RCC, identifying EGFR as the central target. Functional experiments demonstrated that Chrysin significantly reduced the proliferation and migration of RCC cells. Further investigation revealed that Chrysin induced ferroptosis, as evidenced by increased ROS levels, Fe²⁺ accumulation, GSH depletion, and lipid peroxidation.d Through its mechanisms, Chrysin suppressed the PI3K/Akt signaling pathway, which resulted in the reduced expression of SLC7A11 and GPX4. Rescue experiments confirmed that activation of PI3K/Akt reversed Chrysin-induced ferroptosis. Additionally, Chrysin enhanced the sensitivity of RCC cells to sunitinib by potentiating ferroptosis. These findings demonstrate that chrysin enhances sunitinib sensitivity in RCC by targeting the PI3K/Akt/GPX4 axis to induce ferroptosis, providing a novel strategy for RCC treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117531"},"PeriodicalIF":3.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890144","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":"Prolactin impairs erectile function via eNOS suppression independently of testosterone","authors":"Xiaozhi Cheng ,&nbsp;Yunbei Xiao ,&nbsp;Di Qiu ,&nbsp;Lurong Li ,&nbsp;Qi Peng ,&nbsp;Yong Liu ,&nbsp;Yunyun Tian ,&nbsp;Er Zhou ,&nbsp;HuiLiang Zhou","doi":"10.1016/j.taap.2025.117532","DOIUrl":"10.1016/j.taap.2025.117532","url":null,"abstract":"<div><div>Erectile dysfunction (ED) frequently occurs in men with prolactin-secreting pituitary tumors (prolactinomas), even when serum testosterone levels remain normal. The precise mechanisms responsible for this phenomenon are poorly understood. We aimed to explore whether elevated prolactin directly impairs erectile function independently of testosterone, and to identify the underlying molecular pathways involved. Clinical data analysis showed that elevated prolactin levels negatively correlated with erectile function in men with pituitary tumors who maintained normal testosterone levels. Using a prolactinoma rat model induced by diethylstilbestrol, we confirmed that hyperprolactinemia resulted in ED without altering testosterone. Bromocriptine, a dopamine agonist, effectively reduced prolactin levels, restored erectile function, and improved penile endothelial nitric oxide synthase (eNOS) expression without affecting testosterone. Mechanistically, hyperprolactinemia significantly inhibited the phosphoinositide 3-kinase (PI3K)–protein kinase B (Akt)–eNOS signaling pathway in penile tissue. Consistent with animal studies, cultured rat corpus cavernosum endothelial cells exposed to prolactin displayed reduced eNOS expression. Our findings demonstrate that prolactin directly impairs erectile function by suppressing the PI3K–Akt–eNOS pathway independently of testosterone, suggesting new therapeutic targets for treating ED in patients with prolactinoma. Patients with prolactinoma accompanied by normal testosterone levels should be evaluated for erectile dysfunction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117532"},"PeriodicalIF":3.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890145","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":"SACF and GILA assays on AML12 cells show limited predictive value for mouse liver genotoxicity","authors":"Erica Coratella ,&nbsp;Rebecca Bohnert ,&nbsp;Benoit Fischer ,&nbsp;Myriam Lemmens ,&nbsp;Tara Alpert ,&nbsp;Martin Beibel ,&nbsp;Mevion Oertli ,&nbsp;Ulrike Naumann ,&nbsp;Azeddine Elhajouji ,&nbsp;Alex Odermatt ,&nbsp;Silvana Libertini","doi":"10.1016/j.taap.2025.117529","DOIUrl":"10.1016/j.taap.2025.117529","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) has been observed in neonatal mice following the integration of recombinant Adeno-Associated Viruses (rAAV) into the <em>Rian</em> locus. rAAV-related oncogenic risk for patients remains unclear, and the lack of relevant <em>in vitro</em> methods hinders its proper assessment. The soft agar colony-forming (SACF) assay and the growth in low attachment assay (GILA) monitor anchorage-independent growth, a hallmark of transformed adherent cells, and have been previously proposed to assess the tumorigenicity of CRISPR/Cas9-edited human MCF10A cells. Here, we introduce murine versions of SACF and GILA as surrogate <em>in vitro</em> systems to evaluate the risk of HCC development following genome editing or rAAV induced insertional mutagenesis. Selected tumor suppressors linked to HCC onset <em>in vivo</em> were edited through CRISPR/Cas9 in the hepatic murine cell line AML12. The knockout of neurofibromin (<em>Nf2</em>) and the dual inactivation of tumor protein p53 (<em>Tp53)</em> and phosphatase and tensin homolog (<em>Pten)</em> induced anchorage-independence, while the editing of <em>Axin1</em>, <em>Ctnnb1</em> (coding for β-catenin), and tuberous sclerosis complex 1 (<em>Tsc1</em>) did not promote growth in anchorage-free conditions. Additionally, we generated stable AML12 and MCF10A clones with the rAAV genome respectively integrated into <em>Rian</em> and <em>MEG8</em>, the human homolog of <em>Rian</em>; however, these clones did not show anchorage independence when seeded in SACF and GILA. Overall, the murine SACF and GILA exhibit low predictive value for HCC development, failing to detect rAAV- and tumor-suppressors-associated oncogenicity. While further optimization may improve assays performance, these results highlight the need for more appropriate <em>in vitro</em> methodologies to accurately evaluate rAAV genotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117529"},"PeriodicalIF":3.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892302","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":"Downregulation of collagen and elastin genes in murine skin following cisplatin and vincristine treatment","authors":"Miho Kiyama ,&nbsp;Yuan Someya ,&nbsp;Hiroyasu Sakai ,&nbsp;Haruka Kitamura ,&nbsp;Mao Ueda ,&nbsp;Yuya Chigusa ,&nbsp;Shiori Yonamine ,&nbsp;Shinki Soga ,&nbsp;Hayato Nanri ,&nbsp;Risako Kon ,&nbsp;Nobutomo Ikarashi ,&nbsp;Yoshihiko Chiba ,&nbsp;Tomoo Hosoe ,&nbsp;Fumiaki Sato ,&nbsp;Kumiko Ogawa","doi":"10.1016/j.taap.2025.117526","DOIUrl":"10.1016/j.taap.2025.117526","url":null,"abstract":"<div><div>Cancer survivors are increasingly reported to exhibit signs of accelerated aging, largely attributed to the cytotoxic effects of chemotherapy, which may lead to various age-related conditions. Despite this, treatment-induced alterations in physical appearance—particularly changes in skin structure—are often overlooked in clinical practice and remain poorly understood. This study aimed to elucidate the mechanisms by which cytotoxic anticancer drugs affect skin integrity, with a focus on collagen (type I and III) and elastin, key components associated with skin aging. In a murine model, dietary restriction alone, as well as treatment with each of the anticancer drugs used in this study (cisplatin, 5-fluorouracil, vincristine, irinotecan and cyclophosphamide), led to significant weight loss; however, dermal thinning was observed exclusively in the cisplatin and vincristine. This structural deterioration correlated with a pronounced downregulation of Col1a1, Col1a2, Col3a1, and Eln at both the mRNA and protein levels. Mechanistically, this was accompanied by suppression of the TGF-β/Smad signaling pathway, evidenced by reduced TGF-β expression and Smad2 phosphorylation. Furthermore, the gene expression of Loxl1 and Loxl2-enzymes critical for collagen and elastin cross-linking was significantly diminished. These findings suggest that cisplatin and vincristine compromise dermal architecture by disrupting TGF-β signaling and extracellular matrix homeostasis, potentially contributing to premature skin aging in cancer survivors.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117526"},"PeriodicalIF":3.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889466","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}