Toxicology and applied pharmacology最新文献

{"title":"Centromere protein K enhances the activation of YAP1/TAZ signal cascade to drive the progression of clear cell renal cell carcinoma","authors":"Ning Nan","doi":"10.1016/j.taap.2024.117181","DOIUrl":"10.1016/j.taap.2024.117181","url":null,"abstract":"<div><div>Centromere protein K (CENPK) is a newly identified malignancy-related gene that exhibits differential expression in various cancers and plays a crucial role in carcinogenesis. However, it remains uncertain whether CENPK is involved in clear cell renal cell carcinoma (ccRCC). This work aimed to unveil the expression, clinical significance, biological functions, and regulatory mechanisms of CENPK in ccRCC. Through analysis of RNA-seq data obtained from TCGA, a high expression pattern of CENPK was identified in ccRCC, which was found to be associated with pathologic stage, histologic grade, and clinical outcome. The enrichment of CENPK in ccRCC was further verified through the analysis of clinical samples. By conducting cellular functional experiments, we showed an inhibitory effect of CENPK knockdown on the malignant behavior of ccRCC cells. GSEA revealed a close relationship between CENPK and the Hippo–YAP1/TAZ signal cascade. The following experiments demonstrated that the activation of YAP1/TAZ was strongly inhibited by CENPK knockdown, and this change was accompanied by a decrease in the levels of CTGF and CYR61. Blockade of the MST1/2-LATS1/2 axis reversed the suppressive impact of CENPK knockdown on YAP1/TAZ. The tumor-promoting impact observed upon CENPK overexpression was diminished in YAP1 knockout cells. Notably, ccRCC cells with reduced CENPK expression exhibited a diminished capability to form tumors in nude mice. This report highlights the importance of CENPK in ccRCC and sheds new light on the underlying mechanism of this cancer type. Therefore, CENPK has the potential to serve as a viable candidate target for treating ccRCC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117181"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772647","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":"Model-based analysis for investigating the impact of tumor size, lymphocyte and neutrophil on the survival of breast cancer 4T1 tumor-bearing mice","authors":"Qing-yu Yao ,&nbsp;Xin-yu Hou ,&nbsp;Wei-zhe Jian ,&nbsp;Tian-yu Wang ,&nbsp;Ping-yao Luo ,&nbsp;Jun-sheng Xue ,&nbsp;Rong Chen ,&nbsp;Tian-yan Zhou","doi":"10.1016/j.taap.2024.117176","DOIUrl":"10.1016/j.taap.2024.117176","url":null,"abstract":"<div><div>Survival is one of the foremost endpoints in cancer therapy, and parametric survival analysis could comprehensively demonstrate the overall result of various different baseline and longitudinal factors. In this study, the survival of triple negative breast cancer 4T1 tumor-bearing mice treated by gemcitabine (GEM) and dexamethasone (DEX) was investigated with model-based analysis. The tumor size, lymphocyte (LY) and neutrophil (NE) of 4T1 tumor-bearing BALB/c mice were collected, and the PK/PD models of these longitudinal data were established in a sequential manner, respectively. The parametric time-to-event (TTE) model of survival was developed and the PK/PD models were tested and integrated as time-varying prognostic factors. The final model was evaluated and externally validated. LY and NE influence the survival directly, while tumor size showed its indirect impact on survival by affecting LY. The exposure of GEM significantly improved the survival results but DEX did not bring extra benefit. The models established in this study quantitatively characterized the abnormal increasing of LY and NE due to tumor progression in T1 tumor-bearing mice and also demonstrate their relationship with survival outcomes, and further provide a modeling framework to demonstrate potential prognostic factors of survival and evaluate the efficacy of different therapies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117176"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756674","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":"Curcumin alleviated dextran sulfate sodium-induced ulcerative colitis via inhibition of the Wnt/β-catenin signaling pathway and regulation of the differentiation of intestinal stem cells","authors":"Shaojie Liang ,&nbsp;Kun Wang ,&nbsp;Dabin Mao ,&nbsp;Qianqian Ouyang ,&nbsp;Xiaoping Lv ,&nbsp;Liwei Xie ,&nbsp;Dajian Zhu","doi":"10.1016/j.taap.2024.117175","DOIUrl":"10.1016/j.taap.2024.117175","url":null,"abstract":"<div><div>In this study, we investigated the regulatory role of curcumin in the differentiation of intestinal stem cells (ISCs) in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) model mice and explored whether this effect was mediated by the Wnt/β-catenin signaling pathway. We conducted experiments in DSS-induced UC model mice to observe changes in intestinal morphology through HE staining and detect the expression of key proteins in the Wnt/β-catenin signaling pathway. According to these findings, curcumin was found to have a significant impact on the differentiation of ISCs. These results indicated that curcumin inhibited the Wnt/β-catenin signaling pathway and restored ISC differentiation. The effects of curcumin on the Wnt/β-catenin signaling pathway were further confirmed using Wnt/β-catenin agonists. These findings provide a new perspective for understanding the behavior of ISCs in the context of inflammation and offer new insights into the development of novel therapeutic strategies and drugs for UC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117175"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747923","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":"Synthesis and evaluation of novel ethyl ferulate derivatives as potent Keap1 inhibitors to activate the Nrf2/ARE pathway in Parkinson's disease","authors":"Amritha Chakkittukandiyil ,&nbsp;Deepak Vasudevan Sajini ,&nbsp;Emdormi Rymbai ,&nbsp;Deepa Sugumar ,&nbsp;Jinu Mathew ,&nbsp;Suresh Arumugam ,&nbsp;Vadivelan Ramachandran ,&nbsp;Divakar Selvaraj","doi":"10.1016/j.taap.2024.117172","DOIUrl":"10.1016/j.taap.2024.117172","url":null,"abstract":"<div><div>The Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2 related factor 2/Antioxidant Response Elements (Keap1/Nrf2/ARE) pathway is essential for neuronal resilience against the complex pathogenesis of Parkinson's disease (PD). Activating this pathway by covalently modifying Keap1 cysteine residues is a promising strategy for regulating neuroprotective gene expression. Our study aimed to identify phytochemicals that could irreversibly inhibit Keap1. A preliminary docking analysis revealed that ethyl ferulate could covalently bind with Cys151 of Keap1 by Michael's addition reaction. Further, we designed several ethyl ferulate derivatives with improved lipophilicity and assessed their binding affinity with Keap1. The molecules with good binding scores were synthesized and structures were confirmed through ¹H NMR, ¹³C NMR, FT-IR, and mass spectroscopy. Neuroprotection screening was conducted in all-trans retinoic acid differentiated SH-SY5Y cells using rotenone as a disease-inducing agent. Pre-treatment with compounds C2 and C4 significantly mitigated rotenone toxicity. Additionally, C2 and C4 decreased rotenone-induced ROS production and mitochondrial membrane potential loss. C2 and C4 also induced Nrf2 nuclear translocation in SH-SY5Y cells and increased mRNA expression of heme oxygenase-1, an Nrf2-regulated antioxidant response element. In vivo<em>,</em> pretreatment with C2 (50, 100 mg/kg, p.o.) and C4 (50, 100 mg/kg, p.o.) protected against neurodegenerative phenotypes associated with rotenone (1.5 mg/kg, s.c.) induction in Wistar rats. Results indicate, C2 and C4 dose-dependently improved muscle rigidity, catalepsy, and cognitive deficits in rotenone-induced Wistar rats, and mitigated dopaminergic neurodegeneration in the substantia nigra<em>.</em> These findings highlight the potential of ethyl ferulate derivatives in modulating oxidative stress and neurodegeneration in PD via activation of Nrf2.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117172"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740732","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":"Cisplatin caused highly delayed cytotoxicity in the immortalized cells derived from S3 segment of mouse kidney proximal tubules","authors":"Hiroki Taguchi,&nbsp;Daigo Sumi,&nbsp;Ayumi Uemura,&nbsp;Kanako Matsumoto,&nbsp;Hitomi Fujishiro","doi":"10.1016/j.taap.2024.117171","DOIUrl":"10.1016/j.taap.2024.117171","url":null,"abstract":"<div><div>Anti-cancer drug cisplatin (CDDP) causes severe acute kidney injury (AKI). CDDP-induced AKI does not occur immediately after administration, but rather 6 to 10 days after administration. However, the mechanism underling the delayed renal injury by CDDP is not well understood. In a previous investigation using immortalized cells derived from the S1, S2, and S3 segments of the proximal tubules, we found that S3 cells were more sensitive to CDDP than S1 and S2 cells. In this study, we examined whether S1, S2, and S3 cells would be useful in elucidating the mechanism of CDDP-induced delayed renal injury and whether the high sensitivity of S3 cells contributes to CDDP-induced delayed renal injury. Measurement of platinum (Pt) content by ICP-MS showed that Pt accumulation peaked at 15 min after CDDP exposure in each cell type. Even when the medium was replaced with CDDP-free medium after the 15-min CDDP exposure and the cells were further incubated, delayed cytotoxicity was still observed. The S3 cells exhibited greater sensitivity to CCDP than the S1 and S2 cells at all time points after the medium change. To investigate the mechanism of the CDDP-induced delayed cytotoxicity, we examined the cell cycle distribution of cells after CDDP exposure. The results showed that CDDP-induced perturbation of cell cycle was greater in S3 than in S1 and S2 cells. These results suggest that perturbation of the cell cycle in S3 cells due to enhanced CDDP–DNA adduct formation contributes to the high susceptibility of S3 cells to CDDP-induced delayed cytotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117171"},"PeriodicalIF":3.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719856","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":"Curcumin ameliorates astrocyte inflammation through AXL in cuprizone-induced mice","authors":"Wenjing Zhang,&nbsp;Mengjiao Sun,&nbsp;Ning Liu,&nbsp;Xiaoling Li,&nbsp;Jing Sun,&nbsp;Manxia Wang","doi":"10.1016/j.taap.2024.117170","DOIUrl":"10.1016/j.taap.2024.117170","url":null,"abstract":"<div><div>Curcumin has gained global attention owning to its anti-inflammatory, antioxidant, anticancer, and antimicrobial activities. Curcumin has recently been shown to have well-documented effects on neuroinflammation in multiple sclerosis (MS). Astrocytes, the most widely distributed glial cells in the brain, have a significant influence on the regulation of neuroinflammation in MS. However, it is unknown how curcumin exerts neuroprotective effects in astrocytes. To elucidate the mechanism underlying the effects of curcumin on astrocytes, we explored the effect of curcumin on cuprizone (CPZ)-induced mice <em>in vivo</em> and on primary astrocytes <em>in vitro</em>. In this study, we observed that curcumin significantly ameliorated myelin loss and reduced astrocyte activation in the corpus callosum (CC) region in mice induced with CPZ, and in primary astrocytes stimulated with lipopolysaccharide (LPS). Meanwhile, our research indicated that curcumin may exert neuroprotective effects in CPZ-induced mice by downregulating astrocyte-mediated inflammation by AXL. This study provides new insights into possible targeted therapies for MS.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117170"},"PeriodicalIF":3.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717198","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":"Epigenetic modifications control CYP1A1 Inducibility in human and rat keratinocytes","authors":"Lo-Wei Lin,&nbsp;Allison K. Ehrlich,&nbsp;Robert H. Rice","doi":"10.1016/j.taap.2024.117163","DOIUrl":"10.1016/j.taap.2024.117163","url":null,"abstract":"<div><div>Serially passaged rat keratinocytes exhibit dramatically attenuated induction of <em>Cyp1a1</em> by aryl hydrocarbon receptor ligands such as TCDD. However, the sensitivity to induction can be restored by protein synthesis inhibition. Previous work revealed that the functionality of the receptor was not affected by passaging. The present work explored the possibility of epigenetic silencing on CYP1A1 inducibility in both rat and human cells. Use of an array of small molecule epigenetic modulators demonstrated that inhibition of histone deacetylases mimicked the effect of protein synthesis inhibition. Consistent with this finding, cycloheximide treatment also reduced histone deacetylase activity. More importantly, when compared to human <em>CYP1A1</em>, rat <em>Cyp1a1</em> exhibited much greater sensitivity toward epigenetic modulators, particularly inhibitors of histone deacetylases. Other genes in the aryl hydrocarbon receptor domain showed variable and less dramatic responses to histone deacetylase inhibitors. These findings highlight a potential species difference in epigenetics that must be considered when extrapolating results from rodent models to humans and has implications for xenobiotic- or drug-drug interactions where CYP1A1 activity plays an important role.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117163"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695807","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":"Thymoquinone inhibits Neuroinflammatory mediators and vasoconstriction injury via NF-κB dependent NeuN/GFAP/Ki-67 in hypertensive Dams and F1 male pups on exposure to a mixture of Bisphenol-A analogues","authors":"O.S. Okoh ,&nbsp;J.K. Akintunde ,&nbsp;A.J. Akamo ,&nbsp;Ubong Akpan","doi":"10.1016/j.taap.2024.117162","DOIUrl":"10.1016/j.taap.2024.117162","url":null,"abstract":"<div><div>Bisphenol-A (BPA) analogues seem inevitable components of numerous domestic products, but these have been identified as agents of teratogenic disorders. This study, therefore, investigated the effect of thymoquinone (TMQ) on the striatum of hypertensive female rats and their F1 male offsprings, on exposure to a mixture of Bisphenol-B, Bisphenol-F and Bisphenol-S (MBFS). Female rats were divided into normotensive and hypertensive groups; and both were treated with MBFS only, MBFS + TMQ, and TMQ only. Exposure to MBFS and co-treatment with TMQ lasted at least 63 days. Neurobehavioural assessments were conducted using Open Field (OF). A spectrophotometer was used for cholinergic, dopaminergic and adenosinergic enzyme assays; Real-Time PCR for gene expression; and immunohistochemistry for protein quantification; while H&amp;E, cresyl fast violent, and congo red stains were used for histological assessments. From the results, maternal exposure to MBFS mediated striatal dysfunction via p53 and NF-kB upregulation; decreased BCl-2, Ki-67 and NeuN; increased GFAP, nissl bodies and β-amyloid. Dysregulation of cholinergic, dopaminergic and adenosinergic enzymes in addition to decreased nitric oxide levels were also associated with MBFS toxicity. Hypertension was found to exacerbate MBFS toxicity. From OF test; increased anxiety and decreased psychomotor activity were associated with maternal exposure to MBFS. However, co-treatment with thymoquinone prevented striatal dysfunction in hypertensive dams and their F1 male offspring. In conclusion, disruption of the delicate balance between apoptosis and cell proliferation culminating in the reduction of mature neurons is responsible for neurodegeneration and neuropathy associated with MBFS exposure. However, these can be prevented through regular consumption of natural products and supplements rich in thymoquinone.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117162"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693590","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":"Study on the mechanism of brain injury caused by acute diquat poisoning based on metabolomics","authors":"Chaocheng Wang ,&nbsp;Hui Hu ,&nbsp;Junzhao Liu ,&nbsp;Xia Rong ,&nbsp;Jing Zhang ,&nbsp;Yu Du","doi":"10.1016/j.taap.2024.117161","DOIUrl":"10.1016/j.taap.2024.117161","url":null,"abstract":"<div><div>Brain injury following acute diquat poisoning has become increasingly common in moderate to severe cases, with unclear pathogenesis and high mortality. To investigate this, we conducted metabolomics on brain tissue from poisoned rats, combined with clinical biochemical and pathological analyses. In the high-dose group, 24 metabolites showed significant differences compared to the control group: 18 were upregulated, including cytosine, sedoheptulose-7-phosphate, indole, 3-dehydroshikimate, etc.; 6 were downregulated, including 6-phosphogluconic acid, 3-hydroxybenzoic acid, dAMP, etc. In the low-dose group, 10 metabolites showed significant differences: 4 were upregulated, including pentamidine, γ-tocotrienol, benzoylecgonine, etc.; and 6 were downregulated, including dAMP, glutathione, 3-hydroxybenzoic acid, etc. Enrichment analysis identified two key pathways—phenylalanine, tyrosine, and tryptophan biosynthesis, and the pentose phosphate pathway—as involved in brain injury. ROC analysis of six differential metabolites showed that sedoheptulose-7-phosphate, (2<em>R</em>)-2-hydroxy-3-(phosphonatooxy)propanoate, and 3-hydroxybenzoic acid had AUC values above 0.8. These findings suggest that these three metabolites demonstrate strong diagnostic potential for brain injury induced by diquat poisoning. Correlation analysis linked these biomarkers to clinical indicators such as neutrophil count and the eutrophil to lymphocyte ratio, supporting their relevance. This study provides insights into the mechanisms and biomarkers of diquat-induced brain injury, offering a foundation for future treatment and rapid detection.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117161"},"PeriodicalIF":3.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688570","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":"Ginsenoside Rg3 attenuates the stemness of breast cancer stem cells by activating the hippo signaling pathway","authors":"Zhicheng Deng ,&nbsp;Mengdie Ou ,&nbsp;Yonghui Shi ,&nbsp;Guocheng Li ,&nbsp;Li Lv","doi":"10.1016/j.taap.2024.117158","DOIUrl":"10.1016/j.taap.2024.117158","url":null,"abstract":"<div><div>Ginsenoside Rg3 (Rg3), a bioactive compound from ginseng, is gaining attention for its potential in targeting cancer stem cells in cancer therapy. The therapeutic effect of Rg3 on breast cancer stem cells (BCSCs) has not been systematically explored using a suitable approach. Our study leverages a multi-faceted strategy, including network pharmacology, molecular docking, and <em>in vitro</em> experiments validation, to explore the effect of Rg3 against BCSCs. We identified 38 common targets of Rg3 and BCSCs through public databases mining. The analysis of protein-protein interaction network revealed <em>Myc</em>, <em>Stat3</em>, <em>Bcl2</em>, <em>Cdh1</em>, <em>Egf</em>, <em>Il6</em>, <em>Egfr</em>, <em>Nfkb1</em>, <em>Sox2</em> and <em>Sirt1</em> as the top 10 potential targets. Molecular docking further validated Rg3 has robust binding potential with these targets. Utilizing the BCSC-enriched MCF-7 and MDA-MB-231 mammosphere model, <em>in vitro</em> experiments substantiated Rg3's ability to induce apoptosis, suppress proliferation, and inhibit mammospheres formation of BCSCs. Rg3 also decreased the ALDH^high and CD44⁺/CD24^−/low subpopulations and downregulated the expression of cancer stem cell markers such as c-MYC, ALDH1A1, NANOG in BCSCs. After Rg3 treatment, most of the top 10 genes in BCSC-enriched MCF-7 mammospheres showed a significant reduction in expression, with <em>Cdh1</em> (E-cadherin) being the most markedly downregulated. The E-cadherin/catenin complex acts as an upstream regulator of the Hippo signaling pathway, which is crucial for BCSC function and is among the top 20 enriched pathways identified by KEGG analysis. Mechanistically, Rg3 attenuates the stemness of BCSCs by activating the Hippo signaling pathway. This study provides a comprehensive evaluation of Rg3 as a promising therapeutic agent against BCSCs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117158"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676945","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}