Toxicology and applied pharmacology最新文献

{"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":"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":"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}

{"title":"Estimation of species- and sex-specific PFAS pharmacokinetics in mice, rats, and non-human primates using a Bayesian hierarchical methodology","authors":"Todd J. Zurlinden ,&nbsp;Michael W. Dzierlenga ,&nbsp;Dustin F. Kapraun ,&nbsp;Caroline Ring ,&nbsp;Amanda S. Bernstein ,&nbsp;Paul M. Schlosser ,&nbsp;Viktor Morozov","doi":"10.1016/j.taap.2025.117336","DOIUrl":"10.1016/j.taap.2025.117336","url":null,"abstract":"<div><div>The carbon chain length, degree of fluorination, and functional group of <em>per</em>- and polyfluoroalkyl substances (PFAS) influences the bioaccumulation and half-lives of these substances in humans and laboratory animals. Pharmacokinetic (PK) studies using laboratory animals characterize the absorption, distribution, metabolism, and excretion (ADME) of a PFAS and can provide the underlying data for inter-species extrapolation to inform human pharmacokinetics. However, variations in ADME arise due to differences in protein binding and renal and hepatobiliary clearance mechanisms. In particular, sex- and species-specific differences in active transporter abundance and PFAS binding affinity challenge body weight-based extrapolation assumptions from animal models to human PK parameters. Because these protein-dependent changes in ADME do not always scale with species body weight, classic allometric scaling assumptions can fail to account for species-specific transporter-mediated clearance. In addition, study-dependent differences in pharmacokinetic modeling approaches and parameterization techniques can result in large differences among the PK parameters reported in the literature. To better quantify PFAS pharmacokinetics and characterize the underlying uncertainty, we implemented a Bayesian inference hierarchical model to estimate PFAS PK parameters for multiple species (mice, rats, and non-human primates) using numerous single-dose animal studies. Through an alternative parameterization of the one- and two-compartment models, this method improved parameter identifiability and allowed for the use of prior information on PFAS absorption rate, clearance, and volume of distribution. Using reported time-course concentration data, we estimated sex-specific clearance, volume of distribution, and half-life across mice, rats, and non-human primates using a consistent modeling methodology for eight PFAS: PFHxA, PFHxS, PFNA, PFDA, PFBS, PFBA, PFOA, and PFOS. The resulting comparison to available human data demonstrated that standard volume of distribution body-mass scaling (BW¹) for PFAS generally agrees with reported human values while standard assumptions for allometric scaling of clearance (BW^3/4) are not appropriate for most of the PFAS investigated in this study. In addition, we demonstrated that there may be considerable differences in clearance for PFAS in some species when comparing across different sexes and routes of exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117336"},"PeriodicalIF":3.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826461","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":"Honokiol attenuates oxidative stress and vascular calcification via the upregulation of heme oxygenase-1 in chronic kidney disease","authors":"Xuemin Xian ,&nbsp;Xin Zhao ,&nbsp;Xingchen Zhou ,&nbsp;Hanfang Liu ,&nbsp;Changxi Li ,&nbsp;Xinquan Wu ,&nbsp;Yuhang Chen ,&nbsp;Keyue Ye ,&nbsp;Hongwei Yang ,&nbsp;Mingxi Li ,&nbsp;Jianyun Yan ,&nbsp;Xiuli Zhang","doi":"10.1016/j.taap.2025.117318","DOIUrl":"10.1016/j.taap.2025.117318","url":null,"abstract":"<div><div>Vascular calcification (VC) is a common complication of chronic kidney disease (CKD), with oxidative stress identified as a key contributor to VC progression. Honokiol (HKL), a biphenolic compound derived from plants, has been found to be effective in treating various models of cardiovascular disease through the mitigation of oxidative stress. However, its effects on VC remain unexplored. To elucidate the effects of HKL on VC, a CKD rat model, a vitamin D₃-overload-induced mouse model of vascular calcification, and a high-phosphate-induced human vascular smooth muscle cell (VSMC) calcification model were established. Calcification levels were assessed using alizarin red staining, calcium quantification, and western blotting of osteogenic markers. Oxidative stress was assessed by measuring reactive oxygen species. Furthermore, transcriptome sequencing was employed to identify molecules and pathways affected by HKL. HKL was found to significantly reduce calcification in both in vivo and in vitro models. It also mitigated oxidative stress induced by high phosphate in human VSMCs. Mechanistically, HKL upregulated heme oxygenase-1 (HMOX-1), thereby inhibiting oxidative stress and reducing calcification. Pharmacological inhibition of HMOX-1 counteracted the protective effect of HKL against vascular calcification. In summary, the findings suggest that HKL ameliorates VC by upregulating HMOX-1 and decreasing oxidative stress.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117318"},"PeriodicalIF":3.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804280","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":"CB-5083 and luteolin synergistically induce the apoptosis of bladder cancer cells via multiple mechanisms.","authors":"Shuben Sun, Ping Liu, Guohai Xie, Junhua Zheng","doi":"10.1016/j.taap.2025.117333","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117333","url":null,"abstract":"<p><strong>Purpose: </strong>Bladder cancer (BC) is a common urological malignancy for which effective treatments are lacking. In recent years, valosin-containing protein (VCP) has emerged as a potential target for the treatment of cancers. CB-5083 is a VCP inhibitor that has been evaluated in phase I clinical trials. However, drug resistance and severe side effects hamper the application of CB-5083. Mounting evidence suggests that combined treatment is a useful strategy to improve anticancer efficiency with lower toxicity. The aim of this study was to evaluate the combined effects of CB-5083 and luteolin (Lut), a natural flavonoid, on BC cells.</p><p><strong>Methods: </strong>Cellular viability was measured via MTT assays. The cell cycle distribution, degree of cell death and mitochondrial membrane potential were assayed via flow cytometry. mRNA levels were assayed via qRT-PCR. Protein levels were measured via western blotting. RNA interference was applied to knockdown genes. Xenograft experiments were conducted to evaluate the toxicity in vivo.</p><p><strong>Results: </strong>Cotreatment with CB-5083 and luteolin synergistically reduced the viability of BC cells. In addition, cotreatment with CB-5083 and Lut synergistically induced cell cycle arrest at the G1 phase and apoptosis in BC cells. Mechanistically, CB-5083/Lut cooperatively reduced the expression of Bcl-xl and Mcl-1 in BC cells. Moreover, CB-5083 and Lut synergistically induced endoplasmic reticulum (ER) stress in BC cells. The genetic or pharmacological inhibition of ER stress markedly reduced the degree of apoptosis induced by CB-5083, Lut or their combination in BC cells. In addition, combined treatment with CB-5083 and Lut synergistically repressed the growth of BC cells in vivo.</p><p><strong>Conclusion: </strong>Our data suggest that combined treatment with CB-5083 and Lut might be applied to treat BC.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117333"},"PeriodicalIF":3.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804251","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":"Ran drives pancreatic cancer metastasis by activating the osteopontin-PI3K/AKT-androgen receptor signaling cascade","authors":"Lin Deng ,&nbsp;Jingyi Ren ,&nbsp;Dong Liu,&nbsp;Hong Li,&nbsp;Guang Yang,&nbsp;Kairui Wang,&nbsp;Yang Song,&nbsp;Haichuan Su","doi":"10.1016/j.taap.2025.117328","DOIUrl":"10.1016/j.taap.2025.117328","url":null,"abstract":"<div><div>The small GTPase Ran has emerged as a key player in cancer metastasis. Our previous studies demonstrated that Ran drives pancreatic cancer metastasis by modulating androgen receptor (AR) expression. However, the detailed mechanisms by which Ran regulates AR expression remain unclear. This study aimed to elucidate the regulatory mechanisms through which Ran influences AR expression in the context of pancreatic cancer metastasis. We observed elevated levels of Ran, osteopontin (OPN), and AR in metastatic lymph node tissues, with OPN positively correlated with either Ran or AR expression. Ran silencing led to decreased levels of OPN and AR, whereas Ran upregulation increased their expression. Notably, OPN overexpression restored AR levels in Ran-silenced cells, whereas OPN knockdown diminished the inductive effect of Ran on AR expression. Additionally, OPN knockdown decreased AR expression and was associated with reduced activation of the PI3K/AKT signaling pathway. Functional assays revealed that silencing OPN significantly impaired the mobility and invasion of pancreatic cancer cells and restricted hepatic metastasis. Conversely, OPN overexpression restored the impaired metastasis caused by Ran knockdown. Furthermore, inhibiting PI3K/AKT signaling abolished the promoting effects of either Ran or OPN on pancreatic cancer metastasis. Importantly, re-expressing AR reversed the inhibitory effects of Ran or OPN silencing on the mobility and invasion of pancreatic cancer cells. In summary, Ran induces AR expression through the regulation of the OPN-PI3K/AKT signaling cascade. The Ran-OPN-PI3K/AKT-AR signaling pathway is crucial for driving pancreatic cancer metastasis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117328"},"PeriodicalIF":3.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of hydrogen-rich water on spermatogenesis in high-fat diet obese rats","authors":"Mohammad Hossein Rigi ,&nbsp;Seyyedeh Zahra Asghari ,&nbsp;Elaheh Eshtad ,&nbsp;Seyedeh Elnaz Nazari ,&nbsp;Akram Aminian ,&nbsp;Khatereh Kharazmi ,&nbsp;Fereshteh Asgharzadeh ,&nbsp;Amir Avan ,&nbsp;Seyed Mahdi Hassanian ,&nbsp;Tyler W. LeBaron ,&nbsp;Majid Khazaei","doi":"10.1016/j.taap.2025.117334","DOIUrl":"10.1016/j.taap.2025.117334","url":null,"abstract":"<div><div>Obesity can impair spermatogenesis by various mechanisms such as decreased sperm concentration and increased oxidative DNA damage. Hydrogen-rich water (HRW) possesses therapeutic antioxidant properties that may help offer protection to sperm. This study aimed to investigate the therapeutic potential of HRW on spermatogenesis dysfunction in rats with high-fat diet (HFD)-induced obesity. In this experiment, thirty male Wistar Albino rats were divided into three groups. 1) Control group: fed a normal diet, 2) Obese group: fed a HFD (45 % fat), and 3) HFD + HRW group: fed a high-fat diet and received HRW. HRW (1.5 mM) was administered orally every day. After 16 weeks, blood and tissue samples (testis and epididymis) were collected for biochemical and histopathological analysis. Serum LH, FSH and testosterone and oxidative and antioxidative markers, malondialdehyde (MDA), superoxide dismutase (SOD), and total thiol groups were measured in testis and epididymal tissues. The results showed that the HFD significantly increased food intake, body weight, and lee index, all of which were reduced in the HRW-treated obese group. Testis weight, sperm count, Serum LH and histological evaluation of testis including Sertoli and spermatogonia cell counts were significantly lower in the obese group but improved with HRW treatment. Additionally, HRW treatment increased the luminal diameter of seminiferous tubules, epididymal epithelia height, tissue SOD, and total thiol levels, while reducing MDA level in the testis. This study showed that administration of HRW can improve spermatogenesis in obese animals by reducing oxidative stress and ameliorating histological changes in the testis and epididymis, suggesting its potential benefits in combating high-fat diet-induced reproductive dysfunction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117334"},"PeriodicalIF":3.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785859","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":"Jaceosidin overcomes osimertinib resistance in lung cancer by inducing G2/M cycle arrest through targeting DDB1","authors":"Zhijie Chen ,&nbsp;Zhuoying Yang ,&nbsp;Yingying Liu,&nbsp;Zehao Zhou,&nbsp;Biying Men,&nbsp;Liang Yun,&nbsp;Jianjun Jiang,&nbsp;Haotian Ge,&nbsp;Meijuan Dian,&nbsp;Yujing He,&nbsp;Ruihao Zhang,&nbsp;Kaican Cai,&nbsp;Xuguang Rao,&nbsp;Shuan Rao","doi":"10.1016/j.taap.2025.117327","DOIUrl":"10.1016/j.taap.2025.117327","url":null,"abstract":"<div><h3>Background</h3><div>Osimertinib is a third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) widely used to treat advanced non-small cell lung cancer with EGFR mutations. However, resistance to osimertinib frequently develops, limiting its long-term effectiveness.</div></div><div><h3>Purpose</h3><div>This study aimed to establish a lung cancer TKI-resistant model and identify Traditional Chinese Medicine (TCM) components that could reverse TKI resistance, enhancing lung cancer sensitivity to targeted therapies, while exploring the underlying molecular mechanisms.</div></div><div><h3>Materials and methods</h3><div>Osimertinib-resistant cell lines and organoids were developed using a dose-escalation approach. A screen of 302 traditional Chinese medicine monomers revealed compounds that increased sensitivity to osimertinib. RNA sequencing and limited proteolysis coupled with small molecule mapping were employed to investigate the molecular mechanisms by which jaceosidin reverses resistance. The efficacy of the jaceosidin and osimertinib combination was confirmed in cell lines, organoids, and a mouse model.</div></div><div><h3>Results</h3><div>The osimertinib-resistant lung cancer model was successfully established, and 12 compounds were identified that enhanced the sensitivity of resistant cells to osimertinib. Among these, Jaceosidin, a flavonoid compound derived from <em>Eupatorium lindleyanum</em> DC., was confirmed to notably increase osimertinib sensitivity. Mechanistic studies, including limited proteolysis and RNA interference analysis, demonstrated that Jaceosidin directly interacts with Damage Specific DNA Binding Protein 1 (DDB1), promoting its protein expression and downregulating CDK1/Cyclin B1 levels. This interaction induced G2/M cell cycle arrest, thereby sensitizing lung cancer cells to osimertinib. Furthermore, both in vitro and in vivo experiments confirmed that the combination of Jaceosidin and osimertinib significantly inhibited tumor growth in osimertinib-resistant models.</div></div><div><h3>Conclusion</h3><div>These findings offer new insights into the role of DDB1 in overcoming osimertinib resistance and suggest that combining jaceosidin with osimertinib may serve as a promising therapeutic strategy to enhance the efficacy of EGFR-TKIs treatment in resistant Non-small Cell Lung Cancer (NSCLC).</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117327"},"PeriodicalIF":3.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788807","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}