Chemico-Biological Interactions最新文献

{"title":"Comparative DNA damage induced by eight nitrosamines in primary human and macaque hepatocytes","authors":"Ji-Eun Seo ,&nbsp;Xiaobo He ,&nbsp;Matthew Bryant ,&nbsp;Aisar H. Atrakchi ,&nbsp;Timothy J. McGovern ,&nbsp;Karen L. Davis Bruno ,&nbsp;Robert H. Heflich ,&nbsp;Xiaoqing Guo","doi":"10.1016/j.cbi.2025.111538","DOIUrl":"10.1016/j.cbi.2025.111538","url":null,"abstract":"<div><div><em>N</em>-nitrosamines have been increasingly detected in human drugs, raising serious safety concerns due to their potential mutagenicity and carcinogenicity. In order to expand upon the human data available on these drug impurities, we previously used metabolically competent HepaRG human hepatoma cells to evaluate the genotoxicity of eight small-molecule nitrosamines [<em>N</em>-cyclopentyl-4-nitrosopiperazine (CPNP), <em>N</em>-nitrosodibutylamine (NDBA), <em>N</em>-nitrosodiethylamine (NDEA), <em>N</em>-nitrosodimethylamine (NDMA), <em>N</em>-nitrosodiisopropylamine (NDIPA), <em>N</em>-nitrosoethylisopropylamine (NEIPA), <em>N</em>-nitroso-<em>N</em>-methyl-4-aminobutyric acid (NMBA), and <em>N</em>-nitrosomethylphenylamine (NMPA)]. In this study, we used the comet assay to further investigate the DNA damage induced by the eight nitrosamines in primary human hepatocytes (PHHs) from three individual donors and primary macaque hepatocytes (PMHs) from freshly isolated livers of six rhesus macaques. In addition, expression of genes encoding Phase I and II metabolic enzymes and the activities of the enzymes were compared in PHHs and PMHs, and Western blot was used to analyze protein biomarkers of DNA damage and apoptosis in PMHs. All eight nitrosamines induced significant DNA damage in both PHHs and PMHs; with the exception of NDMA, higher fold increases in % tail DNA were detected in PMHs compared to PHHs. Greater interindividual variability in CYP gene expression, enzyme activities, and DNA damage responses was observed in PHHs compared to PMHs. Benchmark concentration (BMC) modeling analysis showed that PHHs had more conservative BMC₅₀ values than PMHs for most nitrosamines tested. Nonetheless, correlation analysis demonstrated that DNA damage data generated by PMHs and 3D HepaRG spheroids were comparable to those of PHHs. Western blot analysis suggested a potential role for the ethyl group in regulating protein expression in the DNA damage and apoptosis pathways for nitrosamines. Overall, this study provides human-relevant DNA damage responses for the eight nitrosamines and indicates that differences in genotoxic potency between PHHs and PMHs are likely related to CYP enzyme activity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111538"},"PeriodicalIF":4.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of the effects of β-Arbutin on the NF-κB pathway in two-dimensional (2D) and three-dimensional (3D) colorectal cancer cell lines","authors":"Emine Terzi ,&nbsp;Tuba Ozdemir-Sanci ,&nbsp;Beyza Ecem Oz-Bedir ,&nbsp;Ferhat Geneci ,&nbsp;Shahla Jafarova ,&nbsp;Tuba Aydin","doi":"10.1016/j.cbi.2025.111533","DOIUrl":"10.1016/j.cbi.2025.111533","url":null,"abstract":"<div><div>Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide and is associated with significant mortality, primarily due to metastatic spread and resistance to therapy. In approximately half of CRC cases, the NF-κB signaling pathway is dysregulated, contributing to tumor progression, cell survival, and invasive behavior. β-Arbutin, a natural β-glucoside compound, has demonstrated potential anticancer activity. This study investigated the suppressive impact of β-Arbutin on NF-κB signaling in CRC, utilizing both conventional 2D and advanced 3D cell culture systems. HT-29 colorectal cancer cells were grown using both two-dimensional (2D) monolayer cultures and three-dimensional (3D) alginate bead models. Cell viability was assessed via WST-1 assay to establish the half-maximal inhibitory concentration (IC₅₀) values for β-Arbutin and the reference drug Sulfasalazine. Flow cytometry was employed to quantify apoptotic cell populations, Caspase 3/7 enzymatic activity, and related protein expression. Immunofluorescence staining further validated the protein levels detected by flow cytometry. All data were statistically analyzed using GraphPad Prism software, with a p-value threshold of &lt;0.05 considered significant. β-Arbutin exhibited a more pronounced reduction in cell viability in 3D culture systems compared to conventional 2D cultures. The compound induced significantly higher apoptosis rates in 3D models (56.46 %) versus 2D cultures (22.11 %; p &lt; 0.0001). Similarly, Caspase 3/7 activity was markedly elevated in β-Arbutin-treated 3D cells (53.56 %) relative to their 2D counterparts (34.04 %; p &lt; 0.0001). Furthermore, β-Arbutin treatment resulted in a more substantial decrease in target protein expression levels in 3D cultures compared to 2D systems. The 3D CRC models demonstrated significantly greater sensitivity to β-Arbutin than 2D cultures, with more robust NF-κB pathway suppression and apoptotic response. This differential efficacy underscores the superior biomimetic properties of 3D culture systems. Our results position β-Arbutin as a potent NF-κB-targeting agent and validate its potential for clinical translation in colorectal cancer therapy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111533"},"PeriodicalIF":4.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A genetic algorithm-based approach for quantitative prediction of drug-drug interactions caused by cytochrome P450 3A inhibitors and inducers in dogs and cats","authors":"Veronica Di Paolo ,&nbsp;Francesco Maria Ferrari ,&nbsp;Italo Poggesi ,&nbsp;Mauro Dacasto ,&nbsp;Francesca Capolongo ,&nbsp;Luigi Quintieri","doi":"10.1016/j.cbi.2025.111537","DOIUrl":"10.1016/j.cbi.2025.111537","url":null,"abstract":"<div><div>A genetic algorithm (GA)-based framework was developed to predict drug-drug interactions (DDIs) caused by cytochrome P450 3A (CYP3A) inhibition or induction in dogs and cats. Area under the plasma concentration-time curve (AUC) ratios, obtained from published <em>in vivo</em> DDI studies, were used to calculate the following parameters: (a) the contribution ratio (CR), which represents the fraction of the dose of the victim drug metabolized via CYP3A, and (b) the inhibitory potency (inhibition ratio; IR) or inducing potency (IC) of the perpetrator drug. AUC ratios of 3 substrates, 4 inhibitors and 1 inducer of CYP3A in cats, and the AUC ratios of 10 substrates, 12 inhibitors and 3 inducers of CYP3A in dogs were successfully predicted and validated by the developed methodology within 50–200 % of observed values. This approach could represent a useful resource to predict the extent of DDIs in clinical scenarios requiring the simultaneous administration of a CYP3A substrate drug with a CYP3A perpetrator.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111537"},"PeriodicalIF":4.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal co-exposure to Cd and PS-NPLs induces offspring ovarian inflammatory aging via promoting M1 macrophage polarization","authors":"Ruiying Zhang ,&nbsp;Penghui Nie ,&nbsp;Yuankun Zhou ,&nbsp;Juanjuan He ,&nbsp;Lihong Wang ,&nbsp;Hengyi Xu ,&nbsp;Fen Fu","doi":"10.1016/j.cbi.2025.111535","DOIUrl":"10.1016/j.cbi.2025.111535","url":null,"abstract":"<div><div>With the growing crisis of plastic pollution, the severe environmental problem threatens human and ecosystem health. And nanoplastics can carry other environmental contaminants, thereby causing severe toxic effects. Cadmium (Cd), as a metal, has been widely concerned because of its long biological half-life, high toxicity and low excretion rate. Additionally, Cd as an endocrine disrupting chemical also has reproductive toxicity and genotoxicity. Studies have found that co-exposed to Cd and PS-NPLs complexes may lead to more severe adverse effects in aquatic and mammals. And the utilization of other non-essential heavy metals such as cadmium are increased due to iron deficiency anemia in women during pregnancy. Therefore, in our study, 8 week-old female C57BL/6 J mice were co-exposed to Cd and NPLs during pregnancy and lactation, and the offspring are raised to four weeks to explore and predict the potential effect on the development of offspring reproductive system by transcriptomics. The results showed that sex hormone levels were interfered in offspring female mice, and gut microbiota disorder and increased LPS levels originated from the mother, which activating TLR4-related signaling pathways, and promoting ovarian M1 macrophage polarization, thereby increasing the risk of ovarian inflammatory aging in female offspring.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111535"},"PeriodicalIF":4.7,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial peptide WK-13-3D promotes apoptosis, autophagy, and ubiquitination in triple-negative breast cancer via binding immunoglobulin protein (BiP)","authors":"Wenjing Zhang ,&nbsp;Fei Ma ,&nbsp;Xuhong Su ,&nbsp;Mingxing Zhu ,&nbsp;Xiuqing Wang","doi":"10.1016/j.cbi.2025.111530","DOIUrl":"10.1016/j.cbi.2025.111530","url":null,"abstract":"<div><h3>Purpose</h3><div>To elucidate the inhibitory mechanism of antimicrobial peptide WK-13-3D on triple-negative breast cancer (TNBC) by targeting the binding immunoglobulin protein (BiP), a key endoplasmic reticulum (ER) chaperone regulating unfolded protein response and tumor survival.</div></div><div><h3>Methods</h3><div>TNBC cell lines (MDA-MB-231 and MDA-MB-468) were treated with WK-13-3D to assess proliferation, migration, invasion, and apoptosis. Pull-down assays identified interacting proteins, and Western blotting (WB) analyzed alterations in BiP, PERK, eIF2α, <em>p</em>-eIF2α, Caspase3, Cleaved-Caspase3, Bax, LC3, P62, AKT, <em>p</em>-AKT, mTOR, and <em>p</em>-mTOR. Transmission electron microscopy examined intracellular structures, while qPCR measured BiP mRNA levels. The effects of WK-13-3D on BiP ubiquitination were explored via co-immunoprecipitation (Co-IP). Animal tumor models were used to confirm the inhibitory effects, with BiP and Ki67 (a nuclear proliferation marker indicating actively dividing tumor cells) expression analyzed by immunohistochemistry (IHC).</div></div><div><h3>Results</h3><div>WK-13-3D inhibited TNBC cell proliferation, migration, and invasion, while promoting apoptosis. Pull-down experiments identified 268 interacting proteins, with BiP being the most frequent. Databases (TIMER and TCGA) showed high BiP expression in breast cancer, associated with poor prognosis. WB assays revealed that WK-13-3D activated ER stress-induced apoptosis and autophagy via BiP. Co-IP demonstrated that WK-13-3D mediated BiP ubiquitination at sites 352 and 547 through K6 and K29 chains. IHC analysis further confirmed decreased Ki67 levels in WK-13-3D-treated tumors, reflecting suppressed proliferative activity. Animal experiments confirmed tumor growth inhibition.</div></div><div><h3>Conclusion</h3><div>WK-13-3D promotes apoptosis, autophagy and Ubiquitination in TNBC by modulating BiP.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111530"},"PeriodicalIF":4.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimethyl sulfate induces zebrafish embryo cardiotoxicity and behavioral disturbances by upregulating oxidative stress levels","authors":"Jiejun Liu ,&nbsp;Jing Wang ,&nbsp;Qiang Yuan ,&nbsp;Zhipeng Wang ,&nbsp;Fasheng Liu ,&nbsp;Xinjun Liao ,&nbsp;Huiming Li ,&nbsp;Shouhua Zhang ,&nbsp;Juhua Xiao ,&nbsp;Zigang Cao","doi":"10.1016/j.cbi.2025.111532","DOIUrl":"10.1016/j.cbi.2025.111532","url":null,"abstract":"<div><div>Dimethyl sulfate (DMS) is a versatile chemical compound used in various industries, including pharmaceuticals, pesticides, dyes, and fragrances. Due to the widely application of Dimethyl sulfate (DMS), it is necessary to study its potential toxicity. According to ecological data analysis, DMS has been identified as a potential environmental hazard, particularly in water bodies. However, its toxicity to aquatic organisms remains largely unexplored. In this study, using zebrafish embryos as a model system, we evaluated the toxicity of DMS for the first time and uncovered significant adverse effects on early embryonic development, characterized by extensive cardiac damage and neurotoxicity. DMS inhibited the activity of antioxidant enzymes, resulting in excessive production of reactive oxygen species (ROS) and subsequent apoptosis of myocardial cells, along with pericardial edema, bradycardia, and elongated SV-BA distance. Additionally, DMS directly induced oxidative stress and altered the activity of acetylcholinesterase (ACHE) and adenosine triphosphatase (ATPase), thereby disrupting the expression of genes involved in neural development and neurotransmission. These findings may contribute to the DMS-induced behavioral abnormalities, such as reduced and unbalanced locomotion in larvae and altered swimming behavior. Importantly, astaxanthin, an antioxidant carotenoid, was able to rescue the embryonic cardiac and neurotoxic effects triggered by DMS exposure, suggesting that DMS primarily induces zebrafish cardiac and neural developmental toxicity through upregulation of oxidative stress. Overall, our study demonstrates the potential of DMS to induce cardiac and neurotoxicity in zebrafish embryos, suggesting toxicity risks to other aquatic organisms and even humans. These findings provide a basis for a comprehensive assessment of DMS toxicity and serve as an early warning for its environmental presence and product residues.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111532"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gaudichaudion H inhibits KRAS-mutant pancreatic cancer cell growth through interfering PDEδ-KRAS interaction","authors":"Lingyu Li ,&nbsp;Qingying Liu ,&nbsp;Yuyu Shao ,&nbsp;Shuo Wang ,&nbsp;Shuangyu Liu ,&nbsp;Xiaoning Wang ,&nbsp;Shuqi Wang ,&nbsp;Dongmei Ren","doi":"10.1016/j.cbi.2025.111529","DOIUrl":"10.1016/j.cbi.2025.111529","url":null,"abstract":"<div><div><em>KRAS</em> mutation results in higher proliferation rates and miserable prognosis of cancers. Targeting the interaction between KRAS and PDE6D provided an alternative strategy to overcome <em>KRAS</em>-mutant pancreatic cancers. Gaudichaudione H (GH) is a prenylated caged xanthone isolated from <em>Garcinia oligantha.</em> In this work, GH was selected as a potential anti-cancer compound by MTT screening of twelve prenylated xanthonoids from <em>G. oligantha.</em> Further studies demonstrated that GH inhibited proliferation of a panel of cancer cell lines and induced pancreatic cancer cell apoptosis. GH suppressed xenograft tumor growth accompanied with decreased phosphorylation of ERK and AKT. Binding with PDEδ and thus interfering the KRAS-PDEδ interaction was verified as the possible mechanism of GH. These findings implicated GH as a promising candidate for the treatment of pancreatic cancers with <em>KRAS</em> mutation, provided novel insight into the underlying mechanisms of GH-induced anticancer effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111529"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting breast cancer cells with 2-indolyl-1,3,4-oxadiazole compounds by inducing apoptosis, paraptosis and autophagy","authors":"Pradeep M. Uppar ,&nbsp;Na Young Kim ,&nbsp;Keshav Kumar Harish ,&nbsp;Narasimha M. Beeraka ,&nbsp;Santhosh L. Gaonkar ,&nbsp;Mahendra Madegowda ,&nbsp;Gautam Sethi ,&nbsp;Kanchugarakoppal S. Rangappa ,&nbsp;Vladimir N. Nikolenko ,&nbsp;Arunachalam Chinnathambi ,&nbsp;Sulaiman Ali Alharbi ,&nbsp;Kwang Seok Ahn ,&nbsp;Basappa Basappa","doi":"10.1016/j.cbi.2025.111528","DOIUrl":"10.1016/j.cbi.2025.111528","url":null,"abstract":"<div><div>While 2-Indolyl-1,3,4-oxadiazole derivatives are recognized for their antibacterial properties, their potential as anticancer agents remains underexplored. This study investigates the anti-breast cancer properties of a novel 2-Indolyl-1,3,4-oxadiazole compound, 5l, focusing on its ability to induce apoptosis, paraptosis, and autophagy, and targeting poly (ADP-ribose) polymerase (PARP1), a critical enzyme in DNA repair. A series of 1,3,4-oxadiazole derivatives (compounds 5a-5m) were synthesized using an optimized multi-step process, enhancing reaction efficiency and yield. In silico molecular docking was used to determine binding efficacy of these derivatives. Lead compound, 5l, underwent cytotoxicity assays against MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cell lines, as well as the non-cancerous MCF-10A cell line. Molecular docking assessed the interaction of 5l with the PARP1 active site. Frontier molecular orbital (FMO) and molecular electrostatic potential (MESP) analyses were conducted to map electron distribution and identify reactive regions within compound 5l. The effects of 5l on cellular processes such as apoptosis, autophagy, and endoplasmic reticulum (ER) integrity were evaluated using live and dead assays, Annexin V staining, ER-tracker dye staining, and acridine orange assays. Western blotting analyzed apoptosis, paraptosis, and autophagy-related genomic instability. The optimized synthesis yielded high-purity 1,3,4-oxadiazole derivatives. Compound 5l displayed significant anticancer activity, with IC50 values of 63.7 μM, 29.1 μM, 50.3 μM, and 39.8 μM for MDA-MB-231, MCF-7, BT-474, and SK-BR-3 cell lines respectively, demonstrating its cytotoxic efficacy. Molecular docking revealed that 5l binds to PARP1 active site with a binding energy of −11.7 kcal/mol, indicating a strong interaction supporting its role as a PARP1 inhibitor. Annexin V assays, ER-tracker dye staining, and Acridine orange assays were used to assess apoptosis, ER integrity, and autophagy. 5l induced upregulation of cleaved PARP and downregulation of Alix-loaded proteins, alongside increased LC3-II expression, indicating autophagy-mediated genomic instability. Compound 5l exhibits potent anti-breast cancer activity through paraptosis, apoptosis, and autophagy-mediated genomic instability and by PARP1 inhibition with typically a low IC50 values, highlighting its potential as a therapeutic agent.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111528"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome profiling and DNA methylation analysis of human hepatocyte cell line HHL-16 in response to aflatoxin B1","authors":"Hang Wu ,&nbsp;Yun Yun Gong ,&nbsp;John Huntriss ,&nbsp;Michael N. Routledge","doi":"10.1016/j.cbi.2025.111531","DOIUrl":"10.1016/j.cbi.2025.111531","url":null,"abstract":"<div><div>Dietary exposure to aflatoxin B1 (AFB1) can cause acute aflatoxicosis and liver cancer, and is associated with immune suppression and growth impairment, but the molecular mechanisms of the health effects are not fully understood. A non-neoplastic human hepatocyte cell line 16 (HHL-16) was utilized to understand the effects of AFB1 on transcriptome and DNA methylation changes, identifying molecular pathways underlying toxicity and health effects. RNA sequencing and bioinformatic analysis (RNA-Seq) was applied to find the genes and pathways affected by AFB1. Bisulfite pyrosequencing was used to assess DNA methylation levels of CpG sites around promoter regions of gene of interest. RNA-sequencing revealed 280 significantly up-regulated and 296 significantly down-regulated genes in HHL-16 cells after 20 μg/ml AFB1 treatment for 24 h. KEGG pathway enrichment analysis indicated that differentially expressed genes (DEGs) were significantly enriched in the following pathways: cytokine-cytokine receptor interaction, NF-kappa B signalling pathway, TNF signalling pathway, IL-17 signalling pathway, amoebiasis, MAPK signalling pathway, and lipid and atherosclerosis. Further DNA methylation analysis found that there was significant hypomethylation at one CpG site of <em>CCL20</em> after 20 μg/ml AFB1 treatment on HHL-16 cells for 24 h. In conclusion, AFB1 modulates the expression of genes related to the pathways that play important roles in inflammatory response, growth, and cancers, and demonstrates the effects of AFB1 on DNA methylation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111531"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor platinum(II) complex 56MESS binds to DNA G-quadruplexes, downregulates expression of c-MYC and k-RAS oncogenes, and triggers DNA damage in cancer cells","authors":"Jaroslav Malina ,&nbsp;Hana Kostrhunova ,&nbsp;Janice R. Aldrich-Wright ,&nbsp;Viktor Brabec","doi":"10.1016/j.cbi.2025.111534","DOIUrl":"10.1016/j.cbi.2025.111534","url":null,"abstract":"<div><div>Previous research indicated that the cytotoxic activity of the antitumor platinum(II) complex [Pt(1<em>S</em>,2<em>S</em>-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]²⁺ (56ME<em>SS</em>) was not primarily attributed to DNA binding, despite the complex being confirmed to localize also in the nucleus. In this study, we have demonstrated that the antiproliferative activity of 56ME<em>SS</em> indeed involves DNA binding. Furthermore, in addition to binding duplex DNA, the complex also interacts with non-canonical secondary DNA structures, such as G-quadruplexes (G4s) and i-Motifs (iMs). This interaction leads to the suppression of G-regulated oncogene expression and disrupts key enzymatic processes associated with DNA, potentially contributing to DNA damage and the biological activity of 56ME<em>SS</em>. These findings build upon previously published results, revealing that the anticancer activity of 56ME<em>SS</em> is significantly more multifaceted than previously understood, involving multiple distinct mechanisms.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111534"},"PeriodicalIF":4.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}