Chemico-Biological Interactions最新文献

{"title":"Demethoxycurcumin induces metabolic crisis and ATF4/ATF3/CHOP-dependent cell death in hepatocellular carcinoma","authors":"Fugen Shangguan ,&nbsp;Hongfei Zhou ,&nbsp;Huachang Zhang ,&nbsp;Thaiyuri Reddy ,&nbsp;Mhaka Panashe Bryan ,&nbsp;Ri Cui ,&nbsp;Jianhu Lin ,&nbsp;Yongping Chen ,&nbsp;Yihu Zheng","doi":"10.1016/j.cbi.2025.111584","DOIUrl":"10.1016/j.cbi.2025.111584","url":null,"abstract":"<div><div>Demethoxycurcumin (DMC) has demonstrated remarkable anti-cancer properties across various tumor types. However, its efficacy in hepatocellular carcinoma (HCC) has not yet been established. Interestingly, the type of cell death induced by DMC was distinct from traditional pathways such as apoptosis, ferroptosis, necroptosis, pyroptosis, cuproptosis, and autophagy, indicating a need for further detailed exploration of its mechanisms. Our investigations revealed that DMC treatment led to a marked increase in oxidative stress, as evidenced by the accumulation of reactive oxygen species (ROS). This increase in ROS disrupted the iron-sulfur (Fe–S) cluster, impairing mitochondrial respiration. Additionally, ROS activation markedly reduced the rate of aerobic glycolysis by interfering with key glycolytic enzymes. The resultant inhibition of these bioenergetic pathways led to a significant depletion of ATP. Moreover, DMC activated the ATF4/ATF3/CHOP signaling axis, and the reduction of CHOP levels mitigated the cytotoxic effects of DMC in HCC cells. In conclusion, DMC initiated oxidative stress, which disrupted bioenergetic metabolism and activated the ATF4/ATF3/CHOP signaling pathway, ultimately leading to cell death in HCC cells. These findings suggest that DMC might have a potential role in the treatment of HCC. However, further validation through in vivo models and clinical trials is required to confirm the therapeutic potential of DMC against HCC. Moreover, more work is still needed to further explore the specific form of cell death induced by DMC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111584"},"PeriodicalIF":4.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192608","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":"Effects of zearalenone on endoplasmic reticulum stress-induced apoptosis via global and gene-specific histone modifications and miRNA-mediated p53-signaling pathway in HEK-293 cells","authors":"Ecem Fatma Karaman ,&nbsp;Mahmoud Abudayyak ,&nbsp;Zeynep Rana Guler ,&nbsp;Sibel Ozden","doi":"10.1016/j.cbi.2025.111585","DOIUrl":"10.1016/j.cbi.2025.111585","url":null,"abstract":"<div><div>Zearalenone (ZEA), a non-steroidal estrogenic mycotoxin produced by <em>Fusarium</em> species, is well-known for its potent estrogen-like effects, which can lead to reproductive toxicity and toxicity in various organs. Although several studies have reported its nephrotoxic effects, the molecular mechanisms underlying ZEA-induced toxicity remain poorly understood. The present study investigates the effects of ZEA on the expression levels of apoptosis and endoplasmic reticulum (ER) stress-related genes, as well as selected chromatin-modifying enzyme coding genes, miRNA profiles associated with cancer pathways, and global histone modifications (H3K4me3, H3K9me3, H3K27me3, and H3K9ac) in human embryonic kidney epithelial (HEK-293) cells exposed to 1–50 μM ZEA for 24 h. The results indicated that 10 and 50 μM ZEA induced apoptosis through upregulating <em>Bcl-2, CASP3, CASP9</em>, and <em>p53</em>. Alterations in the expression levels of ER stress-related genes, such as <em>GRP78, PERK, ATF4, IRE2, CHOP</em>, and <em>eIF2α</em>, could contribute to ZEA-induced toxicity. No significant changes were observed in the expression levels of chromatin-modifying enzyme coding genes, including <em>EZH2, G9a, HAT1, RIZ1, SETD1A,</em> and <em>SIRT1</em>, DNA methylation-related genes such as <em>DNMT1, DNMT3A</em>, and <em>DNMT3B</em>. However, <em>SETD8</em> and <em>Suv39h1</em> exhibited significant changes at 50 μM of ZEA. Moreover, global histone modification levels significantly decreased at 50 μM ZEA exposure for 24 h. Chromatin immunoprecipitation (ChIP) results revealed significant changes in H3K27me3, H3K9me3, and H3K9ac modifications on the <em>ATF4</em>, <em>CHOP</em>, <em>Bcl-2</em>, and <em>p53</em> genes following ZEA exposure. miRNA array analysis showed notable and significant reductions in the expression levels of several miRNAs. The results obtained from this comprehensive study are expected to make a significant contribution to the elucidation of ZEA toxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111585"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178031","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":"Liquiritigenin regulates MAPK (p38/JNK) signaling through inhibition of IRAK4, attenuates inflammatory response, fibrosis and kidney dysfunction in a high-salt diet induced chronic kidney disease","authors":"Weiping Yan ,&nbsp;Lei Wang ,&nbsp;Yan Cao ,&nbsp;Yaru Chen ,&nbsp;Yue Lin ,&nbsp;Yingjia Qian ,&nbsp;Yan Wang ,&nbsp;Zibo Dong","doi":"10.1016/j.cbi.2025.111578","DOIUrl":"10.1016/j.cbi.2025.111578","url":null,"abstract":"<div><div>High salt diet (HSD) has adverse effects on the kidneys and causes chronic kidney disease (CKD), leading to kidney dysfunction, usually accompanied by an inflammatory response and fibrosis. In the present study, an <em>in vivo</em> model of renal injury on a high-salt diet was established and its protective effects were assessed by gavage of liquiritigenin (20, 40 and 60 mg/kg) in CKD male BALB/c mice. An <em>in vitro</em> model of NaCl (80 mM) stimulated HK-2 cells and the underlying the mechanism was investigated thoroughly overexpressing Interleukin-1 Receptor-Associated Kinase 4 <strong>(</strong>IRAK4) to validate the target of liquiritigenin under therapeutic conditions. The results showed that liquiritigenin significantly alleviated the slow weight gain in the high-salt group, as well as reduced the serum levels of blood urea nitrogen (BUN), blood creatinine (CRE), neutrophil gelatinase-associated lipid transport protein (NGAL) and kidney injury molecule-1 (KIM-1) as well as ameliorated the histopathological lesions in the chronic kidney injury as well as suppressed the hyper-inflammatory response and restored the protein levels associated with renal fibrosis. <em>In vitro</em> experimental results showed that liquiritigenin significantly inhibited the expression of KIM-1 and NGAL in HK-2 renal tubular cells, as well as the expression of inflammatory factors and fibrosis-related proteins. Mechanistically, this study is the first to demonstrate that liquiritigenin directly binds to and inhibits IRAK4, a key upstream regulator of inflammatory signaling. By suppressing IRAK4 activation, liquiritigenin effectively attenuates downstream activation of the p38 MAPK and JNK pathways. This novel mechanism highlights the potential of liquiritigenin in mitigating high salt-induced renal inflammation and fibrosis, offering new therapeutic insights for the treatment of CKD.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111578"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188706","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":"Synergistic anti-hypernociceptive interaction between morphine and JM-20 in neuropathic rats. Mechanistic insights into metabolism, transport, and safety","authors":"Bárbara B. Garrido-Suárez ,&nbsp;Gabino Garrido ,&nbsp;Addis Bellma-Menéndez ,&nbsp;Idania Rodeiro-Guerra ,&nbsp;Laia Tolosa ,&nbsp;María Teresa Donato ,&nbsp;María José Gómez-Lechón ,&nbsp;Miguel David Fernández Pérez ,&nbsp;Estael Ochoa-Rodríguez ,&nbsp;Yamila Verdecia-Reyes ,&nbsp;René Delgado-Hernández ,&nbsp;Alejandro Ardiles-Rivera ,&nbsp;Francisco de la Fuente-Vásquez","doi":"10.1016/j.cbi.2025.111575","DOIUrl":"10.1016/j.cbi.2025.111575","url":null,"abstract":"<div><div>This study evaluated the anti-hypernociceptive interaction between morphine and the neuroprotective compound 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) in neuropathic rats. Single and repeated co-administration of both drugs was assessed using the chronic constriction injury (CCI) model, via subcutaneous and oral routes. Isobolographic analysis was performed to determine the nature of the pharmacological interaction. In addition, <em>in silico</em> pharmacokinetic and toxicological profiling was conducted, and JM-20's effects on human UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzyme systems were evaluated <em>in vitro</em>.</div><div>Morphine, JM-20, and their 1:1 fixed-ratio combinations significantly attenuated mechanical hypersensitivity in a dose-dependent manner. The observed ED₅₀ for the combination (2.15 ± 0.07 mg/kg) was significantly lower than the theoretical additive ED₅₀ (8.05 ± 0.58 mg/kg), indicating a synergistic interaction. Repeated morphine administration led to tolerance, while the morphine:JM-20 combination maintained efficacy for 14 days and prevented morphine-induced facilitation of neuropathic hypersensitivity.</div><div>JM-20 did not alter UGT activity, suggesting no interference with morphine glucuronidation or active metabolite formation. However, JM-20 strongly inhibited CYP3A4 and other major CYP isoforms (1A, 2C9, 2D6, 2A6), potentially relevant for interactions with co-administered drugs, though not with morphine. JM-20 may also inhibit P-glycoprotein, possibly enhancing morphine's central bioavailability. <em>In silico</em> and <em>in vitro</em> analyses indicated a potential risk of cardiotoxicity and hepatotoxicity.</div><div>Overall, JM-20 enhances morphine analgesia in neuropathic pain, but further <em>in vivo</em> studies are required to evaluate the long-term safety of this combination.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111575"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188708","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":"Platycodin D reverses tumor necrosis factor-α-induced endothelial dysfunction by increasing nitric oxide through G protein-coupled estrogen receptor-mediated eNOS activity","authors":"Ju Yeon Chae ,&nbsp;Gi Ho Lee ,&nbsp;Seung Yeon Lee ,&nbsp;Gil-Saeng Jeong ,&nbsp;Hwi-yeol Yun ,&nbsp;Eun Hee Han ,&nbsp;Anh Thi Ngoc Bui ,&nbsp;Hye Gwang Jeong","doi":"10.1016/j.cbi.2025.111577","DOIUrl":"10.1016/j.cbi.2025.111577","url":null,"abstract":"<div><div>Platycodin D (PCD) is a saponin extracted from the roots of <em>Platycodon grandiflorum</em> (Jacq.) A. DC., a medicinal plant used in Eastern traditional medicine for many years. PCD is known to exert anti-cancer, antioxidant, and anti-obesity effects, and its preventive effects on cardiovascular disease, including anti-arteriosclerosis properties are being explored. This study examined the protective effects of PCD against endothelial dysfunction in EA.hy926 endothelial cells, particularly in the context of nitric oxide (NO) production mediated by endothelial nitric oxide synthase (eNOS) activity, and explored the underlying molecular mechanisms. The effects of PCD on tumor necrosis factor-α (TNF-α)-triggered endothelial dysfunction were examined using MTT and lactate dehydrogenase, quantitative PCR, western blotting, monocyte adhesion, immunofluorescence, intracellular Ca²⁺, and NO generation assays. PCD alleviated TNF-α-induced monocyte-endothelial cell adhesion via downregulation of VCAM-1 and ICAM-1. PCD also increased NO production and eNOS activity by promoting the phosphorylation of Ca²⁺/calmodulin-dependent protein kinase β (CaMKKβ), Ca²⁺/calmodulin-dependent protein kinase Ⅱα (CaMKⅡα), and AMP-activated protein kinase (AMPK). Importantly, blocking G protein-coupled estrogen receptor (GPER) suppressed NO production and PCD-triggered eNOS activity by reducing the phosphorylation of three kinases, CaMKKβ, AMPK, and CaMKⅡα. Overall, PCD alleviates TNF-α-induced endothelial dysfunction by enhancing NO production, facilitated by eNOS activity. This upregulation is mediated by GPER-dependent Ca²⁺/CaMKKβ/AMPK and Ca²⁺/CaMKⅡα signaling pathways. These findings indicate the potential of PCD as a therapeutic agent for preventing endothelial dysfunction and improving cardiovascular health.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111577"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188707","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":"D-limonene complexed with hydroxypropyl-β-cyclodextrin prevents impaired cardiac excitation-contraction coupling by reducing oxidative stress and cardiac apoptosis in an animal model of cardiotoxicity induced by doxorubicin","authors":"Aimée Obolari Durço ,&nbsp;Diego Santos Souza ,&nbsp;Michael Ramon de Lima Conceição ,&nbsp;Samuel dos Santos Beserra ,&nbsp;Jorge Lucas Teixeira da Fonseca ,&nbsp;Leonardo Loch ,&nbsp;Michel Augusto Silva ,&nbsp;Aldeidia Pereira de Oliveira ,&nbsp;Adriano Antunes de Souza Araujo ,&nbsp;Carla Maria Lins de Vasconcelos ,&nbsp;Jader Santos Cruz ,&nbsp;Danilo Roman-Campos ,&nbsp;Márcio Roberto Viana dos Santos","doi":"10.1016/j.cbi.2025.111580","DOIUrl":"10.1016/j.cbi.2025.111580","url":null,"abstract":"<div><div>Doxorubicin (Dox) is one of the most used drugs in the treatment of various cancers, but its cardiotoxicity limits its use. The aim of this study was to investigate the cardioprotective effect of the formulation <span>d</span>-limonene-hydroxypropyl-β-cyclodextrin (HβDL) on a murine model of Dox-induced cardiotoxicity. Mice were divided into groups: Control (NaCl 0.9 %), Dox (20 mg/kg), and Dox + HβDL (10 mg/kg). Drugs were administered intraperitoneally once every five days. Heart histological parameters, L-type Ca²⁺ current (I_Ca,L), intracellular and mitochondrial reactive species and mitochondrial mass, calcium transient, sarcomeric shortening, redox status (lipoperoxidation, oxidant, and antioxidant enzymes activity), apoptotic and antiapoptotic proteins expression as well NOX-related proteins were evaluated. HβDL prevented heart histological changes, including cellular infiltrate and vacuoles caused by Dox, and also prevented the increases in calcium waves, I_Ca,L, cytoplasmic and mitochondrial reactive species and mitochondrial mass, expression of Bax, Caspase-3, gp91^phox, NOX4 and p22phox, and lipoperaxidation induced by Dox. Moreover, sarcomeric shortening was reduced in the Dox group, but preserved in HβDL treated animals. Glutathione peroxidase activity, which was reduced in Dox group, was also restored in the HβDL group. Our results show the potential cardioprotective effect of HβDL in Dox-induced cardiotoxicity through improved redox status and excitation-contraction coupling and the suppression of apoptotic pathways in cardiomyocytes.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111580"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183514","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":"Sulforaphane treatment of HL-60 cells protects against clozapine toxicity and protein covalent binding: implications for clozapine-induced agranulocytosis","authors":"Md Harunur Rashid ,&nbsp;Newton H. Tran ,&nbsp;Dinesh Babu ,&nbsp;Steven Lockhart ,&nbsp;Othman Eldalal ,&nbsp;Phuong Tran ,&nbsp;Béla Reiz ,&nbsp;Arno G. Siraki","doi":"10.1016/j.cbi.2025.111581","DOIUrl":"10.1016/j.cbi.2025.111581","url":null,"abstract":"<div><div>Clozapine is a critical drug for treatment-resistant schizophrenia patients. However, clozapine is currently considered under-prescribed as it carries a risk of idiosyncratic adverse drug reactions, including severe neutropenia (agranulocytosis). Some stuides reported that clozapine-treated patients that exhibited agranulocytosis had a lower frequency of wild-type NRH: Quinone Oxidoreductase 2 (NQO2) and a higher frequency of mutant NQO2 (NQO2-1541-AA). Sulforaphane is a well-known inducer for the expression of a related enzyme isoform, NQO1, that has protective effects; however, sulforaphane's role in modulating NQO2 expression is unknown, and sulforaphane-mediated protection via NQO1 and NQO2 activation against clozapine toxicity remains uninvestigated. We hypothesized that sulforaphane can induce NQO1 and NQO2 expression, and sulforaphane-mediated NQO1 &amp; NQO2 activation play a protective role against clozapine-induced toxicity.</div><div>Sulforaphane and clozapine HL-60 cell viability were determined to select appropriate treatment concentrations. Immunoblotting was used to investigate NQO1 and NQO2 protein expression and protection against clozapine-protein binding. Glutathione (GSH) was analyzed by microtiter plates, LCMS was used to quantify clozapine metabolites, and UV–Vis spectrophotometry was used to determine myeloperoxidase activity.</div><div>Sulforaphane (1–10 μM) significantly induced NQO1 and NQO2 protein expression. Clozapine's LC50_24h for viability was approximately 50 μM, and sulforaphane did not decrease viability up to 5 μM. Sulforaphane (2.5–5 μM) prevented the clozapine-induced decrease in viability. The formation of clozapine-N-oxide, a less reactive metabolite, was increased in sulforaphane pre-treated groups than in untreated groups. Also, intracellular myeloperoxidase activity increased significantly in the presence of sulforaphane (2.5–10 μM). GSH levels were significantly higher in sulforaphane pre-treated groups, and clozapine covalent protein binding was significantly attenuated by the pre-treatment of sulforaphane.</div><div>Collectively, the results suggest that sulforaphane pre-treatment of HL-60 cells provides significant defenses against the reactive metabolites of clozapine. The induction of NQO2 is novel and requires further studies to demonstrate specifically how it is involved. Sulforaphane-induced increases in GSH in combination with enhanced clozapine-N-oxide formation appear to contribute to decreasing covalent protein binding, which is correlated with clozapine-induced decreases in cell viability and increased myeloperoxidase activity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111581"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176168","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":"Tamoxifen regulates ferroptosis of hepatocytes by targeting SLC1A5 to activate hepatic stellate cells and liver fibrosis","authors":"Sha Shi ,&nbsp;Meiling Zhang ,&nbsp;Chengkai Zhu ,&nbsp;Shanhao Zhu ,&nbsp;Jie Yu ,&nbsp;Qi Sui ,&nbsp;Jiaqi Xu ,&nbsp;Juan Ren ,&nbsp;Jingnan Zhang ,&nbsp;Peng Chen ,&nbsp;Yi Zhang","doi":"10.1016/j.cbi.2025.111586","DOIUrl":"10.1016/j.cbi.2025.111586","url":null,"abstract":"<div><div>Tamoxifen (TAM) is a commonly used drug for breast cancer treatment, mainly inhibiting estrogen receptors to prevent tumor growth. Although TAM has achieved remarkable effects in clinical treatment, recent studies have shown that TAM can cause drug-induced liver injury. However, it's still unclear whether long-term use of TAM can cause liver fibrosis. This study explores whether long-term administration of TAM can cause liver fibrosis and its mechanism. We found that TAM could induce liver injury in mice and significantly up-regulate the expression of activation markers of stellate cells, activating the TGF-β/smad signaling pathway. Additionally, TAM induced an inflammatory response and activated the NF-κB signaling pathway. More importantly, we demonstrated for the first time <em>in vivo</em> and <em>in vitro</em> that TAM-induced hepatocyte ferroptosis, accompanied by glutathione (GSH) depletion, reactive oxygen species (ROS) accumulation, and intracellular ferrous enrichment, and changes in the expression of ferroptosis-related proteins. Ferroptosis inhibitors such as ferrostatin-1 (Fer-1) and DFO ameliorated ferroptosis in hepatocytes. However, these ferroptotic events did not occur in macrophages and hepatic stellate cells (HSCs). Co-culture experiments showed that TAM-induced hepatocytes could increase expression of liver fibrosis-related proteins in HSCs, but this could be abolished by ferroptosis inhibitors. Bioinformatics analysis suggested TAM may regulate hepatocyte ferroptosis through solute carrier family 1 member 5 (SLC1A5). Downregulation of SLC1A5 could inhibit TAM-induced hepatocyte ferroptosis, thereby alleviating HSCs activation and the increased expression of ECM proteins. Our study suggests that TAM induces hepatocyte ferroptosis through SLC1A5, leading to HSC activation and liver fibrosis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111586"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176170","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":"Ilimaquinone induces apoptosis in gastric cancer cells by inhibiting the signal transducer and activator of the transcription 3 pathway","authors":"Jui-Hsin Su ,&nbsp;Li-Yuan Bai ,&nbsp;Chia-Yung Wu ,&nbsp;Chia-Hsien Feng ,&nbsp;Jing-Ru Weng","doi":"10.1016/j.cbi.2025.111582","DOIUrl":"10.1016/j.cbi.2025.111582","url":null,"abstract":"<div><div>Natural marine products possess pharmacological effects and have been a source of novel drugs for centuries. In this study, we explored the anti-tumor activity and underlying mechanism of action of ilimaquinone, a sesquiterpene quinone from marine sponges, in gastric cancer. Three gastric cancer cell lines (KATO III, SCM-1, and AZ521) were cultured. Cell viability, cell cycle, and apoptosis were determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and flow cytometry. The levels of apoptotic proteins, proteins related to autophagy, and signal transducer and activator of transcription 3 (STAT3) were detected using western blotting. Transient transfection experiments were conducted to assess the expression of STAT3 in the gastric cancer cells. Ilimaquinone inhibited cell growth, caused cell cycle arrest in the S phase, and induced apoptosis. In addition, ilimaquinone modulates autophagy, and the viability of gastric cancer cells decreases upon exposure to a combination of the autophagic inhibitor, chloroquine. Notably, ilimaquinone downregulated the expression of p-STAT3 in a concentration- and time-dependent manner in both gastric cancer cell lines. Moreover, the compound-mediated inhibition of gastric cancer cell proliferation was restored by ectopic STAT3 expression. Collectively, these findings demonstrate the value of ilimaquinone in the treatment of gastric cancer.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111582"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169476","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":"Exposure of human neuroblastoma SH-SY5Y cells to amphetamine-type stimulants leads to oxidative-antioxidative imbalance associated with DNA damage and acetylcholine antagonism","authors":"Antonio Zandona ,&nbsp;Andreja Jurič ,&nbsp;Blanka Tariba Lovaković ,&nbsp;Alica Pizent ,&nbsp;Dubravka Rašić ,&nbsp;Nevenka Kopjar ,&nbsp;Maja Katalinić ,&nbsp;Arnes Rešić ,&nbsp;Irena Canjuga ,&nbsp;Marijana Neuberg ,&nbsp;Goran Kozina ,&nbsp;Ana Lucić Vrdoljak ,&nbsp;Irena Brčić Karačonji","doi":"10.1016/j.cbi.2025.111579","DOIUrl":"10.1016/j.cbi.2025.111579","url":null,"abstract":"<div><div>Amphetamine-type stimulants (ATSs) are widely abused substances that impair central and peripheral nervous system functions. The mechanisms of their toxicity on human neuronal cells have not been fully clarified yet but include effects on oxidative-antioxidative balance and interaction with synaptic enzymes/receptors. The aims of this study were to determine oxidant/antioxidant status, DNA integrity and the activity of neurotransmitter system components (monoamine oxidase A, MAO-A and nicotinic acetylcholine receptors, nAChR) in human neuroblastoma SH-SY5Y cells after 24-h exposure to different ATSs. In this matter, we first evaluated cell viability by MTS assay. After determination of the concentrations (near IC₂₅) suitable for conduction of the alkaline comet assay, these were further studied for the extent of DNA damage, along with the levels of malondialdehyde, reactive oxygen species (ROS), glutathione (GSH) and activities of antioxidative enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). The activity of the MAO-A enzyme and nAChR activity were evaluated at concentration range 1–50 μM. Finally, the <em>in silico</em> pharmacokinetic parameters predictions of the tested ATSs were determined. When compared to untreated cells, the most notable result was obtained for amphetamine (AMP), where we observed a significant increase in ROS levels, SOD, GPx and CAT activity, and a decrease in GSH levels. Interestingly, all of the tested ATSs increased the activity of GPx, while the activities of the other enzymes were compound-dependent. The new psychoactive substance (NPS) mephedrone (4-MMC) had a similar effect as AMP, except that it did not affect CAT activity. At the tested concentrations, AMP, methamphetamine (METH) and 4-MMC also showed effects on DNA stability. None of the tested ATSs inhibited MAO-A in the tested concentration range, but AMP, METH, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) inhibited acetylcholine activation of human nAChR. Taken together, significant induction of oxidative stress parameters, increased level of DNA damage detected and inhibition of nAChR activity indicate potential mechanisms of ATS substances action, and represent the direction for further studies to clarify the toxicological risks associated with ATS and/or NPS consumption.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111579"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146836","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}