Chemico-Biological Interactions最新文献

{"title":"The influence of naturally occurring and in silico-informed mutations of MRP1/ABCC1 on the transport of arsenic triglutathione","authors":"William Li ,&nbsp;Yingze Ma ,&nbsp;Yuval Bin Kanner ,&nbsp;Janet R. Zhou ,&nbsp;Assaf Ganoth ,&nbsp;Yossi Tsfadia ,&nbsp;Elaine M. Leslie","doi":"10.1016/j.cbi.2025.111839","DOIUrl":"10.1016/j.cbi.2025.111839","url":null,"abstract":"<div><div>Chronic exposure of humans to arsenic causes skin, bladder, and lung tumors and is associated with multiple non-malignant diseases including atherosclerosis and diabetes mellitus. The multidrug resistance protein 1 (MRP1/gene <em>ABCC1</em>) is an established cellular export pathway for arsenic metabolites including arsenic triglutathione (As(GS)₃). Little is known about the relationship between interindividual variation in susceptibility to arsenic-induced diseases and the highly polymorphic <em>ABCC1</em>. Eleven naturally occurring mutants (C43S-, R230Q-, R433S-, R633Q-, G671V-, R723Q-, A989T-, C1047S-, R1058Q-, V1146I-, and S1512L-MRP1) were tested for leukotriene C₄ (LTC₄, prototypical MRP1 substrate) and As(GS)₃ transport using MRP1-enriched vesicles, prepared from human embryonic kidney 293T cells. Mutant-MRP1 levels and LTC₄ transport activity were similar to wild-type (WT)-MRP1, except R433S-MRP1 LTC₄ transport was reduced by 71 %. As(GS)₃ transport by R230Q-, R433S- and A989T-MRP1-enriched membrane vesicles was reduced to 64 ± 9 %, 30 ± 16 %, and 44 ± 33 % of WT-MRP1, respectively. The reduction in R230Q-, R433S-, and A989T-MRP1 As(GS)₃ transport activity was due to reduced V_max values. Computational modeling indicated structural destabilization of these three mutants, and predicted multiple key As(GS)₃-binding residues in WT-MRP1. Five of these residues were mutated and tested for As(GS)₃ transport activity. As(GS)₃ transport by W553A-, R593E-, and W1246A-MRP1 was 34 ± 9 %, 34 ± 13 %, and 48 ± 13 % of WT-MRP1, respectively, while V554A- and E1089Q-MRP1 activity was similar to WT-MRP1. Thus, naturally occurring and <em>in silico</em> informed mutations negatively affect As(GS)₃ transport by MRP1. Individuals with R230Q-, R433S-, and A989T-MRP1 mutations may be more susceptible to arsenic-induced diseases.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111839"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566737","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":"Investigating the neurodevelopmental toxicity of graphene oxides using 3D human brain organoids and zebrafish models: emphasis on GABAergic neuron alterations at single-cell resolution","authors":"Yuna Chen ,&nbsp;Weichao Zhao ,&nbsp;Lu Gan ,&nbsp;Chaobo Huang ,&nbsp;Xudong Liu ,&nbsp;Dingxin Long ,&nbsp;Yi Cao","doi":"10.1016/j.cbi.2025.111849","DOIUrl":"10.1016/j.cbi.2025.111849","url":null,"abstract":"<div><div>Exposure to graphene oxides (GOs) may induce neurotoxic effects, but the mechanisms and extent of these effects remain unclear, partly due to limitations in traditional neurotoxicity models. In this study, we utilized 3D human brain organoids and zebrafish larvae to investigate GO-induced neurodevelopmental toxicity. In 3D human brain organoids, GOs significantly reduced cellular viability in a dose-dependent manner, with bulk RNA-sequencing indicating minimal impact on neuron-related pathways. However, single-cell RNA-sequencing revealed significant alterations in glutamatergic and GABAergic neurons, particularly in gene ontology terms related to synaptic function and neuronal development. Further analysis showed that GO exposure affected the localization, morphology, and electrophysiological activity of GABAergic neurons. Additionally, key genes involved in neurodegeneration (ko05022) and protein processing in endoplasmic reticulum (ko04141) were dysregulated in GABAergic neurons. <em>In vivo</em> studies using zebrafish larvae demonstrated altered locomotor behaviors, including hyperactivity during dark cycles and reduced swimming distances during light cycles, alongside a loss of GABAergic neurons in specific brain regions. These findings highlight the potential neurodevelopmental toxicity of GOs, especially through their impact on GABAergic neurons, and underscore the value of combining 3D human brain organoids and zebrafish models with single-cell resolution techniques to better understand the neurotoxic effects of nanomaterials.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111849"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145589664","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":"GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism","authors":"Hao Wang ,&nbsp;Xiao-yan Wang ,&nbsp;Jian-bo Ji ,&nbsp;Zong-xue Zheng ,&nbsp;Peng-fei Shang ,&nbsp;Xiu-li Guo","doi":"10.1016/j.cbi.2025.111812","DOIUrl":"10.1016/j.cbi.2025.111812","url":null,"abstract":"<div><div>Liver cancer, primary hepatocellular carcinoma (HCC), posing a significant threat to human health due to its high prevalence and limited treatment options. As a first-line chemotherapeutic agent for HCC, 5-fluorouracil (5-FU) has demonstrated significant efficacy in suppressing tumor cell proliferation through its cytotoxic mechanisms. Yet, prolonged 5-FU administration often induces chemo-resistant phenotypes in cancer cells, severely compromising the long-term efficacy of 5-FU-based treatment regimens and becoming a major barrier to successful HCC therapy. In this study, we investigated the mechanism underlying 5-FU resistance in Bel7402 hepatoma cells and found that it is closely related to metabolic reprogramming of glutamine. Notably, we demonstrated that CB-839, which is an inhibitor of glutamine metabolism's rate-limiting enzyme (glutaminase), has no notable anti-tumor activity alone but effectively enhances resistant HCC cells' sensitivity to 5-FU both in vitro and in vivo. The mechanism underlying this sensitization involves the disruption of cellular redox homeostasis. Specifically, the combination of CB-839 and 5-FU increases the accumulation of reactive oxygen species (ROS) and induces oxidative stress by consuming intracellular glutathione (GSH) reserves. Furthermore, this combination therapy elevates intracellular Fe²⁺levels and promotes lipid peroxidation, ultimately triggering ferroptosis. Collectively, these findings tentatively address certain aspects of the unclear mechanism underlying 5-FU resistance in HCC. Specifically, they may suggest targeting glutamine metabolism as a potential avenue for intervention and offer novel perspectives on understanding this resistance. Concurrently, these discoveries provide some support for optimizing chemotherapy regimens, with the aim of surmounting the current clinical challenges in reversing drug resistance.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111812"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491176","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":"JUN activation by disrupted calcium homeostasis orchestrates a Nox4–inflammasome–PUMA apoptotic triad in obesity-exacerbated renal injury following lower limb ischaemia–reperfusion","authors":"Xiaochen Wang ,&nbsp;Rui Li ,&nbsp;Yuanbing You ,&nbsp;Yidi Gao ,&nbsp;Tiantian Wang ,&nbsp;Jingkang Li ,&nbsp;Qiong Zhang","doi":"10.1016/j.cbi.2025.111828","DOIUrl":"10.1016/j.cbi.2025.111828","url":null,"abstract":"<div><div>Obesity exacerbates renal injury following lower limb ischaemia–reperfusion (LLIRI) through mechanisms involving calcium dysregulation and oxidative-inflammatory-apoptotic cascades. However, the underlying pathways remain to be identified. Thus, this study aimed to elucidate the underlying pathways by using transcriptomics, multi-omics, and pharmacological validation. Utilizing transcriptomics, multi-omics analysis, and targeted biochemical/molecular assays in a high-fat diet-induced obese mouse model of LLIRI, combined with pharmacological validation using nicardipine in human renal tubular cells exposed to oxidative stress, we elucidated the underlying pathways linking calcium dysregulation to renal injury. In high-fat diet-induced obese mice, LLIRI triggered profound renal transcriptomic reprogramming, with 1530 differentially expressed genes significantly enriched in calcium homeostasis disruption (GO:0055074), NF-κB signalling (KEGG:mmu04064), and apoptosis. Mechanistically, LLIRI-induced surge in reactive oxygen species promoted renal calcium influx by downregulating calcium efflux transporters Atp2b4 (PMCA4) and Kcnma1 (BK channel), which led to Ca²⁺ overload. This results in activation of the transcription hub JUN, which orchestrated a triad of injury: oxidative stress, as evidenced by Nox4 upregulation and ATP/NAD⁺ depletion, which elevated lipid (MDA↑), protein (carbonyls↑), and DNA (8-OHdG↑, γ-H₂AX↑) damage; inflammation, as evidenced by tumour necrosis factor-α/interleukin (IL)-1β/IL-18 elevation and macrophage infiltration (F4/80⁺/HMGB1⁺); and apoptosis, as evidenced by PUMA (Bbc3) induction, caspase-3/8 activation, and Bax/Bcl-2 imbalance. In vitro, H₂O₂-induced oxidative stress in human renal tubules replicated Ca²⁺ overload and JUN-driven apoptosis/senescence. Treatment with the L-type calcium channel blocker nicardipine (2.5 μM) attenuated calcium influx, suppressed JUN/Nox4/PUMA expression, reduced caspase activation, and mitigated cellular damage. Our findings establish Ca²⁺ overload-JUN activation as a central axis integrating oxidative, inflammatory, and apoptotic networks in obesity-aggravated LLIRI renal injury. Integrating multi-omics and pharmacological evidence, we identify JUN as a master transcriptional regulator of the Nox4-inflammasome-PUMA apoptotic triad, thereby elucidating a previously unrecognized pathogenic pathway in obesity-exacerbated renal LLIRI. Targeting this axis with calcium channel blockers is a promising therapeutic strategy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111828"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145527202","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":"Multimodal cell death induced by indirubin-3′-oxime through inhibition of Akt/mTOR axis in lung cancer cells","authors":"Na Young Kim ,&nbsp;Shalini V. Gowda ,&nbsp;Kachigere B. Harsha ,&nbsp;D.C. Vinay Kumar ,&nbsp;Chakrabhavi Dhananjaya Mohan ,&nbsp;C.S. Shivakumara ,&nbsp;Kanchugarakoppal S. Rangappa ,&nbsp;Kwang Seok Ahn","doi":"10.1016/j.cbi.2025.111851","DOIUrl":"10.1016/j.cbi.2025.111851","url":null,"abstract":"<div><div>Lung cancer is a major type of malignancy that has contributed to a high mortality rate for many years. Discovering new small molecules with strong cytotoxic effects on lung cancer is crucial for developing new therapies. In this study, we describe the synthesis of a novel triazole-indirubin-3′-oxime derivative (designated as CRM1) and examine its ability to induce distinct forms of cell death, as well as elucidate the cytotoxicity-associated molecular mechanisms in lung cancer cells. CRM1 selectively reduced cell viability in lung cancer cell lines (A549, PC9, and H1299) without significantly affecting the viability of normal lung cells (HEL299). Mechanistic investigations have demonstrated that CRM1 induces paraptosis through the downregulation of Alix and the upregulation of ATF4 and CHOP. This process is associated with disruption of mitochondrial membrane potential, induction of endoplasmic reticulum stress, and accumulation of reactive oxygen species (ROS). CRM1 was observed to induce apoptosis, as indicated by DNA fragmentation, an increase in Sub-G1 cell population, as well as elevated caspase-3 cleavage and Bax expression. CRM1 also promoted autophagy, as evidenced by increased expression of Atg7, phosphorylated Beclin-1, and LC3-II, as well as enhanced autophagosome formation. Pharmacological inhibition studies confirmed the independent induction of apoptosis, paraptosis, and autophagy. Pre-exposure of cancer cells to N-acetyl cysteine abrogated CRM1-induced cytotoxicity. Mechanistic studies demonstrated that CRM1 suppresses the activation of Akt, mTOR, and p70S6K, while the overexpression of Akt counteracts the CRM1-driven cytotoxic effects. CRM1 also synergistically potentiated the cytotoxic efficacy of paclitaxel by co-targeting multiple cell death processes. Collectively, these results suggest CRM1 as a promising cytotoxic candidate with a multimodal mechanism of action in lung cancer cells.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111851"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621067","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":"Platinum(IV) oxaliplatin analog containing axial benzoate ligands induces mitochondrial hyperpolarization and caspase-dependent apoptosis in pancreatic cancer cell models","authors":"Michal Berecka ,&nbsp;Jitka Pracharova ,&nbsp;Nicola Margiotta ,&nbsp;Alessandra Barbanente ,&nbsp;Nicoletta Ditaranto ,&nbsp;Jana Kasparkova ,&nbsp;Viktor Brabec","doi":"10.1016/j.cbi.2025.111792","DOIUrl":"10.1016/j.cbi.2025.111792","url":null,"abstract":"<div><div>This study investigates the molecular mechanisms underlying the antiproliferative effects of the platinum(IV) complex <em>trans</em>-[Pt(OBz)₂(<em>O,C</em>-10-BzODA)(1<em>R</em>,2<em>R</em>-DACH)] (complex <strong>1</strong>; OBz = benzoate, 10-BzODA = 10-benzoyloxy-2-decenoate, DACH = diaminocyclohexane) in pancreatic cancer cell models. Initial findings revealed that complex <strong>1</strong> exhibits substantial antiproliferative activity, positioning it as a promising therapeutic agent for pancreatic cancer, where effective treatment options remain limited. Notably, complex <strong>1</strong> demonstrates significantly greater efficacy compared to platinum(II) drugs, such as cisplatin and oxaliplatin, with IC₅₀ values in the low micromolar range across various pancreatic cancer cell lines. Mechanistic studies suggest that complex <strong>1</strong>'s enhanced activity is attributed to the axial benzoate ligands, which differentiate it from its platinum(II) analog. Complex <strong>1</strong> accumulates intracellular platinum without undergoing reduction in the extracellular environment, and it induces mitochondrial hyperpolarization. This effect is reminiscent of free sodium benzoate but occurs at a much lower extracellular concentration, indicating the crucial role of the benzoate ligands in modulating mitochondrial function. Furthermore, complex <strong>1</strong> triggers caspase-dependent apoptosis in cancer cells and is also effective in 3D tumor cell models, highlighting its potential as an effective anticancer agent. Thus, this work presents a Pt(IV) prodrug bearing benzoate axial ligands that exhibit distinctive chemical and biological behavior compared with previously reported Pt(IV) prodrugs.</div><div>In conclusion, the unique properties of complex <strong>1</strong>, driven by its benzoate ligands, suggest that Pt(IV) complexes represent a promising approach for the development of targeted chemotherapeutic agents for the treatment of pancreatic cancer.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111792"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442417","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":"Cigarette smoke exposure diminishes ovarian reserve in mice by regulating granulosa cells redox homeostasis imbalance through Wnt10b-ERβ feedback loop","authors":"Fang Li ,&nbsp;Mengting Xu ,&nbsp;Yanhui Zhao ,&nbsp;Ying Wang ,&nbsp;Nengyin Hu ,&nbsp;Sailing Ji ,&nbsp;Jianing Miao ,&nbsp;Li Wang ,&nbsp;Lili Wang","doi":"10.1016/j.cbi.2025.111811","DOIUrl":"10.1016/j.cbi.2025.111811","url":null,"abstract":"<div><div>Oxidative stress induced by cigarette smoke (CS) exposure can cause ovarian follicle damage and diminishes reserve in women. Our previous study showed CS exposure caused premature ovarian insufficiency (POI) in mice through oxidative stress and senescence in granulosa cells (GCs) via suppressing the expression of Wnt10b, GPX1/GPX4 and FDX1. However, their roles and molecular relationships in oxidative stress and senescence in GCs after CS exposure as well as their diagnostic value for POI remains unclear. In this study, we found that CS exposure resulted in increased ROS production, reduced antioxidant function, mitochondrial dysfunction, cell cycle arrest and cellular senescence in GCs. And the levels of GPX4, GPX1, FDX1 and Wnt10b were also reduced in GCs of pre-POI patients. Over-expression of Wnt10b or application of diarylpropionitrile (DPN, an ERβ agonist) could alleviate above phenotypic changes caused by CSE exposure, however, over-expression of FDX1 only could partially alleviate. Additionally, the serum FDX1 levels exhibit an association with POI progression and serum follicle stimulating hormone (FSH) levels, yet its diagnostic potential for POI alone remains limited. Moreover, ChIP results demonstrated a feedback regulatory relationship between Wnt10b and ERβ, and ERβ is involved in regulating the expression of GPX1, GPX4 and FDX1. The current study demonstrated the regulatory role of the Wnt10b-ERβ feedback loop on GCs redox homeostasis. Our findings provide a theoretical basis for revealing the molecular mechanism of reduced ovarian reserve in women induced by CS exposure, and may provide potential new targets and ideas for the early clinical prediction and diagnosis of human POI.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111811"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442411","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":"Sex-specific aggressive and emotional behavior in myostatin-deficient mice: Ratio of acylated versus unacylated ghrelin is reduced, but not correlated with butyrylcholinesterase activity level, however parvalbumin expression is lost in the habenular complex","authors":"Barbara Vernus ,&nbsp;Bénédicte Goustard ,&nbsp;Béatrice Chabi ,&nbsp;Christelle Bertrand-Gaday ,&nbsp;Hillary Maillet ,&nbsp;Meghan K. Cash ,&nbsp;Pierre Delobel ,&nbsp;Sylvain Cerda ,&nbsp;Mélanie Macart ,&nbsp;Anne Bonnieu ,&nbsp;Sultan Darvesh ,&nbsp;Arnaud Chatonnet","doi":"10.1016/j.cbi.2025.111813","DOIUrl":"10.1016/j.cbi.2025.111813","url":null,"abstract":"<div><div>Myostatin plays crucial roles in negative regulation of muscle growth. Inactivation of the myostatin gene results in gross muscle hypertrophy. We observed that myostatin knock-out (myostatin-KO) mice are more aggressive than wild-type (WT) mice. Ghrelin is a hormone produced by cells of the gastrointestinal tract that activates cells in the brain and increases the drive to eat. The level of circulating ghrelin affects anxiety, stress, and aggression. Ghrelin controls expression of myostatin in disease-associated cachexia. Butyrylcholinesterase (BChE) is responsible for the deacylation of ghrelin. BChE knock-out mice show higher level of acylated ghrelin and are more aggressive than WT mice. De-acylation of ghrelin by BChE reduces aggression in mice. We hypothesized that the levels of expression of BChE, ghrelin and myostatin could explain the aggressive behavior of myostatin-myostatin-KO mice. Resident/intruder tests shows that male myostatin-KO mice are more aggressive than WT littermates. Female myostatin-KO mice show much higher spontaneous exercise than female WT and males of both genotypes. Behavioral tests (elevated plus maze and light/dark box) show that myostatin-KO mice present anxious behavior without any change in circulating corticosterone. Myostatin-KO mice have a lower acylated/unacylated ghrelin ratio. Female myostatin-KO mice show lower level of BChE activity compared with WT littermates. Comparison of staining for various neurotransmitter systems involved in behavior showed that the only region where there was a difference between WT and myostatin-KO mice was in the habenular complex which involved in regulation of behavior. Reduced ghrelin levels and loss of parvalbumin neurons of the habenular complex could partly explain the behavior of our model.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111813"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477084","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 inhibitory effects of enzalutamide and its phase I metabolite on UDP-glucuronosyltransferase 1A1 (UGT1A1) and risk prediction of drug-drug interactions","authors":"Tingting Zheng,&nbsp;Hang Yin,&nbsp;Hongna Shan,&nbsp;Lihuan Sun,&nbsp;Lili Jiang,&nbsp;Yong Liu","doi":"10.1016/j.cbi.2025.111829","DOIUrl":"10.1016/j.cbi.2025.111829","url":null,"abstract":"<div><div>Enzalutamide (formerly called MDV3100), a second-generation androgen receptor inhibitor primarily used for treating castration-resistant prostate cancer (CRPC), has been shown to regulating UDP-glucuronosyltransferases (UGTs) expression, while its effects on the activity of UGT isoforms remain unclear. This study aimed to systemically investigate the effects of enzalutamide and its phase I metabolite on the UGT activities, and to assess the risk of drug-drug interactions (DDIs) resulting from UGT inhibition. Using high-performance liquid chromatography (HPLC) and enzyme kinetic studies, we evaluated the inhibitory effects of enzalutamide and its main phase I metabolite, N-desmethyl enzalutamide on 12 UGT isoforms and inhibition patterns. Our findings demonstrated that both enzalutamide and its metabolite exhibited potent inhibition against UGT1A1, with evidence of synergistic effects. Enzyme kinetic analysis revealed that both enzalutamide and its metabolite acted as competitive inhibitors of UGT1A1. In vitro-in vivo extrapolation (IVIVE) prediction indicated that concomitant use of enzalutamide with UGT1A1 substrates could induce clinically significant DDIs. Therefore, special caution should be warranted when administering enzalutamide alongside other drugs metabolized by UGT to mitigate potential DDIs.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111829"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145527626","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":"Corrigendum to “Insights into the diagnostic and prognostic value of paraoxonase 1-related variables and inflammatory markers in community-acquired pneumonia” [Chem. Biol. Interact. 418 (2025) 111606]","authors":"Frederic Ballester ,&nbsp;Xavier Gabaldó-Barrios ,&nbsp;Andrea Jiménez-Franco ,&nbsp;Isabel Pujol ,&nbsp;Simona Iftimie ,&nbsp;Jordi Camps ,&nbsp;Sandra Parra ,&nbsp;Antoni Castro ,&nbsp;Jorge Joven","doi":"10.1016/j.cbi.2025.111808","DOIUrl":"10.1016/j.cbi.2025.111808","url":null,"abstract":"","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111808"},"PeriodicalIF":5.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145464978","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}