Nanoplastics (NPs) and chromium (Cr) are ubiquitous in the environment, causing severe pollution and posing significant potential threats to human health. Polylactic acid (PLA) and Cr are among widely used bioplastic and heavy metal, respectively, both capable of contaminating water sources through corresponding pathways and posing substantial risks to human health. Nanoplastics can act as carriers for heavy metals, thereby enhancing their bioaccumulation and toxicity. Therefore, this study investigated the effects of combined exposure to Cr(VI) and PLA NPs on mice kidneys and its potential mechanisms. Results indicated that exposure to PLA NPs alone did not exhibit significant toxic effects on the kidneys. However, combined exposure to Cr(VI) and PLA NPs caused severe kidney damage in mice. This indirectly suggests that Cr(VI) and PLA NPs exhibit synergistic toxicity rather than simple additive effects. Furthermore, combined exposure exacerbated the toxic mechanism by inducing mitochondrial damage and excessive reactive oxygen species (ROS) production, thereby triggering mitophagy. Overactivated mitophagy exacerbated lipid peroxidation by releasing free iron, thereby amplifying ROS-mediated ferroptosis. This study investigates the synergistic renal toxicity of Cr(VI) and PLA NPs, providing scientific evidence for the combined toxicity mechanism of exposure to MNPs and heavy metals.
{"title":"Synergistic kidney toxicity of polylactic acid nanoplastics and Cr(VI): Ferroptosis aggravated by mitophagy","authors":"Yuankun Zhou , Jiajun Guo , Xiaoyan Feng , Hengyi Xu","doi":"10.1016/j.cbi.2026.111915","DOIUrl":"10.1016/j.cbi.2026.111915","url":null,"abstract":"<div><div>Nanoplastics (NPs) and chromium (Cr) are ubiquitous in the environment, causing severe pollution and posing significant potential threats to human health. Polylactic acid (PLA) and Cr are among widely used bioplastic and heavy metal, respectively, both capable of contaminating water sources through corresponding pathways and posing substantial risks to human health. Nanoplastics can act as carriers for heavy metals, thereby enhancing their bioaccumulation and toxicity. Therefore, this study investigated the effects of combined exposure to Cr(VI) and PLA NPs on mice kidneys and its potential mechanisms. Results indicated that exposure to PLA NPs alone did not exhibit significant toxic effects on the kidneys. However, combined exposure to Cr(VI) and PLA NPs caused severe kidney damage in mice. This indirectly suggests that Cr(VI) and PLA NPs exhibit synergistic toxicity rather than simple additive effects. Furthermore, combined exposure exacerbated the toxic mechanism by inducing mitochondrial damage and excessive reactive oxygen species (ROS) production, thereby triggering mitophagy. Overactivated mitophagy exacerbated lipid peroxidation by releasing free iron, thereby amplifying ROS-mediated ferroptosis. This study investigates the synergistic renal toxicity of Cr(VI) and PLA NPs, providing scientific evidence for the combined toxicity mechanism of exposure to MNPs and heavy metals.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111915"},"PeriodicalIF":5.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974894","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}
Pub Date : 2026-01-12DOI: 10.1016/j.cbi.2026.111914
Chaochao Gong , Xiuzhi Zhang , Yu Zhang , Xishi Chen , Hao Lin , Ren-shan Ge , Youming Zhao
11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), a key enzyme in glucocorticoid inactivation, is expressed in human and rat placentas and kidneys. However, the inhibitory effects of alkyl (C1–C20) pyridinium quaternary ammonium disinfectants (PYRs) on 11β-HSD2 remain unexplored. This study evaluated PYRs through inhibitory potency assays, mechanistic investigations, structure-activity relationship (SAR)/3D-QSAR modeling, and molecular docking using human and rat 11β-HSD2 enzymes. Human 11β-HSD2 inhibition by PYRs followed a distinct V-shaped trend: potency increased from C12 to C16 (IC50: C12 = 132.81 μM, C14 = 19.62 μM, C16 = 1.96 μM) but declined beyond C16 (C18 = 14.45 μM, C20 = 100.76 μM). Shorter-chain PYRs (C1–C8) were inactive at ≤100 μM. Rat 11β-HSD2 exhibited a similar inhibition pattern. SPR analysis revealed that C16 displayed the highest binding affinity (KD = 1.98 μM) with human 11β-HSD2. Mechanistic analysis revealed mixed/noncompetitive inhibition, with PYRs binding both the free enzyme and enzyme-substrate complex. In BeWo cells, C12–C20 PYRs inhibited cortisol metabolism at 10–100 μM, whereas C16 was effective at ≥1 μM. Molecular docking indicated PYRs interact with the NAD + binding site in both species. SAR analysis identified lipophilicity, steric bulk, and flexibility as critical inhibitory determinants, with higher values enhancing potency. A 3D-QSAR pharmacophore model confirmed hydrophobic interactions as essential for inhibition. Notably, species-specific binding differences suggest caution when extrapolating rodent data to humans. These findings highlight the endocrine-disrupting potential of PYRs, demonstrating their structure- and species-dependent interference with cortisol metabolism, with implications for chemical safety assessment.
{"title":"Environmental pyridinium disinfectants impair cortisol metabolism via 11β-hydroxysteroid dehydrogenase 2 inhibition: A cross-species risk evaluation","authors":"Chaochao Gong , Xiuzhi Zhang , Yu Zhang , Xishi Chen , Hao Lin , Ren-shan Ge , Youming Zhao","doi":"10.1016/j.cbi.2026.111914","DOIUrl":"10.1016/j.cbi.2026.111914","url":null,"abstract":"<div><div>11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), a key enzyme in glucocorticoid inactivation, is expressed in human and rat placentas and kidneys. However, the inhibitory effects of alkyl (C1–C20) pyridinium quaternary ammonium disinfectants (PYRs) on 11β-HSD2 remain unexplored. This study evaluated PYRs through inhibitory potency assays, mechanistic investigations, structure-activity relationship (SAR)/3D-QSAR modeling, and molecular docking using human and rat 11β-HSD2 enzymes. Human 11β-HSD2 inhibition by PYRs followed a distinct V-shaped trend: potency increased from C12 to C16 (IC<sub>50</sub>: C12 = 132.81 μM, C14 = 19.62 μM, C16 = 1.96 μM) but declined beyond C16 (C18 = 14.45 μM, C20 = 100.76 μM). Shorter-chain PYRs (C1–C8) were inactive at ≤100 μM. Rat 11β-HSD2 exhibited a similar inhibition pattern. SPR analysis revealed that C16 displayed the highest binding affinity (<em>KD</em> = 1.98 μM) with human 11β-HSD2. Mechanistic analysis revealed mixed/noncompetitive inhibition, with PYRs binding both the free enzyme and enzyme-substrate complex. In BeWo cells, C12–C20 PYRs inhibited cortisol metabolism at 10–100 μM, whereas C16 was effective at ≥1 μM. Molecular docking indicated PYRs interact with the NAD <sup>+</sup> binding site in both species. SAR analysis identified lipophilicity, steric bulk, and flexibility as critical inhibitory determinants, with higher values enhancing potency. A 3D-QSAR pharmacophore model confirmed hydrophobic interactions as essential for inhibition. Notably, species-specific binding differences suggest caution when extrapolating rodent data to humans. These findings highlight the endocrine-disrupting potential of PYRs, demonstrating their structure- and species-dependent interference with cortisol metabolism, with implications for chemical safety assessment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111914"},"PeriodicalIF":5.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986150","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}
Pub Date : 2026-01-10DOI: 10.1016/j.cbi.2026.111908
Vanessa da Silva Oliveira , Dahara Keyse Carvalho Silva , Maria Vitória Gomes das Neves , Sergio Santos Silva Junior , Jônatas Sousa Pires dos Santos , Claudia Valeria Campos de Souza , José Maria Barbosa Filho , Osvaldo Andrade Santos-Filho , Milena Botelho Pereira Soares , Cássio Santana Meira
7-Hydroxyflavone (7HF) is a natural flavonoid with recognized antioxidant and anti-inflammatory properties, but its immunomodulatory potential and underlying molecular mechanisms remain poorly defined. This study investigated the immunomodulatory activity of 7HF in human peripheral blood mononuclear cells (PBMCs) and murine splenocytes through in silico and in vitro approaches. Pharmacokinetic and toxicity predictions were obtained with ProTox 3.0. Cytotoxicity and hemolysis assays evaluated the compound safety, whereas lymphoproliferation and cytokine secretion (IL-2 and IFN-γ) were analyzed in PHA- or ConA-stimulated cells with or without the glucocorticoid-receptor (GR) antagonist RU-486. The expression of inflammatory mediators and signaling molecules was quantified by RT-qPCR, and molecular docking assessed the affinity of 7HF for calcineurin and GR. 7HF showed favorable pharmacokinetic predictions, low acute toxicity, and moderate CC50 values in murine splenocytes (74.2 ± 6.1 μM) and human PBMCs (60.1 ± 1.9 μM), with no cytotoxic or hemolytic effects at immunomodulatory concentrations. The compound significantly inhibited lymphocyte proliferation and cytokine production in activated PBMCs and splenocytes, effects partially reversed by RU-486, indicating GR involvement. Gene-expression analysis revealed downregulation of calcineurin subunits (PPP3CA/B/C), PLCG1, NFAT1/2, and pro-inflammatory mediators, with additional modulation of PI3K/AKT, GR, NF-κB/AP-1, and JAK/STAT pathways. Molecular docking confirmed stable interactions of 7HF with both calcineurin and GR, with ChemPLP scores comparable to dexamethasone. Overall, 7HF exhibited selective immunosuppressive activity by modulating multiple signaling pathways involved in lymphocyte activation, supporting its potential as a safe lead compound for developing novel therapeutic agents.
{"title":"In silico and in vitro investigation of the safety and immunomodulatory mechanisms of 7-hydroxyflavone","authors":"Vanessa da Silva Oliveira , Dahara Keyse Carvalho Silva , Maria Vitória Gomes das Neves , Sergio Santos Silva Junior , Jônatas Sousa Pires dos Santos , Claudia Valeria Campos de Souza , José Maria Barbosa Filho , Osvaldo Andrade Santos-Filho , Milena Botelho Pereira Soares , Cássio Santana Meira","doi":"10.1016/j.cbi.2026.111908","DOIUrl":"10.1016/j.cbi.2026.111908","url":null,"abstract":"<div><div>7-Hydroxyflavone (7HF) is a natural flavonoid with recognized antioxidant and anti-inflammatory properties, but its immunomodulatory potential and underlying molecular mechanisms remain poorly defined. This study investigated the immunomodulatory activity of 7HF in human peripheral blood mononuclear cells (PBMCs) and murine splenocytes through <em>in silico</em> and <em>in vitro</em> approaches. Pharmacokinetic and toxicity predictions were obtained with ProTox 3.0. Cytotoxicity and hemolysis assays evaluated the compound safety, whereas lymphoproliferation and cytokine secretion (IL-2 and IFN-γ) were analyzed in PHA- or ConA-stimulated cells with or without the glucocorticoid-receptor (GR) antagonist RU-486. The expression of inflammatory mediators and signaling molecules was quantified by RT-qPCR, and molecular docking assessed the affinity of 7HF for calcineurin and GR. 7HF showed favorable pharmacokinetic predictions, low acute toxicity, and moderate CC<sub>50</sub> values in murine splenocytes (74.2 ± 6.1 μM) and human PBMCs (60.1 ± 1.9 μM), with no cytotoxic or hemolytic effects at immunomodulatory concentrations. The compound significantly inhibited lymphocyte proliferation and cytokine production in activated PBMCs and splenocytes, effects partially reversed by RU-486, indicating GR involvement. Gene-expression analysis revealed downregulation of calcineurin subunits (PPP3CA/B/C), PLCG1, NFAT1/2, and pro-inflammatory mediators, with additional modulation of PI3K/AKT, GR, NF-κB/AP-1, and JAK/STAT pathways. Molecular docking confirmed stable interactions of 7HF with both calcineurin and GR, with ChemPLP scores comparable to dexamethasone. Overall, 7HF exhibited selective immunosuppressive activity by modulating multiple signaling pathways involved in lymphocyte activation, supporting its potential as a safe lead compound for developing novel therapeutic agents.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111908"},"PeriodicalIF":5.4,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961013","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}
Pub Date : 2026-01-09DOI: 10.1016/j.cbi.2026.111909
Nicoletta Polerà , Giada Juli , Giuseppe Agapito , Antonio Procopio , Maria Lucibello , Monica Nardi , Sonia Bonacci , Marianna Milano , Mario Cannataro , Dmitry Lim , Emanuela Altomare , Mariamena Arbitrio
Alzheimer's disease (AD) and neuroblastoma are distinct conditions that affect the nervous system. However, they share some molecular similarities, particularly concerning the amyloid precursor protein (APP) and related pathways. While previous studies have demonstrated a correlation between neurodegenerative diseases and various tumors, the causality and direction of their relationship remain unclear. Oleacein, one of the most abundant polyphenols in Extra Vergin Olive Oil (EVOO) may exert neuroprotective and/or antitumor effects. In this study, we explored the effects of the polyphenol oleacein, obtained by a simple and efficient sustainable semi-synthesis starting from natural oleuropein, on AD-related genes in SHSY5Y, a human neuroblastoma cell line, and in 3Tg-iAstro cells, immortalized astrocytes from the hippocampus of 3xTg-AD mice, to identify potential shared biological pathways.
{"title":"Upregulation of ACHE and BACE2 genes by oleacein in Alzheimer's disease and neuroblastoma","authors":"Nicoletta Polerà , Giada Juli , Giuseppe Agapito , Antonio Procopio , Maria Lucibello , Monica Nardi , Sonia Bonacci , Marianna Milano , Mario Cannataro , Dmitry Lim , Emanuela Altomare , Mariamena Arbitrio","doi":"10.1016/j.cbi.2026.111909","DOIUrl":"10.1016/j.cbi.2026.111909","url":null,"abstract":"<div><div>Alzheimer's disease (AD) and neuroblastoma are distinct conditions that affect the nervous system. However, they share some molecular similarities, particularly concerning the amyloid precursor protein (APP) and related pathways. While previous studies have demonstrated a correlation between neurodegenerative diseases and various tumors, the causality and direction of their relationship remain unclear. Oleacein, one of the most abundant polyphenols in Extra Vergin Olive Oil (EVOO) may exert neuroprotective and/or antitumor effects. In this study, we explored the effects of the polyphenol oleacein, obtained by a simple and efficient sustainable semi-synthesis starting from natural oleuropein, on AD-related genes in SHSY5Y, a human neuroblastoma cell line, and in 3Tg-iAstro cells, immortalized astrocytes from the hippocampus of 3xTg-AD mice, to identify potential shared biological pathways.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111909"},"PeriodicalIF":5.4,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953458","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}
Pub Date : 2026-01-09DOI: 10.1016/j.cbi.2025.111889
Wenrui Lu , Yuxia Yang , Tianqin Deng , Fan Xiao , Yunqi Luo , Peiyi Liu , Jianjun Liu
This study elucidates the role of selenium in male fertility via the SLC7A11-GPX4 ferroptosis pathway. In a six-week dietary intervention, KM mice fed a selenium-deficient diet (<0.01 mg/kg) exhibited significantly decreased prostate indices (P < 0.05) and disrupted seminiferous tubule structure compared to controls, while epididymal sperm counts showed a decreasing trend that did not reach statistical significance. Selenium supplementation (sodium selenite, 3.2 mg/kg) significantly increased testis indices (P < 0.05) and improved tubule organization, with a non-significant increase in sperm counts. Crucially, testicular gpx4 (P < 0.001) and slc7a11 (P < 0.05) gene expression were significantly downregulated in the deficient group. In GC2-spd spermatocytes, the ferroptosis inducer Erastin significantly suppressed proliferation (P < 0.05) and induced ferroptotic ultrastructural damage. Selenomethionine (SeM,5.0 μM) significantly attenuated Erastin-induced proliferation suppression and upregulated GPX4 protein (P < 0.05), while sodium selenite showed non-significant protection. Lentiviral GPX4 knockdown confirmed SeM's effects are GPX4-dependent. In human studies, seminal selenium levels were comparable between groups and showed no correlation with GPX4 or SLC7A11. Oligozoospermia cases exhibited significantly decreased seminal GPX4 (P < 0.001) but unchanged SLC7A11 levels (P = 0.900). However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR<0.001, P < 0.001; SLC7A11: OR = 1.48, P = 0.032), revealing a characteristic biomarker dissociation However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR<0.001, P < 0.001; SLC7A11: OR = 1.48, P = 0.032), revealing a characteristic biomarker dissociation. In conclusion, selenium significantly influences testicular morphology and ferroptosis pathway gene expression in vivo, although its effects on sperm count under these experimental conditions were not statistically significant. In vitro, Selenomethionine effectively mitigates Erastin-induced ferroptosis and proliferation suppression in spermatocytes primarily through GPX4-mediated mechanisms. In patients with oligozoospermia, seminal plasma GPX4 concentration was significantly decreased and was identified as an independent protective factor, while SLC7A11 level was associated with increased risk in multivariable analysis; neither biomarker correlated with seminal plasma selenium concentration.
{"title":"The role of selenium in modulating sperm count and ferroptosis pathways in male reproductive health","authors":"Wenrui Lu , Yuxia Yang , Tianqin Deng , Fan Xiao , Yunqi Luo , Peiyi Liu , Jianjun Liu","doi":"10.1016/j.cbi.2025.111889","DOIUrl":"10.1016/j.cbi.2025.111889","url":null,"abstract":"<div><div>This study elucidates the role of selenium in male fertility via the SLC7A11-GPX4 ferroptosis pathway. In a six-week dietary intervention, KM mice fed a selenium-deficient diet (<0.01 mg/kg) exhibited significantly decreased prostate indices (<em>P</em> < 0.05) and disrupted seminiferous tubule structure compared to controls, while epididymal sperm counts showed a decreasing trend that did not reach statistical significance. Selenium supplementation (sodium selenite, 3.2 mg/kg) significantly increased testis indices (<em>P</em> < 0.05) and improved tubule organization, with a non-significant increase in sperm counts. Crucially, testicular <em>gpx4</em> (<em>P</em> < 0.001) and <em>slc7a11</em> (<em>P</em> < 0.05) gene expression were significantly downregulated in the deficient group. In GC2-spd spermatocytes, the ferroptosis inducer Erastin significantly suppressed proliferation (<em>P</em> < 0.05) and induced ferroptotic ultrastructural damage. Selenomethionine (SeM,5.0 μM) significantly attenuated Erastin-induced proliferation suppression and upregulated GPX4 protein (<em>P</em> < 0.05), while sodium selenite showed non-significant protection. Lentiviral GPX4 knockdown confirmed SeM's effects are GPX4-dependent. In human studies, seminal selenium levels were comparable between groups and showed no correlation with GPX4 or SLC7A11. Oligozoospermia cases exhibited significantly decreased seminal GPX4 (<em>P</em> < 0.001) but unchanged SLC7A11 levels (<em>P</em> = 0.900). However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR<0.001, <em>P</em> < 0.001; SLC7A11: OR = 1.48, <em>P</em> = 0.032), revealing a characteristic biomarker dissociation However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR<0.001, <em>P</em> < 0.001; SLC7A11: OR = 1.48, <em>P</em> = 0.032), revealing a characteristic biomarker dissociation. In conclusion, selenium significantly influences testicular morphology and ferroptosis pathway gene expression in vivo, although its effects on sperm count under these experimental conditions were not statistically significant. In vitro, Selenomethionine effectively mitigates Erastin-induced ferroptosis and proliferation suppression in spermatocytes primarily through GPX4-mediated mechanisms. In patients with oligozoospermia, seminal plasma GPX4 concentration was significantly decreased and was identified as an independent protective factor, while SLC7A11 level was associated with increased risk in multivariable analysis; neither biomarker correlated with seminal plasma selenium concentration.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111889"},"PeriodicalIF":5.4,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145954320","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}
Pub Date : 2026-01-08DOI: 10.1016/j.cbi.2025.111892
Yuanyi Sun , Zhongqian Cen , Shirui Liu , Aijiang Yang , Jingyun Zhang , Qing Li , Xia Hu , Zhengting Hou
Antimony (Sb), a widely used strategic metal, has raised growing concerns due to its environmental persistence and potential toxicity. However, the chronic effects of low-level Sb exposure on hematopoietic function remain poorly understood. In this study, zebrafish (Danio rerio) were exposed to Sb at concentrations of 0, 5, 50, 500, and 5000 μg/L for 28 days to investigate the hematotoxic effects and underlying mechanisms. Biochemical assays revealed that Sb exposure significantly disrupted blood glucose and lipid metabolism, reduced glucose levels, and altered lipid profiles in a concentration-dependent manner. In addition, Sb exposure increased cytokines such as NFAT, M-CSF, and IL-11. Histopathology revealed pronounced damage to the kidney, the primary hematopoietic organ in zebrafish. Single-cell RNA sequencing identified 13 hematopoietic cell populations. Differentially expressed genes were significantly enriched in the IL-17 pathway, with downstream activation of NF-κB and increased expression of TNF-α and MMP-9. These findings provide mechanistic insights into Sb-induced hematopoietic imbalance and renal injury, highlighting the role of IL-17-mediated inflammatory responses in mediating Sb toxicity. Overall, this study offers a valuable reference for ecological risk assessment and health hazard evaluation of Sb contamination.
{"title":"A single cell transcriptomics-based analysis provides mechanistic insights into the chronic low-concentration effects on hematopoietic disruption in zebrafish(Danio rerio) by Antinomy","authors":"Yuanyi Sun , Zhongqian Cen , Shirui Liu , Aijiang Yang , Jingyun Zhang , Qing Li , Xia Hu , Zhengting Hou","doi":"10.1016/j.cbi.2025.111892","DOIUrl":"10.1016/j.cbi.2025.111892","url":null,"abstract":"<div><div>Antimony (Sb), a widely used strategic metal, has raised growing concerns due to its environmental persistence and potential toxicity. However, the chronic effects of low-level Sb exposure on hematopoietic function remain poorly understood. In this study, zebrafish (<em>Danio rerio</em>) were exposed to Sb at concentrations of 0, 5, 50, 500, and 5000 μg/L for 28 days to investigate the hematotoxic effects and underlying mechanisms. Biochemical assays revealed that Sb exposure significantly disrupted blood glucose and lipid metabolism, reduced glucose levels, and altered lipid profiles in a concentration-dependent manner. In addition, Sb exposure increased cytokines such as NFAT, M-CSF, and IL-11. Histopathology revealed pronounced damage to the kidney, the primary hematopoietic organ in zebrafish. Single-cell RNA sequencing identified 13 hematopoietic cell populations. Differentially expressed genes were significantly enriched in the IL-17 pathway, with downstream activation of NF-κB and increased expression of TNF-α and MMP-9. These findings provide mechanistic insights into Sb-induced hematopoietic imbalance and renal injury, highlighting the role of IL-17-mediated inflammatory responses in mediating Sb toxicity. Overall, this study offers a valuable reference for ecological risk assessment and health hazard evaluation of Sb contamination.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111892"},"PeriodicalIF":5.4,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949534","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}
Pub Date : 2026-01-06DOI: 10.1016/j.cbi.2026.111904
Zhe Feng , Lisheng Zhu , Wentian Li , Fang Wang , Qianqian Cheng , Huihui Yang , Yuqing Huang , Wenqi Gao , Hui Lu , Junbao Wang , Han Xiao , Hongjian Gong
Perospirone, an atypical antipsychotic increasingly detected in aquatic environments, raises concerns regarding potential developmental hazards in early vertebrates. As an emerging personal care product (PPCP) contaminant, its developmental neurotoxicity remains poorly characterized. To evaluate its biological effects, zebrafish embryos were exposed to perospirone (nominal 0.1, 1, 10 mg/L) from 5 to 120 hpf. At 5 dpf, larvae exposed to 1 mg/L displayed increased locomotion with anxiety-like features, whereas exposure to 10 mg/L was associated with reduced body length and hyperactivity suppression, together with elevated Caspase 9 and Pro- Caspase 3 expression consistent with apoptosis activation. Neurotransmitter profiling revealed an increase in 5-HIAA and decreases in dopamine and glutamine, accompanied by transcriptomic enrichment of pathways related to serotonergic signaling, oxidative stress, and FOXO/AKT regulation. Besides, molecular docking revealed high-affinity perospirone-AKT1 binding (−7.88 kcal/mol). These multi-omics findings establish that perospirone-induced developmental neurotoxicity stems from AKT/FOXO3a-mediated apoptosis, providing critical insights into its neurotoxicological profile and environmental risks as an emerging pharmaceutical contaminant.
{"title":"Multi-omics and in silico evidence reveal perospirone-induced developmental neurotoxicity in zebrafish via AKT/FOXO3a-mediated apoptosis","authors":"Zhe Feng , Lisheng Zhu , Wentian Li , Fang Wang , Qianqian Cheng , Huihui Yang , Yuqing Huang , Wenqi Gao , Hui Lu , Junbao Wang , Han Xiao , Hongjian Gong","doi":"10.1016/j.cbi.2026.111904","DOIUrl":"10.1016/j.cbi.2026.111904","url":null,"abstract":"<div><div>Perospirone, an atypical antipsychotic increasingly detected in aquatic environments, raises concerns regarding potential developmental hazards in early vertebrates. As an emerging personal care product (PPCP) contaminant, its developmental neurotoxicity remains poorly characterized. To evaluate its biological effects, zebrafish embryos were exposed to perospirone (nominal 0.1, 1, 10 mg/L) from 5 to 120 hpf. At 5 dpf, larvae exposed to 1 mg/L displayed increased locomotion with anxiety-like features, whereas exposure to 10 mg/L was associated with reduced body length and hyperactivity suppression, together with elevated Caspase 9 and Pro- Caspase 3 expression consistent with apoptosis activation. Neurotransmitter profiling revealed an increase in 5-HIAA and decreases in dopamine and glutamine, accompanied by transcriptomic enrichment of pathways related to serotonergic signaling, oxidative stress, and FOXO/AKT regulation. Besides, molecular docking revealed high-affinity perospirone-AKT1 binding (−7.88 kcal/mol). These multi-omics findings establish that perospirone-induced developmental neurotoxicity stems from AKT/FOXO3a-mediated apoptosis, providing critical insights into its neurotoxicological profile and environmental risks as an emerging pharmaceutical contaminant.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111904"},"PeriodicalIF":5.4,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936753","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}
Pub Date : 2026-01-06DOI: 10.1016/j.cbi.2026.111907
Kuang-Ting Liu , Shu-Hao Chang , Kuan-Chen Wu , Zheng-Yi Li , Mao-Chia Chang , Yen-Chu Huang , Mu-Chi Chung , Shih-Chung Wang , Yi-Ju Chen , Jeng-Jer Shieh
Psoriasis and inflammatory bowel disease (IBD) are chronic immune-mediated disorders affecting the skin and gut, respectively, and share underlying mechanisms involving immune dysregulation and microbiota alterations. Imiquimod (IMQ), a compound commonly used to induce psoriasis-like skin inflammation in mice and exacerbate dextran sulfate sodium (DSS)-induced colitis. Accumulated research findings indicate that IMQ-induced reactive oxygen species (ROS) play a crucial role in biological functions and inflammation. In this study, we investigate the role of ROS in the pathogenesis of intestinal colitis and assess its potential as a therapeutic target by exposing mice to IMQ and establishing a novel disease model. Our results demonstrate that IMQ directly induces colitis-like inflammation in the intestines by depleting the mucus layer, reducing mucin 2 production, and increasing intestinal permeability. This induced model exhibits key features of inflammatory bowel disease, including pathological tissue characteristics. IMQ disrupts intestinal tight junctions and weakens barrier function, primarily through the ROS/extracellular signal-regulated kinase pathway. Moreover, antioxidant pretreatment alleviates colitis-like symptoms and restores intestinal barrier integrity. This IMQ-induced colitis model provides new insights into the molecular mechanisms underlying IBD and suggests its utility as a translational platform for assessing the therapeutic potential of redox-modulating interventions.
{"title":"Imiquimod-induced colitis: A novel ROS/ERK-driven model of intestinal inflammation and barrier dysfunction","authors":"Kuang-Ting Liu , Shu-Hao Chang , Kuan-Chen Wu , Zheng-Yi Li , Mao-Chia Chang , Yen-Chu Huang , Mu-Chi Chung , Shih-Chung Wang , Yi-Ju Chen , Jeng-Jer Shieh","doi":"10.1016/j.cbi.2026.111907","DOIUrl":"10.1016/j.cbi.2026.111907","url":null,"abstract":"<div><div>Psoriasis and inflammatory bowel disease (IBD) are chronic immune-mediated disorders affecting the skin and gut, respectively, and share underlying mechanisms involving immune dysregulation and microbiota alterations. Imiquimod (IMQ), a compound commonly used to induce psoriasis-like skin inflammation in mice and exacerbate dextran sulfate sodium (DSS)-induced colitis. Accumulated research findings indicate that IMQ-induced reactive oxygen species (ROS) play a crucial role in biological functions and inflammation. In this study, we investigate the role of ROS in the pathogenesis of intestinal colitis and assess its potential as a therapeutic target by exposing mice to IMQ and establishing a novel disease model. Our results demonstrate that IMQ directly induces colitis-like inflammation in the intestines by depleting the mucus layer, reducing mucin 2 production, and increasing intestinal permeability. This induced model exhibits key features of inflammatory bowel disease, including pathological tissue characteristics. IMQ disrupts intestinal tight junctions and weakens barrier function, primarily through the ROS/extracellular signal-regulated kinase pathway. Moreover, antioxidant pretreatment alleviates colitis-like symptoms and restores intestinal barrier integrity. This IMQ-induced colitis model provides new insights into the molecular mechanisms underlying IBD and suggests its utility as a translational platform for assessing the therapeutic potential of redox-modulating interventions.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111907"},"PeriodicalIF":5.4,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145924426","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}
Pub Date : 2026-01-06DOI: 10.1016/j.cbi.2026.111906
Yin-Fei Xing , Liang Yue , Chen-Hao Wang , Cai-Jiao Zhou , Jia-Qi Ye , Shi-Jie Li , Bin Guo
Cadmium (Cd), a widespread environmental pollutant, has toxic effects on spermatogenesis and sperm motility, but its role in uterine decidualization remains unknown. This study revealed that Cd exposure during early pregnancy might impair the uterine decidualization along with the disordered proliferation and apoptosis of stromal cells, resulting in the reduction of mouse neonatal number and birth weight. After disrupting the binding of Ca2+ and LNR-C, Cd exposure ligand-independently activated the NOTCH1 signaling and then restrained the expression of nuclear TAZ via RBPJ-targeting LATS. Further analysis suggested that Cd exposure contributed to the depletion of glutathione via Gclc that was identified as a direct downstream target of TAZ/TEAD, resulting in intracellular ROS accumulation and subsequent mitochondrial dysfunction. Meanwhile, Cd exposure prevented mitochondrial fusion and facilitated mitochondrial fission together with the fragmented mitochondria, whereas attenuation of intracellular ROS alleviated the imbalance between mitochondrial fusion and fission by Cd exposure. Moreover, improvement of mitochondrial fusion insufficiency and excessive fission rescued the impairment of Cd on decidualization. Collectively, Cd exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission. These findings reveal the toxic effect of Cd on female reproduction and serve as a risk factor for adverse pregnancy outcomes.
{"title":"Cadmium exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission","authors":"Yin-Fei Xing , Liang Yue , Chen-Hao Wang , Cai-Jiao Zhou , Jia-Qi Ye , Shi-Jie Li , Bin Guo","doi":"10.1016/j.cbi.2026.111906","DOIUrl":"10.1016/j.cbi.2026.111906","url":null,"abstract":"<div><div>Cadmium (Cd), a widespread environmental pollutant, has toxic effects on spermatogenesis and sperm motility, but its role in uterine decidualization remains unknown. This study revealed that Cd exposure during early pregnancy might impair the uterine decidualization along with the disordered proliferation and apoptosis of stromal cells, resulting in the reduction of mouse neonatal number and birth weight. After disrupting the binding of Ca<sup>2+</sup> and LNR-C, Cd exposure ligand-independently activated the NOTCH1 signaling and then restrained the expression of nuclear TAZ via RBPJ-targeting LATS. Further analysis suggested that Cd exposure contributed to the depletion of glutathione via Gclc that was identified as a direct downstream target of TAZ/TEAD, resulting in intracellular ROS accumulation and subsequent mitochondrial dysfunction. Meanwhile, Cd exposure prevented mitochondrial fusion and facilitated mitochondrial fission together with the fragmented mitochondria, whereas attenuation of intracellular ROS alleviated the imbalance between mitochondrial fusion and fission by Cd exposure. Moreover, improvement of mitochondrial fusion insufficiency and excessive fission rescued the impairment of Cd on decidualization. Collectively, Cd exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission. These findings reveal the toxic effect of Cd on female reproduction and serve as a risk factor for adverse pregnancy outcomes.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111906"},"PeriodicalIF":5.4,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922135","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}
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