{"title":"Acetyl alkannin, a Shikonin monomer, inhibits the ATM/DDR pathway by targeting ATM and sensitizes cisplatin in solid tumors: A commentary","authors":"Mengqin Guo , Yilin Ma , Chuanbin Wu , Zhengwei Huang","doi":"10.1016/j.cbi.2025.111835","DOIUrl":"10.1016/j.cbi.2025.111835","url":null,"abstract":"","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111835"},"PeriodicalIF":5.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566791","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 : 2025-11-19DOI: 10.1016/j.cbi.2025.111837
Qi Cheng , Yifan Xie , Yingying Hou , Yan Du , Huaxiang Wu
This study systematically investigates the mechanisms by which per- and polyfluoroalkyl substances (PFAS) promote immune dysregulation and trigger autoimmune diseases (ADs). Using an integrated network toxicology and bioinformatics approach, we identified core molecular interactions between PFAS and five ADs—rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), ankylosing spondylitis (AS), and vasculitis. By combining data from STITCH, SwissTargetPrediction, Comparative Toxicogenomics Database, GeneCards, and OMIM, we identified shared targets linked to both PFAS exposure and AD pathogenesis. Functional enrichment analysis was performed using DAVID, and protein-protein interaction networks were constructed with STRING and visualized in Cytoscape to highlight core targets. Gene expression data from the GEO database revealed the upregulation or downregulation of these targets across these ADs. Molecular docking performed with CB-Dock2 confirmed robust binding between six PFAS and core targets, notably IL1B, TNF, IL6 and ALB. Importantly, we identified a common pathological mechanism involving PFAS-mediated disruption of the inflammatory cytokine axis (IL1B, TNF, IL6) and IL-17/Th17 signaling pathway, which triggers ADs. Furthermore, compared to PFOS, its alternative 6:2 Cl-PFESA showed higher binding affinity to core targets, suggesting greater environmental and health risks that warrant re-evaluation. In conclusion, our research has provided novel and important insights into environmental health and ADs by clarifying core targets and potential mechanisms, and has expanded the evidence into the molecular mechanism of PFAS-induced immunotoxicity and linking PFAS exposure to ADs.
{"title":"Per- and polyfluoroalkyl substances trigger autoimmune diseases through inflammatory cytokines-IL-17/Th17 signaling axis","authors":"Qi Cheng , Yifan Xie , Yingying Hou , Yan Du , Huaxiang Wu","doi":"10.1016/j.cbi.2025.111837","DOIUrl":"10.1016/j.cbi.2025.111837","url":null,"abstract":"<div><div>This study systematically investigates the mechanisms by which per- and polyfluoroalkyl substances (PFAS) promote immune dysregulation and trigger autoimmune diseases (ADs). Using an integrated network toxicology and bioinformatics approach, we identified core molecular interactions between PFAS and five ADs—rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), ankylosing spondylitis (AS), and vasculitis. By combining data from STITCH, SwissTargetPrediction, Comparative Toxicogenomics Database, GeneCards, and OMIM, we identified shared targets linked to both PFAS exposure and AD pathogenesis. Functional enrichment analysis was performed using DAVID, and protein-protein interaction networks were constructed with STRING and visualized in Cytoscape to highlight core targets. Gene expression data from the GEO database revealed the upregulation or downregulation of these targets across these ADs. Molecular docking performed with CB-Dock2 confirmed robust binding between six PFAS and core targets, notably IL1B, TNF, IL6 and ALB. Importantly, we identified a common pathological mechanism involving PFAS-mediated disruption of the inflammatory cytokine axis (IL1B, TNF, IL6) and IL-17/Th17 signaling pathway, which triggers ADs. Furthermore, compared to PFOS, its alternative 6:2 Cl-PFESA showed higher binding affinity to core targets, suggesting greater environmental and health risks that warrant re-evaluation. In conclusion, our research has provided novel and important insights into environmental health and ADs by clarifying core targets and potential mechanisms, and has expanded the evidence into the molecular mechanism of PFAS-induced immunotoxicity and linking PFAS exposure to ADs.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111837"},"PeriodicalIF":5.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566748","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 : 2025-11-19DOI: 10.1016/j.cbi.2025.111844
Qian Li , Miao Wang , Juan Zuo , Zaichao Dong , Tongtong Sha , Kangting Luo , Huanxia Zhang , Yanjie Dou , Guoyu Zhou , Yue Ba , Fang-fang Yu
T-2 toxin, the most toxic type A mycotoxin, induces cardiotoxicity and impairs cardiac function. Herein, we investigated the regulatory role of mitophagy in T-2 toxin–induced myocardial injury. Using the Comparative Toxicogenomics Database, we identified 288 rat genes associated with T-2 toxin–induced myocardial injury. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that mitophagy was significantly associated with myocardial injury. Protein–protein interaction network analysis revealed HIF-1α as the core regulatory gene. Rats were exposed to T-2 toxin and assigned to control, low-dose (100 ng/g·bw/day), and high-dose (200 ng/g·bw/day) groups. H9C2 cardiomyocytes were divided into control, low-dose (3 ng/mL), medium-dose (6 ng/mL), and high-dose (12 ng/mL) groups. High-dose T-2 toxin exposure caused significant myocardial damage, increased lactate dehydrogenase and creatine kinase–myocardial band levels, elevated reactive oxygen species (ROS) accumulation, and upregulated HIF-1α expression in the nucleus. Flow cytometry showed that T-2 toxin significantly decreased mitochondrial membrane potential. Transmission electron microscopy revealed mitochondrial swelling, vacuolation, and cristae disruption. Molecular docking and immunofluorescence confirmed direct binding between BNIP3L and LC3. T-2 toxin significantly upregulated HIF-1α, BNIP3L, and LC3 mRNA and protein levels, promoted LC3-I to LC3-II conversion, and suppressed P62 expression in tissues and cells. Immunohistochemistry further confirmed these protein expression trends. Myocardial injury was ameliorated by 2-ME2 by suppressing HIF-1α accumulation and BNIP3L-mediated mitophagy. In summary, T-2 toxin–induced ROS accumulation activated HIF-1α in cardiomyocytes, which regulated BNIP3L–LC3 binding, mediated mitophagy, and ultimately caused myocardial injury.
{"title":"HIF-1α/BNIP3L–mediated mitophagy is involved in T-2 toxin–induced myocardial injury","authors":"Qian Li , Miao Wang , Juan Zuo , Zaichao Dong , Tongtong Sha , Kangting Luo , Huanxia Zhang , Yanjie Dou , Guoyu Zhou , Yue Ba , Fang-fang Yu","doi":"10.1016/j.cbi.2025.111844","DOIUrl":"10.1016/j.cbi.2025.111844","url":null,"abstract":"<div><div>T-2 toxin, the most toxic type A mycotoxin, induces cardiotoxicity and impairs cardiac function. Herein, we investigated the regulatory role of mitophagy in T-2 toxin–induced myocardial injury. Using the Comparative Toxicogenomics Database, we identified 288 rat genes associated with T-2 toxin–induced myocardial injury. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that mitophagy was significantly associated with myocardial injury. Protein–protein interaction network analysis revealed <em>HIF-1α</em> as the core regulatory gene. Rats were exposed to T-2 toxin and assigned to control, low-dose (100 ng/g·bw/day), and high-dose (200 ng/g·bw/day) groups. H9C2 cardiomyocytes were divided into control, low-dose (3 ng/mL), medium-dose (6 ng/mL), and high-dose (12 ng/mL) groups. High-dose T-2 toxin exposure caused significant myocardial damage, increased lactate dehydrogenase and creatine kinase–myocardial band levels, elevated reactive oxygen species (ROS) accumulation, and upregulated HIF-1α expression in the nucleus. Flow cytometry showed that T-2 toxin significantly decreased mitochondrial membrane potential. Transmission electron microscopy revealed mitochondrial swelling, vacuolation, and cristae disruption. Molecular docking and immunofluorescence confirmed direct binding between BNIP3L and LC3. T-2 toxin significantly upregulated HIF-1α, BNIP3L, and LC3 mRNA and protein levels, promoted LC3-I to LC3-II conversion, and suppressed P62 expression in tissues and cells. Immunohistochemistry further confirmed these protein expression trends. Myocardial injury was ameliorated by 2-ME2 by suppressing HIF-1α accumulation and BNIP3L-mediated mitophagy. In summary, T-2 toxin–induced ROS accumulation activated HIF-1α in cardiomyocytes, which regulated BNIP3L–LC3 binding, mediated mitophagy, and ultimately caused myocardial injury.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111844"},"PeriodicalIF":5.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575061","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 : 2025-11-19DOI: 10.1016/j.cbi.2025.111836
Rok Gašperšič , Ajda Taler-Verčič , Boštjan Petrič , Marko Goličnik , Aljoša Bavec
This pilot study evaluated total esterase activity and PON-1 activity in unstimulated and stimulated saliva of periodontitis patients and healthy subjects focusing on relation to clinical data, salivary flow rate, pH, total protein concentration, albumin concentration and active matrix metalloproteinase 8 (aMMP-8) concentration. Healthy participants (n = 20) and periodontitis patients (n = 32) were recruited. Clinical data was recorded, both unstimulated and stimulated saliva samples were collected, and salivary flow rates were determined for each participant. The concentrations of albumin and aMMP-8 were determined with ELISA and ORALyzer, respectively. Total protein concentration, total esterase activity, and PON-1 activity were determined spectrophotometrically. Kinetic data was analyzed with iFIT software. Albumin levels were higher in periodontitis patients compared to healthy controls. While there are no significant differences in the total esterase and PON-1 activities between periodontitis patients and healthy controls, the limiting rate VMAX value showed significant differences but in the Michaelis constant KM value only in stimulated saliva samples. The distribution of aMMP-8 levels above and below the detection limit of 20 ng/mL showed elevated values mainly in periodontitis patients, and this difference was more apparent in stimulated saliva samples. For each parameter assessed in this study, stimulated saliva exhibited greater differences between groups, than unstimulated saliva. The kinetic parameter VMAX, total esterase activity (using the substrate phenyl acetate), and PON-1 activity (using the substrate paraoxon) can present potential markers for periodontitis.
{"title":"Total esterase and paraoxonase activity in human saliva of periodontitis patients and healthy individuals; a pilot study","authors":"Rok Gašperšič , Ajda Taler-Verčič , Boštjan Petrič , Marko Goličnik , Aljoša Bavec","doi":"10.1016/j.cbi.2025.111836","DOIUrl":"10.1016/j.cbi.2025.111836","url":null,"abstract":"<div><div>This pilot study evaluated total esterase activity and PON-1 activity in unstimulated and stimulated saliva of periodontitis patients and healthy subjects focusing on relation to clinical data, salivary flow rate, pH, total protein concentration, albumin concentration and active matrix metalloproteinase 8 (aMMP-8) concentration. Healthy participants (n = 20) and periodontitis patients (n = 32) were recruited. Clinical data was recorded, both unstimulated and stimulated saliva samples were collected, and salivary flow rates were determined for each participant. The concentrations of albumin and aMMP-8 were determined with ELISA and ORALyzer, respectively. Total protein concentration, total esterase activity, and PON-1 activity were determined spectrophotometrically. Kinetic data was analyzed with iFIT software. Albumin levels were higher in periodontitis patients compared to healthy controls. While there are no significant differences in the total esterase and PON-1 activities between periodontitis patients and healthy controls, the limiting rate V<sub>MAX</sub> value showed significant differences but in the Michaelis constant K<sub>M</sub> value only in stimulated saliva samples. The distribution of aMMP-8 levels above and below the detection limit of 20 ng/mL showed elevated values mainly in periodontitis patients, and this difference was more apparent in stimulated saliva samples. For each parameter assessed in this study, stimulated saliva exhibited greater differences between groups, than unstimulated saliva. The kinetic parameter V<sub>MAX</sub>, total esterase activity (using the substrate phenyl acetate), and PON-1 activity (using the substrate paraoxon) can present potential markers for periodontitis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111836"},"PeriodicalIF":5.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575071","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 : 2025-11-19DOI: 10.1016/j.cbi.2025.111838
Zhongchi Xu , Jiaqi Li , Yuyang Hou , Zhewen Deng , Qi Zhang , Bo Ma
Oridonin (ORI), a bioactive diterpenoid isolated from Rabdosia rubescens, possesses anti-inflammatory, antibacterial and anti-tumor medicinal properties. However, its clinical application has been limited due to significant male reproductive toxicity, the underlying mechanisms of which remain elusive. In this study, we explore the potential mechanism of ORI-induced testicular injury and identify potential therapeutic targets for mitigating its reproductive toxicity. GC-MS metabolomics was employed to investigate differential metabolites in the serum of mice subjected to ORI-induced testicular injury. we demonstrated for the first time in vivo and in vitro that ORI-induced testicular ferroptosis, accompanied by cysteine, GSH and NADPH depletion, ROS accumulation, intracellular ferrous enrichment, and changes in the expression of ferroptosis-related proteins. Molecular docking and co-immunoprecipitation (CO-IP) were performed to validate the STUB1-GPX4 interaction and GPX4 ubiquitination. Network toxicology identified potential targets, followed by experimental validation of HIF-1α/HO-1 pathway activation via Western blot, RT-qPCR, and immunohistochemistry (IHC). Mechanistically, ORI induced testicular ferroptosis through two distinct pathways: (1) STUB1-mediated ubiquitination and degradation of GPX4, and (2) activation of the HIF-1α/HO-1 signaling axis, as predicted by network toxicology and confirmed experimentally. Collectively, this study provides the first evidence that ORI exposure induces testicular impairment via dual mechanisms: HIF-1α/HO-1 pathway activation and STUB1-dependent GPX4 ubiquitination, both of which collectively facilitate ferroptosis. These findings not only elucidate the molecular basis of ORI induced-reproductive toxicity but also identify STUB1 and HIF-1α/HO-1 as potential therapeutic targets for prevention and treatment.
{"title":"Oridonin exposure induces testicular impairment through regulating ferroptosis via HIF-1α/HO-1 activation and STUB1-driven GPX4 ubiquitination-dependent degradation","authors":"Zhongchi Xu , Jiaqi Li , Yuyang Hou , Zhewen Deng , Qi Zhang , Bo Ma","doi":"10.1016/j.cbi.2025.111838","DOIUrl":"10.1016/j.cbi.2025.111838","url":null,"abstract":"<div><div>Oridonin (ORI), a bioactive diterpenoid isolated from <em>Rabdosia rubescens</em>, possesses anti-inflammatory, antibacterial and anti-tumor medicinal properties. However, its clinical application has been limited due to significant male reproductive toxicity, the underlying mechanisms of which remain elusive. In this study, we explore the potential mechanism of ORI-induced testicular injury and identify potential therapeutic targets for mitigating its reproductive toxicity. GC-MS metabolomics was employed to investigate differential metabolites in the serum of mice subjected to ORI-induced testicular injury. we demonstrated for the first time <em>in vivo</em> and <em>in vitro</em> that ORI-induced testicular ferroptosis, accompanied by cysteine, GSH and NADPH depletion, ROS accumulation, intracellular ferrous enrichment, and changes in the expression of ferroptosis-related proteins. Molecular docking and co-immunoprecipitation (CO-IP) were performed to validate the STUB1-GPX4 interaction and GPX4 ubiquitination. Network toxicology identified potential targets, followed by experimental validation of HIF-1α/HO-1 pathway activation via Western blot, RT-qPCR, and immunohistochemistry (IHC). Mechanistically, ORI induced testicular ferroptosis through two distinct pathways: (1) STUB1-mediated ubiquitination and degradation of GPX4, and (2) activation of the HIF-1α/HO-1 signaling axis, as predicted by network toxicology and confirmed experimentally. Collectively, this study provides the first evidence that ORI exposure induces testicular impairment via dual mechanisms: HIF-1α/HO-1 pathway activation and STUB1-dependent GPX4 ubiquitination, both of which collectively facilitate ferroptosis. These findings not only elucidate the molecular basis of ORI induced-reproductive toxicity but also identify STUB1 and HIF-1α/HO-1 as potential therapeutic targets for prevention and treatment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111838"},"PeriodicalIF":5.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566732","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 : 2025-11-19DOI: 10.1016/j.cbi.2025.111834
S. García-Carpintero , V. Jehová González , A. Esteban-Arranz , J. Frontiñán-Rubio , E. Vázquez , M. Durán-Prado
The increasing production and application of graphene-related materials (GRMs) and other 2D nanomaterials (2D materials) raise concerns about their potential genotoxicity. This study aims to assess the genotoxic effects of these materials using a modified in vitro comet assay and double-strand break (DSB) detection via the γH2AX assay, which is crucial for determining the safety of these compounds. Chinese hamster ovary cells (CHO–K1) were exposed to graphene oxide (GO), few-layer graphene (FLG), monolayer GO (mlGO), molybdenum disulfide (MoS2), and hexagonal boron nitride (hBN) at concentrations of 0, 0.05, 0.5, 5, 20, and 50 μg/mL for 24 h. Adaptations to the standard comet assay were implemented to address interference caused by 2D material agglomeration, which can hinder accurate DNA damage detection. Controlled, gentle mechanical shaking during incubation minimized agglomeration, improving the visualization of DNA damage. Both the modified in vitro comet assay and γH2AX DSB assay indicated that all materials tested, except mlGO, exhibited genotoxic effects at sublethal concentrations. These findings suggest that certain GRMs should be classified as genotoxic, warranting careful consideration of their potential risks, and recommending the modified comet assay as a reliable tool for 2D material genotoxicity assessment.
{"title":"Development of in vitro DNA damage assays to properly assess the genotoxicity of graphene and other 2D materials","authors":"S. García-Carpintero , V. Jehová González , A. Esteban-Arranz , J. Frontiñán-Rubio , E. Vázquez , M. Durán-Prado","doi":"10.1016/j.cbi.2025.111834","DOIUrl":"10.1016/j.cbi.2025.111834","url":null,"abstract":"<div><div>The increasing production and application of graphene-related materials (GRMs) and other 2D nanomaterials (2D materials) raise concerns about their potential genotoxicity. This study aims to assess the genotoxic effects of these materials using a modified <em>in vitro</em> comet assay and double-strand break (DSB) detection via the γH2AX assay, which is crucial for determining the safety of these compounds. Chinese hamster ovary cells (CHO–K1) were exposed to graphene oxide (GO), few-layer graphene (FLG), monolayer GO (mlGO), molybdenum disulfide (MoS<sub>2</sub>), and hexagonal boron nitride (hBN) at concentrations of 0, 0.05, 0.5, 5, 20, and 50 μg/mL for 24 h. Adaptations to the standard comet assay were implemented to address interference caused by 2D material agglomeration, which can hinder accurate DNA damage detection. Controlled, gentle mechanical shaking during incubation minimized agglomeration, improving the visualization of DNA damage. Both the modified <em>in vitro</em> comet assay and γH2AX DSB assay indicated that all materials tested, except mlGO, exhibited genotoxic effects at sublethal concentrations. These findings suggest that certain GRMs should be classified as genotoxic, warranting careful consideration of their potential risks, and recommending the modified comet assay as a reliable tool for 2D material genotoxicity assessment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111834"},"PeriodicalIF":5.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566815","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 : 2025-11-17DOI: 10.1016/j.cbi.2025.111831
Jin Gu , Yanwen Zheng , Jian Su , Rui Li , Chiyu Zhang , Han Wang , Zhaomin Zhong
Chelidonium majus L. (C. majus) is a notable medicinal plant, esteemed for its antispasmodic and analgesic properties. The principal bioactive compound, chelidonine, acts similarly to morphine as an anesthetic analgesic and inhibits tumor growth by disrupting mitosis. However, the safety profile of C. majus and chelidonine in living organisms remains inadequately characterized. This study found that C. majus causes pericardial edema and reduced body length, with chelidonine being the key component responsible for cardiotoxic effects in zebrafish larvae. These effects of chelidonine treatment include reduced body length, enlargement of the pericardial region, decreased heart rate, and elongation of cardiac chambers. RNA sequencing analysis revealed a significant enrichment of apoptosis-related genes, notably tp53, among the differentially expressed genes. Molecular docking analysis identified four binding sites for chelidonine on the Tp53 protein. Surface plasmon resonance (SPR) results indicated that chelidonine exhibited moderate binding affinity to the TP53 protein, with a dissociation constant (KD) of 3.635 μM. Furthermore, PFN-α, an inhibitor of TP53, demonstrated potential in mitigating the cardiac developmental abnormalities induced by chelidonine. This study demonstrates that the toxicological impact of chelidonine on cardiac development, as well as its interaction with the pro-apoptotic gene tp53, elucidates the underlying mechanisms of toxicity associated with this traditional Chinese herbal compound. These findings offer an experimental foundation for minimizing cardiac-related toxicities during cancer treatments involving chelidonine.
白屈菜（Chelidonium majus L.， C. majus）是一种著名的药用植物，具有抗痉挛和镇痛作用。主要的生物活性化合物，chelidonine，作为麻醉镇痛药的作用类似于吗啡，并通过破坏有丝分裂抑制肿瘤生长。然而，在活的生物体中，大蓟和chelidonine的安全性特征仍然不充分。本研究发现，C. majus引起心包水肿和体长缩短，而chelidonine是斑马鱼幼鱼心脏毒性作用的关键成分。chelidonine治疗的这些影响包括体长缩短、心包区域扩大、心率降低和心室延长。RNA测序分析显示，在差异表达基因中，凋亡相关基因显著富集，尤其是tp53。分子对接分析确定了chelidonine在Tp53蛋白上的四个结合位点。表面等离子体共振（SPR）结果表明，chelidonine与TP53蛋白具有中等的结合亲和力，解离常数（KD）为3.635 μM。此外，TP53的抑制剂PFN-α显示出减轻chelidonine诱导的心脏发育异常的潜力。这项研究表明，chelidonine对心脏发育的毒理学影响，以及它与促凋亡基因tp53的相互作用，阐明了与这种传统中药化合物相关的潜在毒性机制。这些发现为在使用chelidonine治疗癌症期间尽量减少心脏相关毒性提供了实验基础。
{"title":"Activation of the Tp53 apoptosis signaling pathway by chelidonine induces cardiac developmental abnormalities in zebrafish larvae","authors":"Jin Gu , Yanwen Zheng , Jian Su , Rui Li , Chiyu Zhang , Han Wang , Zhaomin Zhong","doi":"10.1016/j.cbi.2025.111831","DOIUrl":"10.1016/j.cbi.2025.111831","url":null,"abstract":"<div><div><em>Chelidonium majus</em> L. (<em>C. majus</em>) is a notable medicinal plant, esteemed for its antispasmodic and analgesic properties. The principal bioactive compound, chelidonine, acts similarly to morphine as an anesthetic analgesic and inhibits tumor growth by disrupting mitosis. However, the safety profile of <em>C. majus</em> and chelidonine in living organisms remains inadequately characterized. This study found that <em>C. majus</em> causes pericardial edema and reduced body length, with chelidonine being the key component responsible for cardiotoxic effects in zebrafish larvae. These effects of chelidonine treatment include reduced body length, enlargement of the pericardial region, decreased heart rate, and elongation of cardiac chambers. RNA sequencing analysis revealed a significant enrichment of apoptosis-related genes, notably <em>tp53</em>, among the differentially expressed genes. Molecular docking analysis identified four binding sites for chelidonine on the Tp53 protein. Surface plasmon resonance (SPR) results indicated that chelidonine exhibited moderate binding affinity to the TP53 protein, with a dissociation constant (K<sub>D</sub>) of 3.635 μM. Furthermore, PFN-α, an inhibitor of TP53, demonstrated potential in mitigating the cardiac developmental abnormalities induced by chelidonine. This study demonstrates that the toxicological impact of chelidonine on cardiac development, as well as its interaction with the pro-apoptotic gene <em>tp53</em>, elucidates the underlying mechanisms of toxicity associated with this traditional Chinese herbal compound. These findings offer an experimental foundation for minimizing cardiac-related toxicities during cancer treatments involving chelidonine.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111831"},"PeriodicalIF":5.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558615","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 : 2025-11-15DOI: 10.1016/j.cbi.2025.111815
Seungjin Jeong , Yu-An Lu , Seokmin Lee , Jae-Il Kim , You-Jin Jeon , Jimin Hyun , Bomi Ryu
Dieckol (DK), a phlorotannin isolated from Ecklonia cava, has been suggested to exert vasodilatory effects through endothelial signaling. In this study, the endothelial–smooth muscle signaling pathway involved in DK-mediated vasodilation was recapitulated using a multistep experimental system that integrates a co-culture of human coronary artery endothelial cells (HCAEC) and human coronary artery Smooth Muscle Cells (HCASMC) with an in vivo zebrafish model. DK activated calcium-dependent signaling pathways in HCAEC, notably via muscarinic acetylcholine receptor M3 (AChM3R) and voltage-dependent calcium channels (VDCC), resulting in increased intracellular calcium levels and nitric oxide (NO) production. These effects were confirmed using specific antagonists. NO produced by HCAEC was subsequently transferred to adjacent HCASMC, leading to reduced expression of contractile proteins such as phosphorylated myosin light chain (p-MLC) and calmodulin (CaM), thereby promoting smooth muscle relaxation. Moreover, DK counteracted phenylephrine-induced vasoconstriction in zebrafish by reinforcing vascular integrity and regulating blood flow dynamics, ultimately restoring vascular patency and hemodynamic homeostasis. Collectively, these results demonstrate that DK induces vasodilation by activating AChM3R– and VDCC–mediated calcium signaling and NO production in endothelial cells, with downstream effects on vascular smooth muscle cells. This study highlights the therapeutic potential of DK for improving vascular function through modulation of endothelial–smooth muscle signaling.
{"title":"Dieckol induces vasodilation via endothelial–smooth muscle crosstalk in co-culture and in vivo zebrafish models","authors":"Seungjin Jeong , Yu-An Lu , Seokmin Lee , Jae-Il Kim , You-Jin Jeon , Jimin Hyun , Bomi Ryu","doi":"10.1016/j.cbi.2025.111815","DOIUrl":"10.1016/j.cbi.2025.111815","url":null,"abstract":"<div><div>Dieckol (DK), a phlorotannin isolated from <em>Ecklonia cava</em>, has been suggested to exert vasodilatory effects through endothelial signaling. In this study, the endothelial–smooth muscle signaling pathway involved in DK-mediated vasodilation was recapitulated using a multistep experimental system that integrates a co-culture of human coronary artery endothelial cells (HCAEC) and human coronary artery Smooth Muscle Cells (HCASMC) with an in vivo zebrafish model. DK activated calcium-dependent signaling pathways in HCAEC, notably via muscarinic acetylcholine receptor M3 (AChM3R) and voltage-dependent calcium channels (VDCC), resulting in increased intracellular calcium levels and nitric oxide (NO) production. These effects were confirmed using specific antagonists. NO produced by HCAEC was subsequently transferred to adjacent HCASMC, leading to reduced expression of contractile proteins such as phosphorylated myosin light chain (<em>p</em>-MLC) and calmodulin (CaM), thereby promoting smooth muscle relaxation. Moreover, DK counteracted phenylephrine-induced vasoconstriction in zebrafish by reinforcing vascular integrity and regulating blood flow dynamics, ultimately restoring vascular patency and hemodynamic homeostasis. Collectively, these results demonstrate that DK induces vasodilation by activating AChM3R– and VDCC–mediated calcium signaling and NO production in endothelial cells, with downstream effects on vascular smooth muscle cells. This study highlights the therapeutic potential of DK for improving vascular function through modulation of endothelial–smooth muscle signaling.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111815"},"PeriodicalIF":5.4,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145544265","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 : 2025-11-15DOI: 10.1016/j.cbi.2025.111830
Peter Mastnak-Sokolov , Damijan Knez , Anže Meden , Nika Strašek Benedik , Svit Ferjančič Benetik , Martina Hrast Rambaher , Maša Zorman , Florian Nachon , Xavier Brazzolotto , Kent Jardemark , Oscar Jungholm , Joseph Bruton , Emilia Strandback , Tomas Nyman , Mohammed Shahid , Stanislav Gobec
Alzheimer's disease (AD) is the leading cause of dementia worldwide, but current therapies provide only symptomatic relief. Multi-target directed ligands (MTDLs) represent a promising approach to address AD pathology by modulating multiple targets with a single molecule. Here we describe quinuclidine carbamates that act simultaneously on butyrylcholinesterase (BChE) and the cholinergic α7 nicotinic receptor (α7 nAChR), thereby approaching cholinergic dysfunction at two levels: by modulating acetylcholine degradation and by direct agonism at this receptor. Starting with the α7 nAChR agonist bradanicline, its amide group was replaced by a carbamate moiety to enhance BChE inhibition while retaining receptor agonism. These quinuclidine carbamates inhibited BChE in the submicromolar range with the desired selectivity over acetylcholinesterase (AChE). In a calcium-flux assay on recombinant HEK293T cells expressing the α7 nAChR, all compounds were agonists of the α7 nAChR in the nanomolar range. Importantly, compound 6b displayed balanced, submicromolar activity against both targets. The crystal structures confirmed non-covalent binding to the active site of human BChE, and the 6b-hBChE complex also revealed an unprecedented flip of Tyr440, representing the first described example of backdoor opening for hBChE. Taken together, these results demonstrate that quinuclidine carbamates are promising dual modulators of hBChE and α7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery.
{"title":"Dual cholinergic modulation in dementia: Quinuclidine carbamates targeting butyrylcholinesterase and α7 nicotinic receptor","authors":"Peter Mastnak-Sokolov , Damijan Knez , Anže Meden , Nika Strašek Benedik , Svit Ferjančič Benetik , Martina Hrast Rambaher , Maša Zorman , Florian Nachon , Xavier Brazzolotto , Kent Jardemark , Oscar Jungholm , Joseph Bruton , Emilia Strandback , Tomas Nyman , Mohammed Shahid , Stanislav Gobec","doi":"10.1016/j.cbi.2025.111830","DOIUrl":"10.1016/j.cbi.2025.111830","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the leading cause of dementia worldwide, but current therapies provide only symptomatic relief. Multi-target directed ligands (MTDLs) represent a promising approach to address AD pathology by modulating multiple targets with a single molecule. Here we describe quinuclidine carbamates that act simultaneously on butyrylcholinesterase (BChE) and the cholinergic α7 nicotinic receptor (α7 nAChR), thereby approaching cholinergic dysfunction at two levels: by modulating acetylcholine degradation and by direct agonism at this receptor. Starting with the α7 nAChR agonist bradanicline, its amide group was replaced by a carbamate moiety to enhance BChE inhibition while retaining receptor agonism. These quinuclidine carbamates inhibited BChE in the submicromolar range with the desired selectivity over acetylcholinesterase (AChE). In a calcium-flux assay on recombinant HEK293T cells expressing the α7 nAChR, all compounds were agonists of the α7 nAChR in the nanomolar range. Importantly, compound <strong>6b</strong> displayed balanced, submicromolar activity against both targets. The crystal structures confirmed non-covalent binding to the active site of human BChE, and the <strong>6b</strong>-hBChE complex also revealed an unprecedented flip of Tyr440, representing the first described example of backdoor opening for hBChE. Taken together, these results demonstrate that quinuclidine carbamates are promising dual modulators of hBChE and α7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111830"},"PeriodicalIF":5.4,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535206","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 : 2025-11-13DOI: 10.1016/j.cbi.2025.111828
Xiaochen Wang , Rui Li , Yuanbing You , Yidi Gao , Tiantian Wang , Jingkang Li , Qiong Zhang
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.
{"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 , Rui Li , Yuanbing You , Yidi Gao , Tiantian Wang , Jingkang Li , 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 Ca<sup>2+</sup> 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<sup>+</sup> depletion, which elevated lipid (MDA↑), protein (carbonyls↑), and DNA (8-OHdG↑, γ-H<sub>2</sub>AX↑) damage; inflammation, as evidenced by tumour necrosis factor-α/interleukin (IL)-1β/IL-18 elevation and macrophage infiltration (F4/80<sup>+</sup>/HMGB1<sup>+</sup>); and apoptosis, as evidenced by PUMA (Bbc3) induction, caspase-3/8 activation, and Bax/Bcl-2 imbalance. In vitro, H<sub>2</sub>O<sub>2</sub>-induced oxidative stress in human renal tubules replicated Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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":"2025-11-13","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}
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