Chemico-Biological Interactions最新文献

{"title":"Direct determination of kinetic parameters for the hydrolysis of a poor substrate by human plasma","authors":"Jure Stojan","doi":"10.1016/j.cbi.2025.111600","DOIUrl":"10.1016/j.cbi.2025.111600","url":null,"abstract":"<div><div>A method for characterizing the kinetic parameters of poor substrates is proposed. The hydrolysis of succinyldicholine by human wild type butyrylcholinesterase from whole plasma was chosen as a model reaction. Since the poor substrate succinyldicholine shows an inhibitory effect on butyrylcholinesterase hydrolysis of the enzyme's optimal substrate butyrylthiocholine, its inhibition constant was determined in the first of three steps, using Ellman's colorimetric detection method. In the second step, this inhibition constant is used to calculate the remaining succinyldicholine concentrations after incubating the enzyme at known initial concentration for various time periods. Finally, the catalytic constant is determined by numerically integrated Michaelis-Menten equation using data for the time course of the residual succinyldicholine concentration. This assumption was then confirmed by simultaneously analyzing all three data sets using the \"ENZO\" fitting tool. Additionally, the results are compared with those collected by another colorimetric method utilizing bromthymol blue to follow a small change in pH during the course of substrate hydrolysis. In this case the hydrolysis of succinyldicholine to succinylmonocholine and subsequently to succinic acid can only be followed by highly concentrated purified wild-type human butyrylcholinesterase. Close values of parameters, determined by two different methods, suggest the approach for revealing enzymes responsible for the metabolization of other xenobiotics, too.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111600"},"PeriodicalIF":4.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290665","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":"Insights into the diagnostic and prognostic value of paraoxonase 1-related variables and inflammatory markers in community-acquired pneumonia","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.2025.111606","DOIUrl":"10.1016/j.cbi.2025.111606","url":null,"abstract":"<div><div>Community-acquired pneumonia (CAP) remains a major health concern, with oxidative stress and inflammation playing key roles in its pathophysiology. This study examines the potential of paraoxonase-1 (PON1)-related variables as biomarkers for diagnosing and managing CAP. A prospective case-control study included 78 patients with community-acquired pneumonia (CAP) who were hospitalized and 80 healthy controls. Serum PON1 concentration (PON1c), PON1 arylesterase (ARE) and paraoxonase (PARX) activities, and inflammatory markers (C-reactive protein, procalcitonin, and C–C motif chemokine ligand 2 were measured and compared with lipid profiles and clinical severity scores. Receiver operating characteristic curve analysis was used to assess their diagnostic and prognostic value. CAP patients exhibited significantly lower ARE and PARX activities but higher PON1c levels than controls, with these changes correlating with increased inflammatory markers and decreased total and high-density lipoprotein cholesterol concentrations. PON1-related variables demonstrated strong diagnostic accuracies (areas under the curve &gt;0.90), outperforming traditional inflammatory markers. However, although these variables provided insights into disease severity and pathophysiology, their prognostic value and ability to differentiate microbial etiologies were limited. These findings suggest that PON1-related variables may serve as promising diagnostic biomarkers for CAP, but their role in prognosis and guiding antimicrobial therapy requires further investigation. Future studies should validate these results in larger and more diverse populations while exploring the mechanistic involvement of PON1 in CAP progression.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111606"},"PeriodicalIF":4.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295512","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":"Characterization of a gene expression biomarker predictive of hypoxia-inducible factor-1 modulation","authors":"J. Christopher Corton,&nbsp;Brian Chorley,&nbsp;Jie Liu","doi":"10.1016/j.cbi.2025.111595","DOIUrl":"10.1016/j.cbi.2025.111595","url":null,"abstract":"<div><div>We describe here a gene expression biomarker that can accurately identify chemicals and genetic conditions that perturb hypoxia-inducible factor-1 (HIF-1), a transcription factor critical for the cellular response to hypoxia involved in the pathophysiology of cancer, inflammation, and ischemia. The HIF-1 biomarker genes were identified from transcript profiles in a variety of human cell lines after hypoxia as well as genetic knockdown of the <em>HIF1A</em> gene. The HIF-1 biomarker of 122 genes was found to be enriched for genes bound by HIF-1 using ChIP-Seq and metabolic pathways regulated by HIF-1 (e.g., gluconeogenesis). Using Ingenuity Pathway Analysis, HIF-1 was the top predicted transcriptional regulator of the genes. The biomarker could identify activation of HIF-1 by overexpression of the <em>HIF1A</em> gene or suppression of the negative regulator, von-Hipple Lindau (<em>VHL</em>) gene; suppression of HIF-1 occurred by inhibition of the expression of <em>HIF1A</em> or the heterodimer partner aryl hydrocarbon receptor nuclear translocator (<em>ARNT)</em>. The biomarker was specific for HIF-1 activation, as activation or suppression of the <em>HIF-2</em> gene was not detected by the biomarker. Using a reference chemical set with 180 positives and 45 negatives, the balanced accuracy of the HIF-1 biomarker to identify activation was 94.1 %. An <em>in-silico</em> screen of a gene expression compendium identified hundreds of potential activators. Eleven of these were selected for verification and all were found to activate HIF-1 biomarker genes in wild-type but not <em>HIF1A</em>-null cells. The HIF-1 biomarker will be a useful tool to identify environmentally relevant chemicals that affect HIF-1 in high-throughput transcriptomics screening studies.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111595"},"PeriodicalIF":4.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276988","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":"Vehicle-specific toxicological profiles of tire wear particles: Physiological, microbial, and transcriptomic disruptions in zebrafish induced by light and heavy-duty vehicle emissions","authors":"Qingxuan Meng,&nbsp;Qianqian Song,&nbsp;Xinrui Meng,&nbsp;Xiaolong Wang,&nbsp;Jing Cong","doi":"10.1016/j.cbi.2025.111602","DOIUrl":"10.1016/j.cbi.2025.111602","url":null,"abstract":"<div><div>Tire wear particles (TWPs) from vehicles have emerged as significant sources of environmental microplastics, releasing hazardous metals and organic contaminants into aquatic ecosystems. However, the differential toxicological effects of TWPs originating from heavy-duty vehicle tire wear particles (HTWPs) versus light-duty vehicle tire wear particles (LTWPs) remain inadequately characterized. Here, we comprehensively evaluated physiological responses, gut microbiota alterations, and liver transcriptomic changes in zebrafish exposed to HTWPs and LTWPs. Scanning electron microscopy (SEM) analysis revealed that HTWPs exhibit rougher surfaces and sharper edges compared to LTWPs. Physiologically, HTWP exposure resulted in marked reductions in body and organ growth metrics and induced sustained oxidative stress responses, whereas LTWPs triggered comparatively milder oxidative effects. Microbial analysis demonstrated significant gut dysbiosis following HTWP exposure, characterized by decreased microbial diversity and an increased abundance of pathogenic <em>Acinetobacter</em>, negatively correlated with hepatic <em>irf1b</em> expression. Functional predictions based on PICRUSt2 further revealed vehicle-specific alterations in gut microbial metabolism: immune- and xenobiotic-related pathways were enriched under HTWP exposure, while LTWP exposure enhanced microbial functions related to lipid metabolism. These functional shifts suggest potential host-microbiota metabolic crosstalk. Transcriptomic analyses indicated particle-type-specific disruptions: HTWPs predominantly impaired carbohydrate metabolism, downregulating critical glycolytic genes (<em>pgk1</em>, <em>pkma</em>), while LTWPs primarily altered lipid metabolic pathways, as evidenced by decreased <em>acacb</em> and increased <em>hadhaa</em> expression. Notably, both HTWP and LTWP exposures activated inflammatory signaling via the MAPK pathway, particularly through upregulation of <em>mapk8a</em>. Quantitative PCR validation confirmed the robustness and reliability of the RNA-seq results. Together, these findings highlight distinct toxicological mechanisms driven by vehicle source and underscore the need for source-specific ecological risk assessments to mitigate the environmental impact of TWP pollution.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111602"},"PeriodicalIF":4.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254967","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":"The use of phosphotriesterase in the synthesis of enantiomerically pure ProTide prodrugs","authors":"Andrew N. Bigley ,&nbsp;Frank M. Raushel","doi":"10.1016/j.cbi.2025.111597","DOIUrl":"10.1016/j.cbi.2025.111597","url":null,"abstract":"<div><div>Outbreaks of viral diseases, such as COVID-19, and chronic viral diseases, such as HIV and hepatitis, have highlighted the need to develop antiviral medications. ProTide nucleotide analogs such as Remdesivir and Sofosbuvir have become an important class of antivirals. The ProTides are phosphonamidate prodrugs, which contain an alanine ester and a phenyl group esterified to a chiral phosphorus of a nucleotide analog. The resulting triester effectively masks the charge on the phosphate moiety to facilitate entry into the cell and are much more effective than the corresponding nucleoside analogs. Once in the cell, the ProTides require activation by cellular enzymes to remove the masking groups on the phosphorus. The activation in the cell is dependent on the stereochemistry of the phosphorus center with the effectiveness of a given isomer differing between tissue types. The ProTides are produced as single isomers at the phosphorus center by chiral chromatography or selective crystallization, but in many cases only a single isomer can be produced, potentially limiting the effectiveness of the ProTides. The phosphotriesterase (PTE) from <em>Brevundimonas diminuta</em> is well known for its ability to selectively hydrolyze chiral phosphotriesters. The extensive directed evolution of PTE has led to the identification of variants that can selectively hydrolyze the phosphonamidate precursor of the ProTides, allowing the preparation of optically pure ProTides. Importantly, the variant In1W-PTE allows the isolation of the pure <em>R</em>_P-isomer while G60A-PTE and W131M-PTE allow the isolation of the pure <em>S</em>_P-isomer, thereby facilitating the efficient preparation of either isomer of the final ProTide.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111597"},"PeriodicalIF":4.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251277","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":"Rational synthesis, activity and mechanism insights of a new aminoquinoline salt against malaria parasites: in vitro and in vivo approaches","authors":"Bruno Assis de Oliveira ,&nbsp;Felipe Oliveira Raimundo ,&nbsp;Wenderson Tinorio de Paula ,&nbsp;Jessica Corrêa Bezerra Bellei ,&nbsp;Nícolas Glanzmann ,&nbsp;Letícia Ferreira Machado ,&nbsp;Amanda Luisa da Fonseca ,&nbsp;Camila Simões Freitas ,&nbsp;Isabelle Karine da Costa Nunes ,&nbsp;Adolfo Firmino Neto ,&nbsp;Vinícius Novaes Rocha ,&nbsp;Henrique Marcelo Gualberto Pereira ,&nbsp;Eduardo Antônio Ferraz Coelho ,&nbsp;Fernando de Pilla Varotti ,&nbsp;Kézia Katiani Gorza Scopel ,&nbsp;Adilson David da Silva","doi":"10.1016/j.cbi.2025.111588","DOIUrl":"10.1016/j.cbi.2025.111588","url":null,"abstract":"<div><div>The lack of an effective vaccine against all <em>Plasmodium</em> species, combined with the emergence and spread of resistance to traditional antimalarials, has, together with other factors, contributed to the failure of malaria eradication campaigns around the world. Therefore, the search for drugs with antiplasmodial activity is one of the priorities of the global scientific community and is strongly supported by the WHO. In this study, 6 synthetic compounds derived from 4-aminoquinolines were synthesized. <em>In silico</em> analyzes of their physicochemical and pharmacokinetic properties suggest that all compounds have good oral bioavailability, while they were not cytotoxic <em>in vitro</em> assays. Although compounds <strong>7</strong> and <strong>9</strong> showed the best IC₅₀ values when evaluated <em>in vitro</em> against <em>P. falciparum</em> (chloroquine-resistant W2 strain), compound <strong>9</strong> showed the best effectiveness <em>in vivo</em>, with rates of inhibition of parasite multiplication varying from 72 to 50 % between days 5 and 9 post-infection. Docking-based inverse virtual screening indicated that compound <strong>9</strong> exhibited potential interaction against 1O5X (Triose-phosphate Isomerase), 2OK8 (Ferredoxin-NADP(+) Reductase), 4C81 (2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF)), and 4N0Z (glutaredoxin 1) targets, while UV–Vis analysis suggested action of compound in the digestive vacuole of the parasite. Together these results suggest that compound <strong>9</strong> is promising as an antimalarial molecule.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111588"},"PeriodicalIF":4.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251318","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":"Mechanism of ferroptosis in hypoxia-induced pulmonary vascular remodeling in hypoxia pulmonary hypertension: a study based on the ACE2-Ang-(1–7)-Mas axis","authors":"Asimuguli Abudukeremu ,&nbsp;Ainiwaer Aikemu ,&nbsp;Tao Yang ,&nbsp;Lei Fang ,&nbsp;Daliya Shanahati ,&nbsp;Yiliyaer Nijiati","doi":"10.1016/j.cbi.2025.111596","DOIUrl":"10.1016/j.cbi.2025.111596","url":null,"abstract":"<div><div>Hypoxic pulmonary hypertension (HPH) is a chronic, progressive pulmonary vascular disease caused by prolonged exposure to low-oxygen conditions. Pulmonary vascular remodeling (PVR) is a key pathological feature of pulmonary artery hypertension (PAH), primarily driven by suppressed cell death and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Current therapies for HPH primarily focus on vasodilation rather than directly targeting PVR, highlighting the need for treatments capable of reversing VR. Ferroptosis, a recently identified form of regulated cell death, has gained attention for its potential to eliminate cancer cells; however, its involvement in PVR remains unclear. We aimed to explore whether induction of ferroptosis could suppress abnormal PASMC proliferation and mitigate hypoxia-induced PVR. In the pulmonary artery, angiotensin-converting enzyme 2 (ACE2) promotes vasodilation and inhibits PASMC proliferation, suggesting a potential therapeutic target. This study demonstrated that the expression levels of ferroptosis-related proteins-glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11)- were significantly upregulated in lung tissues and PASMCs from hypoxia-induced Sugen5416/hypoxia (SuHx) mouse models, suggesting the presence of ferroptosis resistance. Notably, ACE2 activation induced ferroptosis, whereas reduced ACE2 activity led to resistance to ferroptosis. These findings suggest that enhanced ACE2 activity may inhibit abnormal PASMC proliferation and reverse hypoxia-induced PVR, as demonstrated by both in vivo and in vitro experiments. We hypothesize that modulation of ACE2 activity influences PVR through ferroptosis regulation. This study identifies potential therapeutic targets and new research directions for the pathogenesis and treatment of HPH.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111596"},"PeriodicalIF":4.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227979","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":"Semaglutide attenuates lipotoxicity-induced cardiac injury by inhibiting Slc27a2 expression","authors":"Xiaoyu Pan ,&nbsp;Shuqi Wang ,&nbsp;Xiaoman Yang ,&nbsp;Boying Jia ,&nbsp;Shuchun Chen","doi":"10.1016/j.cbi.2025.111583","DOIUrl":"10.1016/j.cbi.2025.111583","url":null,"abstract":"<div><div>The precise mechanism of action of semaglutide in obese patients remains uncertain, although it is evident that the drug confers a significant cardiac benefit. An excessively high-fat diet has been demonstrated to result in an increased expression of solute carrier family 27 member 2 (Slc27a2/FATP2) on cardiomyocyte membranes. This is associated with a number of adverse effects, including lipid deposition in cardiomyocytes, elevated levels of inflammation and oxidative stress, impaired cardiac function, decreased cardiomyocyte viability, and increased apoptosis. The administration of semaglutide was observed to partially reverse the cardiac dysfunction induced by an excessive high-fat diet, to protect cardiomyocytes, and to significantly reduce the expression of Slc27a2. However, the cardioprotective effects of semaglutide were partially counteracted by the use of an adenosine A2A receptor antagonist, whereas the opposite result was observed with an adenosine A2A receptor agonist. In light of these findings, it can be concluded that the adenosine A2A receptor plays a pivotal role in the cardioprotective effects of semaglutide. The reduction of Slc27a2 expression downstream of this receptor has been demonstrated to enhance lipid metabolism and mitigate lipid overdeposition in cardiomyocytes, thereby conferring cardioprotection.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111583"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210425","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":"Inhibition of JMJD3 attenuates acute liver injury by suppressing inflammation and oxidative stress in LPS/D-Gal-induced mice","authors":"Chenhan Bu ,&nbsp;Yueqing Xie ,&nbsp;Jiawei Weng,&nbsp;Youpeng Sun,&nbsp;Hanpeng Wu,&nbsp;Yichun Chen,&nbsp;Yingrong Ye,&nbsp;Ershun Zhou,&nbsp;Zhengtao Yang,&nbsp;Jingjing Wang","doi":"10.1016/j.cbi.2025.111576","DOIUrl":"10.1016/j.cbi.2025.111576","url":null,"abstract":"<div><div>Histone methylation/demethylation represents a pivotal epigenetic mechanism governing heritable gene expression and chromatin architecture, with profound implications for the pathogenesis of hepatic disorders. JMJD3 (KDM6B), a Jumonji domain-containing histone demethylase specifically targeting di- and trimethylated lysine 27 on histone H3 (H3K27me2/3), has emerged as a critical regulator of inflammatory diseases. The study primarily investigates the impact and mechanisms of JMJD3 on acute liver injury. Utilizing both <em>in vitro</em> (LPS-stimulated RAW264.7 macrophages) and <em>in vivo</em> (LPS/<span>d</span>-Galactosamine-induced murine model) systems, we demonstrate that JMJD3 expression is dramatically upregulated during acute liver injury. Strikingly, pharmacological inhibition with the selective JMJD3 inhibitor GSK-J1 or siRNA-mediated JMJD3 silencing robustly attenuated pro-inflammatory cytokine production in macrophages and substantially ameliorated hepatic inflammation and tissue damage in mice. Mechanistically, JMJD3 inhibition elevated global H3K27me3 levels, suppressed NF-κB signaling activation and downstream inflammatory cascades. Furthermore, JMJD3 inhibition activated the Nrf2/HO-1 antioxidant pathway, enhancing cellular defenses against oxidative stress by upregulating key antioxidant enzymes. These findings suggest that JMJD3 orchestrates dual pro-inflammatory and pro-oxidative pathways in liver injury, positioning it as a novel therapeutic target. Our work not only advances the molecular understanding of epigenetic regulation in hepatopathology but also identifies GSK-J1 as a promising pharmacological candidate for mitigating acute hepatic damage.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111576"},"PeriodicalIF":4.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203893","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":"Uremic toxin indoxyl sulfate induces the imbalance of cellular iron metabolism and oxidative stress to interfere with myogenesis in myoblasts","authors":"Jia-Hua Jhuang ,&nbsp;Ching-Chia Wang ,&nbsp;Chih-Kang Chiang ,&nbsp;Shing-Hwa Liu ,&nbsp;Kuo-Cheng Lan","doi":"10.1016/j.cbi.2025.111587","DOIUrl":"10.1016/j.cbi.2025.111587","url":null,"abstract":"<div><div>Chronic kidney disease (CKD) leads to the accumulation of uremic toxins such as indoxyl sulfate (IS), which has been linked to myopathy. Iron is essential for muscle growth and differentiation, with ferrous iron (Fe²⁺) contributing to intracellular oxidative stress. Although IS known to affect muscle differentiation and regeneration, the underlying mechanisms remain poorly understood. Both iron overload and deficiency can negatively impact muscle growth. We hypothesized that IS impairs myoblast differentiation by disrupting the balance between intracellular oxidative stress and iron metabolism. To test this, we exposed C2C12 myoblasts and primary human skeletal muscle myoblasts to IS during the proliferation phase and maintained IS exposure throughout the differentiation process. IS treatment reduced both intracellular reactive oxygen species (ROS) and free Fe²⁺ levels during differentiation. It also altered intracellular iron metabolism and upregulated the gene expression and activity of antioxidant-related enzymes, maintaining the cells in a high-antioxidant state and establishing a new oxidative balance. Unexpectedly, Fe²⁺ (FeSO₄) supplementation, with or without IS, significantly increased ROS levels and further exacerbated the inhibition of myoblast differentiation induced by IS, suggesting that cellular redox homeostasis was disrupted. These findings reveal that IS induces an imbalance in cellular iron metabolism and oxidative stress, providing new insights into an alternative mechanism by which IS inhibits muscle differentiation and regeneration.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111587"},"PeriodicalIF":4.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192609","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}