Toxicology in Vitro最新文献

{"title":"Integrative toxicity assessment of tocotrienol-rich fraction from palm oil using in silico methods and zebrafish embryotoxicity model","authors":"Thenmoly Damodaran ,&nbsp;Najib Sani Yahaya ,&nbsp;Mohd Nizam Mordi","doi":"10.1016/j.tiv.2025.106062","DOIUrl":"10.1016/j.tiv.2025.106062","url":null,"abstract":"<div><div>Tocotrienol-rich fraction (TRF), a natural form of vitamin E derived from palm oil, possesses antioxidant properties. However, its potential embryonic developmental toxicity remains unclear. This study investigated TRF's toxicity using <em>in silico</em> methods and zebrafish embryos. Zebrafish embryos were exposed to TRF (31.25 to 2000 μg/mL) for 96 h post-fertilization (hpf). Mortality, hatching rate, heart rate, and morphological malformations were assessed at 24, 48, 72, and 96 hpf. <em>In silico</em> analysis predicted good pharmacokinetic properties and minimal side effects for five TRF constituents, except for hERG II inhibition, which is associated with cardiac toxicity. TRF exposure up to 96 hpf showed no embryotoxicity in zebrafish at ≤1000 μg/mL. However, TRF at concentrations of ≥1000 μg/mL significantly inhibited hatching rate at 72 hpf, indicating a delay in the hatching process. Additionally, 1000 μg/mL of TRF resulted in reduced heart rate and hypopigmentation in the embryos. Moreover, higher TRF concentrations (≥500 μg/mL) caused morphological malformations including spinal curvature, pericardial edema, and yolk sac edema, in the embryos. These findings suggest that TRF from palm oil is likely safe at concentrations below 500 μg/mL during embryonic development. However, the potential effects of long-term exposure and chronic toxicity warrant further investigation to ensure safety during early pregnancy.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"107 ","pages":"Article 106062"},"PeriodicalIF":2.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ozone and particulate matter co-exposure at the air-liquid interface: Establishing an approach to assess pollutant interactions in vitro","authors":"Andres R. Henriquez ,&nbsp;Marjolaine Godbout-Cheliak ,&nbsp;Alain Filiatreault ,&nbsp;Errol M. Thomson","doi":"10.1016/j.tiv.2025.106060","DOIUrl":"10.1016/j.tiv.2025.106060","url":null,"abstract":"<div><h3>Background</h3><div>Air pollution is a complex mixture of gases and particulates that varies spatially and temporally, making attribution of adverse effects to specific individual air pollutants a challenge. To disentangle effects of mixtures in a controlled setting, reproducible and realistic co-exposures of human-relevant models to gaseous and particulate pollutants are needed. Although air-liquid interface (ALI) exposures offer considerable promise as non-animal models for inhalation toxicity testing, a lack of studies comparing individual and co-exposures to gaseous and particulate pollutants has thus far prevented assessment of their strengths and limitations for disentangling effects of pollutant mixtures.</div></div><div><h3>Methods</h3><div>Using an integrated ALI exposure system, we characterized the interaction between ozone and particles (25 nm fluorescent polystyrene beads) to assess effects on and reproducibility of critical physical endpoints including temperature, humidity, ozone concentration and particle deposition. Particle deposition and concentration were assessed <em>via</em> three independent methods: fluorescence, quartz crystal microbalance (QCM), and airborne particle count. To evaluate the acute biological effects of an air pollutant mixture <em>in vitro</em>, human lung type 2 epithelial-like cells (A549) were exposed at the ALI to air, ozone (O₃), particles, and O₃ + particles (co-exposure) for 1 h (<em>n</em> = 4 independent repeats/exposure type). Cell injury and inflammation were quantified by extracellular lactate dehydrogenase (LDH) activity and release of proinflammatory cytokines (interleukin (IL)-8 and IL-6) respectively 0 and 24 h post-exposure.</div></div><div><h3>Results</h3><div>Exposures were effective at delivering targeted O₃ exposures under controlled temperature and relative humidity. In-well particle deposition and airborne concentration exiting the exposure system, quantified through parallel methods, were consistent, and increased in relation to aerosolized particle concentration. Levels of each pollutant were effectively maintained in the presence of the other. O₃ alone, and co-exposure to O₃ and particles, increased LDH release from A549 cells, indicating pollutant-specific cytotoxicity. In contrast, IL-8 and IL-6 release (24 h &gt; 0 h) were not changed by exposure to the individual pollutants, but tended to increase following co-exposure.</div></div><div><h3>Conclusion</h3><div>The present work establishes the utility of ALI exposure systems to disentangle individual effects of pollutants from a mixture, and highlights the importance of direct experimental characterization of dosimetry and exposure conditions.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"107 ","pages":"Article 106060"},"PeriodicalIF":2.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of organic solvents on the in vitro transport activity of three OATP isoforms","authors":"Rina Saito ,&nbsp;Takeshi Akiyoshi ,&nbsp;Kazunari Tsujii ,&nbsp;Riho Takahashi ,&nbsp;Hiroki Kataoka ,&nbsp;Ayuko Imaoka ,&nbsp;Hisakazu Ohtani","doi":"10.1016/j.tiv.2025.106059","DOIUrl":"10.1016/j.tiv.2025.106059","url":null,"abstract":"<div><h3>Purpose</h3><div><em>In vitro</em> studies of transporter activity often require the addition of organic solvents such as dimethyl sulfoxide (DMSO), methanol, and ethanol, to dissolve substrates and/or inhibitors. Although this may attenuate the transport activity, the influence of different types of organic solvents on transporter activity has not been elucidated. This study aimed to quantitatively assess the impact of organic solvents on the transport activity of organic anion transporting polypeptide (OATP) 1B1, 1A2, and 2B1.</div></div><div><h3>Methods</h3><div>The concentration-dependent influence of DMSO, methanol, and ethanol on the uptake of [³H]estrone 3-sulfate mediated by OATP1A2, OATP2B1 or 2′,7′-dichlorofluorescein (DCF) mediated by OATP1B1 was assessed using HEK293 cells expressed the respective OATP protein and the concentration that reduced the uptake by 20 % (IC₂₀) was calculated.</div></div><div><h3>Results and discussion</h3><div>The uptake activities of OATPs were reduced by methanol and ethanol in a concentration-dependent manner, with IC₂₀ values of 2.4–3.4 % and 0.51–3.8 % respectively. In contrast, DMSO did not affect the OATP2B1-mediated uptake at the maximum concentration (10 %) of DMSO whereas it exhibited concentration-dependent inhibition for OATP1B1 and 1A2 with IC₂₀ values of approximately 3 % and 0.7 %, respectively. This study provides useful information regarding experimental conditions for evaluating OATPs activity <em>in vitro</em>.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"107 ","pages":"Article 106059"},"PeriodicalIF":2.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study","authors":"Lisa Pu ,&nbsp;Joel R. Steele ,&nbsp;Connor R. Phillips ,&nbsp;Jake P. Violi ,&nbsp;Kenneth J. Rodgers","doi":"10.1016/j.tiv.2025.106058","DOIUrl":"10.1016/j.tiv.2025.106058","url":null,"abstract":"<div><div>Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-<em>N</em>-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the <span>l</span>-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with <span>l</span>-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the <span>l</span>-serine biosynthesis pathway and broad disturbances in energy metabolism.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"106 ","pages":"Article 106058"},"PeriodicalIF":2.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of 17β-estradiol and estrogen receptor subtype-specific agonists on Jurkat E6.1 T-cell leukemia cells","authors":"Rahul S. Nair ,&nbsp;Mantavya N. Patel ,&nbsp;Thangamani Kannan ,&nbsp;Shaili Gour ,&nbsp;Murali M. Hariharan ,&nbsp;Vijayarengamani Prasanna ,&nbsp;Anupriya Thirumalai ,&nbsp;Ramanathan Chockalingam ,&nbsp;Ramasamy Vasantharekha ,&nbsp;Srinivasan ThyagaRajan ,&nbsp;Hannah P. Priyanka","doi":"10.1016/j.tiv.2025.106057","DOIUrl":"10.1016/j.tiv.2025.106057","url":null,"abstract":"<div><h3>Background</h3><div>Estrogen signaling plays a crucial role in immune regulation and cancer metabolism, yet its impact on T-cell leukemia remains unclear. In hematological malignancies, estrogen receptor (ER) activation may influence metabolic shifts that affect cell survival and proliferation. This study investigates the <em>in vitro</em> effects of 17β-estradiol and estrogen receptor subtype-specific agonists on Jurkat E6.1 T-cell leukemia cells.</div></div><div><h3>Purpose</h3><div>To assess how estrogen signaling influences metabolic reprogramming, inflammatory response, and survival pathways in Jurkat E6.1 cells through receptor-dependent and independent mechanisms.</div></div><div><h3>Methods</h3><div>Jurkat E6.1 cells incubated with different concentrations of 17β-estradiol (10⁻¹² M, 10⁻¹⁰ M, 10⁻⁸ M) or ER-α agonist 4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (10⁻¹⁰ M, 10⁻⁸ M, 10⁻⁶ M) or ER-β agonist diarylproprionitrile (10⁻¹⁰ M, 10⁻⁸ M, 10⁻⁶ M) with and without non-specific antagonist ICI 182,780 (10⁻⁶ M). The metabolic enzyme activities of hexokinase, pyruvate kinase, and citrate synthase were measured in cell pellets, while supernatants were analyzed for IL-6 and nitric oxide (NO) production. Additionally, PI3K/Akt pathway activation was assessed by measuring p-Akt/Total Akt expression.</div></div><div><h3>Results</h3><div>A shift from glycolysis to oxidative phosphorylation was observed on treatment with 17β-estradiol with significant decline in hexokinase activity and a concomitant increase in activities of pyruvate kinase and citrate synthase.</div></div><div><h3>Conclusion</h3><div>17β-estradiol mediates its effects on Jurkat E6.1 cells <em>in vitro</em> through receptor-subtype dependent and independent mechanisms involving metabolic enzymes (hexokinase, pyruvate kinase, citrate synthase), cytokines (IL-6), nitric oxide, and signaling molecules (p-Akt).</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"106 ","pages":"Article 106057"},"PeriodicalIF":2.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of JAK2/STAT3 by pacritinib synergizes with chemotherapy in esophageal carcinoma","authors":"Lan Han ,&nbsp;Yinyin Sun ,&nbsp;Kai Yang,&nbsp;Cheng Long","doi":"10.1016/j.tiv.2025.106056","DOIUrl":"10.1016/j.tiv.2025.106056","url":null,"abstract":"<div><div>The poor outcomes associated with esophageal carcinoma, particularly in advanced stages, necessitate the development of new treatment strategies. This study examines the efficacy of pacritinib, a multi-kinase inhibitor, both alone and in combination with carboplatin, in preclinical esophageal carcinoma models. Six esophageal carcinoma cell lines (KYSE-70, OE33, FLO-1, KYAE-1, ESO 26, and HCE-6) were treated with pacritinib, resulting in a dose-dependent reduction in cell viability. Combination index (CI) analysis demonstrated strong synergy between pacritinib and carboplatin across this panel of cell lines. In in vivo esophageal carcinoma xenograft model, pacritinib alone significantly reduced tumor growth and improved survival rates compared to control. Notably, the combination of pacritinib and carboplatin further reduced tumor growth and improved survival rates compared to either treatment alone. Toxicity assessment showed that neither single-agent nor combination treatment resulted in significantly altered levels of body weight and serum markers, supporting the safety profile of pacritinib in combination with carboplatin. Mechanistic studies revealed that while pacritinib inhibited the phosphorylation of JAK, STAT3, and IRAK1 in esophageal carcinoma cells, it is the suppression of the JAK/STAT3 pathway, rather than IRAK1, that is responsible for the synergistic effect with carboplatin. Our findings indicate that pacritinib possesses potent anti-tumor activity in esophageal carcinoma and enhances the efficacy of carboplatin through the suppression of JAK/STAT3 signaling, warranting further clinical investigation.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"106 ","pages":"Article 106056"},"PeriodicalIF":2.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of intestinal absorption of five cannabinoids from an ethanolic CBD-rich hemp extract using Caco-2 cells in vitro","authors":"Magali Araujo,&nbsp;Erica Stewart,&nbsp;Yang Zhao,&nbsp;Estatira Sepehr,&nbsp;Cory Vaught,&nbsp;Clara Erice,&nbsp;Robert L. Sprando","doi":"10.1016/j.tiv.2025.106053","DOIUrl":"10.1016/j.tiv.2025.106053","url":null,"abstract":"<div><div>Cannabinoids are highly lipophilic constituents of the hemp plant, which is present in several products intended for consumption. While cannabidiol (CBD) effects to humans have been extensively investigated, there is limited information on other minor cannabinoids. CBD oral bioavailability is low but increases with food and high-fat intake. We used Caco-2 cells <em>in vitro</em> to assess intestinal absorption of five cannabinoids (CBD, CBC, CBG, CBN, and CBDV) present in a CBD-rich hemp extract. We used a fed-state simulated intestinal fluid (Fessif) for dissolution of cannabinoids. Cannabinoids did not alter Caco-2 monolayer integrity. Except for CBC, recovery of cannabinoids decreased significantly after 90-minute incubation, compared to 60-minute incubation. No measurable cannabinoids were identified in the bottom chambers. Recovery of CBD, CBC, CBG and CBN after incubation with hemp extract or cannabinoid mix containing 30 μM CBD was unchanged, but CBDV recovery decreased. With hemp extract or a mix containing 10 μM CBD, recovery of CBD and CBC did not change, CBG recovery was lower (80–82 %), and CBN and CBDV were unquantifiable. This study highlights the challenges of evaluating permeability of cannabinoids by Caco-2 cells to predict intestinal absorption, including the physicochemical properties of these compounds, incubation time and cell properties.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"106 ","pages":"Article 106053"},"PeriodicalIF":2.6,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of skin corrosion and irritation test methods employing ex vivo porcine skin model","authors":"Jeong-hyun Hong ,&nbsp;Kyung-Min Lim","doi":"10.1016/j.tiv.2025.106055","DOIUrl":"10.1016/j.tiv.2025.106055","url":null,"abstract":"<div><div>Skin corrosion and irritation are key local toxicological responses of the skin to chemical exposure. Conventional <em>in vivo</em> methods have limitations such as species difference, ethical concern, and reproducibility issue, necessitating the development of reliable alternatives. We developed skin corrosion (SCT) and irritation test (SIT) methods using <em>ex vivo</em> porcine ear skin based on cell viability and skin barrier disruption. Test chemicals were treated on <em>ex vivo</em> porcine ear skin for 3 min and 60 min (SCT) or 60 min only (SIT). After 40 ± 2 h post-incubation, cell viability assay with CCK-8, and skin barrier test with FITC-dextran penetration were conducted. To evaluate the predictive capacity of the method, 38 reference chemicals (20 corrosives, 8 irritants and 10 no category chemicals) were tested. SCT achieved 96.7 % (29/30) accuracy in identifying corrosives, meeting the performance standards of OECD TG 431 <em>In Vitro</em> Skin Corrosion: Reconstructed Human Epidermis test. The accuracy for subcategorizing corrosive substances into categories 1 A (&lt;25 % at 3 min) and 1B/1C (≥25 % at 3 min, &lt;25 % at 60 min) was 83.3 % (25/30). The accuracy of SIT identifying non-irritant (≥50 % at 60 min) was 83.3 % (15/18). FITC-dextran penetration assay showed a similar accuracy, highlighting its value as an alternative endpoint to identify irritants. Collectively, this study demonstrated that the <em>ex vivo</em> porcine skin model may offer a cost-effective, and reliable alternative for skin hazard testing.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"106 ","pages":"Article 106055"},"PeriodicalIF":2.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmentally relevant concentrations of antimony pose potential risks to human health: An evaluation on human umbilical vein endothelial cells","authors":"Shanshan Wang ,&nbsp;Dongqian Guo ,&nbsp;Xian Chen ,&nbsp;Su-Zhu Chen ,&nbsp;Xi-Wen Cui ,&nbsp;Yong-He Han ,&nbsp;Ping Xiang","doi":"10.1016/j.tiv.2025.106054","DOIUrl":"10.1016/j.tiv.2025.106054","url":null,"abstract":"<div><div>Antimony (Sb) ore exploitation and the use of Sb-containing drugs pose known health risks. This study investigated the toxicity of environmentally relevant concentrations of Sb (0.12–12 mg L⁻¹) on human umbilical vein endothelial cells (HUVECs). The 50 % lethal concentration (LC₅₀) of Sb to HUVECs was 11.4 mg L⁻¹. Exposing to high level of Sb induced cell cycle arrest by altering the expression of cell cycle regulators, inhibiting the transitions of G₀/G₁ to S and S to G₂/M. At 1.2 mg L⁻¹ Sb, <em>CKD6</em> and <em>p21</em> expressions in HUVECs changed to 0.75 and 1.32 folds that of no-Sb control, respectively (<em>p</em> &lt; 0.01). At 12 mg L⁻¹ Sb, <em>CDK2</em>, <em>CKD6</em>, and <em>p27</em> expressions decreased by 1.54, 4.41, and 1.54 folds (<em>p</em> &lt; 0.001), while <em>p21</em> expression increased by 3.03 folds (<em>p</em> &lt; 0.001) as compared to control. Sb also led to cell apoptosis, evidenced by Annexin V-FITC/PI staining and changes in the expressions of <em>Bax</em> (1.21–1.30 folds, <em>p</em> &lt; 0.01) and <em>Bcl-2</em> (0.65–0.83 folds). Oxidative damage was a pivotal factor driving cell apoptosis, probably through down-regulating antioxidant genes (<em>CAT</em>, <em>GPX1</em>, and <em>GSTP1</em>) and up-regulating stress response genes (<em>HO-1</em>, <em>SOD1</em>, and <em>TrxR1</em>). The elevated H₂O₂ generated in mitochondria likely contributed to cell apoptosis due to the imbalance in H₂O₂ metabolism. These findings suggest that environmentally relevant concentrations of Sb can exert cytotoxicity to HUVECs, which should be of potential concern for human cardiovascular disease.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"106 ","pages":"Article 106054"},"PeriodicalIF":2.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolonged exposure to simvastatin affects coenzyme Q9/10 status leading to impaired mitochondrial respiratory capacity and reduced viability of cultured cardiac cells","authors":"Sinenhlanhla X.H. Mthembu ,&nbsp;Sithandiwe E. Mazibuko-Mbeje ,&nbsp;Sonia Silvestri ,&nbsp;Patrick Orlando ,&nbsp;Bongani B. Nkambule ,&nbsp;Christo J.F. Muller ,&nbsp;Luca Tiano ,&nbsp;Phiwayinkosi V. Dludla","doi":"10.1016/j.tiv.2025.106052","DOIUrl":"10.1016/j.tiv.2025.106052","url":null,"abstract":"<div><div>This study investigates the effects of prolonged simvastatin exposure on coenzyme Q_9/10 (CoQ_9/10) levels, an essential component of antioxidant defense, in cultured cardiac cells. Statins, commonly used to manage dyslipidemia and reduce cardiovascular risk, may impair mitochondrial function, but their impact on CoQ₁₀ depletion and oxidative stress is not well understood. We examined the influence of simvastatin on mitochondrial oxidative capacity, reactive oxygen species (ROS) production, and CoQ_9/10 status at concentrations of 0.3, 0.6, 1.25, 2.5, 5, 10, and 20 μM, over durations of 24, 48, and 72 h. Using an in vitro model of cultured H9c2 cardiomyoblasts, our results showed that short-term exposure (24 h) at lower concentrations (&lt;5 μM) enhanced cytosolic and mitochondrial ROS levels without affecting mitochondrial function or CoQ_9/10 status. However, prolonged exposure to higher concentrations (≥10 μM for &gt;48 h) resulted in impaired mitochondrial oxidative capacity, indicated by increased proton leak and elevated ROS levels, which were followed by significantly reduced cell viability. These findings suggest that prolonged, high-dose simvastatin exposure may disrupt the oxidative balance of CoQ_9/10, leading to myocardial injury. This research addresses a gap in understanding the long-term effects of statins on mitochondrial health and underscores the need for further studies to optimize statin therapy and minimize adverse effects on myocardial function.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"106 ","pages":"Article 106052"},"PeriodicalIF":2.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}