Chemico-Biological Interactions最新文献

{"title":"Pantothenic acid alleviates osteoarthritis progression by inhibiting inflammatory response and ferroptosis through the SIRT1/Nrf2 signaling pathway","authors":"Yi Liu ,&nbsp;Yang Wang ,&nbsp;Shengqi Cheng ,&nbsp;Jie Mu ,&nbsp;Guanchen Yin ,&nbsp;Hang Gao","doi":"10.1016/j.cbi.2025.111494","DOIUrl":"10.1016/j.cbi.2025.111494","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a degenerative joint disease that is a major cause of deformity, swelling, pain and even loss of function in the knee joints of the elderly. Pantothenic acid (PA) plays a protective role in many organs due to its antioxidant and anti-inflammatory properties. Herein, we aimed to assess the protective role of PA on osteoarthritis and investigate the underlying molecular mechanism. The levels of inflammatory factors (IL-1β and TNF-α) in knee tissues were measured by ELISA. The Safranin O-Fast Green staining was used to assess the severity of OA and the H&amp;E staining was used to assess the degree of synovitis. In vitro, the levels of iron, MDA, GSH were measured by the detection kits. Western blotting was used to assess the levels of signaling-related proteins. Our results showed that PA significantly attenuated the degree of cartilage degeneration in the MIA-induced osteoarthritis model. PA also reduced the expression of IL-1β, TNF-α, MMP1 and MMP3. In vitro, PA effectively reduced the concentrations of MMP1 and MMP3 in IL-1β-stimulated chondrocytes. PA decreased the levels of Fe²⁺ and MDA, while increasing GSH production and GPX4 and SLC7A11 expression in IL-1β-induced chondrocytes. Meanwhile, we found that PA was able to inhibit the phosphorylation level of p65, IκB protein in chondrocytes, which effectively blocked the NF-κB signaling pathway. Furthermore, PA also increased the level of SIRT1, Nrf2, and HO-1 protein expression. In addition, the inhibition of PA on IL-1β-induced MMPs production and ferroptosis were inhibited by the SIRT1 inhibitor EX-527. In conclusion, PA inhibited chondrocyte ferroptosis and cartilage destruction in osteoarthritis. The mechanism was through activating SIRT1/Nrf2 signaling pathway.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111494"},"PeriodicalIF":4.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738251","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":"Pre-clinical evidence for mitochondria as a therapeutic target for luteolin: A mechanistic view","authors":"Marcos Roberto de Oliveira","doi":"10.1016/j.cbi.2025.111492","DOIUrl":"10.1016/j.cbi.2025.111492","url":null,"abstract":"<div><div>Pre-clinical evidence indicates that mitochondria may be a therapeutic target for luteolin (3′,4’,5,7-tetrahydroxyflavone; LUT) in different conditions. LUT modulates mitochondrial physiology in <em>in vitro</em>, <em>ex vivo</em>, and <em>in vivo</em> experimental models. This flavone exerted mitochondria-related antioxidant and anti-apoptotic effects, stimulated mitochondrial fusion and fission, induced mitophagy, and promoted mitochondrial biogenesis in human and animal cells and tissues. Moreover, LUT modulated the activity of components of the oxidative phosphorylation (OXPHOS) system, improving the ability of mitochondria to produce adenosine triphosphate (ATP) in certain circumstances. The mechanism of action by which LUT promoted mitochondrial benefits and protection are not completely clear yet. Nonetheless, LUT is a potential candidate to be utilized in mitochondrial therapy in the future. In this work, it is explored the mechanisms of action by which LUT modulates mitochondrial physiology in different pre-clinical experimental models.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111492"},"PeriodicalIF":4.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726237","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":"Flavonoids and their role in oxidative stress, inflammation, and human diseases","authors":"Klaudia Jomova ,&nbsp;Suliman Y. Alomar ,&nbsp;Richard Valko ,&nbsp;Jan Liska ,&nbsp;Eugenie Nepovimova ,&nbsp;Kamil Kuca ,&nbsp;Marian Valko","doi":"10.1016/j.cbi.2025.111489","DOIUrl":"10.1016/j.cbi.2025.111489","url":null,"abstract":"<div><div>Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2<img>C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2–related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111489"},"PeriodicalIF":4.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of novel aldose reductase inhibitor drug on gut microbiota composition and metabolic health in ZDF 'lean' rats","authors":"Marek Lepáček ,&nbsp;Pavol Boďo ,&nbsp;Marta Šoltésová Prnová ,&nbsp;Mária Bučková ,&nbsp;Domenico Pangallo ,&nbsp;Jelena Pavlović","doi":"10.1016/j.cbi.2025.111490","DOIUrl":"10.1016/j.cbi.2025.111490","url":null,"abstract":"<div><div>A novel multi-target drug, cemtirestat, inhibiting aldose reductase (ALR2) has been developed to prevent secondary diabetic complications and act as an antioxidant against hyperglycemia-related processes. This study examines cemtirestat's impact on gut microbiome composition, drug metabolism, and therapeutic efficacy in male Zucker diabetic fatty (ZDF) \"Lean\" rats. Rats were divided into the control group (C) and the treated group (T), which received 7.7 mg/kg/day cemtirestat for two months, with weekly monitoring of food, fluid intake, and weight gain. Stool, urine, and plasma samples were analyzed biochemically, and fecal DNA was sequenced using Oxford Nanopore Technology. Treated rats exhibited less weight gain, likely due to cemtirestat's antioxidant effects. Biochemical analyses revealed no significant changes in glucose, liver enzymes, or cholesterol. Although there was a slight increase in alanine aminotransferase (ALT), our study found that levels of other liver enzymes such as aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin remained within normal limits, suggesting the observed increase in ALT was not indicative of drug-induced liver injury. LefSe microbiome analysis revealed an enrichment of beneficial bacteria like <em>Blautia</em> and <em>Faecalibacterium</em> in treated rats. Microbial community structure did not distinctly separate treated from control groups, but differences emerged over time. DeSeq2 analysis identified varying genera abundances over weeks, with treated samples enriched in beneficial bacteria by Week 8. Correlation analysis linked plasma insulin levels positively with <em>Prevotella</em> and negatively with <em>Clostridium</em> and <em>Lactobacillus</em>. Cemtirestat's impact on weight and microbiota suggests the potential to improve gut health. Further research is required to uncover cemtirestat's mechanism in diabetes management, drug metabolism, and therapeutic efficacy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111490"},"PeriodicalIF":4.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor AMSP-30 m attenuates CCl4-induced liver fibrosis in mice by inhibiting the sonic hedgehog pathway","authors":"Lili Lu ,&nbsp;Yuchen Ma ,&nbsp;Qing Tao ,&nbsp;Jing Xie ,&nbsp;Xiao Liu ,&nbsp;Yongkang Wu ,&nbsp;Yang Zhang ,&nbsp;Xiuli Xie ,&nbsp;Mingming Liu ,&nbsp;Yong Jin","doi":"10.1016/j.cbi.2025.111480","DOIUrl":"10.1016/j.cbi.2025.111480","url":null,"abstract":"<div><div>Liver fibrosis is a passive and irreversible wound healing process caused by chronic liver injury. Research has shown that the upregulation of hypoxia inducible factor-1 alpha (HIF-1α) is closely related to the occurrence and development of liver fibrosis and HIF-1 α may be a promising target for the treatment of liver fibrosis. AMSP-30 m is a newly developed novel HIF-1α inhibitor by our group, which has strong anti-tumor and anti-inflammatory effects. In this study, we described the therapeutic effect and specific mechanism of AMSP-30 m on carbon tetrachloride (CCl₄) induced liver fibrosis in mice. Liver fibrosis induced by CCl₄ in mice and liver fibrosis induced by cobalt dichloride (CoCl₂) in LX-2 cells (human hepatic stellate cell (HSC) line) were studied. Hematoxylin &amp; eosin (H&amp;E)and Masson's trichrome staining were used to observe pathological conditions. Western Blot, immunofluorescence and immunohistochemistry were used to detect protein expression and localization in cells, and quantitative real-time PCR analysis (qRT-PCR) was used to detect mRNA expression. Biochemical detection kits were used to detect alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The results demonstrated that AMSP-30 m significantly alleviated pathological symptoms, reduced ALT and AST levels, and inhibited the expression of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1α1) in CCl₄-induced liver fibrosis in mice. AMSP-30 m could significantly reduce the expression of HIF-1α and sonic hedgehog (Shh) pathway related proteins (Smoothened (Smo), Shh, and glioma-associated oncogene-1 (Gli-1)) in CCl₄ induced liver fibrosis mice. AMSP-30 m also played a similar role in the CoCl₂-induced anoxic liver fibrosis model of LX-2 cells<strong>.</strong> Further experiments showed that Cyclopamine (a Shh inhibitor) could significantly inhibit the increase of α-SMA and COL1α1 resulting from HIF-1α but not significantly inhibit HIF-1α induced by CoCl₂ in LX-2 cells. And the combination of Cyclopamine and AMSP-30 m further reduced the expression of α-SMA and COL1α1 induced by HIF-1α. In summary, this study demonstrates that the HIF-1α inhibitor AMSP-30 m exerts a robust anti-fibrotic effect by inhibiting the Shh pathway, which is identified as a critical underlying mechanism. These findings suggest a promising therapeutic strategy for the treatment of liver fibrosis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111480"},"PeriodicalIF":4.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672016","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":"Role of the interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) signaling in superoxide anion-triggered inflammation and pain behavior in mice","authors":"Sergio M. Borghi ,&nbsp;Thacyana T. Carvalho ,&nbsp;Mariana M. Bertozzi ,&nbsp;Cátia C.F. Bernardy ,&nbsp;Ana C. Zarpelon ,&nbsp;Felipe A. Pinho-Ribeiro ,&nbsp;Cássia Calixto-Campos ,&nbsp;Victor Fattori ,&nbsp;José C. Alves-Filho ,&nbsp;Thiago M. Cunha ,&nbsp;Fernando Q. Cunha ,&nbsp;Rubia Casagrande ,&nbsp;Waldiceu A. Verri Jr.","doi":"10.1016/j.cbi.2025.111476","DOIUrl":"10.1016/j.cbi.2025.111476","url":null,"abstract":"<div><div>Reactive oxygen species such as superoxide anion have varied roles in inflammation and pain, which can be mimicked by potassium superoxide (KO₂), the superoxide anion donor. Interleukin (IL)-33 has pleiotropic functions by activating its receptor suppression of tumorigenicity 2 (ST2). However, the role of IL-33/ST2 signaling in inflammatory pain initiated by reactive oxygen species (ROS) such as superoxide anion has not been investigated, which was the aim of the present study. IL-33 levels were assessed by enzyme-linked immunosorbent assay (ELISA). Mechanical and thermal hyperalgesia and overt pain were evaluated by electronic von Frey, hot plate, and abdominal writhing/paw flinching/licking, respectively. Edema and leukocyte recruitment (myeloperoxidase assay and total/differential cell count), antioxidant capacity, superoxide anion production and lipid peroxidation were assessed. Paw skin and spinal cord messenger ribonucleic acid (mRNA) expression of pro-inflammatory mediators and glial markers in the spinal cord were evaluated. Immunofluorescence was used to detect spinal glial and neuronal c-Fos activation. KO₂ injection triggered IL-33 production in the paw skin and spinal cord of mice, induced hyperalgesia, edema, neutrophil recruitment to the paw tissue, overt pain-like behavior, and leukocyte recruitment to the peritoneum that were reduced in ST2 deficient mice. In the paw skin and spinal cord, KO₂ triggered IL-33/ST2-dependent oxidative stress, and mRNA expression of inflammatory molecules, which were reduced by ST2 deficiency. KO₂ induced spinal cord glial (at mRNA/protein levels) and neuronal activation in IL-33/ST2-dependent manner. IL-33/ST2 signaling mediates, at least in part, superoxide anion-induced inflammatory pain by modulating local and spinal inflammatory events.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111476"},"PeriodicalIF":4.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643627","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":"A MALDI-MSI-based approach to characterize the spatial distribution of cylindrospermopsin and lipid alterations in rat intestinal tissue","authors":"Antonio Casas-Rodríguez ,&nbsp;Cristina María López-Vázquez ,&nbsp;Remedios Guzmán-Guillén ,&nbsp;Nahúm Ayala ,&nbsp;Ana María Cameán ,&nbsp;Angeles Jos ,&nbsp;Eduardo Chicano-Gálvez","doi":"10.1016/j.cbi.2025.111479","DOIUrl":"10.1016/j.cbi.2025.111479","url":null,"abstract":"<div><div>Global warming and eutrophication of water bodies are driving the increase in cyanobacterial blooms, which produce toxins such as cylindrospermopsin (CYN). This compound has multiple toxic effects, and following CYN exposure, its distribution in the body varies, particularly in organs such as the liver and kidneys, suggesting its potential for bioaccumulation in key tissues. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI-MSI) enables visualization of the spatial distribution of a wide range of molecules. In this study, using MALDI-MSI, a new method was developed and optimized for the detection of CYN, and its quantitative spatiotemporal distribution was analyzed for the first time in intestinal samples from rats orally exposed to this toxin (500 μg/kg body weight) and sacrificed 0, 2, 4, 6 and 24 h after exposure. Furthermore, the impact of CYN on the intestinal lipid profile was evaluated. The method was validated in terms of linearity, sensitivity, and precision, measuring CYN in mimetic tissue sections at different concentrations (1–100 ppm), allowing its successful application to visualize CYN distribution in rat intestines. The results revealed alterations in different lipid families involved in the inflammatory response, increased oxidative stress, and progressive damage to the integrity of the cell membrane.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111479"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635032","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":"Potent inhibition of human monoamine oxidase A and B by phenolic compounds and polyunsaturated fatty acids in tobacco smoke","authors":"Sa Weon Hong ,&nbsp;Ali Heydari ,&nbsp;Paris R. Watson ,&nbsp;Paul H. Teesdale-Spittle ,&nbsp;Rachel Page ,&nbsp;Peter T. Northcote ,&nbsp;Robert A. Keyzers ,&nbsp;Mikhail Vyssotski ,&nbsp;Penelope Truman","doi":"10.1016/j.cbi.2025.111477","DOIUrl":"10.1016/j.cbi.2025.111477","url":null,"abstract":"<div><div>Smoking is a main cause of premature death and preventable disease in the world. Interestingly, animal studies indicate that inhibition of monoamine oxidase (MAO), key enzymes for the degradation of neurotransmitters, increased self-administration of nicotine. The purpose of this study was to identify and characterize the potential MAO inhibitors in tobacco smoke responsible for MAO inhibition in smokers. A bioassay-guided isolation from an extract of tobacco smoke showed that catechol, 4-methylcatechol, hydroquinone, α-linolenic acid, and linoleic acid all displayed potent human MAO inhibitory activity. Additionally, the tobacco catechols 4-ethylcatechol and 4-vinylcatechol were included to test their inhibitory potencies. Catechol, 4-methylcatechol, 4-ethylcatechol, and hydroquinone are potent and irreversible MAO inhibitors. Among the phenolic compounds tested, 4-methylcatechol and 4-ethylcatechol inhibited MAO A with IC₅₀ values of 10.0 and 12.6 μM, respectively, reducing to 0.27 and 0.43 μM after 1 h preincubation. In addition, α-linolenic acid and linoleic acid competitively inhibited MAO A with <em>K</em>_i values of 10.50 and 6.95 μM, respectively. These results suggest that MAO inhibition by phenolics and polyunsaturated fatty acids in tobacco smoke may be important contributors to the MAO inhibition experienced by smokers and to the enhancement of nicotine dependence this MAO inhibition is believed to cause.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111477"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence and mechanisms of exogenous aryl hydrocarbon receptor ligands on the viability of mouse germ cells","authors":"Yimin Cheng ,&nbsp;Yebin Yang ,&nbsp;Chen Chen ,&nbsp;Feifeng Zhang ,&nbsp;Shenglin Peng ,&nbsp;Xinsheng Xiao ,&nbsp;Zhen Peng","doi":"10.1016/j.cbi.2025.111478","DOIUrl":"10.1016/j.cbi.2025.111478","url":null,"abstract":"<div><div>Environmental pollution is a significant contributor to male infertility. Numerous environmental pollutants, such as PCB118, act as exogenous ligands for the aryl hydrocarbon receptor (AhR). However, the role of AhR in mediating the effects of environmental pollutants on male reproductive functions remains inadequately understood. In the present study, we assessed the viability of GC-1 and GC-2 cells using the CCK-8 assay. Immunofluorescence and Western blotting techniques were employed to investigate the distribution and protein expression levels of AhR within these cell lines. Alterations in reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were evaluated using DCFH-DA dye and the JC-1 assay, respectively. Furthermore, we investigated changes in the expression levels of Nrf2, Cleaved-Caspase 3, Cleaved-Caspase 8, Bcl-2, and Bax through Western blot analysis. Our findings indicate that PCB118 and the AhR-specific agonist CAY10465 diminish the viability of GC-1 and GC-2 cells, facilitate the nuclear translocation and expression of AhR protein, elevate ROS levels, and reduce MMP. Moreover, these agents markedly increase the levels of Cleaved-Caspase 3 and Cleaved-Caspase 8 while decreasing the Bax/Bcl-2 ratio. Notably, the AhR antagonist CH223191 and resveratrol have the capacity to restore the functionality of GC-1 and GC-2 cells by mitigating the effects of PCB118 and CAY10465. Based on these observations, we propose that exogenous AhR ligands PCB118 and CAY10465 promote the nuclear translocation and upregulation of AhR expression in GC-1 and GC-2 cells. This process subsequently induces mitochondrial oxidative stress, wich activates the apoptotic signaling pathway and ultimately compromises cellular viability.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111478"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631124","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":"Mechanisms of toxicity caused by bisphenol analogs in human in vitro cell models","authors":"Rafia Afroze Rifa,&nbsp;Macarena Gisele Rojo,&nbsp;Ramon Lavado","doi":"10.1016/j.cbi.2025.111475","DOIUrl":"10.1016/j.cbi.2025.111475","url":null,"abstract":"<div><div>Bisphenol analogs, structurally similar to bisphenol A (BPA), are widely used in various industries as a safer alternative to BPA. However, these alternatives also present risks, such as inflammation and potential connections to chronic diseases like cancer and diabetes, highlighting the need for further research into their toxicity mechanisms. Building on our previous cytotoxicity research, this study delves into the mechanisms of toxicity associated with bisphenol analogs (bisphenol AF, bisphenol AP, bisphenol E, and bisphenol P) on human <em>in vitro</em> cell models (HepaRG, Caco-2, HMC3, and HMEC-1). In this study, we assessed the impact of these compounds on key cellular stress markers: reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm), and mitochondrial calcium levels. Results revealed dose-dependent increases in oxidative stress and decrease in mitochondrial membrane potential (ΔΨm), with Caco-2 cells (enterocytes) exhibiting the highest sensitivity, indicating tissue-specific vulnerability. Notably, bisphenol AF, bisphenol AP and bisphenol P were identified as the most potent analogs in inducing ROS, affecting mitochondrial integrity and calcium homeostasis among all cell models. This research highlights the importance of understanding analog-specific and cell-specific responses to bisphenol compounds, providing a foundation for improved regulatory strategies to mitigate health risks associated with their exposure.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111475"},"PeriodicalIF":4.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630990","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}