Archives of Toxicology最新文献

{"title":"Marine bacteria and fungi: the hidden treasure of oceans in the biodegradation of microplastics and hydrocarbons integrated with omics technologies.","authors":"Silla Jahnavi, K V Devendu, Sruti Saha, Parry Dey, W Jabez Osborne","doi":"10.1007/s00204-026-04495-9","DOIUrl":"https://doi.org/10.1007/s00204-026-04495-9","url":null,"abstract":"<p><p>Marine microorganisms play a crucial role in maintaining oceanic ecosystem stability by mediating essential biogeochemical cycles, nutrient cycling and natural attenuation of environmental pollutants through diverse metabolic processes. Owing to their remarkable metabolic diversity, marine bacteria, fungi, and archaea possess the ability to utilize complex organic compounds as carbon and energy sources enabling them to transform and degrade a wide range of contaminants in aquatic environments, making them key agents in marine bioremediation. Among these, the most persistent pollutants threatening the marine ecosystem are the Microplastics (MPs) and hydrocarbons, both of which originate largely from anthropogenic activities including plastic waste accumulation, industrial discharge, petroleum extraction and accidental spills. MPs, are plastic particles of size less than or equal to 5 mm, produced due to the fragmentation of larger plastic debris while hydrocarbons consist of complex mixtures of aliphatic and aromatic compounds including polycyclic aromatic hydrocarbons (PAHs) and BTEX compounds. In marine systems, MPs frequently act as carriers for hydrocarbons and other contaminants, facilitating the formation of specialized microbial biofilms known as the plastisphere. Microbial degradation of these pollutants involves sequential processes including surface colonization, enzymatic depolymerization, biofragmentation, assimilation and mineralization. Several studies have reported the potential of marine bacteria and fungi in the degradation of MPs and HCs through the synthesis of key enzymes such as PETase and MHETase for MPs and laccases, peroxidases for HCs. Recent advances in omics technologies including metagenomics, metabolomics, proteomics, and transcriptomics have significantly improved our understanding of microbial community dynamics, degradation pathways, and functional genes involved in pollutant degradation. Therefore, integration of recent technologies alongside conventional methods could enhance the remediation process. In this review, we have collated the collective role of marine microorganisms in the biodegradation of MPs and hydrocarbons, highlighting their key degradation mechanisms, microbial interactions and the contributions of omics based approaches in advancing marine bioremediation research.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434979","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":"Developmental neurotoxicity of atrazine: decreased synaptic spine density and miRNA-driven GluN2A downregulation in primary hippocampal neurons.","authors":"Melania Maria Serafini, Agnese Graziosi, Miriam Midali, Luca Ghelli, Giacomo Grumelli, Giulia Sita, Emanuela Corsini, Marina Marinovich, Fabiana Morroni, Barbara Viviani","doi":"10.1007/s00204-026-04490-0","DOIUrl":"10.1007/s00204-026-04490-0","url":null,"abstract":"<p><p>Atrazine (ATZ) is a triazine herbicide and a persistent environmental contaminant. Its use is associated with effects on the nervous system in experimental models. Behavioral and molecular alterations have been reported after exposure, but the cellular mechanisms underlying atrazine-induced developmental neurotoxicity remain unclear, particularly at the synaptic level. In this study, we investigated the effects of ATZ exposure on glutamatergic synaptic maturation in rat primary hippocampal neurons. Neuronal cultures were exposed to ATZ throughout the in vitro developmental period, and structural and molecular endpoints were assessed. Dendritic spines were analyzed by confocal microscopy, and the expression of glutamatergic receptor subunits was evaluated by Western blot and RT-qPCR. In parallel, microRNA expression profiles targeting NMDA receptor subunits were examined to explore post-transcriptional regulatory mechanisms. ATZ exposure induced a selective reduction in dendritic spine density, without detectable changes in spine morphology. This structural effect was accompanied by a selective decrease in the NMDA receptor subunit GluN2A at both protein and mRNA levels, while GluN1, GluN2B, and AMPA receptor subunits were unaffected. Notably, GluN2A downregulation was preceded by the upregulation of microRNAs predicted to target the GRIN2A transcript, indicating a microRNA-mediated regulatory mechanism. Overall, these results demonstrate that ATZ can interfere with hippocampal synaptic maturation by selectively modulating NMDA receptor subunit composition through epigenetic mechanisms. This study identifies dendritic spine and GluN2A regulation as sensitive endpoints of ATZ-induced developmental neurotoxicity and provides mechanistic insight into how early synaptic processes may be affected by this herbicide.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434884","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":"Chalcones as multitarget modulators in non-small cell lung cancer: mechanistic insights and therapeutic perspectives.","authors":"Ellen Mayara Souza Cruz, Virginia Márcia Concato-Lopes, Mariana Barbosa Detoni, Manoela Daiele Gonçalves-Lens, Milena Cremer de Souza, Fabrício Seidy Ribeiro Inoue, Angélica Paulina Nunes, Elaine da Silva Siqueira, Ana Carolina Jacob Rodrigues, Yasmin Munhoz Dos Santos-Destro, Natália Concimo Santos, João Manoel de Sousa Silva, Éder Ignácio da Silva, Maiara Voltarelli Providello, Danielle Lazarin-Bidóia, Fábio Rodrigues Ferreira Seiva, Wander Rogério Pavanelli","doi":"10.1007/s00204-026-04501-0","DOIUrl":"https://doi.org/10.1007/s00204-026-04501-0","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, and the search for novel therapeutic strategies is ongoing. Chalcones, a class of naturally occurring and synthetically derived open-chain flavonoid precursors, have attracted attention because of their chemical versatility and broad biological activity. This review synthesizes current findings on the molecular mechanisms through which chalcones exert their effects in NSCLC, including modulation of oxidative stress, epithelial-mesenchymal transition, DNA damage responses, and diverse cell death pathways. Chalcones have been shown to interfere with key signaling cascades, such as TGF-β, PI3K/AKT/mTOR, JAK/STAT, and Wnt/β-catenin, with reported effects on tumor proliferation, migration, invasion, and therapy resistance. Their structural flexibility enables chemical optimization aimed at improve potency, selectivity, and pharmacokinetic profiles, supporting further preclinical investigation. Despite promising preclinical results, challenges remain regarding pharmacokinetics, bioavailability, and context-dependent off-target effects. Future research should prioritize integrated mechanistic studies, structure-activity relationship analyses, selective cytotoxicity assessment, and advanced delivery strategies to improve tumor specificity. Chalcones represent chemically versatile multitarget scaffolds for further optimization in NSCLC, particularly in strategies aimed at exploiting epithelial-mesenchymal plasticity, redox adaptation, and regulated cell death.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434826","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":"Ancestry informative genetic variants associated with tobacco metabolic and detoxification capacity measured by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) among smokers.","authors":"Oladimeji Lanade, Zhongxuan He, Yan Zhou, Elizabeth Blackman, Denise Gibbs, Sharon Harrison, Karthik Devarajan, Mark Andrake, Roland L Dunbrack, Gerald Nkogbu, Aditi Wagh, Michael Slifker, Cherie Erkmen, Freda Patterson, Aditi Satti, Heather-Dawn Lawson-Myers, Robin Roberts, Don Mitchell, Jeffery C Liu, Joel Erblich, Camille Ragin","doi":"10.1007/s00204-026-04505-w","DOIUrl":"10.1007/s00204-026-04505-w","url":null,"abstract":"<p><p>Tobacco use remains the leading preventable cause of cancer mortality worldwide, with marked disparities in cancer incidence and outcomes across racial and ethnic groups. This study investigates the genetic determinants of tobacco carcinogen metabolism among smokers, focusing on ancestry-informative markers (AIMs) near genes involved in metabolic activation (Phase I), detoxification (Phase II), and transport (Phase III) of tobacco-specific carcinogens. Using data from 274 smokers recruited in the United States and the Caribbean, we measured urinary NNAL (a metabolite of NNK) to classify metabolic phenotypes and performed genotyping with a customized array enriched for AIMs. Most participants (94%) were classified as poor metabolizers of NNAL, with a higher prevalence among Black/African American smokers. Multivariable analyses, after adjusting for age, sex, assay batch, and number of cigarettes smoked per day, identified 14 AIMs near Phase I, II, and III pathway genes significantly associated with NNAL metabolizer phenotype, with African ancestry alleles conferring increased odds of poor metabolism. Functional annotation revealed that most significant AIMs overlapped regulatory regions, and the CYP3A5 rs776746 variant demonstrated structural disruption likely to impair enzymatic activity. Majority of participants had high African ancestry and were poor NNAL metabolizers, consistent with the observed association between African ancestry and poor NNAL metabolism. These findings highlight the biological basis for tobacco-related cancer disparities and underscore the importance of integrating genetic ancestry and metabolic phenotyping in risk assessment and personalized prevention strategies for tobacco-associated cancers.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434729","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":"Repeated aminoglycoside exposure activates interferon-stimulated genes in human renal proximal tubular models.","authors":"Vidya Chandrasekaran, Tamara Meijer, Martin O Leonard, Anja Wilmes, Paul Jennings","doi":"10.1007/s00204-026-04494-w","DOIUrl":"10.1007/s00204-026-04494-w","url":null,"abstract":"<p><p>Aminoglycosides remain clinically important antibiotics, but their use is limited by nephrotoxicity. Although proximal tubular accumulation mediated by megalin is well established, the downstream cellular response is still incompletely understood. Here, we compared repeated-dose transcriptomic responses to gentamicin and tobramycin in a panel of human proximal tubular models comprising primary proximal tubular epithelial cells (PTEC; three donors), human iPSC-derived proximal tubular-like cells (PTL; three donors), RPTEC/TERT1 cells, and HK-2 cells. Cells were exposed daily for seven days to 12, 250, or 450 µg/mL gentamicin or tobramycin, and gene expression was assessed using the TempO-Seq EU-ToxRisk v2.1 panel followed by DESeq2 analysis. Primary PTEC and PTL showed the clearest and most coherent response, characterised by strong induction of interferon-stimulated genes including IFI27, IFI6, IFIT1-3, ISG15, MX1, OAS1, UBE2L6, USP18, IFI44L, HERC6, and RSAD2. Targeted regulator analysis showed strong enrichment of overlapping ISGF3, IRF7, and IRF1 target networks, consistent with a dominant interferon-stimulated gene program, together with a smaller NF-κB-associated inflammatory branch. In contrast, RPTEC/TERT1 and HK-2 cells showed weaker and less coherent responses. Tobramycin generally induced a stronger and more consistent transcriptional response than gentamicin across responsive models. These data identify a robust innate immune-like transcriptional signature in human proximal tubular models following repeated aminoglycoside exposure and support primary PTEC and PTL as more informative in vitro systems for mechanistic investigation of aminoglycoside nephrotoxicity.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434998","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":"Involvement of lysosomal proteins in morphology-driven toxicity of (nano)fibers.","authors":"Rico Ledwith, Carla Ribalta, Mario Pink, Andrea Haase, Verónica I Dumit","doi":"10.1007/s00204-026-04503-y","DOIUrl":"https://doi.org/10.1007/s00204-026-04503-y","url":null,"abstract":"<p><p>Fiber morphology (length > 5 μm; respirable diameter < 3 μm) and biopersistence have been linked to their potential to cause fibrosis, lung cancer, and malignant pleural mesothelioma. Among the mechanisms involved, frustrated phagocytosis occurs when macrophages attempt but fail to fully internalize and clear long rigid fibers. Although nanofibers could meet these criteria and trigger frustrated phagocytosis, their small diameters may enable them to entangle, causing them to lose their fiber-like morphology and affecting their toxicological potential. The toxicological assessment of (nano)fibers relies on animal studies; therefore, there is an urgent need to establish in vitro alternatives. Carbon nanotubes, the most commercially prevalent class of nanofibers, have been extensively investigated, and some have demonstrated pathogenic potential, by causing inflammation initiated by cathepsin B translocation from the lysosomes into the cytosol. Independent studies have indicated that only long and rigid carbon nanofibers lead to a decrease of lysosomal enzymes (including multiple cathepsins) inside macrophages and increased levels in the extracellular environment. Thus, different roles for cathepsin B have been proposed in response to nanofiber exposure. To reconcile these observations, this review examines the underlying mechanisms by assessing in vitro studies, particularly how in vitro macrophages respond to carbon-based nanomaterials of distinct morphologies, discusses the limitations of current in vitro models, and evaluates potential approaches for assessing nanofiber toxicity.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434964","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":"Impact of low-frequency electromagnetic fields on DNA instability caused by environmentally and occupationally relevant chemicals in lymphocytes of donors with different demographic characteristics.","authors":"Miroslav Mišík, Michael Kundi, Franziska Ferk, Hans-Peter Hutter, Armen Nersesyan, Michael Grusch, Siegfried Knasmueller","doi":"10.1007/s00204-026-04509-6","DOIUrl":"https://doi.org/10.1007/s00204-026-04509-6","url":null,"abstract":"<p><p>Aim of this study was to find out if demographic factors (age and body weight) have an impact on the sensitivity of peripheral lymphocytes towards DNA damage caused by extremely low frequency electromagnetic fields (ELF-EMF), to which humans are exposed worldwide. Cells from three different groups (young normal-weight, young obese, and old normal-weight individuals) were treated with different intensities of ELF-EMF (50 Hz, 50, 200 and 1000 µT) in combination with genotoxic agents, which cause damage to the genetic material via different molecular mechanisms. BPDE (benzo[a]pyrene diol epoxide) is a metabolite of the polycyclic aromatic hydrocarbon benzo(a)pyrene (B(a)P); 4-nitroquinoline oxide (4NQO) is a UV-mimetic agent; the metal compounds NiCl₂ and CrO₃ induce cross-links and oxidative damage. The cells were treated with radiation in combination with the different chemicals (simultaneous and sequential exposure), subsequently, DNA damage was monitored using single-cell gel electrophoresis (SCGE) experiments. We found no evidence for induction of genetic damage by the radiation in cells from the different groups. However, a decrease of damage was observed in combined experiments with NiCl₂, and an increase of DNA migration was detected in some experiments with BPDE. These findings indicate that ELF-EMF does not cause DNA damage in lymphocytes regardless of the age and body weight of the donors. Furthermore, our results show that the radiation has an impact on the extent of DNA damage caused by specific environmentally and occupationally relevant exposures and may increase the genotoxic effects of polycyclic aromatic hydrocarbons.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434814","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":"AhR activation triggers the synergistic genotoxicity between benzo[a]pyrene and aflatoxin B1 in metabolic-competent HepaRP cells.","authors":"Anis Messaoudi, Marie Garcia, Marc Audebert, Julien Vignard, Gladys Mirey","doi":"10.1007/s00204-026-04491-z","DOIUrl":"https://doi.org/10.1007/s00204-026-04491-z","url":null,"abstract":"<p><p>Human dietary exposure involves multiple contaminants, raising concerns about \"cocktail\" effects ignored by single-compound risk assessment. Benzo[a]pyrene (BaP) and aflatoxin B1 (AFB1) are co-occurring food contaminants requiring cytochrome P450-mediated bioactivation. They both form DNA-reactive metabolites and are classified as genotoxic carcinogens. Here, BaP and AFB1 genotoxicity was evaluated individually and in binary combination in metabolically competent HepaRP cells using γH2AX as DNA damage biomarker. Concentrations were selected to reflect physiologically relevant levels (BaP: 0.125-10 µM; AFB1: 0.01-2 µM). Benchmark concentration (BMC) analysis with the PROAST covariate approach allowed deriving potency estimates, predicting mixture effects under dose addition hypothesis. Cells co-exposed to BaP-AFB1 presented a synergistic increase in γH2AX foci number compared to additive model predictions. Mechanistic investigations identified aryl hydrocarbon receptor (AhR) signaling as a key driver of this interaction. First, AhR pharmacological activation with β-naphthoflavone (BNF) recapitulated the effects of BaP, enhancing the genotoxicity induced by AFB1 exposure. In contrast AhR inhibition with CH223191 reduced DNA damage in cells treated with BaP, BaP-AFB1 or BNF-AFB1. Consistent with the metabolic interaction hypothesis, BaP or BNF alone or in mixture with AFB1 increased the expression and activity of CYP1 family enzymes, while CH223191 prevented these responses. Finally, non-genotoxic polycyclic aromatic hydrocarbons (PAHs) as fluoranthene and phenanthrene also enhanced AFB1 genotoxicity. Altogether, these results underline the importance of AhR-dependent metabolic activation in synergistic interaction within mixtures, supporting the necessity of mechanistic knowledge to improve risk assessment, notably for co-exposure to food contaminants.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434841","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":"Cell line identity rather than medium composition determines transcriptomic profiles of HepaRG and HuH7 cells cultured in chemically defined or serum-based media: comparison with primary human hepatocytes.","authors":"Ahmed S M Ali, Heike Sprenger, Albert Braeuning, Jens Kurreck","doi":"10.1007/s00204-026-04502-z","DOIUrl":"10.1007/s00204-026-04502-z","url":null,"abstract":"<p><p>Standardized and reproducible cell models are key to replace animal testing in toxicology. The composition of culture medium is a major, yet frequently undercontrolled, determinant of cell state in vitro. For decades, fetal bovine serum (FBS) has been routinely incorporated into liver cell culture. Its undefined and lot-to-lot variable composition can, however, confound cell identity and experimental reproducibility. Chemically defined media (CDM) represent an alternative approach that can improve standardization, but the consequences of transitioning from FBS-supplemented media (FBS-SM) to CDM remain insufficiently characterized in hepatic models, particularly with respect to metabolic and detoxification programs that govern xenobiotic metabolism and hepatotoxicity readouts. Here, we systematically assessed how replacing FBS-SM with CDM remodels transcriptomic profiles in two widely used human hepatic cell lines (HepaRG and HuH7 cells) and compared the results to that obtained from primary human hepatocytes (PHH). Global transcriptomic analyses indicated that cell type was the primary driver of variance, whereas medium induced a model-dependent secondary effect. Functional interpretation showed preferential enhancement of xenobiotic metabolism and transport-associated programs in HepaRG cells, while HuH7 cells response was dominated by lipid/sterol homeostasis and stress-linked processes. Benchmarking against PHH based on hepatic identity and detoxification gene panels further supported improved PHH alignment for HepaRG cells under CDM compared to cultures with FBS-SM, with limited improvement for HuH7 cells. Collectively, these findings show that medium effects must be interpreted in the context of cell line identity and indicate that HepaRG cells cultured in CDM provide a more PHH-like transcriptomic background for in vitro studies of xenobiotic metabolism and hepatotoxicity-related readouts than HuH7 cells.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434769","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":"Integrated quantitative proteomics reveals stress-associated network remodeling induced by mitragynine in RSC96 Schwann cells.","authors":"Hasriadi Hasriadi, Dasuni Wasana Peththa Wadu, Thorsang Weerakul, Chutichot Pattamadilok, Boonchoo Sritularak, Pasarapa Towiwat","doi":"10.1007/s00204-026-04461-5","DOIUrl":"https://doi.org/10.1007/s00204-026-04461-5","url":null,"abstract":"<p><p>Mitragynine, the principal alkaloid of Mitragyna speciosa (kratom), exhibits opioid-like analgesic effects but is associated with tolerance following prolonged exposure. Schwann cells are particularly vulnerable to chemically induced toxicity, and disruption of their homeostatic functions has been implicated in neurotoxic injury. The cellular mechanisms underlying this adaptive response remain poorly understood. In this study, an integrated quantitative proteomics and systems biology approach was performed to investigate mitragynine-induced molecular remodeling in RSC96 Schwann cells. Cells were exposed to 20 µM mitragynine, the highest non-cytotoxic concentration, for 72 h and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic profiling. Differentially expressed proteins were characterized through Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway mapping, InterPro domain annotation, and protein-protein interaction network reconstruction using STRING and BioGRID. Proteomic profiling identified 91 significantly altered proteins, comprising 60 downregulated and 31 upregulated proteins. Functional enrichment revealed coordinated suppression of translational machinery, cytoskeletal organization, and metabolic pathways associated with Schwann cell homeostasis. Network reconstruction highlighted AMP-activated protein kinase (AMPK) as a high-centrality node within the downregulated interaction network. Upregulated proteins were enriched in xenobiotic stress responses, aminoacyl-tRNA biosynthesis, and chromatin remodeling pathways. Structural similarity analysis revealed limited overlap between the mitragynine scaffold and morphine despite their shared receptor target. These findings suggest that chronic mitragynine exposure induces coordinated proteomic and network-level remodeling in Schwann cells, identifying regulatory pathways consistent with tolerance-related cellular adaptation and peripheral neurotoxic risk.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410107","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}