Toxicology in Vitro最新文献

Toxicoproteomic study of fipronil in SH-SY5Y cells reveals induction of endoplasmic reticulum stress and necrotic cell death as neurodegenerative mechanisms 氟虫腈在SH-SY5Y细胞中的毒性蛋白质组学研究揭示了内质网应激和坏死细胞死亡是神经退行性机制

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-29 DOI: 10.1016/j.tiv.2025.106098

Theetat Ruangjaroon , N. Monique Paricharttanakul , Daranee Chokchaichamnankit , Chantragan Srisomsap , Kriengsak Lirdprapamongkol , Jisnuson Svasti

{"title":"Toxicoproteomic study of fipronil in SH-SY5Y cells reveals induction of endoplasmic reticulum stress and necrotic cell death as neurodegenerative mechanisms","authors":"Theetat Ruangjaroon , N. Monique Paricharttanakul , Daranee Chokchaichamnankit , Chantragan Srisomsap , Kriengsak Lirdprapamongkol , Jisnuson Svasti","doi":"10.1016/j.tiv.2025.106098","DOIUrl":"10.1016/j.tiv.2025.106098","url":null,"abstract":"<div><div>Exposure to pesticides has been considered as a risk factor for developing neurodegenerative diseases. The increasing use of fipronil, a phenylpyrazole insecticide, poses a risk to human health. This study aims to use toxicoproteomics for exploring neurodegenerative mechanism of fipronil in SH-SY5Y human neuroblastoma cells. In this study, fipronil at sub-cytotoxic and cytotoxic concentrations (43 and 78 μM) caused increases in superoxide level from 3 to 48 h after treatment, while intracellular glutathione level was decreased at 48 h. Neurite outgrowth of the cells was impaired by fipronil at both concentrations, while significant increase of cell death via apoptosis and necrosis modes were observed with fipronil at cytotoxic concentration. Pretreatment with antioxidant <em>N</em>-acetylcysteine (NAC) effectively relieved impairment of neurite outgrowth and induction of cell death by fipronil. Proteomic analysis showed that expression of proteins involving endoplasmic reticulum (ER) stress and unfolded protein responses were predominantly affected by fipronil. Immunoblotting confirmed the increased expression of ER stress markers, GRP78/BiP (78 kDa glucose-regulated protein/Binding immunoglobulin protein) and PDI (protein disulfide isomerase), in fipronil-treated cells. Improved understanding of the neurotoxic mechanism of fipronil may help in developing a strategy for reducing risk of neurodegenerative development from intense and prolonged use of fipronil.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"108 ","pages":"Article 106098"},"PeriodicalIF":2.6,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178811","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}

引用次数: 0

Use of centromeric probe to identify micronuclei origin and its advantages in genetic toxicology studies 利用着丝粒探针鉴定微核起源及其在遗传毒理学研究中的优势

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-26 DOI: 10.1016/j.tiv.2025.106087

G. Tamizh Selvan , P. Venkatachalam

{"title":"Use of centromeric probe to identify micronuclei origin and its advantages in genetic toxicology studies","authors":"G. Tamizh Selvan , P. Venkatachalam","doi":"10.1016/j.tiv.2025.106087","DOIUrl":"10.1016/j.tiv.2025.106087","url":null,"abstract":"<div><div>Fluorescence <em>in situ</em> hybridization (FISH) and karyotyping have long been considered essential for chromosomal examination to analyse the stable chromosome aberrations such as translocations after exposure to genotoxic agents. To improve speed of chromosomal analysis in genetic toxicology investigations, we employed the cytokinesis-block micronucleus (CBMN) assay with human pan-centromeric probes, to measure chromosome segregation errors and to differentiate mechanism of action of genotoxic agents. Whole-blood collected from healthy volunteers were exposed to X-rays, bleomycin (BLM), Colchicine (COL) and Mitomycin-C (MMC), arrested at cytokinesis stage and processed for conventional giemsa staining and pan-centromeric FISH to analyse the composition of MN to differentiate between aneugen and clastogen effects. One-way ANOVA with Tukey's multiple comparison test exhibited a significant (<em>p</em> < 0.001) increase in the MN observed using giemsa stained and centromere FISH binucleated cells in all those genotoxic agents when compared to its unexposed lymphocytes cultures. The CBMN with centromere FISH, predominantly shows MNCN<sup>-ve</sup> cells in lymphocytes exposed to X-rays (67.4 % and 83.3 %), BLM (79.4 % and 79.2 %) and MMC (81.5 % and 73.2) while, COL treatment resulted in significantly (<em>p</em> < 0.05) higher MNCN<sup>+ve</sup> cells (79.6 % and 82.4 %) for the different concentrations of those agents. Centromere FISH enables to identify the origin of MN induced by different genotoxic agents. Thus, a significant development in genetic toxicology is heralded by the incorporation of centromeric probe in modern analytical workflows.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"108 ","pages":"Article 106087"},"PeriodicalIF":2.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168142","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}

引用次数: 0

Development of a TK6-derived cell line expressing four human cytochrome P450s for genotoxicity testing 表达4种人类细胞色素p450的tk6衍生细胞系的建立及其遗传毒性试验

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-26 DOI: 10.1016/j.tiv.2025.106085

Xilin Li , Yuhan Wang , Hannah Xu , Xiaobo He , Si Chen , Xiaoqing Guo , Mugimane G. Manjanatha , Tong Zhou , Jessica Bonzo , Nan Mei

{"title":"Development of a TK6-derived cell line expressing four human cytochrome P450s for genotoxicity testing","authors":"Xilin Li , Yuhan Wang , Hannah Xu , Xiaobo He , Si Chen , Xiaoqing Guo , Mugimane G. Manjanatha , Tong Zhou , Jessica Bonzo , Nan Mei","doi":"10.1016/j.tiv.2025.106085","DOIUrl":"10.1016/j.tiv.2025.106085","url":null,"abstract":"<div><div>Metabolism is essential for <em>in vitro</em> genotoxicity testing. We previously developed a panel of TK6 cell lines, each expressing one of 14 human cytochrome P450 (CYP) enzymes, demonstrating their ability to effectively bioactivate indirect genotoxicants without relying on a rodent liver S9 fraction. In the present study, we extended this work by developing a TK6 cell line co-expressing four human CYP enzymes, including CYP2A6, CYP2E1, CYP2C19, and CYP3A4 (designated as TK6-4CYP), and subsequently assessed its capability to metabolize and activate pro-genotoxicants. Human lymphoblastoid TK6 cells were sequentially transduced with lentiviral vectors carrying CYP2A6/2E1 and CYP2C19/3A4, resulting in more than a 2<sup>10</sup>-fold increase in mRNA expression levels for each CYP compared to parental cells. RNA sequencing revealed selective upregulation of the four CYPs. Their protein expression and enzymatic activities were also confirmed. TK6-4CYP cells were subsequently tested with four CYP-metabolized pro-genotoxicants, including <em>N</em>-nitroso-diethylamine (NDEA) metabolized by CYP2A6, <em>N</em>-nitroso-dimethylamine (NDMA) by CYP2E1, <em>N</em>-nitroso-propranolol (NNP) by CYP2C19, and riddelliine by CYP3A4, in the micronucleus assay, cell cycle analysis, and comet assay. Significant increases were observed in the percentage (%) of micronuclei induction, G2/M phase arrest, and % DNA in tails with all compounds except riddelliine, which showed increases in % micronuclei induction and G2/M phase arrest but no positive response in the comet assay. This study establishes proof-of-concept for using a TK6 cell model co-expressing multiple drug-metabolizing enzymes for genotoxicity evaluation.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"108 ","pages":"Article 106085"},"PeriodicalIF":2.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168141","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}

引用次数: 0

Transcriptomic dose-response by UVC and heavy ion radiation reveal pathways to immune impairment UVC和重离子辐射的转录组剂量反应揭示了免疫损伤的途径

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-24 DOI: 10.1016/j.tiv.2025.106086

Mingming Tian , Xiaolin Ding , Yue Pang , Dan Xu , Yeqing Sun , Pu Xia

{"title":"Transcriptomic dose-response by UVC and heavy ion radiation reveal pathways to immune impairment","authors":"Mingming Tian , Xiaolin Ding , Yue Pang , Dan Xu , Yeqing Sun , Pu Xia","doi":"10.1016/j.tiv.2025.106086","DOIUrl":"10.1016/j.tiv.2025.106086","url":null,"abstract":"<div><div>Irradiation-induced immune impairment has been linked to human immune diseases, such as myelodysplastic syndromes (MDS) and leukemia. Global molecular responses to genome instability in immune cells can be identified by using transcriptomics. However, it is hard to link the molecular mechanism to the disease outcomes in the previous mechanistic studies. Here, transcriptomic dose-responses in human CD4+ T lymphocytes exposed to ultraviolet and heavy ion radiation were revealed by identification of the gene expression patterns of differential expression genes (DEGs) and calculating the point of departure (POD) of each DEG and molecular pathway, which provided an opportunity for quantitively illustrating the biological process of irradiation-induced immune impairments. Two potential adverse outcome pathways (AOPs) to irradiation-related leukemia were identified by mapping the molecular pathways into the biological event cascades, which provided phenotypic anchoring for the toxicological mechanisms. In addition, this study also revealed that NOP14/ NOP14-AS1 could be potential biomarkers of irradiation-induced immune impairment. Our works strengthen the use of AOP network in the next-generation risk assessment of irradiation-related diseases.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"108 ","pages":"Article 106086"},"PeriodicalIF":2.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147586","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}

引用次数: 0

Molecular mechanistic approach to reveal decitabine's effect on DNMT gene modulation and its inhibitory role in heavy metal-induced proliferation in urinary bladder cancer cell line 地西他滨对重金属诱导的膀胱癌细胞DNMT基因调控及抑制作用的分子机制研究。

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-23 DOI: 10.1016/j.tiv.2025.106082

Deepika Saini , Pankaj Kumar Chaudhary , Ganesh Kumar Verma , Jitendra Kumar Chaudhary , Raman Kumar , Sarama Saha , Partha Roy , Bela Goyal , Ramasare Prasad , Anissa Atif Mirza-Shariff

{"title":"Molecular mechanistic approach to reveal decitabine's effect on DNMT gene modulation and its inhibitory role in heavy metal-induced proliferation in urinary bladder cancer cell line","authors":"Deepika Saini , Pankaj Kumar Chaudhary , Ganesh Kumar Verma , Jitendra Kumar Chaudhary , Raman Kumar , Sarama Saha , Partha Roy , Bela Goyal , Ramasare Prasad , Anissa Atif Mirza-Shariff","doi":"10.1016/j.tiv.2025.106082","DOIUrl":"10.1016/j.tiv.2025.106082","url":null,"abstract":"<div><div>Heavy metals are pervasive environmental and occupational carcinogens known to induce uncontrolled cell proliferation. They influence a number of cellular processes, including proliferation, metabolism, apoptosis, and carcinogenesis. Among the several underlying mechanisms of carcinogenesis, metal-induced aberrant modulation of DNA methyltransferase (DNMT) activity may play crucial role. In this context, our study explored the proliferative and/or cytotoxic effects of heavy metals on the T24 urinary bladder cancer cell line. Additionally, we evaluated the effects of heavy metals and the chemotherapeutic agent decitabine on DNMT expression and activity. For investigative purposes, T24 cells were exposed to different heavy metals; namely, lead (Pb), chromium (Cr), cadmium (Cd), nickel (Ni), and arsenic (As) at concentrations ranging from 0.5 to 32 μM for 24, 48, and 72 h, as well as to decitabine (1 to 64 μM) for 72 h. Post-incubation, cell proliferation and migration increased, and mitochondrial membrane potential decreased significantly in the presence of heavy metals, especially Cr and Cd. Moreover, in the presence of Cr and Cd, expression of DNMT1 and DNMT3b genes enhanced significantly. Furthermore, decitabine treatment effectively inhibited Cd- and Cr-induced proliferation and downregulated expression of DNMT genes. In conclusion, heavy metals such as Cd and Cr may contribute to urinary bladder carcinogenesis through DNMT upregulation, while decitabine showedprotective effects by suppressing DNMT expression and inhibiting cell proliferation.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"108 ","pages":"Article 106082"},"PeriodicalIF":2.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144155","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}

引用次数: 0

Haemostasis-altering effects of Milos viper (Macrovipera schweizeri) venom 巨蟒毒液的止血作用

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-22 DOI: 10.1016/j.tiv.2025.106081

Ignazio Avella , Lennart Schulte , Maik Damm , Wolfgang Wüster , Andreas Vilcinskas , Tim Lüddecke

{"title":"Haemostasis-altering effects of Milos viper (Macrovipera schweizeri) venom","authors":"Ignazio Avella , Lennart Schulte , Maik Damm , Wolfgang Wüster , Andreas Vilcinskas , Tim Lüddecke","doi":"10.1016/j.tiv.2025.106081","DOIUrl":"10.1016/j.tiv.2025.106081","url":null,"abstract":"<div><div>Haemotoxicity is one of the primary symptoms of viperid envenomation, manifesting in cardiovascular and haemostatic disturbances such as hypotension, haemorrhage, and coagulopathy. Bites by the Milos viper (<em>Macrovipera schweizeri</em>) have been reported to induce symptoms affecting the blood system, including fibrinogenolysis, erythrocytopenia, and venom-induced consumption coagulopathy. Consistent with these reports, its venom contains a variety of haemotoxic components and has been observed to exert strong procoagulant activity on human plasma. However, a more comprehensive analysis of the effects of Milos viper venom on haemostasis is currently lacking. Here, we present an in vitro evaluation of the haemostasis-altering properties of <em>M. schweizeri</em> venom. We conducted bioassays on key haematological targets to assess the thrombin-like, plasmin-like, coagulation Factor Xa-like, and haemolytic activities of Milos viper venom. A clear, positive concentration-dependent effect was observed in the thrombin-like and the plasmin-like activity assays, ranging from 1.6 % to 77.4 % and from 5.8 % to 82.5 %, respectively. The relatively comparable, pronounced activities detected at higher venom concentrations for these two haematological targets may align with the fibrinogenolysis and consumption coagulopathy described following <em>M. schweizeri</em> envenomation. Conversely, the assays revealed negligible Factor Xa-like and haemolytic activities. Our analysis provides a detailed overview of the haemostasis-altering potential of the toxin arsenal of <em>M. schweizeri</em>, shedding new light on its coagulotoxic effects.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"107 ","pages":"Article 106081"},"PeriodicalIF":2.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138129","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}

引用次数: 0

Detection of skin sensitization hazards in medical device materials using a combination of three alternative in vitro testing methods 使用三种可选的体外测试方法组合检测医疗器械材料中的皮肤致敏危害。

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-21 DOI: 10.1016/j.tiv.2025.106084

Masayuki Okada, Harumi Tabata, Keiki Suzuki, Atsushi Kaneki

{"title":"Detection of skin sensitization hazards in medical device materials using a combination of three alternative in vitro testing methods","authors":"Masayuki Okada, Harumi Tabata, Keiki Suzuki, Atsushi Kaneki","doi":"10.1016/j.tiv.2025.106084","DOIUrl":"10.1016/j.tiv.2025.106084","url":null,"abstract":"<div><div>This study attempted to detect the skin sensitization hazards of medical device materials by combining multiple <em>in vitro</em> alternative testing methods. Nine materials were extracted using organic solvents, and the re-dissolved solutions were evaluated using the Amino acid Derivative Reactivity Assay (ADRA), Epidermal Sensitization Assay (EpiSensA), and human Cell Line Activation test (h-CLAT). The combined results of each test were compared with those of the Guinea Pig Maximization Test (GPMT) results. The findings of ADRA and h-CLAT were consistent with the GPMT results for seven of the nine materials, and EpiSensA was consistent with the GPMT results for eight of the nine materials. The findings of the “2 out of 3” and Sequential Testing Strategy (STS) approaches were compared with the GPMT results. The GMPT results for all nine materials were correctly predicted when the “2 out of 3” approach was used. When the STS was used, it correctly predicted the GMPT results for eight of the nine materials. Therefore, integrating the ADRA, EpiSensA, and h-CLAT may provide an effective testing method for detecting skin sensitization hazards of organic solvent extracts from medical device materials.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"108 ","pages":"Article 106084"},"PeriodicalIF":2.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132866","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}

引用次数: 0

In vitro metabolic clearance of malathion in rats and humans 马拉硫磷在大鼠和人体内的体外代谢清除率。

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-17 DOI: 10.1016/j.tiv.2025.106080

Gopinath Nallani , Appavu Chandrasekaran , Kelem Kassahun , Li Shen , Rick Reiss , Paul Whatling

{"title":"In vitro metabolic clearance of malathion in rats and humans","authors":"Gopinath Nallani , Appavu Chandrasekaran , Kelem Kassahun , Li Shen , Rick Reiss , Paul Whatling","doi":"10.1016/j.tiv.2025.106080","DOIUrl":"10.1016/j.tiv.2025.106080","url":null,"abstract":"<div><div><em>In vitro</em> intrinsic clearance of malathion was determined in adult and juvenile rat and human liver microsomes. Due to rapid elimination with no detectable levels of the parent, clearance rates of malathion were calculated from formation kinetics of its metabolites: malathion monocarboxylic acid (MMCA) and malaoxon. To correlate <em>in vitro</em> data to <em>in vivo</em> exposure, pharmacokinetics (PK) study was performed in adult rats following a single <em>i.v.</em> (10 mg/kg bw) or oral dose (150 mg/kg bw). The <em>in vitro</em> kinetics data indicate that the metabolic clearance of malathion <em>via</em> formation of MMCA was at the same rate in adult and juvenile human liver microsomes (HLM), but in rat liver microsomes (RLM) the rate was about 10-fold higher in adults compared to juveniles. The rate of formation of malaoxon among the two species and age groups was within 3.5-fold difference. The formation kinetics of malaoxon represented <0.5 % of that observed for MMCA in both rats and humans. As seen in the <em>in vitro</em> results, following <em>i.v.</em> or oral dosing in rats, malathion was not detectable with MMCA being the major metabolite. The kinetics data from this study were useful for the development of a PBPK model for malathion.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"107 ","pages":"Article 106080"},"PeriodicalIF":2.6,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103114","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}

引用次数: 0

Selective JAK-1 inhibitor Upadacitinib and peptide PD29 modulate the JAK and TGF-β/Smad signaling pathways reducing experimental dermal fibrosis 选择性JAK-1抑制剂Upadacitinib和肽PD29调节JAK和TGF-β/Smad信号通路，减少实验性皮肤纤维化。

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-15 DOI: 10.1016/j.tiv.2025.106078

Ayşe Koçak , Cemre Ural , Zahide Cavdar , Sulen Sarioğlu , Gül Akdoğan , Merih Birlik

{"title":"Selective JAK-1 inhibitor Upadacitinib and peptide PD29 modulate the JAK and TGF-β/Smad signaling pathways reducing experimental dermal fibrosis","authors":"Ayşe Koçak , Cemre Ural , Zahide Cavdar , Sulen Sarioğlu , Gül Akdoğan , Merih Birlik","doi":"10.1016/j.tiv.2025.106078","DOIUrl":"10.1016/j.tiv.2025.106078","url":null,"abstract":"<div><div>This study investigates the antifibrotic and anti-inflammatory effects of Janus kinase (JAK) inhibitors and the PD29 peptide in the context of systemic sclerosis (SSc), a condition characterized by dermal thickening, chronic inflammation, and excessive extracellular matrix deposition. Pulmonary arterial hypertension (PAH) and pulmonary fibrosis represent serious and often fatal complications associated with SSc. The pathogenesis of SSc involves dysregulation of immune responses and aberrant activation of signaling pathways, including TGF-β/Smad.</div><div>The antifibrotic properties of upadacitinib, a selective JAK1 inhibitor, and PD29 peptide were evaluated using a bleomycin-induced SSc mouse model and primary human lung fibroblasts. Both agents, administered individually or in combination, significantly attenuated dermal thickening, myofibroblast transdifferentiation, collagen deposition, and activation of the TGF-β1 signaling axis.</div><div>In vivo and in vitro analyses demonstrated that upadacitinib and PD29 downregulated key fibrotic markers, including α-SMA, JAK1, TGF-β1, Smad2, and collagen-1, at both the gene and protein levels. Furthermore, treatment significantly reduced systemic inflammatory cytokines, including IL-6 and TNF-α. Notably, combination therapy exhibited a more pronounced effect compared to monotherapy.</div><div>These findings suggest that upadacitinib and PD29 exert potent antifibrotic and anti-inflammatory effects through suppression of TGF-β1-mediated Smad2/3 signaling, predominantly via inhibition of JAK1 activation. Consequently, JAK inhibitors and PD29 represent promising therapeutic candidates for the management of fibrosis in systemic sclerosis.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"107 ","pages":"Article 106078"},"PeriodicalIF":2.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095670","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}

引用次数: 0

Cadmium sulfide nanoparticles (CdSNPs) modulate key oncogenic pathways in PA1 ovarian cancer cells: Insights from transcriptomic analysis 硫化镉纳米颗粒（CdSNPs）调节PA1卵巢癌细胞的关键致癌途径：来自转录组学分析的见解

IF 2.6 3区医学

Toxicology in Vitro Pub Date : 2025-05-13 DOI: 10.1016/j.tiv.2025.106079

Aditi Bhatnagar , Abhay Dev Tripathi , Sonali Kumari, Abha Mishra

{"title":"Cadmium sulfide nanoparticles (CdSNPs) modulate key oncogenic pathways in PA1 ovarian cancer cells: Insights from transcriptomic analysis","authors":"Aditi Bhatnagar , Abhay Dev Tripathi , Sonali Kumari, Abha Mishra","doi":"10.1016/j.tiv.2025.106079","DOIUrl":"10.1016/j.tiv.2025.106079","url":null,"abstract":"<div><div>Transcriptomics has become a useful tool for comparing the levels of gene expression in healthy and malignant cells, holding potential for the discovery of new cancer therapies. This study used RNA-sequencing and transcriptome analysis on the PA1 ovarian cancer cell line to examine the potential of Cadmium Sulfide Nanoparticles (CdSNPs) as a therapeutic agent. A total of 5.42 Gb of high-quality reads was estimated based on the findings of gene expression techniques, comprising 2.25 Gb of treated PA1 cells and 3.17 Gb of control cells. Of these, 1641 genes with padj<0.001 and log2 foldchange >2 were found to be significantly regulated DEGs (differentially expressed genes). Analysis of gene ontology (GO) assays demonstrates the molecular mechanism behind CdSNPs anticancer effects. GO:0006915, GO:0012501, GO:1903561, and GO:0070588 are a few significant highlights of elevated GO (enriched DEGs) that are involved in apoptotic pathways, extracellular vesicles, programmed cell death, and Ca++ signaling. KEGG analysis elucidated that up and downregulated DEGs were enriched in a few pathways: calcium signaling pathway, Apoptosis, and TNF signaling pathway. Important pathways like MAP kinase, JAK/STAT, cAMP, and folate biosynthesis, showed inhibitory effects on ovarian cancer cell proliferation. The results of this work provide insight into possible therapeutic approaches employing CdSNPs and encourage additional research using a variety of cell lines and in vivo models to improve ovarian cancer treatment.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"107 ","pages":"Article 106079"},"PeriodicalIF":2.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071508","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}

引用次数: 0