Current Research in Toxicology最新文献

{"title":"Investigation of in vitro biotransformation of tris (1-chloro-2-propyl) phosphate and confirmation in human urine","authors":"Fatima den Ouden ,&nbsp;Andrea Estévez-Danta ,&nbsp;Lidia Belova ,&nbsp;Celine Gys ,&nbsp;Anna Klimowska ,&nbsp;Maarten Roggeman ,&nbsp;Natan Van Wichelen ,&nbsp;José Benito Quintana ,&nbsp;Rosario Rodil ,&nbsp;Giulia Poma ,&nbsp;Adrian Covaci","doi":"10.1016/j.crtox.2024.100164","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100164","url":null,"abstract":"<div><p>Tris (1-chloro-2-propyl) phosphate (TCIPP) is one of the major organophosphate flame retardants present in the indoor and outdoor environment. Knowledge of biotransformation pathways is important to elucidate potential bioavailability and toxicity of TCIPP and to identify relevant biomarkers. This study aimed to identify TCIPP metabolites through <em>in vitro</em> human metabolism assays and finally to confirm these findings in urine samples from an occupationally exposed population to propose new biomarkers to accurately monitor exposure to TCIPP.</p><p>TCIPP was incubated with human liver microsomes and human liver cytosol to identify Phase I and Phase II metabolites, by liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Using a suspect-screening approach, the established biomarkers bis (1-chloro-2-propyl) hydrogen phosphate (BCIPP) and 1-hydroxy-2-propyl bis (1-chloro-2-propyl) phosphate (BCIPHIPP) were identified. In addition, carboxyethyl bis (1-chloro-2-propyl) phosphate (TCIPP-M1), bis (1-chloropropan-2-yl) (-oxopropan-2-yl) phosphate (TCIPP-M2) and 1-chloro-3-hydroxypropan-2-yl bis (1-chloropropan-2-yl) phosphate (TCIPP-M3) were identified. TCIPP-M2, an intermediate product, was not reported before in literature. In urine samples, apart from BCIPP and BCIPHIPP, TCIPP-M1 and TCIPP-M3 were identified for the first time. Interestingly, BCIPP showed the lowest detection frequency, likely due to the poor sensitivity for this compound. Therefore, TCIPP-M1 and TCIPP-M3 could serve as potential additional biomarkers to more efficiently monitor TCIPP exposure in humans.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100164"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000173/pdfft?md5=93edeb407f8b80274045e09c6485a17a&pid=1-s2.0-S2666027X24000173-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sunitinib malate induces cell death in adult human cardiac progenitor cells","authors":"Robert Walmsley ,&nbsp;Derek S. Steele ,&nbsp;Sotiris Papaspyros ,&nbsp;Andrew J. Smith","doi":"10.1016/j.crtox.2024.100167","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100167","url":null,"abstract":"<div><p>Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impacts of sunitinib on these cells. This study aimed to characterise the toxic effects of sunitinib in human CPCs, applying sunitinib concentrations equivalent to clinical plasma levels to these cells <em>in vitro</em>. Cell viability was reduced by 26.5 ± 6.6 % by 2 μM sunitinib for 24 h (<em>p</em> &lt; 0.01); this concentration also induced fold-change increases in gene expression of: calpain (3.1 ± 0.73, <em>p</em> &lt; 0.05), FAS (2.3 ± 0.8, <em>p</em> &lt; 0.05) and BAX (1.9 ± 0.2, <em>p</em> &lt; 0.05), and a decrease in BCL-2 (3.5 ± 0.0, <em>p</em> &lt; 0.001), <em>vs</em>. control (1.0 ± 0.0). This was affirmed by sunitinib inducing fold changes in protein expression of: calpain-1 (2.5 ± 0.5, <em>p</em> &lt; 0.05); FAS receptor (2.1 ± 0.2, <em>p</em> &lt; 0.05) and BAX (2.1 ± 0.2, <em>p</em> &lt; 0.05) <em>vs</em>. control (1.0 ± 0.0). These results indicated that sunitinib induced apoptosis in CPCs, but negative annexin V staining and lack of protection by caspase inhibitors indicated this was not the cell death pathway activated. Further investigation found sunitinib was concentrated in the lysosomes and autophagosomes within CPCs, but did not induce accumulation of acidic organelles. In conclusion, these data confirm that cell death is caused by sunitinib in CPCs at concentrations equivalent to clinical plasma levels, inducing cell death pathway signals that lead to non-apoptotic cell death.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100167"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000203/pdfft?md5=4e2738196d2fda4a1c0103db46288bc7&pid=1-s2.0-S2666027X24000203-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing the effects of three neonicotinoids on embryogenesis of the South African clawed frog Xenopus laevis","authors":"Hannah Flach ,&nbsp;Carla Brendler ,&nbsp;Martina Schöpf,&nbsp;Lilly Xu,&nbsp;Julia Schneider,&nbsp;Kathrin Dewald,&nbsp;Petra Dietmann,&nbsp;Michael Kühl,&nbsp;Susanne J. Kühl","doi":"10.1016/j.crtox.2024.100169","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100169","url":null,"abstract":"<div><p>Neonicotinoids (NEOs) are widely used insecticides that are ubiquitous in agricultural use. Since NEOs are found in natural waters as well as in tap water and human urine in regions where NEOs are widely used, NEOs pose a potential hazard to non-target organisms such as animals and humans. Some of the commonly detected NEOs are imidacloprid (IMD), thiamethoxam (TMX), and its metabolite clothianidin (CLO). Although previously published scientific information, including an assessment of the environmental risks, particularly for bees, had resulted in a ban on the outdoor use of these three NEOs in the EU – their use is now only permitted in closed greenhouses – these NEOs continue to be used in agriculture in many other parts of the world. Therefore, a detailed study and comparison of the effects of NEOs on the embryonic development of non-target organisms is needed to further define the risk profiles.</p><p>Embryos of the South African clawed frog <em>Xenopus laevis</em>, a well-established aquatic model, were exposed to different concentrations of IMD, TMX, or CLO (0.1–100 mg/L) to study and compare the possible effects of a single contaminant in natural water bodies on early embryogenesis. The results included a reduced body length, a smaller orbital space, impaired cranial cartilage and nerves, and an altered heart structure and function. At the molecular level, NEO exposure partially resulted in an altered expression of tissue-specific factors, which are involved in eye, cranial placode, and heart development<em>.</em></p><p>Our results suggest that the NEOs studied negatively affect the embryonic development of the non-target organism <em>X. laevis</em>. Since pesticides, especially NEOs, pollute the environment worldwide, it is suggested that they are strictly controlled and monitored in the areas where they are used. In addition, the question arises as to whether pesticide metabolites also pose a risk to the environment and need to be investigated further so that they can be taken into account when registering ingredients.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100169"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000227/pdfft?md5=638dfdd1ee6da1222c6310f335755964&pid=1-s2.0-S2666027X24000227-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140643963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crowdsourcing AOP development: Leveraging the thesis literature review to identify knowledge gaps and facilitate research translation","authors":"Jacob I. Reynolds ,&nbsp;Judy Choi ,&nbsp;Brian P. Johnson","doi":"10.1016/j.crtox.2024.100191","DOIUrl":"10.1016/j.crtox.2024.100191","url":null,"abstract":"<div><p>Chemical risk assessment still primarily relies on extrapolation of data from high-confidence <em>in vivo</em> studies. Emerging 21st Century Toxicology tools and approaches have potential to figure more prominently in chemical risk assessment, but many challenges in translating this research into assessments remain. One of these tools, the Adverse Outcome Pathway (AOP) Wiki provides a framework to map and evaluate adverse chemical dynamics, that is the biochemical and physiological effects that occur after chemical exposure. The AOP-guided targeted review of relevant literature, described here, shares similarities with a doctoral thesis or literature review but forces critical evaluation of each step in a pathway including those of central dogma. Additionally, it provides valuable translational regulatory relevance. Data gaps identified through this process can be targeted areas of study in the thesis itself to increase translational relevance. One of the challenges with this tool is that many AOPs are under- or undeveloped. To help fill this need, a concerted effort by subject matter experts to speed the development of AOPs supported under the Organization for Economic Cooperation and Development (OECD) framework would benefit this translational problem. As a case study, we present our experience developing AOP 460: Antagonism of Smoothened receptor leading to orofacial clefting (OECD AOP workplan project 1.101) as part of a graduate literature review. AOP development offers clear benefits to the regulatory and academic communities and increased dissemination of AOPs replete with the most current state of scientific knowledge will promote research translation and increased risk assessment capabilities.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100191"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000446/pdfft?md5=c2419829dcdc8264778e5365bcbe94c1&pid=1-s2.0-S2666027X24000446-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141953746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxicity and inhibitory potential of CUDC-101 in non-small cell lung cancer cells with rare EGFR L861Q mutation","authors":"Chunhong Chu ,&nbsp;Huixia Xu ,&nbsp;Chenxue Liu ,&nbsp;Xiangkai Wei ,&nbsp;Lanxin Li ,&nbsp;Rui Wang ,&nbsp;Wenrui Cui ,&nbsp;Guoliang Zhang ,&nbsp;Chenyang Liu ,&nbsp;Ke Wang ,&nbsp;Lei An ,&nbsp;Fei He","doi":"10.1016/j.crtox.2024.100194","DOIUrl":"10.1016/j.crtox.2024.100194","url":null,"abstract":"<div><div>The epidermal growth factor receptor (EGFR) represents an effective target for the treatment of non-small cell lung cancer. In the treatment of classical EGFR mutations, EGFR tyrosine kinase inhibitors have achieved desirable clinical efficacy. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the L861Q mutation has not been fully established. In this study, the four cell lines containing the L861Q mutation were constructed by CRISPR and the anti-tumour effects of CUDC-101 on them were investigated in vitro by various chemosensitivity methods, with afatinib serving as a positive control. The results demonstrated that CUDC-101 inhibited the proliferation and clonogenic capacity on the four cells through the ERK or AKT pathways, decreased the mitochondrial membrane potential of the cells, blocked the cell cycle and promoted apoptosis. Our findings suggest that CUDC-101 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation L861Q.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100194"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142531775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytoprotective effects of α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol on 7-ketocholesterol – Induced oxiapoptophagy: Major roles of PI3-K / PDK-1 / Akt signaling pathway and glutathione peroxidase activity in cell rescue","authors":"Aline Yammine ,&nbsp;Imen Ghzaiel ,&nbsp;Vivien Pires ,&nbsp;Amira Zarrouk ,&nbsp;Omar Kharoubi ,&nbsp;Hélène Greige-Gerges ,&nbsp;Lizette Auezova ,&nbsp;Gérard Lizard ,&nbsp;Anne Vejux","doi":"10.1016/j.crtox.2024.100153","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100153","url":null,"abstract":"<div><p>On murine N2a cells, 7-ketocholesterol induced an oxiapotophagic mode of cell death characterized by oxidative stress (reactive oxygen species overproduction on whole cells and at the mitochondrial level; lipid peroxidation), apoptosis induction (caspase-9, −3 and −7 cleavage, PARP degradation) and autophagy (increased ratio LC3-II / LC3-I). Oxidative stress was strongly attenuated by diphenyleneiodonium chloride which inhibits NAD(P)H oxidase. Mitochondrial and peroxisomal morphological and functional changes were also observed. Down regulation of PDK1 / Akt signaling pathways as well as of GSK3 / Mcl-1 and Nrf2 pathways were simultaneously observed in 7-ketocholesterol-induced oxiapoptophagy. These events were prevented by α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol. The inhibition of the cytoprotection by LY-294002, a PI3-K inhibitor, demonstrated an essential role of PI3-K in cell rescue. The rupture of oxidative stress in 7-ketocholesterol-induced oxiapoptophagy was also associated with important modifications of glutathione peroxidase, superoxide dismutase and catalase activities as well as of glutathione peroxidase-1, superoxide dismutase-1 and catalase level and expression. These events were also counteracted by α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol. The inhibition of the cytoprotection by mercaptosuccinic acid, a glutathione peroxidase inhibitor, showed an essential role of this enzyme in cell rescue. Altogether, our data support that the reactivation of PI3-K and glutathione peroxidase activities by α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol are essential to prevent 7KC-induced oxiapoptophagy.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100153"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000069/pdfft?md5=cc94eed3c51e0bb23ed2a0f7ac637582&pid=1-s2.0-S2666027X24000069-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139737550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen sulfide donor NaHS inhibits formaldehyde-induced epithelial-mesenchymal transition in human lung epithelial cells via activating TGF-β1/Smad2/3 and MAPKs signaling pathways","authors":"Haopei Wang ,&nbsp;Miaomiao Jia ,&nbsp;Yuxin Chang,&nbsp;Xingwei Ling,&nbsp;Wenyan Qi,&nbsp;Hongtao Chen,&nbsp;Feipeng Chen,&nbsp;Haiyang Bai,&nbsp;Yuhan Jiang,&nbsp;Chengfan Zhou","doi":"10.1016/j.crtox.2024.100199","DOIUrl":"10.1016/j.crtox.2024.100199","url":null,"abstract":"<div><div>Formaldehyde (FA) long term exposure leads to abnormal pulmonary function and small airway obstruction of the patients. Hydrogen sulfide (H₂S) is one of the recognized gaseous transmitters involved in a wide range of cellular functions. It is unknown the involvement of H₂S in FA-induced lung injury. The purpose of this study is to investigate the therapeutic potential and mechanism of H₂S on FA-induced epithelial-mesenchymal transition (EMT) of human lung epithelial cells. The cell viability of Beas2B and A549 cells after FA treatment were assessed using MTT assay. The endogenous H₂S was visualized by fluorescence microscopy using of the 7-azido-4-methylcoumarin (AzMC). Cell morphology was observed under phase contrast microscope. The mRNAs and proteins level were evaluated by reverse transcription-polymerase chain reaction and western blotting assays. FA treatment downregulated the endogenous H₂S levels and the mRNAs and proteins level of H₂S synthesizing enzymes, such as cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in Beas2B and A549 cells. FA treatment changed the cell morphology of Beas2B cells from cuboid to a spindle-shape, while declined the protein level of E-cadherin and increased the protein level of Vimentin. Moreover, FA treatment increased the proteins level of transforming growth factor-β1 (TGF-β1), phosphorylated-Smad2 (p-Smad2), phosphorylated-Smad3 (p-Smad3), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-c-Jun N-terminal kinase (p-JNK), and phosphorylated-P38 (p-P38). Furthermore, the inhibitors of TGF-β receptor type 1 (TGFβRI) and mitogen-activated protein kinases (MAPKs) signaling pathways reversed FA-induced decrease in E-cadherin expression and increase in Vimentin expression in Beas2B cells. Sodium hydrogen sulfide (NaHS) increased the level of H₂S, while reversed FA-induced the low expression of E-cadherin and the high expression of Vimentin, TGF-β1, p-Smad2, p-Smad3, p-ERK, p-JNK, and p-P38. These findings indicates FA treatment downregulating the endogenous H₂S in human lung epithelial cells. NaHS may inhibit FA-induced EMT in human lung epithelial cells via modulating TGF-β1/Smad2/3 and MAPKs signaling pathways. Therefore, we demonstrated that supplementation of exogenous H₂S may inhibit FA-induced lung injury.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100199"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142531776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen replacement therapy reverses spatial memory loss and pyramidal cell neurodegeneration in the prefrontal cortex of lead-exposed ovariectomized Wistar rats","authors":"Abiodun Shukrat Lasisi-Sholola ,&nbsp;Sodiq Opeyemi Hammed ,&nbsp;Richard Adedamola Ajike ,&nbsp;Roland Eghoghosoa Akhigbe ,&nbsp;Oladele Ayobami Afolabi","doi":"10.1016/j.crtox.2024.100200","DOIUrl":"10.1016/j.crtox.2024.100200","url":null,"abstract":"<div><h3>Background</h3><div>Although menopause is a component of chronological aging, it may be induced by exposure to heavy metals like lead. Interestingly, lead exposure, just like the postmenopausal state, has been associated with spatial memory loss and neurodegeneration; however, the impact of hormone replacement therapy (HRT) on menopause and lead-induced spatial memory loss and neurodegeneration is yet to be reported.</div></div><div><h3>Aim</h3><div>The present study investigated the effect and associated mechanism of HRT on ovariectomized-driven menopausal state and lead exposure-induced spatial memory loss and neurodegeneration.</div></div><div><h3>Materials and methods</h3><div>Thirty adult female Wistar rats were randomized into 6 groups (n = 5 rats/group); the sham-operated vehicle-treated, ovariectomized (OVX), OVX + HRT, lead-exposed, OVX + lead, and OVX + Lead + HRT groups. Treatment was daily via gavage and lasted for 28 days.</div></div><div><h3>Results</h3><div>Ovariectomy and lead exposure impaired spatial memory deficit evidenced by a significant reduction in novel arm entry, time spent in the novel arm, alternation, time exploring novel and familiar objects, and discrimination index. These findings were accompanied by a marked distortion in the histology of the prefrontal cortex, and a decline in serum dopamine level and pyramidal neurons. In addition, ovariectomy and lead exposure induced metabolic disruption (as depicted by a marked rise in lactate level and lactate dehydrogenase and creatinine kinase activities), oxidative stress (evidenced by a significant increase in MDA level, and decrease in GSH level, and SOD and catalase activities), inflammation (as shown by significant upregulation of myeloperoxidase activity, and TNF-α and IL-1β), and apoptosis (evidenced by a rise in caspase 3 activity) of the prefrontal cortex. The observed biochemical and histological perturbations were attenuated by HRT.</div></div><div><h3>Conclusions</h3><div>This study revealed that HRT attenuated ovariectomy and lead-exposure-induced spatial memory deficit and pyramidal neurodegeneration by suppressing oxidative stress, inflammation, and apoptosis of the prefrontal cortex.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100200"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model","authors":"Gaby A.M. Eliesen ,&nbsp;Milou Fransen ,&nbsp;Hedwig van Hove ,&nbsp;Petra H.H. van den Broek ,&nbsp;Rick Greupink","doi":"10.1016/j.crtox.2024.100149","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100149","url":null,"abstract":"<div><p>Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced to the European market in 2017, for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. In the treatment of women with autoimmune diseases, pregnancy is a relevant issue, as such diseases typically affect women in their reproductive years. Currently, there is limited data on the use of tofacitinib during pregnancy. To estimate the extent of placental transfer in the absence of clinical data, we conducted <em>ex vivo</em> dual-side perfused human placental cotyledon perfusions. Term placentas were perfused for 180 min with tofacitinib (100 nM, added to the maternal circuit) in a closed-closed configuration. At the end of the perfusions, drug concentrations in the maternal and fetal reservoirs were near equilibrium, at 35.6 ± 5.5 and 24.8 ± 4.7 nM, respectively. Transfer of tofacitinib was similar to that observed for the passive diffusion marker antipyrine (100 µg/mL, added to the maternal reservoir). Final antipyrine maternal and fetal concentrations amounted to 36.9 ± 3.0 and 36.7 ± 1.3 µg/mL, respectively. In conclusion, in the <em>ex vivo</em> perfused placenta tofacitinib traverses the placental barrier rapidly and extensively. This suggests that substantial fetal tofacitinib exposure will take place after maternal drug dosing.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100149"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000021/pdfft?md5=750bbc6c92fbedeaeb8bafe931bcf4db&pid=1-s2.0-S2666027X24000021-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139419305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D human stem-cell-derived neuronal spheroids for in vitro neurotoxicity testing of methylglyoxal, highly reactive glycolysis byproduct and potent glycating agent","authors":"Teresa Coccini ,&nbsp;Francesca Caloni ,&nbsp;Luciana Alessandra Russo ,&nbsp;Laura Villani ,&nbsp;Davide Lonati ,&nbsp;Uliana De Simone","doi":"10.1016/j.crtox.2024.100176","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100176","url":null,"abstract":"<div><p>Human-derived three-dimensional (3D) <em>in vitro</em> models are advanced <em>human cell-based</em> model for their complexity, relevance and application in toxicity testing. Intracellular accumulation of methylglyoxal (MGO), the most potent glycating agent in humans, mainly generated as a by-product of glycolysis, is associated with age-related diseases including neurodegenerative disorders.</p><p>In our study, 3D human stem-cell-derived neuronal spheroids were set up and applied to evaluate cytotoxic effects after short-term (5 to 48 h) treatments with different MGO concentrations, including low levels, taking into consideration several biochemical endpoints.</p><p>In MGO-treated neurospheroids, reduced cell growth proliferation and decreased cell viability occurred early from 5-10 μM, and their compactness diminished starting from 100 μM, apparently without affecting spheroid size. MGO markedly caused loss of the neuronal markers MAP-2 and NSE from 10-50 μM, decreased the detoxifying Glo1 enzyme from 50 μM, and activated NF-kB by nuclear translocation.</p><p>The cytochemical evaluation of the 3D sections showed the presence of necrotic cells with loss of nuclei. Apoptotic cells were observed from 50 μM MGO after 48 h, and from 100 μM after 24 h. MGO (50–10 µM) also induced modifications of the cell–cell and cell-ECM interactions. These effects worsened at the higher concentrations (300–500 µM).</p><p>In 3D neuronal spheroids, MGO tested concentrations comparable to human samples levels measured in MGO-associated diseases, altered neuronal key signalling endpoints relevant for the pathogenesis of neurodegenerative diseases and aging. The findings also demonstrated that the use of 3D neuronal spheroids of human origin can be useful in a strategy <em>in vitro</em> for testing MGO and other dicarbonyls evaluation.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100176"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X2400029X/pdfft?md5=215eca89a24ba4180c3d12b699dc970d&pid=1-s2.0-S2666027X2400029X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141308252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}