{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T13:55:55Z","timestamp":1792936555498,"version":"4.5.0"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001030","name":"National Heart Foundation of Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001030","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Preeclampsia is a complex pregnancy disorder characterized by the new onset of hypertension and organ dysfunction, often leading to significant maternal and fetal morbidity and mortality. Placental dysfunction is a hallmark feature of preeclampsia, which is often caused by inappropriate trophoblast cell function in association with oxidative stress, inflammation and\/or pathological hypoxia. This study explores the role of oxidative stress in trophoblast cell-based models mimicking the preeclamptic placenta and evaluates potential therapeutic strategies targeting these mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Uric acid (UA) and malondialdehyde (MDA) concentrations were measured in human plasma from women with preeclampsia (n = 24) or normotensive controls (n = 14) using colorimetric assays. Custom-made first trimester trophoblast cell line, ACH-3P, was exposed to various preeclampsia-like stimuli including hypoxia mimetic (dimethyloxalylglycine or DMOG, 1\u00a0mM), inflammation (tumour necrosis factor or TNF-\u03b1, 10\u00a0ng\/mL) or mitochondria dysfunction agent, (Rhodamine-6G or Rho-6G, 1\u00a0\u03bcg\/mL), \u00b1 aspirin (0.5\u00a0mM), metformin (0.5\u00a0mM), AD-01 (100\u00a0nM) or resveratrol (15\u00a0\u00b5M), for 48\u00a0h. Following treatments, UA\/MDA, proliferation (MTT), wound scratch and cytometric bead, assays, were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, MDA plasma concentration was increased in the preeclampsia group compared to healthy controls (p &amp;lt; 0.001) whereas UA showed a trend towards an increase (p = 0.06); when adjusted for differences in gestational age at blood sampling, MDA remained (p &amp;lt; 0.001) whereas UA became (p = 0.03) significantly correlated with preeclampsia. Our 2D first trimester trophoblast cell-based <jats:italic>in vitro<\/jats:italic> model of placental stress as observed in preeclampsia, mimicked the increase in UA concentration following treatment with DMOG (p &amp;lt; 0.0001), TNF-\u03b1 (p &amp;lt; 0.05) or Rho-6G (p &amp;lt; 0.001) whereas MDA cell concentration increased only in the presence of DMOG (p &amp;lt; 0.0001) or Rho-6G (p &amp;lt; 0.001). Metformin was able to abrogate DMOG- (p &amp;lt; 0.01), Rho-6G- (p &amp;lt; 0.0001) or TNF-\u03b1- (p &amp;lt; 0.01) induced increase in UA, or DMOG- (p &amp;lt; 0.0001) or TNF-\u03b1- (p &amp;lt; 0.05)induced increase in MDA. AD-01 abrogated UA or MDA increase in the presence of TNF-\u03b1 (p &amp;lt; 0.001) or Rho-6G (p &amp;lt; 0.001)\/DMOG (p &amp;lt; 0.0001), respectively. The preeclampsia-like stimuli also mimicked adverse impact on trophoblast cell proliferation, migration and inflammation, most of which were restored with either aspirin, metformin, resveratrol, or AD-01 (p &amp;lt; 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our 2D <jats:italic>in vitro<\/jats:italic> models recapitulate the response of the first trimester trophoblast cells to preeclampsia-like stresses, modelling inappropriate placental development, and demonstrate therapeutic potential of repurposed treatments.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2025.1539496","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T07:25:01Z","timestamp":1740727501000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Evaluating oxidative stress targeting treatments in in vitro models of placental stress relevant to preeclampsia"],"prefix":"10.3389","volume":"13","author":[{"given":"Dinara","family":"Afrose","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt D.","family":"Johansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Nikolic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"Karadzov Orlic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeljko","family":"Mikovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Stefanovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoran","family":"Cakic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M.","family":"Hansbro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"McClements","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/AOG.0000000000003018","volume":"133","year":"2019","journal-title":"Obstet. 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