{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:19:52Z","timestamp":1790173192731,"version":"4.1.0"},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T00:00:00Z","timestamp":1550102400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T00:00:00Z","timestamp":1550102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL128628"],"award-info":[{"award-number":["HL128628"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Increased inflammation and abnormal placentation are common features of a wide spectrum of pregnancy-related disorders such as intra uterine growth restriction, preeclampsia and preterm birth. The inflammatory response of the human placenta has been mostly investigated in relation to cytokine release, but the direct molecular consequences on trophoblast differentiation have not been investigated. This study measured the general effects of LPS on both extravillous and villous trophoblast physiology, and the involvement of the transcription factors PPAR\u03b3 and NF-\u03baB, specifically using 1<jats:sup>st<\/jats:sup>trimester explants and HTR-8\/ SVneo cell line models. While both proteins are known for their roles in inflammatory pathways, PPAR\u03b3 has been identified as an important molecule in trophoblast differentiation, suggesting its potential role in mediating a\u00a0crosstalk between inflammation and trophoblast differentiation. Here, LPS (1\u2009\u00b5g\/ml) exposure of first trimester placental villous explants resulted in secretion of inflammatory cytokines, induction of apoptosis and reduction in trophoblast cell proliferation. Additionally, LPS significantly reduced expression of the trophoblast differentiation proteins GCM1 and \u03b2-hCG, and increased invasion of the extravillous trophoblast. Activation of PPAR\u03b3 by Rosiglitazone (10\u2009\u00b5M) reversed the LPS-mediated effects on inflammatory cytokine release, trophoblast apoptosis and proliferation compared to controls. Lastly, markers of trophoblast differentiation and invasion reverted to control levels upon activation of PPAR\u03b3 and concomitant inhibition of NF-\u03baB (either by Rosiglitazone or NF-\u03baB specific inhibitor), revealing a new role for NF-\u03baB in trophoblast invasion. This study reveals a novel PPAR\u03b3 - NF-\u03baB axis that coordinates inflammatory and differentiation pathways in the human placenta. The ability to reverse trophoblast-associated inflammation with Rosiglitazone offers promise that the PPAR\u03b3 \u2013 NF-\u03baB pathway could one day provide a therapeutic target for placental dysfunction associated with both inflammation and abnormal trophoblast differentiation.<\/jats:p>","DOI":"10.1038\/s41598-018-38336-2","type":"journal-article","created":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T11:03:38Z","timestamp":1550142218000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Rosiglitazone blocks first trimester in-vitro placental injury caused by NF-\u03baB-mediated inflammation"],"prefix":"10.1038","volume":"9","author":[{"given":"Leena","family":"Kadam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Kilburn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora","family":"Baczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid Reza","family":"Kohan-Ghadr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Kingdom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Drewlo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,14]]},"reference":[{"key":"38336_CR1","doi-asserted-by":"publisher","unstructured":"Mor, G., Cardenas, I., Abrahams, V. & Guller, S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 1221(1), 80\u20137, https:\/\/doi.org\/10.1111\/j.1749-6632.2010.05938.x (2011).","DOI":"10.1111\/j.1749-6632.2010.05938.x"},{"issue":"6","key":"38336_CR2","first-page":"2505","volume":"86","author":"DF Benyo","year":"2001","unstructured":"Benyo, D. F. et al. Expression of inflammatory cytokines in placentas from women with preeclampsia. The Journal of clinical endocrinology and metabolism 86(6), 2505\u20132512 (2001).","journal-title":"The Journal of clinical endocrinology and metabolism"},{"issue":"1","key":"38336_CR3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/j.1600-0897.2007.00486.x","volume":"58","author":"A Sharma","year":"2007","unstructured":"Sharma, A., Satyam, A. & Sharma, J. Leptin, IL\u201010 and Inflammatory Markers (TNF\u2010\u03b1, IL\u20106 and IL\u20108) in Pre\u2010Eclamptic, Normotensive Pregnant and Healthy Non\u2010Pregnant Women. American Journal of Reproductive Immunology 58(1), 21\u201330 (2007).","journal-title":"American Journal of Reproductive Immunology"},{"key":"38336_CR4","doi-asserted-by":"publisher","first-page":"790605","DOI":"10.1155\/2010\/790605","volume":"2010","author":"T Boutsikou","year":"2010","unstructured":"Boutsikou, T. et al. Circulating Levels of Inflammatory Markers in Intrauterine Growth Restriction. Mediators of Inflammation 2010, 790605 (2010).","journal-title":"Mediators of Inflammation"},{"issue":"5","key":"38336_CR5","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1067\/mob.2000.109035","volume":"183","author":"BH Yoon","year":"2000","unstructured":"Yoon, B. H. et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. American Journal of Obstetrics and Gynecology 183(5), 1124\u20131129 (2000).","journal-title":"American Journal of Obstetrics and Gynecology"},{"issue":"4 Pt 1","key":"38336_CR6","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/0029-7844(96)00224-4","volume":"88","author":"A Steinborn","year":"1996","unstructured":"Steinborn, A. et al. Elevated placental cytokine release, a process associated with preterm labor in the absence of intrauterine infection. Obstet Gynecol 88(4 Pt 1), 534\u20139 (1996).","journal-title":"Obstet Gynecol"},{"issue":"2","key":"38336_CR7","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1095\/biolreprod.102.013102","volume":"69","author":"DR Balkundi","year":"2003","unstructured":"Balkundi, D. R. et al. Regulation of FasL\/Fas in human trophoblasts: possible implications for chorioamnionitis. Biol Reprod 69(2), 718\u201324 (2003).","journal-title":"Biol Reprod"},{"issue":"Suppl 2","key":"38336_CR8","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1046\/j.1365-3016.2001.00010.x","volume":"15","author":"CJ Lockwood","year":"2001","unstructured":"Lockwood, C. J. & Kuczynski, E. Risk stratification and pathological mechanisms in preterm delivery. Paediatric and perinatal epidemiology 15(Suppl 2), 78\u201389 (2001).","journal-title":"Paediatric and perinatal epidemiology"},{"issue":"2","key":"38336_CR9","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0165-0378(96)00998-9","volume":"32","author":"Y Wang","year":"1996","unstructured":"Wang, Y. & Walsh, S. W. TNF alpha concentrations and mRNA expression are increased in preeclamptic placentas. J Reprod Immunol 32(2), 157\u201369 (1996).","journal-title":"J Reprod Immunol"},{"issue":"6","key":"38336_CR10","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1067\/mob.2001.112906","volume":"184","author":"DN Leung","year":"2001","unstructured":"Leung, D. N. et al. Increased placental apoptosis in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 184(6), 1249\u201350 (2001).","journal-title":"Am J Obstet Gynecol"},{"issue":"4 Pt 1","key":"38336_CR11","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1016\/S0002-9378(96)80034-2","volume":"175","author":"DM Svinarich","year":"1996","unstructured":"Svinarich, D. M. et al. Induction and posttranslational expression of cytokines in a first-trimester trophoblast cell line by lipopolysaccharide. Am J Obstet Gynecol 175(4 Pt 1), 970\u20133 (1996).","journal-title":"Am J Obstet Gynecol"},{"issue":"1","key":"38336_CR12","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-5-46","volume":"5","author":"V Zaga-Clavellina","year":"2007","unstructured":"Zaga-Clavellina, V. et al. In vitro secretion profiles of interleukin (IL)-1beta, IL-6, IL-8, IL-10, and TNF alpha after selective infection with Escherichia coli in human fetal membranes. Reprod Biol Endocrinol 5(1), 46 (2007).","journal-title":"Reprod Biol Endocrinol"},{"issue":"4","key":"38336_CR13","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.placenta.2009.01.013","volume":"30","author":"M Jovanovic","year":"2009","unstructured":"Jovanovic, M. & Vicovac, L. Interleukin-6 stimulates cell migration, invasion and integrin expression in HTR-8\/SVneo cell line. Placenta 30(4), 320\u20138 (2009).","journal-title":"Placenta"},{"issue":"2","key":"38336_CR14","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1210\/jc.2003-031351","volume":"89","author":"S Bauer","year":"2004","unstructured":"Bauer, S. et al. Tumor necrosis factor-alpha inhibits trophoblast migration through elevation of plasminogen activator inhibitor-1 in first-trimester villous explant cultures. The Journal of clinical endocrinology and metabolism 89(2), 812\u2013822 (2004).","journal-title":"The Journal of clinical endocrinology and metabolism"},{"issue":"1","key":"38336_CR15","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1093\/humrep\/der362","volume":"27","author":"L Anton","year":"2012","unstructured":"Anton, L. et al. Lipopolysaccharide induces cytokine production and decreases extravillous trophoblast invasion through a mitogen-activated protein kinase-mediated pathway: possible mechanisms of first trimester placental dysfunction. Hum Reprod 27(1), 61\u201372 (2012).","journal-title":"Hum Reprod"},{"issue":"9","key":"38336_CR16","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1515\/BC.2005.101","volume":"386","author":"M Cramer","year":"2005","unstructured":"Cramer, M. et al. NF-kappaB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells. Biol Chem 386(9), 865\u201372 (2005).","journal-title":"Biol Chem"},{"issue":"4","key":"38336_CR17","first-page":"517","volume":"76","author":"M Ziche","year":"1997","unstructured":"Ziche, M. et al. Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. Laboratory investigation; a journal of technical methods and pathology 76(4), 517\u2013531 (1997).","journal-title":"Laboratory investigation; a journal of technical methods and pathology"},{"issue":"Suppl A","key":"38336_CR18","doi-asserted-by":"publisher","first-page":"S83","DOI":"10.1053\/plac.2001.0648","volume":"22","author":"M Knofler","year":"2001","unstructured":"Knofler, M., Vasicek, R. & Schreiber, M. Key regulatory transcription factors involved in placental trophoblast development\u2013a review. Placenta 22(Suppl A), S83\u201392 (2001).","journal-title":"Placenta"},{"key":"38336_CR19","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1371\/journal.pone.0008055","volume":"4","author":"MM Parast","year":"2009","unstructured":"Parast, M. M. et al. PPAR\u03b3 Regulates Trophoblast Proliferation and Promotes Labyrinthine Trilineage Differentiation. PLoS ONE 4, 11 (2009).","journal-title":"PLoS ONE"},{"issue":"5","key":"38336_CR20","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1038\/cdd.2009.1","volume":"16","author":"D Baczyk","year":"2009","unstructured":"Baczyk, D. et al. Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast. Cell death and differentiation 16(5), 719\u2013727 (2009).","journal-title":"Cell death and differentiation"},{"issue":"12","key":"38336_CR21","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1016\/j.placenta.2009.09.006","volume":"30","author":"K Handschuh","year":"2009","unstructured":"Handschuh, K. et al. Expression and Regulation by PPAR\u03b3 of hCG \u03b1- and \u03b2-subunits: Comparison between Villous and Invasive Extravillous Trophoblastic Cells. Placenta 30(12), 1016\u20131022 (2009).","journal-title":"Placenta"},{"key":"38336_CR22","doi-asserted-by":"crossref","unstructured":"Schaiff, W.T., M.G. Carlson, and S.D. Smith, Peroxisome Proliferator-Activated Receptor-\u03b3 Modulates Differentiation of Human Trophoblast in a Ligand-Specific Manner 1. Peroxisome Proliferator-Activated Receptor-\u03b3 Modulates Differentiation of Human Trophoblast in a Ligand-Specific Manner 1, (2000).","DOI":"10.1210\/jcem.85.10.6885"},{"issue":"10","key":"38336_CR23","doi-asserted-by":"publisher","first-page":"4504","DOI":"10.1210\/endo.142.10.8448","volume":"142","author":"A Tarrade","year":"2001","unstructured":"Tarrade, A. et al. PPAR gamma\/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation. Endocrinology 142(10), 4504\u20134514 (2001).","journal-title":"Endocrinology"},{"issue":"1-2","key":"38336_CR24","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.mce.2006.02.009","volume":"249","author":"TW Schaiff","year":"2006","unstructured":"Schaiff, T. W., Barak, Y. & Sadovsky, Y. The pleiotropic function of PPAR\u03b3 in the placenta. Molecular and Cellular Endocrinology 249(1-2), 10\u201315 (2006).","journal-title":"Molecular and Cellular Endocrinology"},{"issue":"2","key":"38336_CR25","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.jri.2007.05.004","volume":"77","author":"T Fournier","year":"2008","unstructured":"Fournier, T. et al. Role of nuclear receptors and their ligands in human trophoblast invasion. Journal of Reproductive Immunology 77(2), 161\u2013170 (2008).","journal-title":"Journal of Reproductive Immunology"},{"issue":"4","key":"38336_CR26","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/S1097-2765(00)80209-9","volume":"4","author":"Y Barak","year":"1999","unstructured":"Barak, Y. et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4(4), 585\u201395 (1999).","journal-title":"Mol Cell"},{"issue":"10","key":"38336_CR27","doi-asserted-by":"publisher","first-page":"4969","DOI":"10.1210\/en.2010-0131","volume":"151","author":"K Nadra","year":"2010","unstructured":"Nadra, K. et al. PPARgamma in placental angiogenesis. Endocrinology 151(10), 4969\u201381 (2010).","journal-title":"Endocrinology"},{"issue":"4","key":"38336_CR28","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/S1097-2765(00)80210-5","volume":"4","author":"N Kubota","year":"1999","unstructured":"Kubota, N. et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4(4), 597\u2013609 (1999).","journal-title":"Mol Cell"},{"issue":"6","key":"38336_CR29","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1530\/REP-08-0496","volume":"137","author":"SJ Holdsworth-Carson","year":"2009","unstructured":"Holdsworth-Carson, S. J. et al. Preterm and infection-driven preterm labor: the role of peroxisome proliferator-activated receptors and retinoid X receptor. Reproduction (Cambridge, England) 137(6), 1007\u20131015 (2009).","journal-title":"Reproduction (Cambridge, England)"},{"issue":"3","key":"38336_CR30","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.placenta.2009.12.009","volume":"31","author":"SJ Holdsworth-Carson","year":"2010","unstructured":"Holdsworth-Carson, S. J. et al. Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta 31(3), 222\u2013229 (2010).","journal-title":"Placenta"},{"issue":"6","key":"38336_CR31","doi-asserted-by":"publisher","first-page":"2476","DOI":"10.4049\/jimmunol.1502055","volume":"196","author":"Y Xu","year":"2016","unstructured":"Xu, Y. et al. An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment. J Immunol 196(6), 2476\u201391 (2016).","journal-title":"J Immunol"},{"key":"38336_CR32","doi-asserted-by":"crossref","unstructured":"Kadam, L., et al., Rosiglitazone Regulates TLR4 and Rescues HO-1 and NRF2 Expression in Myometrial and Decidual Macrophages in Inflammation-Induced Preterm Birth. Reprod Sci, 1933719117697128. (2017)","DOI":"10.1177\/1933719117697128"},{"issue":"10","key":"38336_CR33","doi-asserted-by":"publisher","first-page":"4667","DOI":"10.1210\/jc.2002-020613","volume":"87","author":"M Lappas","year":"2002","unstructured":"Lappas, M. et al. Regulation of proinflammatory cytokines in human gestational tissues by peroxisome proliferator-activated receptor-gamma: effect of 15-deoxy-Delta(12,14)-PGJ(2) and troglitazone. J Clin Endocrinol Metab 87(10), 4667\u201372 (2002).","journal-title":"J Clin Endocrinol Metab"},{"issue":"7","key":"38336_CR34","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/S0022-2275(20)33479-9","volume":"40","author":"U Edvardsson","year":"1999","unstructured":"Edvardsson, U. et al. Rosiglitazone (BRL49653), a PPAR\u03b3-selective agonist, causes peroxisome proliferator-like liver effects in obese mice. Journal of Lipid Research 40(7), 1177\u20131184 (1999).","journal-title":"Journal of Lipid Research"},{"issue":"3","key":"38336_CR35","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/S0006-291X(03)00418-2","volume":"303","author":"G Hong","year":"2003","unstructured":"Hong, G. et al. PPAR\u03b3-dependent anti-inflammatory action of rosiglitazone in human monocytes: suppression of TNF\u03b1 secretion is not mediated by PTEN regulation. Biochemical and Biophysical Research Communications 303(3), 782\u2013787 (2003).","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"2","key":"38336_CR36","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/S0014-2999(02)01946-5","volume":"448","author":"T Shiojiri","year":"2002","unstructured":"Shiojiri, T. et al. PPAR\u03b3 ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice. European journal of pharmacology 448(2), 231\u2013238 (2002).","journal-title":"European journal of pharmacology"},{"issue":"1","key":"38336_CR37","first-page":"BR21","volume":"15","author":"K Celi\u0144ski","year":"2008","unstructured":"Celi\u0144ski, K. et al. Rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma)-specific agonist, as a modulator in experimental acute pancreatitis. Medical Science Monitor 15(1), BR21\u2013BR29 (2008).","journal-title":"Medical Science Monitor"},{"issue":"1S","key":"38336_CR38","first-page":"17A","volume":"47","author":"J Patel","year":"1998","unstructured":"Patel, J., Miller, E. & Patwardhan, R. Rosiglitazone (BRL49653) monotherapy has significant glucose lowering effect in type 2 diabetic patients. Diabetes 47(1S), 17A (1998).","journal-title":"Diabetes"},{"issue":"14","key":"38336_CR39","doi-asserted-by":"publisher","first-page":"9539","DOI":"10.1074\/jbc.274.14.9539","volume":"274","author":"GT Baxter","year":"1999","unstructured":"Baxter, G. T. et al. Tumor Necrosis Factor-\u03b1 Mediates Both Apoptotic Cell Death and Cell Proliferation in a Human Hematopoietic Cell Line Dependent on Mitotic Activity and Receptor Subtype Expression. Journal of Biological Chemistry 274(14), 9539\u20139547 (1999).","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"38336_CR40","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2369-5-8","volume":"5","author":"M W\u00f6rnle","year":"2004","unstructured":"W\u00f6rnle, M. et al. Effects of chemokines on proliferation and apoptosis of human mesangial cells. BMC Nephrology 5(1), 8 (2004).","journal-title":"BMC Nephrology"},{"issue":"4","key":"38336_CR41","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1136\/gut.35.4.530","volume":"35","author":"FJ Kubben","year":"1994","unstructured":"Kubben, F. J. et al. Proliferating cell nuclear antigen (PCNA): a new marker to study human colonic cell proliferation. Gut 35(4), 530\u20135 (1994).","journal-title":"Gut"},{"key":"38336_CR42","first-page":"637251","volume":"2014","author":"K Levytska","year":"2014","unstructured":"Levytska, K. et al. PPAR- \u03b3 Regulates Trophoblast Differentiation in the BeWo Cell Model. PPAR. Research 2014, 637251 (2014).","journal-title":"Research"},{"issue":"4","key":"38336_CR43","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.placenta.2010.01.004","volume":"31","author":"S Camolotto","year":"2010","unstructured":"Camolotto, S. et al. Expression and transcriptional regulation of individual pregnancy-specific glycoprotein genes in differentiating trophoblast cells. Placenta 31(4), 312\u20139 (2010).","journal-title":"Placenta"},{"issue":"6771","key":"38336_CR44","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/35001608","volume":"403","author":"S Mi","year":"2000","unstructured":"Mi, S. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403(6771), 785\u20139 (2000).","journal-title":"Nature"},{"issue":"2","key":"38336_CR45","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1093\/humupd\/dmi043","volume":"12","author":"JL James","year":"2006","unstructured":"James, J. L., Stone, P. R. & Chamley, L. W. The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy. Human reproduction update 12(2), 137\u2013144 (2006).","journal-title":"Human reproduction update"},{"issue":"12","key":"38336_CR46","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1242\/dev.120.12.3657","volume":"120","author":"CH Damsky","year":"1994","unstructured":"Damsky, C. H. et al. Integrin switching regulates normal trophoblast invasion. Development 120(12), 3657\u20133666 (1994).","journal-title":"Development"},{"key":"38336_CR47","doi-asserted-by":"publisher","unstructured":"Pascual, G. et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437(7059), 759\u201363, https:\/\/doi.org\/10.1038\/nature03988 (2005).","DOI":"10.1038\/nature03988"},{"issue":"4","key":"38336_CR48","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.2353\/ajpath.2009.081022","volume":"175","author":"B Koos","year":"2009","unstructured":"Koos, B. et al. Platelet-Derived Growth Factor Receptor Expression and Activation in Choroid Plexus Tumors. Am J Pathol 175(4), 1631\u20137 (2009).","journal-title":"Am J Pathol"},{"key":"38336_CR49","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.mce.2016.01.004","volume":"423","author":"QL Bo","year":"2016","unstructured":"Bo, Q. L. et al. Rosiglitazone pretreatment protects against lipopolysaccharide-induced fetal demise through inhibiting placental inflammation. Mol Cell Endocrinol 423, 51\u20139 (2016).","journal-title":"Mol Cell Endocrinol"},{"issue":"2","key":"38336_CR50","first-page":"33","volume":"94","author":"L Li","year":"2016","unstructured":"Li, L. et al. Effects of Lipopolysaccharide on Human First Trimester Villous Cytotrophoblast Cell Function In vitro. Biology of Reproduction 94(2), 33 (2016).","journal-title":"Biology of Reproduction"},{"key":"38336_CR51","doi-asserted-by":"crossref","unstructured":"Koh, Y.Q., et al., Differential response to lipopolysaccharide by JEG-3 and BeWo human choriocarcinoma cell lines. Differential response to lipopolysaccharide by JEG-3 and BeWo human choriocarcinoma cell lines, (2014).","DOI":"10.1016\/j.ejogrb.2013.12.032"},{"issue":"11","key":"38336_CR52","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1016\/j.placenta.2015.09.004","volume":"36","author":"LM Gierman","year":"2015","unstructured":"Gierman, L. M. et al. Toll-like receptor profiling of seven trophoblast cell lines warrants caution for translation to primary trophoblasts. Placenta 36(11), 1246\u20131253 (2015).","journal-title":"Placenta"},{"issue":"7","key":"38336_CR53","doi-asserted-by":"publisher","first-page":"4286","DOI":"10.4049\/jimmunol.173.7.4286","volume":"173","author":"VM Abrahams","year":"2004","unstructured":"Abrahams, V. M. et al. Divergent trophoblast responses to bacterial products mediated by TLRs. Journal of immunology (Baltimore, Md.: 1950) 173(7), 4286\u20134296 (2004).","journal-title":"Journal of immunology (Baltimore, Md.: 1950)"},{"issue":"1","key":"38336_CR54","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/S0741-8329(99)00054-3","volume":"20","author":"CY Chang","year":"2000","unstructured":"Chang, C. Y., Tucci, M. & Baker, R. C. Lipopolysaccharide-stimulated nitric oxide production and inhibition of cell proliferation is antagonized by ethanol in a clonal macrophage cell line. Alcohol 20(1), 37\u201343 (2000).","journal-title":"Alcohol"},{"issue":"11","key":"38336_CR55","doi-asserted-by":"publisher","first-page":"5860","DOI":"10.4049\/jimmunol.168.11.5860","volume":"168","author":"N Munshi","year":"2002","unstructured":"Munshi, N. et al. Lipopolysaccharide-induced apoptosis of endothelial cells and its inhibition by vascular endothelial growth factor. J Immunol 168(11), 5860\u20136 (2002).","journal-title":"J Immunol"},{"issue":"1","key":"38336_CR56","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1046\/j.1341-8076.2003.00066.x","volume":"29","author":"K Asagiri","year":"2003","unstructured":"Asagiri, K. et al. Involvement of peroxynitrite in LPS-induced apoptosis of trophoblasts. J Obstet Gynaecol Res 29(1), 49\u201355 (2003).","journal-title":"J Obstet Gynaecol Res"},{"issue":"4","key":"38336_CR57","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1530\/REP-09-0341","volume":"139","author":"M Jovanovic","year":"2010","unstructured":"Jovanovic, M. et al. Interleukin-8 (CXCL8) stimulates trophoblast cell migration and invasion by increasing levels of matrix metalloproteinase (MMP)2 and MMP9 and integrins alpha5 and beta1. Reproduction 139(4), 789\u201398 (2010).","journal-title":"Reproduction"},{"issue":"1","key":"38336_CR58","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/0002-9378(88)90810-1","volume":"158","author":"RS Berkowitz","year":"1988","unstructured":"Berkowitz, R. S. et al. Effects of products of activated leukocytes (lymphokines and monokines) on the growth of malignant trophoblast cells in vitro. American Journal of Obstetrics and Gynecology 158(1), 199\u2013203 (1988).","journal-title":"American Journal of Obstetrics and Gynecology"},{"issue":"4","key":"38336_CR59","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1111\/j.1447-0756.2007.00551.x","volume":"33","author":"H Seki","year":"2007","unstructured":"Seki, H. et al. TNF-alpha from monocyte of patients with pre-eclampsia-induced apoptosis in human trophoblast cell line. J Obstet Gynaecol Res 33(4), 408\u201316 (2007).","journal-title":"J Obstet Gynaecol Res"},{"key":"38336_CR60","doi-asserted-by":"crossref","unstructured":"Fajas, L., et al., PPAR[gamma] controls cell proliferation and apoptosis in an RB-dependent manner. Oncogene, 0000. 22(27): 4186\u20134193.","DOI":"10.1038\/sj.onc.1206530"},{"issue":"2","key":"38336_CR61","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.vph.2009.06.004","volume":"51","author":"Y Ren","year":"2009","unstructured":"Ren, Y. et al. PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation. Vascular Pharmacology 51(2), 169\u2013174 (2009).","journal-title":"Vascular Pharmacology"},{"key":"38336_CR62","doi-asserted-by":"crossref","unstructured":"Saryu Malhotra, S., P. Suman, and S. K G, Alpha or beta human chorionic gonadotropin knockdown decrease BeWo cell fusion by down-regulating PKA and CREB activation. Sci Rep, 5.(2015)","DOI":"10.1038\/srep11210"},{"issue":"6","key":"38336_CR63","first-page":"1506","volume":"77","author":"S Yagel","year":"1993","unstructured":"Yagel, S. et al. High levels of human chorionic gonadotropin retard first trimester trophoblast invasion in vitro by decreasing urokinase plasminogen activator and collagenase activities. The Journal of Clinical Endocrinology & Metabolism 77(6), 1506\u20131511 (1993).","journal-title":"The Journal of Clinical Endocrinology & Metabolism"},{"issue":"8","key":"38336_CR64","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/S0143-4004(98)90019-4","volume":"19","author":"M Zygmunt","year":"1998","unstructured":"Zygmunt, M. et al. Invasion of cytotrophoblastic JEG-3 cells is stimulated by hCG in vitro. Placenta 19(8), 587\u2013593 (1998).","journal-title":"Placenta"},{"issue":"2-3","key":"38336_CR65","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.placenta.2006.01.019","volume":"28","author":"K Handschuh","year":"2007","unstructured":"Handschuh, K. et al. Human chorionic gonadotropin expression in human trophoblasts from early placenta: comparative study between villous and extravillous trophoblastic cells. Placenta 28(2-3), 175\u2013184 (2007).","journal-title":"Placenta"},{"issue":"2","key":"38336_CR66","first-page":"283","volume":"80","author":"F Rodesch","year":"1992","unstructured":"Rodesch, F. et al. Oxygen Measurements in Endometrial and Trophoblastic Tissues During Early Pregnancy. Obstetrics & Gynecology 80(2), 283\u2013285 (1992).","journal-title":"Obstetrics & Gynecology"},{"issue":"10","key":"38336_CR67","doi-asserted-by":"publisher","first-page":"2699","DOI":"10.1093\/humrep\/del212","volume":"21","author":"JL James","year":"2006","unstructured":"James, J. L., Stone, P. R. & Chamley, L. W. The effects of oxygen concentration and gestational age on extravillous trophoblast outgrowth in a human first trimester villous explant model. Hum Reprod 21(10), 2699\u2013705 (2006).","journal-title":"Hum Reprod"},{"issue":"2","key":"38336_CR68","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1172\/JCI118447","volume":"97","author":"O Genbacev","year":"1996","unstructured":"Genbacev, O. et al. Hypoxia alters early gestation human cytotrophoblast differentiation\/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest 97(2), 540\u201350 (1996).","journal-title":"J Clin Invest"},{"issue":"17","key":"38336_CR69","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1002\/bdr2.1149","volume":"109","author":"Y Yang","year":"2017","unstructured":"Yang, Y. et al. Hypoxic Stress Forces Adaptive and Maladaptive Placental Stress Responses in Early Pregnancy. Birth Defects Res 109(17), 1330\u20131344 (2017).","journal-title":"Birth Defects Res"},{"issue":"1","key":"38336_CR70","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1262\/jrd.2016-110","volume":"63","author":"Y Yang","year":"2017","unstructured":"Yang, Y. et al. Departure from optimal O2 level for mouse trophoblast stem cell proliferation and potency leads to most rapid AMPK activation. J Reprod Dev 63(1), 87\u201394 (2017).","journal-title":"J Reprod Dev"},{"issue":"Suppl A","key":"38336_CR71","doi-asserted-by":"publisher","first-page":"S76","DOI":"10.1016\/j.placenta.2006.12.006","volume":"28","author":"T Fournier","year":"2007","unstructured":"Fournier, T. et al. Involvement of PPARgamma in human trophoblast invasion. Placenta 28(Suppl A), S76\u201381 (2007).","journal-title":"Placenta"},{"issue":"1","key":"38336_CR72","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-10-437","volume":"10","author":"M Yan","year":"2010","unstructured":"Yan, M. et al. Correlation of NF-\u03baB signal pathway with tumor metastasis of human head and neck squamous cell carcinoma. BMC Cancer 10(1), 437 (2010).","journal-title":"BMC Cancer"},{"key":"38336_CR73","doi-asserted-by":"crossref","unstructured":"Davuluri, G., et al., WAVE3-NF\u03baB Interplay Is Essential for the Survival and Invasion of Cancer Cells. PLoS One, 9(10) (2014).","DOI":"10.1371\/journal.pone.0110627"},{"issue":"1","key":"38336_CR74","doi-asserted-by":"publisher","first-page":"F38","DOI":"10.1152\/ajprenal.00590.2010","volume":"302","author":"C Kuper","year":"2012","unstructured":"Kuper, C., Beck, F. X. & Neuhofer, W. Toll-like receptor 4 activates NF-kappaB and MAP kinase pathways to regulate expression of proinflammatory COX-2 in renal medullary collecting duct cells. Am J Physiol Renal Physiol 302(1), F38\u201346 (2012).","journal-title":"Am J Physiol Renal Physiol"},{"issue":"1","key":"38336_CR75","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1124\/jpet.104.074484","volume":"312","author":"PL Podolin","year":"2005","unstructured":"Podolin, P. L. et al. Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T. cell Proliferation. J Pharmacol Exp Ther 312(1), 373\u201381 (2005).","journal-title":"cell Proliferation. J Pharmacol Exp Ther"},{"issue":"26","key":"38336_CR76","doi-asserted-by":"publisher","first-page":"27199","DOI":"10.1074\/jbc.M403107200","volume":"279","author":"MI Wickremasinghe","year":"2004","unstructured":"Wickremasinghe, M. I. et al. Transcriptional mechanisms regulating alveolar epithelial cell-specific CCL5 secretion in pulmonary tuberculosis. J Biol Chem 279(26), 27199\u2013210 (2004).","journal-title":"J Biol Chem"},{"issue":"7","key":"38336_CR77","doi-asserted-by":"crossref","first-page":"3483","DOI":"10.4049\/jimmunol.158.7.3483","volume":"158","author":"H Moriuchi","year":"1997","unstructured":"Moriuchi, H., Moriuchi, M. & Fauci, A. S. Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chemokine that blocks HIV infection. J Immunol 158(7), 3483\u201391 (1997).","journal-title":"J Immunol"},{"issue":"4","key":"38336_CR78","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1128\/MCB.10.4.1498","volume":"10","author":"MA Collart","year":"1990","unstructured":"Collart, M. A., Baeuerle, P. & Vassalli, P. Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell Biol 10(4), 1498\u2013506 (1990).","journal-title":"Mol Cell Biol"},{"issue":"1","key":"38336_CR79","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1084\/jem.171.1.35","volume":"171","author":"AN Shakhov","year":"1990","unstructured":"Shakhov, A. N. et al. Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med 171(1), 35\u201347 (1990).","journal-title":"J Exp Med"},{"issue":"7059","key":"38336_CR80","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/nature03988","volume":"437","author":"G Pascual","year":"2005","unstructured":"Pascual, G. et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-\u03b3. Nature 437(7059), 759\u2013763 (2005).","journal-title":"Nature"},{"issue":"1","key":"38336_CR81","doi-asserted-by":"publisher","first-page":"E174","DOI":"10.1152\/ajpendo.90632.2008","volume":"297","author":"AHV Remels","year":"2009","unstructured":"Remels, A. H. V. et al. PPAR\u03b3 inhibits NF-\u03baB-dependent transcriptional activation in skeletal muscle. American Journal of Physiology-Endocrinology and Metabolism 297(1), E174\u2013E183 (2009).","journal-title":"American Journal of Physiology-Endocrinology and Metabolism"},{"issue":"6","key":"38336_CR82","first-page":"2505","volume":"86","author":"DF Benyo","year":"2001","unstructured":"Benyo, D. F. et al. Expression of Inflammatory Cytokines in Placentas from Women with Preeclampsia1. The Journal of Clinical Endocrinology & Metabolism 86(6), 2505\u20132512 (2001).","journal-title":"The Journal of Clinical Endocrinology & Metabolism"},{"issue":"5","key":"38336_CR83","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.placenta.2003.10.014","volume":"25","author":"CP Chen","year":"2004","unstructured":"Chen, C. P. et al. Decreased placental GCM1 (glial cells missing) gene expression in pre-eclampsia. Placenta 25(5), 413\u201321 (2004).","journal-title":"Placenta"},{"issue":"6","key":"38336_CR84","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1002\/pd.329","volume":"22","author":"RO Bahado-Singh","year":"2002","unstructured":"Bahado-Singh, R. O. et al. The role of hyperglycosylated hCG in trophoblast invasion and the prediction of subsequent pre-eclampsia. Prenatal Diagnosis 22(6), 478\u2013481 (2002).","journal-title":"Prenatal Diagnosis"},{"key":"38336_CR85","doi-asserted-by":"crossref","unstructured":"Baczyk, D., et al., DREAM mediated regulation of GCM1 in the human placental trophoblast. PloS one, 8(1) (2013).","DOI":"10.1371\/journal.pone.0051837"},{"issue":"3","key":"38336_CR86","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1095\/biolreprod62.3.739","volume":"62","author":"BA Kilburn","year":"2000","unstructured":"Kilburn, B. A. et al. Extracellular matrix composition and hypoxia regulate the expression of HLA-G and integrins in a human trophoblast cell line. Biol Reprod 62(3), 739\u201347 (2000).","journal-title":"Biol Reprod"},{"issue":"11","key":"38336_CR87","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.placenta.2012.09.007","volume":"33","author":"S Drewlo","year":"2012","unstructured":"Drewlo, S., Levytska, K. & Kingdom, J. Revisiting the housekeeping genes of human placental development and insufficiency syndromes. Placenta 33(11), 952\u20134 (2012).","journal-title":"Placenta"},{"issue":"3","key":"38336_CR88","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1093\/humrep\/der436","volume":"27","author":"RE Leach","year":"2012","unstructured":"Leach, R. E. et al. High throughput, cell type-specific analysis of key proteins in human endometrial biopsies of women from fertile and infertile couples. Human Reproduction 27(3), 814\u2013828 (2012).","journal-title":"Human Reproduction"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-38336-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-38336-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-38336-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T16:50:38Z","timestamp":1694623838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-38336-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,14]]},"references-count":88,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["38336"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-38336-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,14]]},"assertion":[{"value":"21 May 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2018"}}