{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:45:18Z","timestamp":1767807918751,"version":"3.49.0"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dicle University Scientific Research Platform","award":["TIP.24.031"],"award-info":[{"award-number":["TIP.24.031"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with oxidative stress and mitochondrial dysfunction. NRF1 and NRF2 are transcription factors that regulate mitochondrial activity and antioxidant defense. This study investigated their expression patterns in placentas from preeclamptic and severe preeclamptic pregnancies by immunohistochemical and bioinformatical methods. Methods: Placentas from 40 healthy controls, 40 PE, and 40 sPE patients were analyzed by histological and immunohistochemical techniques. Protein\u2013protein interaction networks for NRF1, NRF2, and PE-related proteins were constructed using Search Tool for the Retrieval of Interacting Genes\/Proteins (STRING) and Cytoscape software, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis performed via ShinyGO, with significance set at false discovery rate (FDR) &lt; 0.05. Results: NRF1 expression was significantly decreased in PE and sPE groups compared to controls, with notably negative staining in syncytial knots and fibrinoid areas. Conversely, NRF2 expression significantly increased, showing intense positivity in syncytiotrophoblasts, stromal cells, and vascular structures. Pathway analysis revealed that decreased NRF1 expression was associated with glutathione metabolism, hypoxia inducible factor-1 (HIF-1) signaling, and AMP-Activated Protein Kinase (AMPK) signaling pathways. Increased NRF2 expression was associated predominantly with inflammatory and immune response pathways, including AGE-RAGE signaling and pathogen\u2013response pathways. Conclusions: Differential expressions of NRF1 and NRF2 in preeclamptic placentas reflect distinct yet interconnected responses to oxidative stress and inflammation. These transcription factors have potential clinical relevance as biomarkers for PE severity assessment and as targets for future therapeutic interventions.<\/jats:p>","DOI":"10.3390\/life16010089","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T12:34:21Z","timestamp":1767789261000},"page":"89","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NRF1 and NRF2 Expression in Preeclamptic Placentas: A Comparative Observational Study"],"prefix":"10.3390","volume":"16","author":[{"given":"\u015eehmus","family":"Kaplan","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Sur, Diyarbak\u0131r, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"U\u011fur","family":"Karabat","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Sur, Diyarbak\u0131r, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhyiddin","family":"Sancar","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Sur, Diyarbak\u0131r, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6384-9146","authenticated-orcid":false,"given":"F\u0131rat","family":"A\u015f\u0131r","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical Faculty, Dicle University, 21280 Sur, Diyarbak\u0131r, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elif","family":"A\u011fa\u00e7ayak","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Medical Faculty, Dicle University, 21280 Sur, Diyarbak\u0131r, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","unstructured":"American College of Obstetricians and Gynecologists (2013). Hypertension in pregnancy: Report of the American College of Obstetricians and Gynecologists\u2019 Task Force on Hypertension in Pregnancy. Obstet. Gynecol., 122, 1122\u20131131."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1385\/ENDO:19:1:103","article-title":"Role of placenta in preeclampsia","volume":"19","author":"Myatt","year":"2002","journal-title":"Endocrine"},{"key":"ref_3","first-page":"10","article-title":"Placental vimentin expression in preeclampsia and gestational diabetes mellitus","volume":"30","author":"Asir","year":"2024","journal-title":"Gynecol. Obstet. Reprod. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101861","DOI":"10.1016\/j.redox.2021.101861","article-title":"Role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia","volume":"40","author":"Guerby","year":"2021","journal-title":"Redox Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.5830\/CVJA-2016-009","article-title":"Pre-eclampsia: Its pathogenesis and pathophysiolgy","volume":"27","author":"Gathiram","year":"2016","journal-title":"Cardiovasc. J. Afr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11567","DOI":"10.1073\/pnas.0603363103","article-title":"Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function","volume":"103","author":"Wang","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sekine, H., and Motohashi, H. (2021). Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer. Cancers, 13.","DOI":"10.3390\/cancers13030541"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kim, M.J., and Jeon, J.H. (2022). Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052846"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ngo, V., and Duennwald, M.L. (2022). Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease. Antioxidants, 11.","DOI":"10.3390\/antiox11122345"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tossetta, G., Fantone, S., Piani, F., Crescimanno, C., Ciavattini, A., Giannubilo, S.R., and Marzioni, D. (2023). Modulation of NRF2\/KEAP1 Signaling in Preeclampsia. Cells, 12.","DOI":"10.3390\/cells12111545"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102470","DOI":"10.1016\/j.redox.2022.102470","article-title":"Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks","volume":"57","author":"Hu","year":"2022","journal-title":"Redox Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Peng, X., Hou, R., Yang, Y., Luo, Z., and Cao, Y. (2022). Current Studies of Mitochondrial Quality Control in the Preeclampsia. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.836111"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103661","DOI":"10.1016\/j.redox.2025.103661","article-title":"Oxidative stress response and NRF2 signaling pathway in autism spectrum disorder","volume":"83","author":"Davinelli","year":"2025","journal-title":"Redox Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"(2020). Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstet. Gynecol., 135, e237\u2013e260.","DOI":"10.1097\/AOG.0000000000003891"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"A\u015f\u0131r, F., Erdemci, F., \u00c7ank\u0131r\u0131, Z., Korak, T., Ba\u015faran, S.\u00d6., Kaplan, \u00d6., Y\u00fckselmi\u015f, \u00d6., D\u00f6nmezdil, N., Ayaz, H., and Kaplan, \u015e. (2024). Zonisamide Ameliorated the Apoptosis and Inflammation in Cerebellar Tissue of Induced Alcohol Addiction Animal Model. Life, 14.","DOI":"10.3390\/life14070795"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"A\u015f\u0131r, F., \u00d6zalp, Z., Y\u00fclek, \u00d6.U., Erdemci, F., Korak, T., and Ta\u015f, F. (2024). CITED1 expression in odontogenic cysts. BMC Oral. Health, 24.","DOI":"10.1186\/s12903-024-04413-4"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e3465","DOI":"10.21769\/BioProtoc.3465","article-title":"Semi-quantitative Determination of Protein Expression using Immunohistochemistry Staining and Analysis: An Integrated Protocol","volume":"9","author":"Crowe","year":"2019","journal-title":"Bio-Protocol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1007\/s10895-023-03498-4","article-title":"GFP Transfection Alters Protein Expression Patterns in Prostate Cancer Cells: A Proteomic Study","volume":"35","author":"Yanar","year":"2025","journal-title":"J. Fluoresc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e70124","DOI":"10.1002\/jbt.70124","article-title":"Thymoquinone and Metabolic Reprogramming in Breast Cancer: A New Dimension From Proteomic Analysis","volume":"39","author":"Korak","year":"2025","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ege, S., Akduman, H., A\u015f\u0131r, A., and Korak, T. (2025). Excessive Weight Gain During Pregnancy Increased Ponoxarase 1 Level in Neonatal Cord Blood. Antioxidants, 14.","DOI":"10.3390\/antiox14010105"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, Y., Ji, X., Shi, H., Liu, S., and Yu, H. (2025). tiRNA-Gln-CTG is Involved in the Regulation of Trophoblast Cell Function in Pre-eclampsia and Serves as a Potent Biomarker. Front. Biosci., 30.","DOI":"10.31083\/FBL26345"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gokalp-Ozkorkmaz, E., Asir, F., Basaran, S.O., Agacayak, E., Sahin, F., Kaya, S., Erdogan, G., and Deveci, E. (2018). Examination of Bcl-2 and Bax Protein Levels for Determining the Apoptotic Changes in Placentas with Gestational Diabetes and Preeclampsia. Proceedings, 2.","DOI":"10.3390\/proceedings2251548"},{"key":"ref_23","first-page":"219","article-title":"WIPI-2 protein expression increases in the placentas of patients with preeclampsia","volume":"31","year":"2023","journal-title":"Perinat. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1053\/plac.1998.0383","article-title":"The role of reactive nitrogen\/oxygen intermediates in cytokine-induced trophoblast apoptosis","volume":"20","author":"Smith","year":"1999","journal-title":"Placenta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1128\/MCB.21.2.644-654.2001","article-title":"Mitochondrial DNA instability and peri-implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice","volume":"21","author":"Huo","year":"2001","journal-title":"Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kweider, N., Huppertz, B., Wruck, C.J., Beckmann, R., Rath, W., Pufe, T., and Kadyrov, M. (2012). A role for Nrf2 in redox signalling of the invasive extravillous trophoblast in severe early onset IUGR associated with preeclampsia. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047055"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1007\/s43032-021-00464-y","article-title":"Placental Mitochondrial Abnormalities in Preeclampsia","volume":"28","author":"Vangrieken","year":"2021","journal-title":"Reprod. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32410","DOI":"10.1038\/srep32410","article-title":"Mitochondrial role in adaptive response to stress conditions in preeclampsia","volume":"6","author":"Vishnyakova","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.tem.2013.12.003","article-title":"Cellular and molecular longevity pathways: The old and the new","volume":"25","author":"Nikoletopoulou","year":"2014","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.freeradbiomed.2004.04.035","article-title":"A comprehensive study of oxidative stress and antioxidant status in preeclampsia and normal pregnancy","volume":"37","author":"Llurba","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"F414","DOI":"10.1152\/ajprenal.00463.2014","article-title":"Interactions between HIF-1\u03b1 and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease","volume":"309","author":"Li","year":"2015","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111132","DOI":"10.1016\/j.mehy.2023.111132","article-title":"Pre-eclampsia and eclampsia pathogenesis utilizes iron released by a hemolytic protozoan parasite","volume":"178","author":"Roe","year":"2023","journal-title":"Med. Hypotheses"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shen, C.Y., Lu, C.H., Wu, C.H., Li, K.J., Kuo, Y.M., Hsieh, S.C., and Yu, C.L. (2020). The Development of Maillard Reaction, and Advanced Glycation End Product (AGE)-Receptor for AGE (RAGE) Signaling Inhibitors as Novel Therapeutic Strategies for Patients with AGE-Related Diseases. Molecules, 25.","DOI":"10.3390\/molecules25235591"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jri.2019.07.004","article-title":"The two-stage placental model of preeclampsia: An update","volume":"134\u2013135","author":"Staff","year":"2019","journal-title":"J. Reprod. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5148","DOI":"10.1093\/nar\/29.24.5148","article-title":"Two thyroid hormone-mediated gene expression patterns in vivo identified by cDNA expression arrays in rat","volume":"29","author":"Weitzel","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Torres-Torres, J., Espino, Y.S.S., Martinez-Portilla, R., Borboa-Olivares, H., Estrada-Gutierrez, G., Acevedo-Gallegos, S., Ruiz-Ramirez, E., Velasco-Espin, M., Cerda-Flores, P., and Ramirez-Gonzalez, A. (2024). A Narrative Review on the Pathophysiology of Preeclampsia. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147569"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/jn\/134.3.489","article-title":"Glutathione metabolism and its implications for health","volume":"134","author":"Wu","year":"2004","journal-title":"J. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1631\/jzus.B2101024","article-title":"Reduced cell invasion may be a characteristic of placental defects in pregnant women of advanced maternal age at single-cell level","volume":"23","author":"Zhang","year":"2022","journal-title":"J. Zhejiang Univ. Sci. 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