PMID- 34467607 OWN - NLM STAT- MEDLINE DCOM- 20220328 LR - 20230918 IS - 1600-0897 (Electronic) IS - 1046-7408 (Linking) VI - 86 IP - 6 DP - 2021 Dec TI - The role of nuclear factor erythroid 2-related factor 2 (NRF2) in normal and pathological pregnancy: A systematic review. PG - e13496 LID - 10.1111/aji.13496 [doi] AB - OBJECTIVE: A homeostatic balance between reactive oxygen species production and the antioxidant redox system is an important component of normal pregnancy. Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) preserves cellular homeostasis by enhancing the cell's innate antioxidant status to reduce oxidative stress and inflammatory damage to the cell during pregnancy. Active Nrf2, in the nucleus of the cell, transactivates various antioxidant genes. The objective of this systematic review was to synthesize evidence on the role of Nrf2 in various adverse pregnancy outcomes (APOs). METHODS: We conducted a systematic review of the role of Nrf2 in pregnancy. Articles written in English, Portuguese, and Spanish were obtained from three different databases from inception until January 2021. The titles, abstracts and full text were reviewed independently by six reviewers. The quality of the included studies was assessed using a quality assessment tool developed to assess basic science and clinical studies. Nrf2 expression (gene and protein), functional contributions, and association with APOs were assessed. RESULTS: A total of 747 citations were identified; 80 were retained for full review. Most studies on Nrf2 have been carried out using placental tissues and placenta-derived cells. Limited studies have been conducted using fetal membranes, uterus, and cervix. Nuclear translocation of Nrf2 results in transactivation of antioxidant enzymes, including glutathione peroxidase, hemeoxygenase-1, and superoxide dismutase in gestational cells during pregnancy. This antioxidant response maintains cellular homeostasis during pregnancy. This promotes trophoblast cell survival and prevents cell death and abnormal angiogenesis in the placenta. Excessive and insufficient Nrf2 response may promote oxidative and reductive stress, respectively. This Nrf2 dysregulation has been associated with APOs including gestational diabetes mellitus, intrauterine growth restriction, reproductive toxicity, preeclampsia, and preterm birth. CONCLUSION: Several studies have localized and reported an association between Nrf2's differential expression in reproductive tissues and the pathogenesis of APOs. However, a comprehensive functional understanding of Nrf2 in reproductive tissues is still lacking. Nrf2's activation and functions are complex, and therefore, current in vitro and in vivo studies are limited in their experimental approaches. We have identified key areas for future Nrf2 research that is needed to fill knowledge gaps. CI - (c) 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. FAU - Tantengco, Ourlad Alzeus G AU - Tantengco OAG AUID- ORCID: 0000-0002-4535-8837 AD - Division of Basic & Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA. AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Philippines. FAU - de Castro Silva, Mariana AU - de Castro Silva M AUID- ORCID: 0000-0002-2251-9730 AD - Department of Pathology, Botucatu Medical School, Universidade Estadual Paulista, UNESP, Botucatu, Sao Paulo, Brazil. FAU - Shahin, Hend AU - Shahin H AD - Division of Basic & Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA. FAU - Bento, Giovana Fernanda Cosi AU - Bento GFC AD - Department of Pathology, Botucatu Medical School, Universidade Estadual Paulista, UNESP, Botucatu, Sao Paulo, Brazil. FAU - Cursino, Geovanna Cristofani AU - Cursino GC AD - Department of Pathology, Botucatu Medical School, Universidade Estadual Paulista, UNESP, Botucatu, Sao Paulo, Brazil. FAU - Cayenne, Samir AU - Cayenne S AD - The University of Texas at Austin, Austin, Texas, USA. FAU - da Silva, Marcia Guimaraes AU - da Silva MG AUID- ORCID: 0000-0002-4663-7926 AD - Department of Pathology, Botucatu Medical School, Universidade Estadual Paulista, UNESP, Botucatu, Sao Paulo, Brazil. FAU - Menon, Ramkumar AU - Menon R AUID- ORCID: 0000-0001-9213-6105 AD - Division of Basic & Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA. LA - eng GR - R01 HD100729/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review PT - Systematic Review DEP - 20210919 PL - Denmark TA - Am J Reprod Immunol JT - American journal of reproductive immunology (New York, N.Y. : 1989) JID - 8912860 RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Reactive Oxygen Species) RN - EC 1.15.1.1 (Superoxide Dismutase) SB - IM MH - Female MH - Humans MH - NF-E2-Related Factor 2/*metabolism MH - Oxidative Stress/*physiology MH - Placenta/*metabolism MH - Pregnancy MH - Premature Birth/metabolism MH - Reactive Oxygen Species/metabolism MH - Superoxide Dismutase/metabolism MH - Trophoblasts/metabolism OTO - NOTNLM OT - antioxidant OT - gestational diabetes mellitus OT - oxidative stress OT - preeclampsia OT - preterm birth OT - reproductive toxicity EDAT- 2021/09/02 06:00 MHDA- 2022/03/29 06:00 CRDT- 2021/09/01 07:47 PHST- 2021/08/23 00:00 [revised] PHST- 2021/07/13 00:00 [received] PHST- 2021/08/24 00:00 [accepted] PHST- 2021/09/02 06:00 [pubmed] PHST- 2022/03/29 06:00 [medline] PHST- 2021/09/01 07:47 [entrez] AID - 10.1111/aji.13496 [doi] PST - ppublish SO - Am J Reprod Immunol. 2021 Dec;86(6):e13496. doi: 10.1111/aji.13496. Epub 2021 Sep 19.