Table 2.
NRF2 modulation by natural and synthetic compounds.
| Modulator | Model Studied | Results | Reference |
|---|---|---|---|
| Procyanidin B2 | Placental explants and a PE rat model | Procyanidin B2 inhibits sFlt-1 secretion and ameliorates endothelial dysfunction and impaired angiogenesis via the NRF2/PPARγ axis. | [118] |
| Resveratrol | HUVEC incubated with plasma from PE patients | Antioxidant response element (ARE) activity was increased. The addition of resveratrol by NRF2 activation also occurred. | [120] |
| Resveratrol | Term placental explants and HUVEC treated with TNF-α and resveratrol | NRF2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells. | [123] |
| Silibinin | HTR8/SVneo exposed to H2O2 |
Silibinin protects the trophoblast from apoptosis, enhancing the activation of NRF2. | [124] |
| Fisetin | PE rat model | Reduction in hypertension and proteinuria; reduction in TNF-α, IL-6, IL-1β, MDA and the sFlt-1/PlGF ratio; and promoting the NRF2/HO-1 pathway in placental tissues. | [127] |
| Apocyanin | PE rat model | Reduction in preeclampsia symptoms with combined treatment of apocyanin and aspirin by activating the PI3K/NRF2/HO-1 pathway. | [130] |
| Sulforaphane | HUVEC and placental explants | In HUVEC, reduction in endothelin-1, VCAM1, ICAM1 and E-selectin. In placental explants, reduction in sFlt-1, endoglin and activin A. In HUVEC, induction of activation and nuclear translocation of NRF2, and induction of HO-1. NRF2 silencing blocked some but not all of sulforaphane’s effects and did not prevent inhibition of trophoblast secretion of sFlt-1 or activin A. | [132] |
| Crocin | PE rat model | Crocin upregulated protein levels of NRF2 and HO-1. | [134] |
| Astragaloside IV | PE rat model | Improvements in clinical signs of preeclampsia, reduction in placental cellular oxidative stress and strengthening of the NRF2/HO-1 signaling pathway in placental tissues. | [137] |
| Pyrroloquinoline quinone | PE rat model | Pyrroloquinoline quinone improved the antioxidation effect in preeclampsia models, activating the NRF2 pathway. | [140] |
| 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) | PE mouse model | HTHQ treatment induced NRF2 expression and nuclear translocation, increasing HO-1 expression in placentas. | [144] |
| Coenzyme Q10 | PE rat model | Coenzyme Q10 protected the rats from preeclampsia through activating the NRF2/HO-1 pathway. | [150] |
| Melatonin | Pregnant sows | Increase in mRNA levels of antioxidant-related genes involved in the NRF2/ARE pathway (NRF2, SOD, GPx1 and NQO1). | [154] |
| Melatonin | PE rat model | Increased NRF2, PlGF and HO-1 placental levels with reduction in blood pressure and urine protein content, and recovery in the fetus alive ratio, fetal weight and fetal weight/placental weight ratio. | [155] |
| Melatonin | Placental explants | Improved oxidative stress, presumably due to the potentiation of NRF2 and HO-1. | [157] |
| Tert-butylhydroquinone (tBHQ) | HTR-8/SVneo | Increased NRF2 protein and HO-1 mRNA expression after stimulation with tBHQ. HO-1 was located in the cytoplasm and NRF2 was located in both the nucleus and cytoplasm. | [160] |
| Simvastatin | JAR cells exposed to hypoxia and treated with diethyl maleate (DEM) | In hypoxia conditions, activation of NRF2 signaling depending on KEAP1 inhibition. | [162] |
| ML385 and CDDO-Im |
PE rat model, HTR-8/SVneo and hESC cells | ML385 treatment reduced SBP and proteinuria in PE rats while treatment with CDDO-Im increased proteinuria and systolic blood pressure, worsening PE. HO-1 expression decreased in the PE group compared with the control group while it increased after CDDO-Im treatment compared with the PE group. ML385 did not alter HO-1 expression in placental tissue. NRF2 inhibition increased CCL2, IL-1β, TNF-α, AT1R and ROS in the embryonic tissues. NRF2 knockdown in HTR-8/SVneo and hESC cells suppressed cell proliferation, improved apoptosis and invasion and increased ROS and HO-1 expression. | [163] |