Abstract
Oxygen and glucose deprivation (OGD)-reoxygenation (OGDR) induces oxidative injury to endometrial cells in vitro. We tested the potential effect of ginsenoside Rh3 (GRh3) in the process. Our results show that GRh3 activated Nrf2 signaling in T-HESC cells and primary murine endometrial cells. GRh3 induced Nrf2 Ser-40 phosphorylation and Keap1-Nrf2 disassociation, causing Nrf2 protein stabilization and nuclear translocation, which led to transcription and expression of antioxidant response element-dependent genes (HO1, NQO1 and GCLC). In T-HESC cells and primary murine endometrial cells, GRh3 potently attenuated OGDR-induced reactive oxygen species production, lipid peroxidation and mitochondrial depolarization, as well as cell viability reduction and necrosis. Activation of Nrf2 is required for GRh3-induced anti-OGDR actions in endometrial cells. Nrf2 inhibition, by Nrf2 shRNA, knockout (through CRISPR-Cas9-editing) or S40T mutation, abolished GRh3-induced endometrial cell protection against OGDR. Additionally, forced activation of Nrf2, by Keap1 knockout, mimicked and nullified GRh3-induced anti-OGDR actions in T-HESC cells. Together, we conclude that GRh3 protects endometrial cells from OGDR via activation of Nrf2 signaling.
Highlights
Postpartum hemorrhage is a common but severe complication in clinical obstetrics [1,2,3]
We first tested whether ginsenoside Rh3 (GRh3) could activate Nuclear-factor-E2-related factor 2 (Nrf2) signaling in endometrial cells
Performing the coimmunoprecipitation (“Co-IP”) assay, we show that Nrf2 associated with its suppressor protein Kelch-like ECHassociated protein 1 (Keap1) in the untreated T-HESC human endometrial cells (Figure 1A)
Summary
Postpartum hemorrhage is a common but severe complication in clinical obstetrics [1,2,3]. Ischemia will cause further oxidative damage to the endometrium [1,2,3]. The postpartum hemorrhage is often more likely to occur in the aged parturient. Existing studies have shown that ischemia-reperfusion will induce profound reactive oxygen species (ROS). Production [4,5,6], oxidative stress, and lipid peroxidation as well as substantial protein damage and profound DNA injury, and eventually endometrial cell death [1,2,3,4,5,6]. Our group has been using an in vitro oxygen and glucose deprivation (OGD)-reoxygenation (OGDR) procedure [7, 8], that mimics ischemiareperfusion injury to cultured endometrial cells
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