Melatonin regulates proliferation, apoptosis and invasion of trophoblasts in preeclampsia by inhibiting endoplasmic reticulum stress

Abstract

Aims Clinical evidence indicated the activation of endoplasmic reticulum stress (ERS) in pregnant women with preeclampsia (PE), and the regulatory role of melatonin (MT) in ERS. This study aims to explore the possible effect and mechanism of MT on ERS and on the infiltration of trophoblasts in PE. Methods The serum expression levels of MT and GRP78 in pregnant women with PE were measured. The cell proliferation, invasion, migration and apoptosis of trophoblasts were also determined. The trophoblast cell infiltration in placenta tissues was detected in EVOS image system. The expressions of ERS related proteins were measured by RT‐qPCR and western blot. Key results The PE‐serum treatment on HTR‐8/SVneo cells led to activated ERS and suppressed cell biological functions. PE mouse models after MT treatment or 4‐PBA treatment had reduced blood pressure, proteinuria, apoptosis and increased foetus and placenta weight, in addition to enhanced cell infiltration. Conclusions In vivo and in vitro evidence demonstrated MT can simultaneously suppress ERS and ASK1/JNK signal pathway in PE to promote the infiltration of trophoblasts.

Obese mothers supplemented with melatonin during gestation and lactation ameliorate the male offspring’s pancreatic islet cellular composition and beta-cell function

“…13 Also, melatonin signaling influences the placenta directly 17 and regulates the proliferation, apoptosis, and invasion of trophoblasts in preeclampsia by inhibiting endoplasmic reticulum (ER) stress. 18 In addition, we have demonstrated recently that melatonin supplementation in obese mothers can alleviate the development of nonalcoholic liver disease in their male offspring by decreasing lipogenesis and increasing beta-oxidation in the liver tissue. 19 These findings allow us to hypothesize that maternal melatonin supplementation during gestation and lactation in a known model of diet-induced obesity (DIO) in mice 20,21 would mitigate the development of altered glucose metabolism and insulin resistance, inflammation, ER stress, oxidative stress, and islet remodeling and beta-cell dysfunction in adult male offspring.…”

“…13 Also, melatonin signaling influences the placenta directly 17 and regulates the proliferation, apoptosis, and invasion of trophoblasts in preeclampsia by inhibiting endoplasmic reticulum (ER) stress. 18 In addition, we have demonstrated recently that melatonin supplementation in obese mothers can alleviate the development of nonalcoholic liver disease in their male offspring by decreasing lipogenesis and increasing beta-oxidation in the liver tissue. 19…”

Phenylbutyric acid inhibits hypoxia‐induced trophoblast apoptosis and autophagy in preeclampsia via the PERK/ATF‐4/CHOP pathway

“…Normally, ERS stimulates the unfolded protein response of cells, promoting the normal folding of proteins or degrading the abnormally folded proteins (Li et al, 2016;Luan et al, 2023). In contrast, ERS dysregulation can interfere with normal cellular function and cause cellular regulation through endoplasmic reticulum-associated apoptotic pathways, leading to disease development (Zhou et al, 2022). This suggests that targeting excessive ERS may restore trophoblast function and alleviate PE.…”

“…Additionally, 4-PBA has alleviated renal injury associated with ERS inhibition, and the potential mechanism is PERK/ATF-4/CHOP pathway inhibition (Zhong et al, 2021). In addition, Zhou et al (2022) and penicillin−streptomycin. PE cell models were prepared by subjecting the cells to a hypoxic condition, as previously (Ma et al, 2019).…”

“…Excessive endoplasmic reticulum stress (ERS) is believed to be linked to increased placental apoptosis in PE patients (Du et al, 2017). A clinical trial has also shown that ERS is activated in the serum of pregnant women with PE (Zhou et al, 2022). Normally, ERS stimulates the unfolded protein response of cells, promoting the normal folding of proteins or degrading the abnormally folded proteins (Li et al, 2016;Luan et al, 2023).…”