Melatonin Improves Mitochondrial Respiration in Syncytiotrophoblasts From Placentas of Obese Women

Ireland, Kayla E.; Maloyan, Alina; Myatt, Leslie

doi:10.1177/1933719117704908

Cited by 26 publications

(15 citation statements)

References 52 publications

(84 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite an increased total and nuclear protein fraction in BeWo cells exposed to H/R, Nrf2 activation is inhibited by melatonin resulting in the activation of cell death via the cleavage of PARP-1. In contrast, human primary vCTBs exposed to H/R and treated with melatonin showed increased autophagy and Nrf2 activity, which corroborates previous data showing a protective role of melatonin for normal placental cells [20, 36].…”

Section: Discussionsupporting

confidence: 90%

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

2019

View full text Add to dashboard Cite

Melatonin has protective roles in normal cells and cytotoxic actions in cancer cells, with effects involving autophagy and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor pathways. Hypoxia/reoxygenation (H/R) induces oxidative damage and apoptosis. These consequences activate autophagy, which degrades damaged cellular content, as well as activates Nrf2 the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor, and thereby the expression of protective genes. Melatonin has protective roles in normal cells and cytotoxic actions in cancer cells, with effects involving autophagy and Nrf2 pathways. The current study shows melatonin to differentially modulate autophagy and Nrf2 pathways in tumor and normal placental cells exposed to H/R. BeWo, a human placental choriocarcinoma cell line, and primary villous cytotrophoblasts isolated from normal term placenta, were maintained in normoxia (8% O2) for 24 h or exposed to hypoxia (0.5% of O2 for 4 h) followed by 20 h of normoxia, creating a situation of H/R, in the presence or absence of 1 mM melatonin. Melatonin induced a 7-fold increase in the activation of 5' adenosine monophosphate-activated protein kinase (AMPK)α, an upstream modulator of autophagy, rising to a 16-fold increase in BeWo cells co-exposed to H/R and melatonin, compared to controls. H/R induced autophagosome formation via the increased expression of Beclin-1 (by 94%) and ATG7 (by 97%) in BeWo cells. Moreover, H/R also induced autophagic activity, indicated by the by the 630% increase in P62, and increased Nrf2 by 314% in BeWo cells. In H/R conditions, melatonin reduced autophagic activity by 74% and Nrf2 expression activation by 300%, leading to BeWo cell apoptosis. In contrast, In human primary villous cytotrophoblasts, H/R induced autophagy and Nrf2, which melatonin further potentiated, thereby affording protection against H/R. This study demonstrates that melatonin differentially modulates autophagy and the Nrf2 pathway in normal vs. tumor trophoblast cells, being cytoprotective in normal cells whilst increasing apoptosis in tumoral trophoblast cells.

show abstract

Section: Discussionsupporting

confidence: 90%

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

2019

View full text Add to dashboard Cite

show abstract

“…Previous work has shown melatonin to be produced, and to have important protective functions, in primary human trophoblasts as well as in the pregnancy [20, 21, 36, 37]. H/R increases oxidative stress levels and lowers primary villous trophoblast viability, with melatonin affording protection against such H/R effects ([20]; Fagundes, et al in press ).…”

Section: Discussionmentioning

confidence: 99%

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Sagrilo-Fagundes

Bienvenue-Pariseault

Vaillancourt

2018

Preprint

View full text Add to dashboard Cite

HighlightsH/R induces autophagy and Nrf2 in tumoral and primary trophoblast cells.Melatonin inhibits autophagy and Nrf2 under H/R, inducing BeWo cell death.Melatonin increases autophagy and Nrf2 under H/R conditions, promoting primary villous trophoblast cells survival.AbstractHypoxia/reoxygenation (H/R) induces oxidative damage and apoptosis. These consequences activate autophagy, which degrades damaged cellular content, as well as inducing the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor, and thereby the expression of protective genes. Melatonin has protective roles in normal cells and cytotoxic actions in cancer cells, with effects involving autophagy and Nrf2 pathways. The current study shows melatonin to differentially modulate autophagy and Nrf2 pathways in tumor and normal placental cells exposed to H/R. BeWo, a human placental choriocarcinoma cell line, and primary villous cytotrophoblasts isolated from normal term placenta, were maintained in normoxia (8% O2) for 24 h or exposed to hypoxia (0.5% of O2 for 4 h) followed by 20 h of normoxia, creating a H/R, in the presence or absence of 1 mM melatonin. Melatonin induced a 7-fold increase in the activation of 5’ adenosine monophosphate-activated protein kinase (AMPK)α, an upstream modulator of autophagy, rising to a 16-fold increase in cells co-exposed to H/R and melatonin, compared to controls. H/R induced autophagosome formation via the increased expression of Beclin-1 (by 94 %) and ATG7 (by 97%). H/R also induced autophagic activity, indicated by the by the 630% increase in P62, and increased Nrf2 by 314%. In H/R conditions, melatonin reduced autophagy by 74% and Nrf2 expression by 66%, leading to BeWo cell apoptosis. In contrast, in human primary villous cytotrophoblasts, H/R induced autophagy and Nrf2, which melatonin further potentiated, thereby affording protection against H/R. This study demonstrates that melatonin differentially modulates autophagy and the Nrf2 pathway in normal vs. tumor trophoblast cells, being cytoprotective in normal cells whilst increasing apoptosis in tumoral trophoblast cells.

show abstract

“…A recent clinical trial indicates the efficacy of a nighttime administered low dose aspirin in the prophylaxis of early preeclampsia . Melatonin has also been proposed as a therapeutic option for preeclampsia and IUGR, given melatonin's utility in improving the viability of human trophoblasts exposed in vitro to hypoxia/reoxygenation (H/R), as well as improving the mitochondrial respiration status of syncytiotrophoblast in obese women …”

Section: Introductionmentioning

confidence: 99%

Melatonin modulates autophagy and inflammation protecting human placental trophoblast from hypoxia/reoxygenation

Sagrillo-Fagundes

Salustiano

Ruano

et al. 2018

Journal of Pineal Research

View full text Add to dashboard Cite

Melatonin has been proposed as a possible treatment for the deleterious effects of hypoxia/reoxygenation (H/R), such as autophagy, inflammation, and apoptosis. Pathological pregnancies, such as preeclampsia, are associated with placental H/R, and decreased placental melatonin synthesis as well as lower melatonin levels in the placenta and maternal plasma. However, the effects of exogenous melatonin on inflammation and autophagy induced by pregnancy complications associated with H/R await investigation. This study aimed to determine as to whether melatonin protects human primary villous trophoblasts against H/R-induced autophagy, inflammation, and apoptosis. Human primary villous cytotrophoblasts were isolated and immunopurified from normal term placentas. These cells were then exposed or not to 1 mmol/L melatonin for 72 hour in normoxia (8% O ), thereby inducing differentiation into syncytiotrophoblast that was then exposed to H/R (0.5% O , for 4 hour) or normoxia. H/R decreased endogenous melatonin synthesis (by 68%) and interleukin (IL)-10 levels (by 72%), coupled to increased tumor necrosis factor (TNF) (by 114%), IL-6 (by 55%), and NFκB (by 399%), compared to normoxia. Melatonin treatment reversed the H/R effect, restoring IL-10, TNF, and IL-6 levels to those of the normoxia condition. Melatonin, as well as NFκB inhibition, enhanced autophagy activation, consequently increasing syncytiotrophoblast survival in H/R conditions. This study suggests that H/R, which is present in pregnancy complications, inhibits endogenous melatonin production, thereby contributing to reduced syncytiotrophoblast viability. Results indicate that exogenous melatonin treatment may afford protection against H/R-induced damage, thereby enhancing placental cell survival, and contributing to improved fetal outcomes.

show abstract

Melatonin Improves Mitochondrial Respiration in Syncytiotrophoblasts From Placentas of Obese Women

Cited by 26 publications

References 52 publications

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Melatonin modulates autophagy and inflammation protecting human placental trophoblast from hypoxia/reoxygenation

Contact Info

Product

Resources

About