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Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction

Background and Objectives: Fetal growth restriction (FGR) is associated with fetal mortality and is a risk factor for cerebral palsy and future lifestyle-related diseases. Despite extensive research, no effective treatment strategy is available for FGR. Mammalian target of rapamycin (mTOR) signaling...

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Autores principales: Tsuchiya, Kyoka, Tanaka, Kayo, Tanaka, Hiroaki, Maki, Shintaro, Enomoto, Naosuke, Takakura, Sho, Nii, Masafumi, Toriyabe, Kuniaki, Katsuragi, Shinji, Ikeda, Tomoaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767347/
https://www.ncbi.nlm.nih.gov/pubmed/33371356
http://dx.doi.org/10.3390/medicina56120722
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author Tsuchiya, Kyoka
Tanaka, Kayo
Tanaka, Hiroaki
Maki, Shintaro
Enomoto, Naosuke
Takakura, Sho
Nii, Masafumi
Toriyabe, Kuniaki
Katsuragi, Shinji
Ikeda, Tomoaki
author_facet Tsuchiya, Kyoka
Tanaka, Kayo
Tanaka, Hiroaki
Maki, Shintaro
Enomoto, Naosuke
Takakura, Sho
Nii, Masafumi
Toriyabe, Kuniaki
Katsuragi, Shinji
Ikeda, Tomoaki
author_sort Tsuchiya, Kyoka
collection PubMed
description Background and Objectives: Fetal growth restriction (FGR) is associated with fetal mortality and is a risk factor for cerebral palsy and future lifestyle-related diseases. Despite extensive research, no effective treatment strategy is available for FGR. Mammalian target of rapamycin (mTOR) signaling is important for the growth of fetal organs and its dysregulation is associated with miscarriage. Here, we focused on mTOR signaling and investigated how the activities of phospho-ribosomal protein S6 (rps6) and phospho-eukaryotic translation initiation factor 4E (eIF-4E), which act downstream of mTOR signaling in the human placenta, change following treatment of FGR with tadalafil and aimed to elucidate the underlying mechanism of action. Placental hypoxia was investigated by immunostaining for hypoxia-inducible factor (HIF)-2α. Materials and Methods: Phosphor-rps6 and phosphor-eIF4E expression were examined by Western blotting and enzyme-linked immunosorbent assay, respectively. Results: HIF-2α expression significantly increased in FGR placenta compared with that in the control placenta but decreased to control levels after tadalafil treatment. Levels of phospho-rps6 and phospho-eIF-4E were significantly higher in FGR placenta than in control placenta but decreased to control levels after tadalafil treatment. Conclusions: Tadalafil restored the levels of HIF-2α, phospho-rps6, and eIF-4E in FGR placenta to those observed in control placenta, suggesting that it could be a promising treatment strategy for FGR.
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spelling pubmed-77673472020-12-28 Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction Tsuchiya, Kyoka Tanaka, Kayo Tanaka, Hiroaki Maki, Shintaro Enomoto, Naosuke Takakura, Sho Nii, Masafumi Toriyabe, Kuniaki Katsuragi, Shinji Ikeda, Tomoaki Medicina (Kaunas) Article Background and Objectives: Fetal growth restriction (FGR) is associated with fetal mortality and is a risk factor for cerebral palsy and future lifestyle-related diseases. Despite extensive research, no effective treatment strategy is available for FGR. Mammalian target of rapamycin (mTOR) signaling is important for the growth of fetal organs and its dysregulation is associated with miscarriage. Here, we focused on mTOR signaling and investigated how the activities of phospho-ribosomal protein S6 (rps6) and phospho-eukaryotic translation initiation factor 4E (eIF-4E), which act downstream of mTOR signaling in the human placenta, change following treatment of FGR with tadalafil and aimed to elucidate the underlying mechanism of action. Placental hypoxia was investigated by immunostaining for hypoxia-inducible factor (HIF)-2α. Materials and Methods: Phosphor-rps6 and phosphor-eIF4E expression were examined by Western blotting and enzyme-linked immunosorbent assay, respectively. Results: HIF-2α expression significantly increased in FGR placenta compared with that in the control placenta but decreased to control levels after tadalafil treatment. Levels of phospho-rps6 and phospho-eIF-4E were significantly higher in FGR placenta than in control placenta but decreased to control levels after tadalafil treatment. Conclusions: Tadalafil restored the levels of HIF-2α, phospho-rps6, and eIF-4E in FGR placenta to those observed in control placenta, suggesting that it could be a promising treatment strategy for FGR. MDPI 2020-12-21 /pmc/articles/PMC7767347/ /pubmed/33371356 http://dx.doi.org/10.3390/medicina56120722 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tsuchiya, Kyoka
Tanaka, Kayo
Tanaka, Hiroaki
Maki, Shintaro
Enomoto, Naosuke
Takakura, Sho
Nii, Masafumi
Toriyabe, Kuniaki
Katsuragi, Shinji
Ikeda, Tomoaki
Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction
title Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction
title_full Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction
title_fullStr Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction
title_full_unstemmed Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction
title_short Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction
title_sort tadalafil treatment ameliorates hypoxia and alters placental expression of proteins downstream of mtor signaling in fetal growth restriction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767347/
https://www.ncbi.nlm.nih.gov/pubmed/33371356
http://dx.doi.org/10.3390/medicina56120722
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