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The role of AKT and FOXO3 in preventing ovarian toxicity induced by cyclophosphamide.

Identifieur interne : 000664 ( Main/Exploration ); précédent : 000663; suivant : 000665

The role of AKT and FOXO3 in preventing ovarian toxicity induced by cyclophosphamide.

Auteurs : Bao-Fang Zhang [République populaire de Chine] ; Yaxin Hu [République populaire de Chine] ; Xinyan Liu [République populaire de Chine] ; Zhuo Cheng [République populaire de Chine] ; Yu Lei [République populaire de Chine] ; Yongmei Liu [République populaire de Chine] ; Xueke Zhao [République populaire de Chine] ; Mao Mu [République populaire de Chine] ; Lei Yu [République populaire de Chine] ; Ming-Liang Cheng [République populaire de Chine]

Source :

RBID : pubmed:30071053

Descripteurs français

English descriptors

Abstract

Cyclophosphamide (CTX) has immunosuppressive effects and has been wildly used as one anti-cancer drug in clinical. Significant toxicity has been noticed particularly in the reproductive system. CTX promotes the maturation of ovarian follicles, decreases follicular reserve, and ultimately lead to ovarian failure or even premature ovarian failure (POF). The placental extract (HPE) has been shown to have some beneficial impact on reproductive system; however, little is known regarding to the effect of HPE on protecting CTX-induced ovarian injury and the mechanism involved. Whether human placental extracts (HPE) has a protective effect on CTX-induced toxicity on ovarian was studied by using a CTX-induced ovarian injury animal model. The effects of HEP on histopathology, the number of atretic follicles, the weight of the ovary, serum hormone levels, and apoptosis in granulosa cells were studied in mice with CTX or control vehicle. Our results have demonstrated that HPE inhibited p-Rictor, reduced the expression of Bad, Bax and PPAR, and activated Akt and Foxo3a (increased their phosphorylation). Mice treated with HPE showed higher ovarian weight, lower number of atretic follicles, higher serum levels of the hormones E2 and progesterone, and lower apoptosis and serum levels of LH and FSH in granulosa cells, than that in the control animal group. Our data show that ovarian injury can be attenuated by HPE. HPE likely protects follicular granulosa cells from undergoing significant apoptosis and reduce atresia follicle formation, therefore, alleviates CTX-induced ovarian injury.

DOI: 10.1371/journal.pone.0201136
PubMed: 30071053
PubMed Central: PMC6071999


Affiliations:


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Le document en format XML

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<term>Animals (MeSH)</term>
<term>Antineoplastic Agents, Alkylating (toxicity)</term>
<term>Apoptosis (drug effects)</term>
<term>Apoptosis (physiology)</term>
<term>Cyclophosphamide (toxicity)</term>
<term>Dose-Response Relationship, Drug (MeSH)</term>
<term>Female (MeSH)</term>
<term>Forkhead Box Protein O3 (metabolism)</term>
<term>Hormones (blood)</term>
<term>Humans (MeSH)</term>
<term>Mice, Inbred C57BL (MeSH)</term>
<term>Organ Size (MeSH)</term>
<term>Ovary (drug effects)</term>
<term>Ovary (metabolism)</term>
<term>Ovary (pathology)</term>
<term>Peroxisome Proliferator-Activated Receptors (antagonists & inhibitors)</term>
<term>Peroxisome Proliferator-Activated Receptors (metabolism)</term>
<term>Phosphorylation (drug effects)</term>
<term>Placental Extracts (pharmacology)</term>
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<term>Primary Ovarian Insufficiency (metabolism)</term>
<term>Primary Ovarian Insufficiency (prevention & control)</term>
<term>Protective Agents (pharmacology)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
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<term>bcl-2-Associated X Protein (antagonists & inhibitors)</term>
<term>bcl-2-Associated X Protein (metabolism)</term>
<term>bcl-Associated Death Protein (antagonists & inhibitors)</term>
<term>bcl-Associated Death Protein (metabolism)</term>
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<term>Agents protecteurs (pharmacologie)</term>
<term>Animaux (MeSH)</term>
<term>Antinéoplasiques alcoylants (toxicité)</term>
<term>Apoptose (effets des médicaments et des substances chimiques)</term>
<term>Apoptose (physiologie)</term>
<term>Compagnon de mTOR insensible à la rapamycine (antagonistes et inhibiteurs)</term>
<term>Compagnon de mTOR insensible à la rapamycine (métabolisme)</term>
<term>Cyclophosphamide (toxicité)</term>
<term>Extrait placentaire (pharmacologie)</term>
<term>Femelle (MeSH)</term>
<term>Hormones (sang)</term>
<term>Humains (MeSH)</term>
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<term>Insuffisance ovarienne primitive (métabolisme)</term>
<term>Insuffisance ovarienne primitive (prévention et contrôle)</term>
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<term>Ovaire (effets des médicaments et des substances chimiques)</term>
<term>Ovaire (métabolisme)</term>
<term>Phosphorylation (effets des médicaments et des substances chimiques)</term>
<term>Protéine Bad (antagonistes et inhibiteurs)</term>
<term>Protéine Bad (métabolisme)</term>
<term>Protéine Bax (antagonistes et inhibiteurs)</term>
<term>Protéine Bax (métabolisme)</term>
<term>Protéine O3 à motif en tête de fourche (métabolisme)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Relation dose-effet des médicaments (MeSH)</term>
<term>Récepteurs activés par les proliférateurs de peroxysomes (antagonistes et inhibiteurs)</term>
<term>Récepteurs activés par les proliférateurs de peroxysomes (métabolisme)</term>
<term>Souris de lignée C57BL (MeSH)</term>
<term>Taille d'organe (MeSH)</term>
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<term>Peroxisome Proliferator-Activated Receptors</term>
<term>Rapamycin-Insensitive Companion of mTOR Protein</term>
<term>bcl-2-Associated X Protein</term>
<term>bcl-Associated Death Protein</term>
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<keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en">
<term>Hormones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Forkhead Box Protein O3</term>
<term>Peroxisome Proliferator-Activated Receptors</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>Rapamycin-Insensitive Companion of mTOR Protein</term>
<term>bcl-2-Associated X Protein</term>
<term>bcl-Associated Death Protein</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Placental Extracts</term>
<term>Protective Agents</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en">
<term>Antineoplastic Agents, Alkylating</term>
<term>Cyclophosphamide</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Ovaire</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Compagnon de mTOR insensible à la rapamycine</term>
<term>Protéine Bad</term>
<term>Protéine Bax</term>
<term>Récepteurs activés par les proliférateurs de peroxysomes</term>
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<keywords scheme="MESH" qualifier="chemically induced" xml:lang="en">
<term>Primary Ovarian Insufficiency</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Apoptosis</term>
<term>Ovary</term>
<term>Phosphorylation</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Apoptose</term>
<term>Ovaire</term>
<term>Phosphorylation</term>
</keywords>
<keywords scheme="MESH" qualifier="induit chimiquement" xml:lang="fr">
<term>Insuffisance ovarienne primitive</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Ovary</term>
<term>Primary Ovarian Insufficiency</term>
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<term>Compagnon de mTOR insensible à la rapamycine</term>
<term>Insuffisance ovarienne primitive</term>
<term>Ovaire</term>
<term>Protéine Bad</term>
<term>Protéine Bax</term>
<term>Protéine O3 à motif en tête de fourche</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Récepteurs activés par les proliférateurs de peroxysomes</term>
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<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Ovary</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Agents protecteurs</term>
<term>Extrait placentaire</term>
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<term>Apoptose</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en">
<term>Apoptosis</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en">
<term>Primary Ovarian Insufficiency</term>
</keywords>
<keywords scheme="MESH" qualifier="prévention et contrôle" xml:lang="fr">
<term>Insuffisance ovarienne primitive</term>
</keywords>
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<term>Antinéoplasiques alcoylants</term>
<term>Cyclophosphamide</term>
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<term>Animals</term>
<term>Dose-Response Relationship, Drug</term>
<term>Female</term>
<term>Humans</term>
<term>Mice, Inbred C57BL</term>
<term>Organ Size</term>
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<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Femelle</term>
<term>Humains</term>
<term>Relation dose-effet des médicaments</term>
<term>Souris de lignée C57BL</term>
<term>Taille d'organe</term>
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<front>
<div type="abstract" xml:lang="en">Cyclophosphamide (CTX) has immunosuppressive effects and has been wildly used as one anti-cancer drug in clinical. Significant toxicity has been noticed particularly in the reproductive system. CTX promotes the maturation of ovarian follicles, decreases follicular reserve, and ultimately lead to ovarian failure or even premature ovarian failure (POF). The placental extract (HPE) has been shown to have some beneficial impact on reproductive system; however, little is known regarding to the effect of HPE on protecting CTX-induced ovarian injury and the mechanism involved. Whether human placental extracts (HPE) has a protective effect on CTX-induced toxicity on ovarian was studied by using a CTX-induced ovarian injury animal model. The effects of HEP on histopathology, the number of atretic follicles, the weight of the ovary, serum hormone levels, and apoptosis in granulosa cells were studied in mice with CTX or control vehicle. Our results have demonstrated that HPE inhibited p-Rictor, reduced the expression of Bad, Bax and PPAR, and activated Akt and Foxo3a (increased their phosphorylation). Mice treated with HPE showed higher ovarian weight, lower number of atretic follicles, higher serum levels of the hormones E2 and progesterone, and lower apoptosis and serum levels of LH and FSH in granulosa cells, than that in the control animal group. Our data show that ovarian injury can be attenuated by HPE. HPE likely protects follicular granulosa cells from undergoing significant apoptosis and reduce atresia follicle formation, therefore, alleviates CTX-induced ovarian injury.</div>
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