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Human Placental Extracts Improve Ovarian Function by Reducing Follicular Atresia in Mice with CTX-Induced Premature Ovarian Fail

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Human Placental Extracts Improve Ovarian Function by Reducing Follicular Atresia in Mice with CTX-Induced Premature Ovarian Fail r Biomar ula ke c rs Zhang et al., J Mol Biomark Diagn 2017, 9:1 le o & M D f i a DOI: 10.4172/2155-9929.1000373 o g l Journal of Molecular Biomarkers n a o n r s i u s o J ISSN: 2155-9929 & Diagnosis Research Article Open Access Human Placental Extracts Improve Ovarian Function by Reducing Follicular Atresia in Mice With CTX-Induced Premature Ovarian Failure Bao-Fang Zhang1,2#, Lei Yu2#, YongMei Liu2, Xue Ke Zhao2, Li Li Zhu2, Ming-Liang Cheng2* and YaXin Hu2 1The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, P.R China 2The Affiliated Hospital, Guizhou Medical University, Beijing, Guiyang, Guizhou, P.R China #These authors contributed equally to this work and should be considered as co-first authors Abstract The details of the pathogenic mechanisms underlying premature ovarian failure (POF) remain unknown. Accumulating evidence suggests that primordial follicle inactivity, disorders affecting follicular survival and growth and follicular atresia may affect an individual’s susceptibility to POF. The Rictor/mTORC2/Akt/Foxo3a pathway plays a central role in cytoskeletal construction and follicle survival. As a stronger alkylating agent that exerts immunosuppressive effects, cyclophosphamide (CTX) is widely used in clinical practice, especially in cancer. However, it also has significant reproductive toxicity. CTX accelerates the development of ovarian follicles into mature follicles, resulting in a decreased follicular reserve and ultimately leading to ovarian failure or even POF. We have sought to research effective methods to reduce the damage caused by CTX. Here, we investigated the protective role of human placental extracts on CTX-induced ovarian injury in mice. We describe the effects of HEP on histopathology, the number of atretic follicles, the weight of the ovary, serum hormone levels and apoptosis in granulosa cells. Our data show that ovarian injury can be effectively attenuated by HPE administration. Ovarian weight was higher, the number of atretic follicles was lower, the serum levels of the hormones E2 and P were higher, and the rate of apoptosis and the serum levels of the hormones LH and FSH were lower in granulosa cells in mice treated with HPE for 2 weeks than in the control group. At the molecular level, our results demonstrated that HPE can be used to inhibit the expression of p-Rictor, Bad, Bax and PPAR and activate the expression of p-Akt and p-Foxo3a, thus preventing follicular granulosa cells from undergoing a higher rate of apoptosis and blocking atresia follicle formation. These effects alleviated CTX-induced ovarian injury by affecting the Rictor/mTORC2/Akt/Foxo3a signalling pathway. Keywords: Premature Ovarian Failure (POF); Ovarian function; on recent reports, a mouse model of POF was constructed using Follicular atresia; Cyclophosphamide (CTX) 4-vinylcyclohexene diepoxide (VCD) [6,7]. In these mice, Rictor and the molecular functions of its downstream effector mTORC2 were Introduction affected in that both of these are apoptosis-related proteins were In premature ovarian failure (POF), the ovaries become overexpressed. These effects accelerated follicular atresia and apoptosis, dysfunctional or are lost, and persistent amenorrhea and sexual leading to the loss of ovarian functions. atrophy are observed in some affected women before the age of 40 [1]. Human placental extracts (HPE) perform many functions, such as POF can result from hereditary, metabolic, infectious, autoimmune, enhancing immunity, regulating endocrine processes, extending youth, iatrogenic (radiotherapy and chemotherapy) and other causes [2]. repairing damaged skin, eliminating ageing skin, beautifying skin, Moreover, patients with hormonal disorders may exhibit vasomotor restraining inflammation, and performing anti-allergic functions [8]. and psychiatric symptoms, such as a hectic fever with unsteady movement, perspiration, daze, heart palpitations, and decreased Thus, in this study, we had the following aims: libido. The mechanisms involved in POF remain unclear, and clinical treatments, especially chemotherapy, play important roles as iatrogenic (i) To explore the influence of HPE on ovarian function and factors [3]. histopathological analysis, to determine the number of atretic follicles, the weight of the ovary and body, and serum hormone levels, and to Because cyclophosphamide (CTX) is a cheap and effective therapy, it is widely used as a treatment for many conditions, including cancer, haematologic diseases, primary angiitis of the central nervous *Corresponding author: Ming-Liang Cheng, The Affiliated Hospital, system, chronic inflammatory demyelinating polyneuropathy (CIDP), Guizhou Medical University, Beijing Road 9, Guiyang 550004, Guizhou, P.R rheumatoid arthritis, nephrotic syndrome. CTX exerts a toxic effect by China, Tel: + 86 0851-86770352; E-mail: [email protected] covalently binding to DNA, causing abnormal complementary base Received December 12, 2017; Accepted December 28, 2017; Published December pairings, misstructured and dysfunctional cells and irreversible injury 30, 2017 in the ovary [4]. Citation: Zhang B, Yu L, Liu YM, Zhao XK, Zhu LL, et al. (2018) Human Placental CTX accelerates the maturation of ovarian primordial follicles Extracts Improve Ovarian Function by Reducing Follicular Atresia in Mice With CTX-Induced Premature Ovarian Failure. J Mol Biomark Diagn 9: 373. doi: into mature follicles, reducing ovarian reserves and thereby leading to 10.4172/2155-9929.1000373 ovarian failure in young female patients with POF [5]. Recently, the proliferation, development and maturation of ovary germ cells are Copyright: © 2018 Zhang B, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted regulated by the mechanistic target of rapamycin (mTOR) pathway, use, distribution, and reproduction in any medium, provided the original author and in which Rictor, mTORC2, Akt, and Foxo3a play key roles. Based source are credited. J Mol Biomark Diagn, an open access journal Volume 9 • Issue 1 • 1000373 ISSN:2155-9929 Citation: Zhang B, Yu L, Liu YM, Zhao XK, Zhu LL, et al. (201) Human Placental Extracts Improve Ovarian Function by Reducing Follicular Atresia in Mice With CTX-Induced Premature Ovarian Failure. J Mol Biomark Diagn 9: 373. doi: 10.4172/2155-9929.1000373 Page 2 of 6 quantify apoptosis in granulosa cells in a mouse model of CTX-induced status of granulosa cell. Briefly, 100 µL cells at 5 × 105/mL were ovarian injury and transferred into 5 mL flow tubes. Annexin V/fluorescein isothiocyanate (FITC) (5 µL) was added, and apoptotic rates were detected based on (ii) To use Western blot analysis to detect the expression levels the fluorescence of Annexin V/FITC with a flow cytometer (Coulter of p-Rictor, mTORC2, p-Akt, p-Foxo3a, Bad, Bax, and PPAR to Epics XL; Beckman Coulter, Fullerton, CA, USA). investigate the molecular mechanisms by which HPE alleviates the ovarian injuries induced by CTX. Western blotting Materials and Methods The protein concentration of the whole ovary lysate was determined by BCA kit (Pierce, Rockford, IL). Lysates were electrophoresed on Animal experiments a disulfide-reduced 12% SDS PAGE, transferred to Immobilon-P Female C57BL mice 36, 8 weeks old, 16~20 g, SPF grade, membrane (Millipore Corp., Bedford, MA), probed and stripped Institutional and national guidelines for the care and use of animals followed by re-probing with indicated antibodies, and developed with were followed and all experimental procedures involving animals were the enhanced chemiluminescent (ECL) system (Pharmacia Biotech, approved by the IACUC (institutional animal care and use committee) Piscataway, NJ). The expression of GAPDH protein was used as a of University of Alabama of Birmingham (Permit Number:2015. 011- loading control. For densitometric analysis of band intensity, a specific 0003). The mice were individually housed in plastic cages at room band on the ECL-developed film was subjected to densitometric temperature (22°C) and maintained on an artificial cycle of 12-h analysis (Adobe Photoshop). The densitometric readings were pooled light and 12-h dark. Surgical preparations involved anesthetization and averaged from three independent experiments. The background with a xylazine/ketamine mixture. The mice were then sacrificed by of densitometric reading on the ECL-developed film was subtracted. cervical dislocation. Ovarian tissue was precisely dissected, immersed Data analysis in liquid nitrogen, and stored at -80°C until further analysis. All procedures were approved by institutional ethics committee and Data from at least three independent duplicates were expressed performed in accordance with the guidelines on animal ethics. The as mean ± SD. Differences between two groups were analyzed with cisplatin (Cyclophosphamide Baxter 0054-4130-25) was administered Student’s t-test. For animal studies, each experimental and control intraperitoneally once daily at doses of 2.0 g/g for 14 days. Control group contained 5 to 8 animals and repeated twice. A p value of < 0.05 animals received injections of phosphate buffered saline(PBS) at doses was considered statistically significant. All statistical analyses were done of 2.0 g/g, HPE animals received injections of HPE (National medicine with the SPSS 20.0 software program (SPSS Inc, Chicago, IL, USA). permission number H20046260) at doses of 1.2 ml/kg. After induction of POF, different doses of HPE (Group CH+++: high dose 2.4 ml/kg, Results Group CH++:
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