Effects of quercetin and rosuvastatin each alone or in combination on cyclophosphamide-induced premature ovarian failure in female albino mice

Background: Cyclophosphamide (CP) causes premature ovarian failure (POF) due to ovarian toxicity. The toxicity mechanism is attributed to oxidative stress, inflammation, and apoptosis. We assessed whether quercetin and rosuvastatin could promote ovarian protection against CP ovotoxicity. Methods: A total of 80 female BALB/c mice were randomly assigned; 10 mice into each of eight groups. Group 1 (control), group 2 (EH), group 3 (CP), group 4 (QH), group 5 (QL), group 6 (RH), group 7 (RL), and group 8 (COM). Results: Quercetin and rosuvastatin groups (4:8) showed signs of restored ovarian function in the form of a significant, dose-dependent increase in primordial follicles number, serum anti-Mullerian hormone level, and ovarian tissue glutathione level ( p < 0.05) versus group 3, and a significant, dose-dependent decrease in atretic follicles number and ovarian tissue level of malondialdehyde ( p < 0.05) versus group 3. Immunohistochemistry analysis demonstrated a lower expression of caspase and nuclear factor-kappa B of groups (4:8) versus group 3, although quercetin and rosuvastatin showed a nonsignificant reduction in tumor volume. Conclusions: We demonstrated the protective effect of quercetin and rosuvastatin against ovarian toxicity and POF induced by CP without compromising its antitumor effect.

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Chemoprotective effects of plasma derived from mice of different ages and genders on ovarian failure after cyclophosphamide treatment

Journal of Ovarian Research ◽

10.1186/s13048-020-00735-3 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Soghra Bahmanpour ◽

Eisa Moradiyan ◽

Farzaneh Dehghani ◽

Nehleh Zarei-fard

Keyword(s):

Blood Plasma ◽

Premature Ovarian Failure ◽

Ovarian Tissue ◽

Young Female ◽

Ovarian Failure ◽

Control Group ◽

Protective Effects ◽

Primordial Follicles ◽

Chemotherapy Drugs ◽

Different Ages

Abstract Background Premature ovarian failure is one of the major side effects of chemotherapy drugs. Blood plasma contains several factors that might lead to the repair of different tissues. Objective The chemoprotective effects of plasma derived from mice with different ages and genders were assessed on ovarian tissue in cyclophosphamide-treated mice. Methods Forty-two adult female mice were divided into six groups as follows: (A) control; (B) 0.9% sodium chloride as vehicle; (C) cyclophosphamide; (D) cyclophosphamide + young male blood plasma; (E) cyclophosphamide + old male blood plasma; (F) cyclophosphamide + young female blood plasma. Ovarian failure was induced by injecting cyclophosphamide. On the 1st day, three groups received simultaneous injections of 150 μL intraperitoneal and 70 μL intravenous plasma derived from mice of different ages and genders. Each plasma type (150 μL) was then injected intraperitoneally every other 3 days for 19 days. On day 21, the dissected ovaries were stained for stereological analysis. Also, estrogen and progesterone levels were measured. Results Cyclophosphamide had damaging effects on ovarian parameters and led to reduced hormone levels in comparison with the control group. However, treating with young female and, old male blood plasma, to a lesser degree, showed beneficial effects on the number of primordial follicles, pre-antral follicles, and granulosa cells. Also, these two treatments had protective effects on the volume of ovarian parameters as well as estrogen and progesterone levels in comparison with the cyclophosphamide group (P < 0.05). Conclusion Plasma derived from mice of different ages and genders can ameliorate premature ovarian failure against the adverse effects of cyclophosphamide.

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Establishment of a Mouse Model of Premature Ovarian Failure Using Consecutive Superovulation

Cellular Physiology and Biochemistry ◽

10.1159/000495895 ◽

2018 ◽

Vol 51 (5) ◽

pp. 2341-2358 ◽

Cited By ~ 4

Author(s):

Xiaowei Nie ◽

Youjin Dai ◽

Yuan Zheng ◽

Dan Bao ◽

Qin Chen ◽

...

Keyword(s):

Mouse Model ◽

Premature Ovarian Failure ◽

Cell Apoptosis ◽

Quantitative Polymerase Chain Reaction ◽

Oocyte Quality ◽

Ovarian Failure ◽

Control Group ◽

Mrna Levels ◽

Primordial Follicles ◽

Ovarian Aging

Background/Aims: This study investigated the effect of consecutive superovulation on the ovaries and established a premature ovarian failure (POF) model in mice. Methods: The mouse POF model was induced by 5-15 consecutive superovulation treatments with pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG) and prostaglandin F2α (PGF2α). Normal adult mice were compared with mice displaying natural ovarian aging. The following serum biochemical parameters were measured: including follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), inhibin B (INH B), malondialdehyde (MDA), total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. Follicles were counted using H&E staining. Levels of 8-hydroxyguanosine (8-OhdG), 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), anti-Mullerian hormone (AMH) and CDKN2A/ p16 (p16) were detected using immunohistochemical staining. Reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE) staining. Cell apoptosis was detected using an in situ TUNEL fluorescence staining assay. Levels of proteins involved in ROS-related pathways and the p16 protein were detected using Western blotting. Sod1, Sod2 and Sod3 mRNA levels were detected using quantitative polymerase chain reaction (Q-PCR). Oocyte quality was evaluated using in vitro fertilization (IVF) and zygote culture. Results: Consecutive superovulation groups presented lower P, E2, SOD, GSH-Px and INH B levels, significantly higher FSH, LH, MDA and ROS levels, and significantly fewer primordial follicles compared with the control group. Consecutive superovulation groups presented significantly increased levels of Sod2, 8-OhdG, 4-HNE, NTY, significantly increased levels of the SIRT1 and FOXO1 proteins, significantly increased levels of the senescence-associated protein p16, as well as decreased AMH, Sod1 and Sod3 levels and increased granulosa cell apoptosis compared with the control group. Conclusion: Consecutive superovulation significantly decreased ovarian function and oocyte quality and increased oxidative stress and apoptosis in the ovary via a mechanism involving the p16 and SIRT1/FOXO1 signaling pathways. These findings suggest that consecutive superovulation may be used to establish a mouse model of ovarian aging.

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Expectations and limitations of ovarian tissue transplantation

Zygote ◽

10.1017/s0967199417000338 ◽

2017 ◽

Vol 25 (4) ◽

pp. 391-403 ◽

Cited By ~ 11

Author(s):

N.J. Donfack ◽

K.A. Alves ◽

V.R. Araújo ◽

A. Cordova ◽

J.R. Figueiredo ◽

...

Keyword(s):

Premature Ovarian Failure ◽

Ovarian Function ◽

Ex Vivo ◽

Ovarian Tissue ◽

Ovarian Failure ◽

Tissue Transplantation ◽

Endocrine Function ◽

Embryo Cryopreservation ◽

Pelvic Cavity ◽

Ovarian Tissue Transplantation

SummaryConstant progress in the diagnosis and treatment of cancer disease has increased the number and prognosis of cancer survivors. However, the toxic effects of chemotherapy and radiotherapy on ovarian function have resulted in premature ovarian failure. Patients are, therefore, still expecting methods to be developed to preserve their fertility successfully. Several potential options are available to preserve fertility in patients who face premature ovarian failure, including immature or mature oocyte and embryo cryopreservation. However, for children or prepubertal women needing immediate chemotherapy, cryopreservation of ovarian tissue is the only alternative. The ultimate aim of this strategy is to implant ovarian tissue into the pelvic cavity (orthotopic site) or in a heterotopic site once oncological treatment is completed and the patient is disease free. Transplantation of ovarian tissue with sufficiently large numbers of follicles could potentially restore endocrine function and allow multiple cycles for conception. However, the success of ovarian tissue transplantation still has multiple challenges, such as the low number of follicles in the graft that may affect their longevity as well as the survival of the tissue during ex vivo processing and subsequent transplantation. Therefore, this review aims to summarize the achievements of ovary grafting and the potential techniques that have been developed to improve ovarian graft survival.

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The Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells in Mice Premature Ovarian Failure

BioMed Research International ◽

10.1155/2013/690491 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 25

Author(s):

Shufang Wang ◽

Ling Yu ◽

Min Sun ◽

Sha Mu ◽

Changyong Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Granulosa Cells ◽

Premature Ovarian Failure ◽

Ovarian Function ◽

Treated Group ◽

Ovarian Failure ◽

Control Group ◽

Wild Type

Mesenchymal stem cells, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as promising cellular therapeutics for the treatment of several diseases. Mesenchymal-like cells derived from Wharton’s Jelly, called umbilical cord matrix stem cells (UCMSCs), reportedly secrete a variety of cytokines and growth factors, acting as trophic suppliers. Here, we used UCMSCs to treat premature ovarian failure (POF). Ovarian function was evaluated by ovulation and the number of follicles. Apoptosis of the granulosa cells (GC) was analyzed by TUNEL staining. We found that after transplantation of the UCMSCs, apoptosis of cumulus cells in the ovarian damage model was reduced and the function of the ovary had been recovered. The sex hormone level was significantly elevated in mice treated with UCMSCs. The number of follicles in the treated group was higher than in the control group. Our results demonstrate that UCMSCs can effectively restore ovary functionality and reduce apoptosis of granulosa cells. We compared the RNA expression of the UCMSCs treated group with the POF model and wild-type control group and found that the UCMSC group is most similar to the wild-type group. Our experiments provide new information regarding the treatment of ovarian function failure.

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Effects of Single Transplantation and Multiple Transplantation of Human Umbilical Cord Mesenchymal Stem Cells on the Recovery of Ovarian Function in the Treatment of Premature Ovarian Failure in Mice

10.21203/rs.3.rs-115773/v1 ◽

2020 ◽

Author(s):

Xiaodan Lv ◽

Chunyi Guan ◽

Ying Li ◽

Xing Su ◽

lu Zhang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Premature Ovarian Failure ◽

Ovarian Function ◽

Ovarian Tissue ◽

Ovarian Failure ◽

Mouse Serum ◽

Enzyme Linked Immunosorbent Assay ◽

Human Umbilical Cord

Abstract Background: Previous studies have reported that transplantation of mesenchymal stem cells (MSCs) from many human tissues can improve ovarian dysfunction. However, the therapeutic effects of single injection of MSCs and multiple injections of MSCs on premature ovarian failure (POF) have not been reported yet. In this study, we used long-term follow-up to study the effect of human umbilical cord mesenchymal stem cell (hUC-MSCs) on the functional recovery of mouse POF models. Methods: In this study, we used a mouse model of premature ovarian failure induced by the combination of 120mg/kg cyclophosphamide and 30mg/kg busulfan. Enzyme-linked immunosorbent assay (ELISA) was used to detect estradiol (E2) and follicle stimulating hormone (FSH) levels in mouse serum. Evaluate ovarian function by counting follicles, ovarian weight, number of proliferating cells, anti-Mullerian hormone (AMH) and oocytes. Results: Our study shows that hUC-MSCs have obvious therapeutic effect for the POF mice model, and treatment effect of multiple transplantation is better than single transplantation. Mesenchymal stem cells were detected in follicular granulosa cells with tracer of the ovarian tissue freezing slice, which show hUC-MSCs to selectively migration and stay in damaged tissues. Genome Array screened a number of differentially expressed genes, the hUC-MSCs can change the level of expression of certain genes in the ovarian tissue, thus affecting ovarian function, and laid the foundation for us to further explore the mechanism of hUC-MSCs treatment of premature ovarian failure. Conclusion: This study demonstrated that hUC-MSCs transplantation significantly restored ovarian function after chemotherapy-induced damage.

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The Effectiveness of Anti-Apoptotic Agents to Preserve Primordial Follicles and Prevent Tissue Damage during Ovarian Tissue Cryopreservation and Xenotransplantation

International Journal of Molecular Sciences ◽

10.3390/ijms22052534 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2534

Author(s):

Sanghoon Lee ◽

Hyun-Woong Cho ◽

Boram Kim ◽

Jae Kwan Lee ◽

Tak Kim

Keyword(s):

Tissue Damage ◽

Ovarian Function ◽

Ovarian Tissue ◽

Slow Freezing ◽

Ovarian Tissue Cryopreservation ◽

Second Step ◽

Control Group ◽

Dna Breaks ◽

Primordial Follicles ◽

Tissue Cryopreservation

The purpose of this study is to investigate the effectiveness of sphingosine-1-phosphate (S1P) and Z-VAD-FMK (Z-VAD) as anti-apoptotic agents to preserve ovarian function and prevent tissue damage during ovarian tissue cryopreservation and transplantation. This study consisted of two steps, in vitro and in vivo. In the first step, human ovarian tissues were cryopreserved using slow-freezing media alone, S1P, or Z-VAD (control, S1P, Z-VAD group); based on the outcomes in these groups, Z-VAD was selected for subsequent xenotransplantation. In the second step, human frozen/thawed ovarian tissues were grafted into fifty mice divided into three groups: slow-freezing/thawing and transplantation without an anti-apoptotic agent (Trans-control) and xenotransplantation with or without Z-VAD injection (Trans-Z-VAD-positive and Trams-Z-VAD-negative groups, respectively). In the first step, the Z-VAD group had a significantly higher primordial follicular count than the S1P (p = 0.005) and control groups (p = 0.04). Transplanted ovarian tissues were obtained 4 weeks after transplantation (second step). Angiogenesis was significantly increased in the Z-VAD-negative (p = 0.03) and -positive (p = 0.04) groups compared to the control group. This study demonstrated that slow-freezing and transplantation with Z-VAD is an effective method for preserving primordial follicle counts, decreasing double-strand DNA breaks, and increasing angiogenesis in a mouse model. Further molecular and clinical studies are needed to confirm these results.

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Intra-Ovarian Injection of Bone Marrow c-Kit+ Cells Induced Ovarian Rejuvenation in Menopausal Rats

10.21203/rs.3.rs-52171/v1 ◽

2020 ◽

Author(s):

Sepideh Sheshpari ◽

Mahnaz Shahnazi ◽

Shahin Ahmadian ◽

Mohammad Nouri ◽

Mehran Mesgari Abbasi ◽

...

Keyword(s):

Bone Marrow ◽

Rat Model ◽

Premature Ovarian Failure ◽

Ovarian Function ◽

Substantial Reduction ◽

Ovarian Failure ◽

Reproductive Age ◽

Control Group ◽

Premature Menopause ◽

Post Transplantation

Abstract Background: Premature ovarian failure (POF) is a condition caused by ovarian insuffiency during the reproductive age that affects ~1% of women globally. Many attempts have been collected to find feasible and effective approach to reduce POF consequences in females. In this regard, cell-based therapies with certain cell types are touted as novel and hopeful therapeutic intervention in the clinical setting. Methods: To evaluate the restoration of ovarian function after intra-ovarian transplantation of bone marrow-derived c-Kit+ cells, a rat model of ovarian failure was produced. Rats were treated with 160 mg/kg/BW of 4-vinylcyclohexene dioxide (VCD) for 15 consecutive days. Using magnetic-activated cell sorting (MACS) technique, freshly isolated rat bone marrow-derived c-Kit+ and c-Kit- cells (4×105 cells/10 µL) were enriched and transplanted into the ovaries of treatment and control animals, respectively. Prior to transplantation as well as 2, 4, 6, and 8 weeks post-transplantation, randomly-selected rats were euthanized and ovarian tissues were subjected to pathohistological examinations and real-time PCR analyses.Results: Premature ovarian failure (POF) status was confirmed by the presence of pathological features and a decreased number of immature and mature follicles compared with control group (p<0.05). Histological examination revealed a substantial reduction of atretic follicles in POF rats receiving c-Kit+ cells in comparison with POF rats that did not receive these cells (p<0.05). Compared with control samples, angiogenesis-related genes, Angpt2 and KDR, showed increased and decreased expression in POF ovaries, respectively (p<0.05). c-Kit+ cells had potential to restore angiogenesis in the ovarian tissue to within normal ranges. Systemic levels of FSH did not significantly change in pre- or post-transplantation time points for any group (p>0.05). Notable reduction of collagen deposition was found in c-Kit treated rats. Transplantation of c-Kit+ cells also restored the reduced fertility rate (p<0.05).Conclusions: Our findings suggest that intra-ovarian administration of bone marrow-derived c-Kit+ cells can modulate angiogenesis signaling and pathological changes, leading to the rejuvenation of ovarian function of a rat model of premature menopause.

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Curcumin exerts a protective effect against premature ovarian failure in mice

Journal of Molecular Endocrinology ◽

10.1530/jme-17-0214 ◽

2018 ◽

Vol 60 (3) ◽

pp. 261-271 ◽

Cited By ~ 28

Author(s):

Zhengjie Yan ◽

Youjin Dai ◽

Heling Fu ◽

Yuan Zheng ◽

Dan Bao ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Protective Effect ◽

Premature Ovarian Failure ◽

Ovarian Function ◽

Ovarian Failure ◽

Protective Agent ◽

Primordial Follicles ◽

Expression Levels ◽

P16 Expression

This study was designed to investigate the protective effect of curcumin against d-galactose (d-gal)-induced premature ovarian failure (POF) in mice. A mouse POF model was induced by subcutaneous injection of d-gal (200 mg/kg/day) daily for 42 days. Mice in the curcumin group received both d-gal treatment and intraperitoneal injection of curcumin (100 mg/kg/day) for 42 days. Ovarian function, oxidative stress and apoptosis were evaluated. The P, E2 and SOD levels were higher, and the FSH, LH and MDA levels were significantly lower in the curcumin group than those in the d-gal group. The proportion of primordial follicles was also significantly higher in the curcumin group than that in the d-gal group. In addition, curcumin treatment after d-gal administration resulted in significantly lower Sod2, Cat, 8-OhdG, 4-HNE, NTY and senescence-associated protein P16 expression levels, higher Amh expression levels and less apoptosis in granulosa cells than was observed in the d-gal group. Moreover, the p-Akt, Nrf2 and HO-1 protein expression levels were significantly higher and the apoptosis-related cleaved caspase-3 and -9 protein expression levels were markedly lower in the curcumin group than in the d-gal group. In conclusion, curcumin effectively inhibited d-gal-induced oxidative stress, apoptosis and ovarian injury via a mechanism involving the Nrf2/HO-1 and PI3K/Akt signaling pathways, suggesting that curcumin is a potential protective agent against POF.

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