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

2018 ◽  
Vol 51 (5) ◽  
pp. 2341-2358 ◽  
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.

scholarly journals Effects of Irbesartan Pretreatment on Pancreatic β-Cell Apoptosis in STZ-Induced Acute Prediabetic Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Cuihong Chen ◽  
Li Li ◽  
Haijing Qin ◽  
Zhenxing Huang ◽  
Jing Xian ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Mouse Model ◽  
Mrna Expression ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Cell Damage ◽  
Quantitative Polymerase Chain Reaction ◽  
Fasting Blood Glucose ◽  
Mitogen Activated Protein Kinase ◽  
Control Group

The current study was performed to investigate the effects and potential effects of irbesartan pretreatment on pancreatic β-cell apoptosis in a streptozotocin- (STZ-) induced acute mouse model of prediabetes. Twenty-four male BALB/C mice (18–22 g) were randomly divided into three groups: normal control group (NC, n=6), STZ group (STZ, n=8), and irbesartan + STZ group (IRB + STZ, n=10). In the IRB + STZ group, mice were administered irbesartan (300 mg/kg per day) by gavage for one week. The STZ group and IRB + STZ group received STZ (80 mg/kg by intraperitoneal (IP) injection once). The NC group received normal saline (80 mg/kg by IP injection once). Fasting blood glucose prior to STZ injection and presacrifice was analysed using samples withdrawn from the caudal vein to confirm the induction of prediabetes. Haematoxylin and eosin staining, immunohistochemical detection of insulin, and apoptosis analysis were performed. Reverse transcription-quantitative polymerase chain reaction was used to detect angiotensin II type 1 receptor (AT1R), caspase-3, and p38 mitogen-activated protein kinase (MAPK) mRNA expression. Blood glucose was significantly higher in the STZ group (9.01 ± 1.1089 vs 4.78 ± 0.7026) and IRB + STZ group (7.86 ± 1.1811 vs 4.78 ± 0.7026) compared with the NC group (P<0.05). In comparison to the STZ group, the islet cell damage was marginally improved in the IRB + STZ group, and the IRB + STZ group had a significantly lower apoptotic rate than the STZ group (22.42 ± 8.3675 vs 50.86 ± 5.3395, P<0.001). AT1R expression in the IRB + STZ group was lower than that in the STZ group (1.56 ± 1.2207 vs 3.92 ± 2.4392, P<0.05). The mRNA expression of caspase-3 in pancreatic tissue was significantly lower in the IRB + STZ group than in the STZ group (0.90 ± 0.7272 vs 1.88 ± 1.0572, P<0.05). Similarly, the IRB + STZ group also had lower p38MAPK levels than the STZ group (1.16 ± 1.0642 vs 2.55 ± 1.7925, P>0.05). In conclusion, irbesartan pretreatment improved glucose levels and insulin secretion and decreased islet β-cell apoptosis to protect islet β cells in an STZ-induced acute prediabetic mouse model.

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

2019 ◽  
Vol 38 (11) ◽  
pp. 1283-1295 ◽  
Author(s):  
MA Elkady ◽  
S Shalaby ◽  
F Fathi ◽  
S El-Mandouh
Keyword(s):  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Tissue ◽  
Ovarian Failure ◽  
Control Group ◽  
Primordial Follicles ◽  
Ovarian Toxicity ◽  
Versus Group ◽  
Group 3 ◽  
Dose Dependent

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.

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

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.

scholarly journals CD36 regulates β cell differentiation and influences type 2 diabetic sepsis

2021 ◽  
Author(s):  
Huogen Liu ◽  
Ling Gu ◽  
Yundi Shi ◽  
Hailin Shu ◽  
Fengming Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Differentiation ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Cell Clone ◽  
Quantitative Polymerase Chain Reaction ◽  
Control Group ◽  
Β Cell ◽  
Type 2 Diabetic

Abstract Background This study aimed to investigate the diagnostic function of CD36 in type 2 diabetic (T2DM) sepsis complications (T2DSC) and its effect on β-cell differentiation. Methods First, Age - and sex-matched T2DM patients, T2DSC patients and healthy people (50 cases each) were included. Quantitative polymerase chain reaction was used to measure CD36, FOXO1, PDX1, MAFA, insulin, SOX9, Neurog3 and NANOG expression in blood samples. Second, cultured human β-cell line EndoC-βH1 and the interference and overexpression of CD36. Cell clone, apoptosis, inflammatory cytokine, oxidative stress and β-cell differentiation related proteins were also analysed. Third, examined the role of CD36 in high glucose, LPS-induced β-cell. Results CD36 mRNA, and endocrine progenitor β-cell biomarkers SOX9, Neurog3 and NANOG were significantly increased in T2DM than control group, whereas the β-cell maturation biomarkers FOXO1, PDX1, MAFA and insulin were significantly decreased. Compared with the T2DM group, CD36 and FOXO1 were significantly increased in T2DSC, but PDX1, insulin, MAFA, SOX9, Neurog3 and NANOG were significantly decreased. The receiver operating characteristic curve revealed that CD36 was useful for distinguishing T2MD and T2DSC from the control group. Furthermore, CD36 overexpression increased β-cell apoptosis and the secretion of IL-1β, IL-8 TNF-α, malondialdehyde and reactive oxygen species. CD36 induced cell defferentiation. Lastly, CD36 knockdown could inhibit the high glucose and LPS-induced cell apoptosis, inflammatory, oxidative stress and cell defferentiation. Conclusion Significant increase in CD36 can be used as a biomarker for T2MD and T2DSC. CD36 promotes T2MD or T2DSC development by inducing β-cell inflammatory and oxidative stress and defferentiation.

scholarly journals Ovarian aging and premature ovarian failure

2014 ◽  
Vol 15 (3) ◽  
pp. 190-196 ◽  
Author(s):  
Yavuz Emre Sukur ◽  
Icten Balik Kivancli ◽  
Batuhan Ozmen
Keyword(s):  
Premature Ovarian Failure ◽  
Ovarian Failure ◽  
Ovarian Aging

Biological bases of premature ovarian failure

1998 ◽  
Vol 10 (1) ◽  
pp. 73 ◽  
Author(s):  
Roger G. Gosden ◽  
Malcolm J. Faddy
Keyword(s):  
Mathematical Model ◽  
Causal Relationship ◽  
Premature Ovarian Failure ◽  
Ovarian Failure ◽  
Fixed Number ◽  
Human Ovary ◽  
Primordial Follicles

The ovary is endowed at birth with a fixed number of primordial follicles, which steadily dwindles throughout life as a result of atresia and recruitment towards ovulation. In addition to age, the number varies allometrically between species, larger and longer-lived animals tending to have more follicles initially and these disappear at a slower rate. A causal relationship between follicle depletion and menopause clearly exists, and there is a gradual acceleration of follicle wastage in the human ovary beginning more than a decade before the end of menstrual life. A mathematical model has provided confirmatory evidence of this relationship, and indicates that menopause is triggered by a threshold number of follicles which varies stochastically with a mean of 1100

Targeting TMPRSS6 Using Antisense Technology for the Treatment of Beta-Thalassemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 753-753 ◽  
Author(s):  
Shuling Guo ◽  
Mariam Aghajan ◽  
Carla Casu ◽  
Sara Gardenghi ◽  
Sheri Booten ◽  
...  
Keyword(s):  
Mouse Model ◽  
Targeted Delivery ◽  
Serum Iron ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Beta Thalassemia ◽  
Control Group ◽  
Mrna Levels ◽  
Antisense Technology ◽  
Wide Range

Abstract Antisense technology is a powerful drug discovery approach for identifying oligonucleotide analogs that can specifically modify RNA expression through multiple mechanisms including RNase H-mediated degradation of RNA and modulation of RNA splicing. We have successfully applied this technology towards targeting a number of transcripts in a wide-range of therapeutic areas. Beta-thalassemia, one of the most common genetic disorders worldwide, is characterized by reductions in beta-globin and ineffective erythropoiesis. This in turn leads to suppression of hepcidin, a peptide hormone that serves as the master regulator of iron homeostasis. Inappropriately low levels of hepcidin trigger increased dietary iron absorption resulting in iron overload, which is the major cause of morbidity and mortality in beta-thalassemia patients. TMPRSS6 is a transmembrane serine protease mainly produced by hepatocytes that negatively regulates hepcidin expression. Previous mouse and human genetic data from multiple groups suggest that lowering TMPRSS6 expression could up-regulate hepcidin and ameliorate many of the disease symptoms associated with β-thalassemia. We identified potent antisense oligonucleotides (ASOs) against mouse TMPRSS6. Downregulation of TMPRSS6 with ASO treatment resulted in dose-dependent hepcidin upregulation and reduction in serum iron and transferrin saturation in normal mice. In a mouse model of beta-thalassemia (th3/+ mice), which effectively recapitulates beta-thalassemia intermedia in humans, TMPRSS6 reduction resulted in induction of hepcidin and dramatic reductions of serum transferrin saturation (from 55-63% in control group down to 20-26% in treatment group). Liver iron concentration (LIC) was also greatly reduced (40-50%). Moreover, anemia endpoints were significantly improved with ASO treatment, including increases in red blood cells (~30-40%), hemoglobin (~2 g/dl), and hematocrit (~20%); reduction of splenomegaly; decreases in serum erythropoietin levels; improved erythroid maturation as indicated by a strong reduction in reticulocyte number and a normalized proportion between the pool of erythroblasts and enucleated erythroid cells. Encouraged by the strong pharmacology of TMPRSS6 suppression in animal models, we initiated an effort to identify a human TMPRSS6 clinical candidate with a liver-targeted delivery strategy. Over 2000 ASOs were screened in cell lines and the most active compounds were evaluated in rodent tolerability studies. A human TMPRSS6 transgenic mouse model was established enabling evaluation of ASO activity toward human TMPRSS6 transcript in vivo. Furthermore, lead compounds were tested in a 3-month study in normal monkeys. With repeated dosing, TMPRSS6 mRNA levels in monkey liver were reduced by >90%, accompanied by time-dependent reductions of serum iron (from ~100-120ug/dl to <40ug/dl), transferrin saturation (from ~30-35% to <10%), and hemoglobin. These compounds were well tolerated in rodents and in monkeys. Collectively, our data demonstrate that TMPRSS6 ASO could be an effective therapeutic for patients with beta-thalassemia and related disorders. A Phase 1 clinical trial is planned to initiate in 2016. Disclosures Guo: Isis Pharmaceuticals: Employment, Other: Shareholder. Aghajan:Isis Pharmaceuticals: Employment, Other: Shareholder. Booten:Isis Pharmaceuticals: Employment, Other: Shareholder. Monia:Isis Pharmaceuticals: Employment, Other: Shareholder.

scholarly journals Protective Effect of Yang Mi Ryung® Extract on Noise-Induced Hearing Loss in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-11
Author(s):  
Min Soo Kim ◽  
SeongAe Kwak ◽  
Heumyoung Baek ◽  
Zewu Li ◽  
Seong-Kyu Choe ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Protective Effect ◽  
Hair Cells ◽  
Noise Exposure ◽  
Preventive Intervention ◽  
Apoptotic Cell ◽  
Quantitative Polymerase Chain Reaction ◽  
Control Group ◽  
Mrna Levels ◽  
Noise Induced Hearing Loss

Noise-induced hearing loss (NIHL) results from the damage of the delicate hair cells inside the ear after excessive stimulation of noise. Unlike certain lower animals such as amphibians, fishes, and birds, in humans, hair cells cannot be regenerated once they are killed or damaged; thus, there are no therapeutic options to cure NIHL. Therefore, it is more important to protect hair cells from the noise before the damage occurs. In this study, we report the protective effect of Yang Mi Ryung extract (YMRE) against NIHL; this novel therapeutic property of YMRE has not been reported previously. Our data demonstrates that the hearing ability damaged by noise is markedly restored in mice preadministrated with YMRE before noise exposure, to the level of normal control group. Our study also provides the molecular mechanism underlying the protective effect of YMRE against NIHL by showing that YMRE significantly blocks noise-induced apoptotic cell death and reduces reactive oxygen species (ROS) production in cochleae. Moreover, quantitative polymerase chain reaction (qPCR) analysis demonstrates that YMRE has anti-inflammatory properties, suppressing the mRNA levels of TNFα and IL-1β induced by noise exposure. In conclusion, YMRE could be a useful preventive intervention to prevent hearing impairment induced by the exposure to excessive noise.

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