Glutathione S-transferase theta 1 expressed in granulosa cells as a biomarker for oocyte quality in age-related infertility

2008 ◽  
Vol 90 (4) ◽  
pp. 1026-1035 ◽  
Author(s):  
Megumu Ito ◽  
Miho Muraki ◽  
Yuji Takahashi ◽  
Misa Imai ◽  
Tohru Tsukui ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Oocyte Quality ◽  
Glutathione S Transferase ◽  
Age Related

scholarly journals Constitutive Expression of TERT Enhances β-Klotho Expression and Improves Age-Related Deterioration in Early Bovine Embryos

2021 ◽  
Vol 22 (10) ◽  
pp. 5327
Author(s):  
Lianguang Xu ◽  
Muhammad Idrees ◽  
Myeong-Don Joo ◽  
Tabinda Sidrat ◽  
Yiran Wei ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Constitutive Expression ◽  
Growth Factor Receptor ◽  
Oocyte Quality ◽  
Low Fertility ◽  
Treatment Groups ◽  
Age Related ◽  
Early Embryos ◽  
Plasmid Injection ◽  
Telomere Lengthening

Age-associated decline in oocyte quality is one of the dominant factors of low fertility. Aging alters several key processes, such as telomere lengthening, cell senescence, and cellular longevity of granulosa cells surrounding oocyte. To investigate the age-dependent molecular changes, we examined the expression, localization, and correlation of telomerase reverse transcriptase (TERT) and β-Klotho (KLB) in bovine granulosa cells, oocytes, and early embryos during the aging process. Herein, cumulus-oocyte complexes (COCs) obtained from aged cows (>120 months) via ovum pick-up (OPU) showed reduced expression of β-Klotho and its co-receptor fibroblast growth factor receptor 1 (FGFR1). TERT plasmid injection into pronuclear zygotes not only markedly enhanced day-8 blastocysts’ development competence (39.1 ± 0.8%) compared to the control (31.1 ± 0.5%) and D-galactose (17.9 ± 1.0%) treatment groups but also enhanced KLB and FGFR1 expression. In addition, plasmid-injected zygotes displayed a considerable enhancement in blastocyst quality and implantation potential. Cycloastragenol (CAG), an extract of saponins, stimulates telomerase enzymes and enhances KLB expression and alleviates age-related deterioration in cultured primary bovine granulosa cells. In conclusion, telomerase activation or constitutive expression will increase KLB expression and activate the FGFR1/β-Klotho pathway in bovine granulosa cells and early embryos, inhibiting age-related malfunctioning.

scholarly journals Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders

2020 ◽  
Author(s):  
Yan Gong ◽  
Jesse Li-Ling ◽  
Dongsheng Xiong ◽  
Jiajing Wei ◽  
Taiqing Zhong ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Oocyte Retrieval ◽  
Ovarian Response ◽  
Oocyte Quality ◽  
Enzyme Linked Immunosorbent Assay ◽  
Altered Expression ◽  
Age Related ◽  
Tertiary Teaching ◽  
Poor Ovarian Responders

Abstract Background: Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes play important roles in folliculogenesis. Altered expression of the two have been found among patients with poor ovarian response (POR). In this prospective cohort study, we have determined the expression of the GDF9 and BMP15 genes in follicle fluid (FF) and granulosa cells (GCs) derived from poor ovarian responders grouped by age, and explored its correlation with the outcome of in vitro fertilization and embryo transfer (IVF-ET) treatment.Methods: A total of 196 patients with POR were enrolled from a tertiary teaching hospital. The patients were diagnosed by the Bologna criteria and sub-divided into group A (< 35 year old), group B (35-40 year old), and group C (> 40 year old). A GnRH antagonist protocol was conducted for all patients, and FF and GCs were collected after oocyte retrieval. Expression of the GDF9 and BMP15 genes in the FF and GCs was determined with enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting.Results: Compared with group C, groups A and B had significantly more two pronuclei (2PN) oocytes and transplantable embryos, in addition with higher rates of implantation and clinical pregnancy (P < 0.05). The expression level of GDF9 and BMP15 genes in the FF and GCs differed significantly among the three groups (P < 0.05), showing a trend of decline along with age. Conclusions: For poor ovarian responders, in particular those over 40, the expression of GDF9 and BMP15 is declined with increased age and in accompany with poorer oocyte quality and IVF outcome.

196 GLUTATHIONE S-TRANSFERASE THETA1 (GSTT1) IS DIFFERENTIALLY REGULATED FROM OTHER GLUTATHIONE S-TRANSFERASES IN GRANULOSA CELLS

2011 ◽  
Vol 23 (1) ◽  
pp. 198
Author(s):  
M. Muraki ◽  
Y. Takahashi ◽  
T. Ishii ◽  
S. Kyuwa ◽  
Y. Yoshikawa
Keyword(s):  
Granulosa Cells ◽  
Expression Patterns ◽  
Oocyte Quality ◽  
Water Soluble ◽  
Regulation Mechanism ◽  
Related Factor ◽  
Age Related ◽  
Significant Difference ◽  
Glutathione S Transferases ◽  
The Difference

Oxidative stress is a major source of aging that damages genomic and mitochondrial DNA, causing female reproductive disorders. Glutathione S-transferases (GST) are known to detoxify the metabolites of genotoxic molecules to more water-soluble and readily excretable forms. Therefore, most GST have been considered to be down-regulated by aging. We recently demonstrated that only GSTT1 is up-regulated in granulosa cells from aged, infertile patients and aged mice, although other kinds of GST are down-regulated in these cells (Ito et al. 2008 Fertil. Steril. 90, 1026–1035). Measurement of the GSTT1 level in granulosa cells binding to the patient’s oocytes could be used in the selection of oocytes of high quality, meaning that the GSTT1 level in granulosa cells could be a good indicator of age-related infertility. To do that, an understanding of the concrete relationship between aging and GSTT1 up-regulation is necessary. However, the regulation mechanism of GSTT1 in granulosa cells remains unclear. In the present study, we attempted to examine the difference in expression mechanisms between GSTT1 and other GST. First, the expression patterns of GSTT1 and GSTP (a major member of the GST) in aged granulosa cells from patients were observed by immunostaining. The GSTT1 was up-regulated (young: 25 to 34 years old, N = 9; aged: 38 to 43 years old, N = 12; P < 0.05) but the GSTP was down-regulated (young: 28 to 30 years, N = 5; aged: 38 to 42 years, N = 7; P < 0.05) in the aged group. Nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor that regulates the expression of most GST, so in the next experiment, we examined the expression patterns of GSTT1 and GSTP in granulosa cells from Nrf2-disrupted (Nrf2–/–) mice by immunostaining. The GSTP was down-regulated in granulosa cells of Nrf2–/– mice compared with those of Nrf2+/– mice, although a significant difference was not observed in GSTT1. In addition, we confirmed these results by using mouse embryonic fibroblasts (MEF) from Nrf2–/– and Nrf2+/– mice, and the same results were obtained. Our previous experiment showed that GSTT1 was induced by FSH in human granulosa-like tumour cells (KGN cells). We analysed the expression level of other genes in FSH-stimulated KGN cells. The transcription levels of GSTP and Nrf2 were not induced by FSH. These results suggest that the expression of GSTT1 is not regulated by Nrf2 and is differentially regulated from other GST. The difference in regulation mechanisms between GSTT1 and other GST may result in the up-regulation of GSTT1 in the aging granulosa cells, and it may contribute to the constitution of the diagnosis of oocyte quality using the GSTT1 measurement.

scholarly journals Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yan Gong ◽  
Jesse Li-Ling ◽  
Dongsheng Xiong ◽  
Jiajing Wei ◽  
Taiqing Zhong ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Clinical Trial Registry ◽  
Altered Expression ◽  
Vitro Fertilization ◽  
Age Related ◽  
Tertiary Teaching ◽  
Poor Ovarian Responders

Abstract Background Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes play important roles in folliculogenesis. Altered expression of the two have been found among patients with poor ovarian response (POR). In this prospective cohort study, we have determined the expression of the GDF9 and BMP15 genes in follicle fluid (FF) and granulosa cells (GCs) derived from poor ovarian responders grouped by age, and explored its correlation with the outcome of in vitro fertilization and embryo transfer (IVF-ET) treatment. Methods A total of 196 patients with POR were enrolled from a tertiary teaching hospital. The patients were diagnosed by the Bologna criteria and sub-divided into group A (< 35 year old), group B (35–40 year old), and group C (> 40 year old). A GnRH antagonist protocol was conducted for all patients, and FF and GCs were collected after oocyte retrieval. Expression of the GDF9 and BMP15 genes in the FF and GCs was determined with enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Results Compared with group C, groups A and B had significantly more two pronuclei (2PN) oocytes and transplantable embryos, in addition with higher rates of implantation and clinical pregnancy (P <  0.05). The expression level of GDF9 and BMP15 genes in the FF and GCs differed significantly among the three groups (P <  0.05), showing a trend of decline along with age. The ratio of GDF9/BMP15 mRNA levels were similar among the three groups (P > 0.05). The relative levels of GDF9 and BMP15 proteins in GCs have correlated with the relative mRNA levels in GCs and protein concentrations in FF (P <  0.05). Conclusions For poor ovarian responders, in particular those over 40, the expression of GDF9 and BMP15 is declined along with increased age and in accompany with poorer oocyte quality and IVF outcome, whilst the ratio of GDF9/BMP15 mRNA levels remained relatively constant. Trial registration Chinese Clinical Trial Registry Center (ChiCTR1800016107). Registered on 11 May 2018.

scholarly journals Molecular Mechanisms Responsible for Increased Vulnerability of the Ageing Oocyte to Oxidative Damage

2017 ◽  
Vol 2017 ◽  
pp. 1-22 ◽  
Author(s):  
Bettina P. Mihalas ◽  
Kate A. Redgrove ◽  
Eileen A. McLaughlin ◽  
Brett Nixon
Keyword(s):  
Oxidative Damage ◽  
Molecular Mechanisms ◽  
Spindle Assembly Checkpoint ◽  
Assisted Reproductive Technologies ◽  
Reproductive Technologies ◽  
Oocyte Quality ◽  
Protein Repair ◽  
Protective Mechanisms ◽  
Pronounced Increase ◽  
Age Related

In their midthirties, women experience a decline in fertility, coupled to a pronounced increase in the risk of aneuploidy, miscarriage, and birth defects. Although the aetiology of such pathologies are complex, a causative relationship between the age-related decline in oocyte quality and oxidative stress (OS) is now well established. What remains less certain are the molecular mechanisms governing the increased vulnerability of the aged oocyte to oxidative damage. In this review, we explore the reduced capacity of the ageing oocyte to mitigate macromolecular damage arising from oxidative insults and highlight the dramatic consequences for oocyte quality and female fertility. Indeed, while oocytes are typically endowed with a comprehensive suite of molecular mechanisms to moderate oxidative damage and thus ensure the fidelity of the germline, there is increasing recognition that the efficacy of such protective mechanisms undergoes an age-related decline. For instance, impaired reactive oxygen species metabolism, decreased DNA repair, reduced sensitivity of the spindle assembly checkpoint, and decreased capacity for protein repair and degradation collectively render the aged oocyte acutely vulnerable to OS and limits their capacity to recover from exposure to such insults. We also highlight the inadequacies of our current armoury of assisted reproductive technologies to combat age-related female infertility, emphasising the need for further research into mechanisms underpinning the functional deterioration of the ageing oocyte.

scholarly journals The Impact of Aging on Macroautophagy in the Pre-ovulatory Mouse Oocyte

2021 ◽  
Vol 9 ◽  
Author(s):  
Alexandra E. Peters ◽  
Shandelle J. Caban ◽  
Eileen A. McLaughlin ◽  
Shaun D. Roman ◽  
Elizabeth G. Bromfield ◽  
...  
Keyword(s):  
Image Analysis ◽  
Degradation Mechanism ◽  
Oocyte Quality ◽  
Poor Quality ◽  
Depth Image ◽  
Age Related ◽  
Gene And Protein Expression ◽  
Quantitative Image ◽  
Autophagy Pathway ◽  
The Impact

Accompanying the precipitous age-related decline in human female fertility is an increase in the proportion of poor-quality oocytes within the ovary. The macroautophagy pathway, an essential protein degradation mechanism responsible for maintaining cell health, has not yet been thoroughly investigated in this phenomenon. The aim of this study was to characterize the macroautophagy pathway in an established mouse model of oocyte aging using in-depth image analysis-based methods and to determine mechanisms that account for the observed changes. Three autophagy pathway markers were selected for assessment of gene and protein expression in this model: Beclin 1; an initiator of autophagosome formation, Microtubule-associated protein 1 light chain 3B; a constituent of the autophagosome membrane, and lysosomal-associated membrane protein 1; a constituent of the lysosome membrane. Through quantitative image analysis of immunolabeled oocytes, this study revealed impairment of the macroautophagy pathway in the aged oocyte with an attenuation of both autophagosome and lysosome number. Additionally, an accumulation of amphisomes greater than 10 μm2 in area were observed in aging oocytes, and this accumulation was mimicked in oocytes treated with lysosomal inhibitor chloroquine. Overall, these findings implicate lysosomal dysfunction as a prominent mechanism by which these age-related changes may occur and highlight the importance of macroautophagy in maintaining mouse pre-ovulatory oocyte quality. This provides a basis for further investigation of dysfunctional autophagy in poor oocyte quality and for the development of therapeutic or preventative strategies to aid in the maintenance of pre-ovulatory oocyte health.

scholarly journals Antioxidants in erythrocytes in aging and dementia

2013 ◽  
Vol 59 (4) ◽  
pp. 443-451 ◽  
Author(s):  
E.A. Kosenko ◽  
L.A. Tikhonova ◽  
A.C. Poghosyan ◽  
Y.G. Kaminsky
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glutathione Peroxidase ◽  
Antioxidant Status ◽  
Transferase Activity ◽  
Glutathione S Transferase ◽  
Age Related ◽  
Organic Hydroperoxides

Age of patients and brain oxidative stress may contribute to pathogenesis of Alzheimer's disease (AD). Erythrocytes (red blood cells, RBC) are considered as passive “reporter cells” for the oxidative status of the whole organism and are not well studied in AD. The aim of this work was to assess whether the antioxidant status of RBC changes in aging and AD. Blood was taken from AD and non-Alzheimer's dementia patients, aged-matched and younger controls. In vivo antioxidant status was assessed in each of the study subjects by measuring RBC levels of Н О , organic hydroperoxides, glutathione (GSH) and glutathione disulfide (GSSG), activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, and glucose-6-phosphate dehydrogenase. In both aging and dementia, oxidative stress in RBC was shown to increase and to be expressed in elevated concentrations of H O and organic hydroperoxides, decreased the GSH/GSSG ratio and glutathione S-transferase activity. Decreased glutathione peroxidase activity in RBC may be considered as a new peripheral marker for Alzheimer’s disease while alterations of other parameters of oxidative stress reflect age-related events.

scholarly journals BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging

2019 ◽  
Vol 26 (1) ◽  
pp. 43-57 ◽  
Author(s):  
Volkan Turan ◽  
Kutluk Oktay
Keyword(s):  
Clinical Evidence ◽  
Strand Break ◽  
Oocyte Quality ◽  
Repair Pathway ◽  
Dsb Repair ◽  
Ovarian Aging ◽  
Age Related ◽  
Dna Double Strand Break ◽  
Targeted Treatments ◽  
Oocyte Aging

Abstract BACKGROUND Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated (ATM)-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and ATM-mediated DNA DSB repair in ovarian aging. OBJECTIVE AND RATIONALE Although there are several competing or complementary theories, given the growing evidence tying BRCA function and ATM-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. SEARCH METHODS We searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. OUTCOMES Laboratory studies provided robust and reproducible evidence that BRCA1 function and ATM-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other ATM-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related ATM-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. WIDER IMPLICATIONS The existing data suggest that the BRCA-related ATM-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.

Glutathione metabolism in heart and liver of the aging rat

1994 ◽  
Vol 72 (1-2) ◽  
pp. 58-61 ◽  
Author(s):  
M. Stio ◽  
T. Iantomasi ◽  
F. Favilli ◽  
P. Marraccini ◽  
B. Lunghi ◽  
...  
Keyword(s):  
Rat Heart ◽  
Reduced Glutathione ◽  
Age Groups ◽  
Glutathione Metabolism ◽  
Oxidized Glutathione ◽  
Glutathione S Transferase ◽  
Age Related ◽  
Glutamylcysteine Synthetase ◽  
Old Rats ◽  
Glucose 6 Phosphate Dehydrogenase

A comprehensive study on glutathione metabolism in rat heart and liver as a function of age was performed. In the heart, reduced glutathione, total glutathione, and the glutathione redox index showed a decrease during aging, while oxidized glutathione levels increased in 5-month-old rats with respect to the young animals and remained quite constant in 14- and 27-month-old rats. In the liver, the highest levels of reduced glutathione were found in the 2-month-old rats, while oxidized glutathione reached a peak at 5 months. Glutathione-associated enzymes showed age-related changes. Glutathione peroxidase, unaffected by aging in the heart, decreased in the liver of the 27-month-old rats. In the heart and the liver, the highest values of glutathione S-transferase were found at 5 months and 27 months, respectively. Glucose-6-phosphate dehydrogenase followed a similar trend in both heart and liver. Glutathione reductase also showed the same behaviour in heart and in liver, increasing in old rats with respect to the other age groups. A decrease in γ-glutamylcysteine synthetase was found in the heart and liver of 27-month-old rats in comparison with the 2-month-old ones. In conclusion, a decreased antioxidant capability has been demonstrated in both heart and liver of old rats.Key words: glutathione metabolism, age, rat heart, rat liver.

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