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.

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 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 Biology of Early-Stage Operable Breast Cancer and Its Impact on Clinical Outcome

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1417
Author(s):  
Binafsha M. Syed ◽  
Andrew R. Green ◽  
Emad A. Rakha ◽  
David A.L. Morgan ◽  
Ian O. Ellis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Histological Grade ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Progesterone Receptors ◽  
Biological Characteristics ◽  
Cancer Specific Survival ◽  
Age Related ◽  
Significant Difference

As age advances, breast cancer (BC) tends to change its biological characteristics. This study aimed to explore the natural progression of such changes. The study included 2383 women with clinically T0-2N0-1M0 BC, managed by primary surgery and optimal adjuvant therapy in a dedicated BC facility. Tissue micro-arrays were constructed from their surgical specimens and indirect immunohistochemistry was used for analysis of a large panel (n = 16) of relevant biomarkers. There were significant changes in the pattern of expression of biomarkers related to luminal (oestrogen receptor (ER), progesterone receptors (PgR), human epidermal growth factor receptor (HER-2), E-cadherin, MUC1, bcl2 CK7/8, CK18 and bcl2) and basal (CK5/6, CK14, p53 and Ki67) phenotypes, lymph node stage, histological grade and pathological size when decade-wise comparison was made (p < 0.05). The ages of 40 years and 70 years appeared to be the milestones marking a change of the pattern. There were significantly higher metastasis free and breast cancer specific survival rates among older women with ER positive tumours while there was no significant difference in the ER negative group according to age. Biological characteristics of BC show a pattern of change with advancing age, where 40 years and 70 years appear as important milestones. The pattern suggests <40 years as the phase with aggressive phenotypes, >70 years as the less aggressive phase and 40–70 years being the transitional phase.

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 Telomere Dysfunction in Oocytes and Embryos From Obese Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Juan Ge ◽  
Congyang Li ◽  
Hongzheng Sun ◽  
Yongan Xin ◽  
Shuai Zhu ◽  
...  
Keyword(s):  
Embryo Development ◽  
High Frequency ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Oocyte Quality ◽  
Telomere Dysfunction ◽  
Obese Mice ◽  
High Fat ◽  
Telomere Shortening ◽  
Early Embryos

Maternal obesity impairs oocyte quality and embryo development. However, the potential molecular pathways remain to be explored. In the present study, we examined the effects of obesity on telomere status in oocytes and embryos obtained from mice fed with high-fat diet (HFD). Of note, telomere shortening was observed in both oocytes and early embryos from obese mice, as evidenced by the reduced expression of telomerase reverse transcriptase and activity of telomerase. Moreover, quantitative analysis of telomere dysfunction-induced foci (TIFs) revealed that maternal obesity induces the defective telomeres in oocytes and embryos. Meanwhile, the high frequency of aneuploidy was detected in HFD oocytes and embryos as compared to controls, accompanying with the increased incidence of apoptotic blastocysts. In conclusion, these results indicate that telomere dysfunction might be a molecular pathway mediating the effects of maternal obesity on oocyte quality and embryo development.

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 Blockade of Platelet-Derived Growth Factor Signaling Inhibits Choroidal Neovascularization and Subretinal Fibrosis in Mice

2020 ◽  
Vol 9 (7) ◽  
pp. 2242
Author(s):  
Ye Liu ◽  
Kousuke Noda ◽  
Miyuki Murata ◽  
Di Wu ◽  
Atsuhiro Kanda ◽  
...  
Keyword(s):  
Growth Factor ◽  
Choroidal Neovascularization ◽  
Vision Loss ◽  
Growth Factor Receptor ◽  
Neutralizing Antibody ◽  
Age Related Macular Degeneration ◽  
Platelet Derived Growth Factor ◽  
Growth Factor Signaling ◽  
Age Related ◽  
Subretinal Fibrosis

Neovascular age related macular degeneration (nAMD) leads to severe vision loss worldwide and is characterized by the formation of choroidal neovascularization (CNV) and fibrosis. In the current study, we aimed to investigate the effect of blockade for platelet derived growth factor receptor-β (PDGFR-β) on the formation of choroidal neovascularization and fibrosis in the laser-induced CNV model in mice. Firstly, the presence of PDGFR-β in CNV lesions were confirmed. Intravitreal injection of PDGFR-β neutralizing antibody significantly reduced the size of CNV and subretinal fibrosis. Additionally, subretinal hyperreflective material (SHRM), a landmark feature on OCT as a risk factor for subretinal fibrosis formation in nAMD patients was also suppressed by PDGFR-β blockade. Furthermore, pericytes were abundantly recruited to the CNV lesions during CNV formation, however, blockade of PDGFR-β significantly reduced pericyte recruitment. In addition, PDGF-BB stimulation increased the migration of the rat retinal pericyte cell line, R-rPCT1, which was abrogated by the neutralization of PDGFR-β. These results indicate that blockade of PDGFR-β attenuates laser-induced CNV and fibrosis through the inhibition of pericyte migration.

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