Expression of pro-apoptotic and anti-apoptotic proteins in granulosa cells of women with diminished ovarian reserve

Kuran, Sibel Bulgurcuoğlu; ALTUN, Ayşe; Balcı, Burçin Karamustafaoğlu; Keskin, İlknur; Hocaoğlu, Meryem

doi:10.1007/s10815-022-02422-2

Cited by 6 publications

(4 citation statements)

References 40 publications

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“…In the ovarian follicle, CCs form a direct barrier between the oocyte and external environment. Owing to their bidirectional communication, CCs have a direct impact on the maturation and development of the oocyte ( Bulgurcuoglu et al , 2022 ; Tian et al , 2023 ). In this study, we performed transcriptome sequencing to obtain expression data for CCs from mature follicles of young women (<38 years) undergoing ovarian stimulation.…”

Section: Discussionmentioning

confidence: 99%

Increased serine synthesis in cumulus cells of young infertile women with diminished ovarian reserve

et al. 2023

Human Reproduction

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STUDY QUESTION What are the differences in gene expression of cumulus cells (CCs) between young women with diminished ovarian reserve (DOR) and those of similar age with normal ovarian reserve (NOR)? SUMMARY ANSWER Gene expression and metabolome profiling analysis demonstrate that the de novo serine synthesis pathway (SSP) is increased in the CCs of young women with DOR. WHAT IS KNOWN ALREADY The incidence of DOR has risen, tending to present at younger ages. Its mechanisms and aetiologies are still poorly understood. Abnormal metabolism is present in luteinized CCs of patients with DOR. Previous studies have revealed that mitochondrial dysfunction and impaired oxidative phosphorylation in CCs are related to DOR in women of advanced age. The pathogenic mechanisms likely differ between young women with DOR and cases associated with advanced maternal age. Several studies have examined amino acid metabolism in the follicle, with a focus on embryo development, but less information is available about CCs. The physiological significance of de novo serine synthesis in follicles and oocytes remains largely unknown. STUDY DESIGN, SIZE, DURATION CC samples were obtained from 107 young infertile women (age <38 years) undergoing ICSI, from July 2017 to June 2019, including 54 patients with DOR and 53 patients with NOR. PARTICIPANTS/MATERIALS, SETTING, METHODS Oocyte development data were analysed retrospectively. Comprehensive genome-wide transcriptomics of CCs was performed. Differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to categorize the functions of the DEGs and identify significantly enriched pathways. The transcript and protein levels of key enzymes involved in serine synthesis were verified in additional samples using quantitative real-time PCR (qRT-PCR) (n = 10) and capillary western blotting (n = 36). Targeted metabolomics of amino acids in CC extracts was performed by ultrahigh-performance liquid MS (UHPLC–MS/MS). MAIN RESULTS AND THE ROLE OF CHANCE The number of oocytes (2.4 ± 2.2 versus 12.1 ± 5.3) and metaphase II oocytes (2.1 ± 2.0 versus 9.9 ± 4.9) retrieved was significantly decreased in the DOR versus the NOR group, respectively (P < 0.0001). The rates of fertilization (80.7% versus 78.8%), viable embryos (73.7% versus 72.5%), and high-quality embryos (42.8% versus 49.0%) did not differ between the DOR and NOR groups, respectively (P > 0.05). A total of 95 DEGs were found by transcriptome sequencing. GO and KEGG analyses demonstrated that the DEGs were linked to amino acid metabolism and suggested significantly higher activity of the de novo SSP in the CCs of young women with DOR. Further qRT-PCR and capillary western blotting revealed that key enzymes (PHGDH, PSAT1, PSPH, and SHMT2) involved in de novo serine synthesis were upregulated, and UHPLC–MS/MS analysis showed increases in serine and glycine (a downstream product of serine) levels in the CCs of young patients with DOR. Our data clearly demonstrate that the de novo SSP, which diverts 3-phosphoglycerate from glycolysis to serine synthesis, was upregulated in young DOR CCs. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Regarding the reproductive capacity of young patients DOR, the pregnancy outcomes were not analysed. The sample size was limited, and only women undergoing ICSI were examined since this was a prerequisite for the acquisition of CCs, which may cause selection bias. The exact mechanisms by which the SSP in CCs regulates ovarian reserve still require further study. WIDER IMPLICATIONS OF THE FINDINGS Our research presents new evidence that alterations of the SSP in CCs of young infertile women are associated with DOR. We believe this is a significant contribution to the field, which should be key for understanding the cause and mechanisms of ovarian hypofunction in young women. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants from the Ministry of Science and Technology of China (2018YFC1005001) and National Natural Science Foundation of China (31601197). There were no competing interests. TRIAL REGISTRATION NUMBER N/A.

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Section: Discussionmentioning

confidence: 99%

Increased serine synthesis in cumulus cells of young infertile women with diminished ovarian reserve

et al. 2023

Human Reproduction

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“…9 Granulosa cell (GC) apoptosis is a physiological phenomenon in follicles that induces follicular atresia and decreases follicle number. 25,26 Apoptosis occurs through two different pathways as follows: extrinsic and intrinsic pathways. 27 The extrinsic pathway is triggered by the binding of a ligand to a transmembrane death receptor, which, in turn, binds to the ligand and recruits an articulated protein containing the corresponding death domain to activate downstream Caspase-3 to execute cell death.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Mechanisms and Experimental Verification of Yulin Formula in the Treatment of Diminished Ovarian Reserve via Network Pharmacology

Wang¹,

Zhao²,

Miao³

et al. 2023

DDDT

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The aim of this study is to examine, using network pharmacology analysis and experimental validation, the pharmacological processes by which Yulin Formula (YLF) reduces cyclophosphamide-induced diminished ovarian reserve (DOR). Methods: First, information about the active components, associated targets, and related genes of YLF and DOR was gathered from open-access databases. The primary targets and pathways of YLF to reduce DOR were predicted using studies of functional enrichment from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Protein-Protein Interaction (PPI) networks. Second, we built a cyclophosphamide-induced diminished ovarian reserve (DOR) rat model to verify the primary target proteins implicated in the predicted signaling pathway to explore the mechanism of improve ovarian function of YLF. Results: 98 targets met the targets of the 82 active ingredients in YLF and DOR after searching the intersection of the active ingredient targets and DOR targets. Fourteen targets, including AKT and Caspase-3 among others, were hub targets, according to the PPI network study. The PI3K/AKT pathway was revealed to be enriched by numerous targets by the GO and KEGG enrichment studies, and it was used as a target for in vivo validation. Animal studies showed that YLF administration not only reduced the number of atretic follicles, the proportion of TUNEL-positive ovarian cells, the rate of apoptosis of granulosa cells (GCs) and the proportion of abnormal mitochondria in DOR rats, but also reversed the high expression of Caspase-3, Caspase-9, BAX, cytochrome C, PI3K and P-AKT, improving the ovarian reserve in cyclophosphamide (CTX)-induced DOR rats. Conclusion: Our research results predicted the active ingredients and potential targets of YLF-interfering DOR by an integrated network pharmacology approach, and experimentally validated some key target proteins participated in the predicted signaling pathway. A more comprehensive understanding of the pharmacological mechanism of YLF for DOR treatment was obtained.

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“…Diminished ovarian reserve (DOR) refers to the phenomenon of decreased fertility due to both of the quantitative and qualitative reduction in oocytes. DOR can lead to the decreased menstruation, sparse menstruation, or premature ovarian failure [1]. DOR is a female endocrine disorder with many pathogenic factors including heredity, environment, immunity, psychology, living habit, etc [2].…”

Section: Introductionmentioning

confidence: 99%

The diminished ovarian reserve with chronic stress induced by tripterygium with chronic unpredictable mild stress in SD rats

Wang

Liu

2023

Preprint

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Aim: To establish a rat model of DOR combined with chronic unpredictable mild stress (CUMS), and to explore the effect of chronic adverse psychological stress on ovarian reserve dysfunction, so as to provide experimental basis for further research. Methods: The rats were randomly divided into control group, CUMS group, DOR group and DOR +CUMS group, with 10 rats in each group, given fed normally, chronic mild unpredictable stress, Tripterygium glycoside tablets and Tripterygium glycoside tablets with CUMS intervention in proper order for 21 days. We observed the body mass, estrous cycle, behavioral testing, the hematoxylin and eosin (H&E) staining of ovarian tissue, the serum levels (E2, FSH, 5-HT and GnRH) and Apoptotic granulosa cells of ovarian tissue. Results: After an 21-days exposure, in DOR group or DOR+CUMS group the serum levels of E2 was reduced and the FSH was raised. In DOR group, the estrous cycle was disordered, the ovary was slightly atrophied and the ovarian tissue structure was not clear, the number of follicles and the content of follicular fluid were small, the cell layers was reduced, and inflammatory cell infiltration was visible, the change was more obvious in DOR+CUMS group. In CUMS group and DOR+CUMS group, the OFT, SPT and 5-HT were lower and the GnRH was higher than in control group. About the TUNEL, the AI in the DOR group, the CUMS group and DOR+CUMS group were higher. Conclusions: Our outcomes state that we could established an rat model of psychological stress-induced DOR successfully which can be used for further study.

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Expression of pro-apoptotic and anti-apoptotic proteins in granulosa cells of women with diminished ovarian reserve

Cited by 6 publications

References 40 publications

Increased serine synthesis in cumulus cells of young infertile women with diminished ovarian reserve

Increased serine synthesis in cumulus cells of young infertile women with diminished ovarian reserve

Investigation of the Mechanisms and Experimental Verification of Yulin Formula in the Treatment of Diminished Ovarian Reserve via Network Pharmacology

The diminished ovarian reserve with chronic stress induced by tripterygium with chronic unpredictable mild stress in SD rats

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