scholarly journals Advanced Oxidation Protein Products Induce G1/G0-Phase Arrest in Ovarian Granulosa Cells via the ROS-JNK/p38 MAPK-p21 Pathway in Premature Ovarian Insufficiency

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Xing-Yu Zhou ◽  
Jun Zhang ◽  
Ying Li ◽  
Ying-Xue Chen ◽  
Xiao-Min Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
P38 Mapk ◽  
Granulosa Cells ◽  
Advanced Oxidation ◽  
Premature Ovarian Insufficiency ◽  
Advanced Oxidation Protein Products ◽  
Ovarian Insufficiency ◽  
Sd Rats ◽  
Phase Arrest ◽  
G0 Phase

The mechanism underlying the role of oxidative stress and advanced oxidation protein products (AOPPs) in the aetiology of premature ovarian insufficiency (POI) is poorly understood. Here, we investigated the plasma AOPP level in POI patients and the effects of AOPPs on granulosa cells both in vitro and in vivo. KGN cells were treated with different AOPP doses, and cell cycle distribution, intracellular reactive oxygen species (ROS), and protein expression levels were measured. Sprague–Dawley (SD) rats were treated daily with PBS, rat serum albumin, AOPP, or AOPP+ N-acetylcysteine (NAC) for 12 weeks to explore the effect of AOPPs on ovarian function. Plasma AOPP concentrations were significantly higher in both POI and biochemical POI patients than in controls and negatively correlated with anti-Müllerian hormone and the antral follicle count. KGN cells treated with AOPP exhibited G1/G0-phase arrest. AOPP induced G1/G0-phase arrest in KGN cells by activating the ROS-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK)-p21 pathway. Pretreatment with NAC, SP600125, SB203580, and si-p21 blocked AOPP-induced G1/G0-phase arrest. In SD rats, AOPP treatment increased the proportion of atretic follicles, and NAC attenuated the adverse effects of AOPPs in the ovary. In conclusion, we provide mechanistic evidence that AOPPs may induce cell cycle arrest in granulosa cells via the ROS-JNK/p38 MAPK-p21 pathway and thus may be a novel biomarker of POI.

MicroRNA‐127‐5p impairs function of granulosa cells via HMGB2 gene in premature ovarian insufficiency

2020 ◽  
Vol 235 (11) ◽  
pp. 8826-8838
Author(s):  
Xinyue Zhang ◽  
Yujie Dang ◽  
Ran Liu ◽  
Shidou Zhao ◽  
Jinlong Ma ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency

scholarly journals Expression profiles of circular RNA in granulosa cells from women with biochemical premature ovarian insufficiency

Epigenomics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 319-332
Author(s):  
Xing-Yu Zhou ◽  
Ying Li ◽  
Jun Zhang ◽  
Yu-Dong Liu ◽  
Jing Zhe ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Granulosa Cells ◽  
Bioinformatics Analysis ◽  
Expression Profiles ◽  
Circular Rna ◽  
Premature Ovarian Insufficiency ◽  
Circular Rnas ◽  
Ovarian Insufficiency ◽  
Paired Samples ◽  
Foxo Signaling Pathway

Aim: To identify the expression profiles and potential functions of circular RNAs (circRNAs) in granulosa cells (GCs) from women with biochemical premature ovarian insufficiency (bPOI). Patients & methods: CircRNAs microarray analysis was performed to GCs from 8 patients with bPOI and 8 control women, followed by qRT-PCR in 15 paired samples. CircRNA–miRNA networks and the prediction of their enriched signaling pathways were conducted by bioinformatics analysis. Results: A total of 133 upregulated and 424 downregulated circRNAs was identified in women with bPOI. We constructed circRNA–miRNA networks and found that the most predominantly enriched signaling pathways were the FoxO signaling pathway and cellular senescence. Conclusion: CircRNAs are differentially expressed in bPOI, which might contribute to the pathogenesis of bPOI.

scholarly journals F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation

Blood ◽  
2012 ◽  
Vol 119 (13) ◽  
pp. 3132-3141 ◽  
Author(s):  
Bill B. Chen ◽  
Jennifer R. Glasser ◽  
Tiffany A. Coon ◽  
Chunbin Zou ◽  
Hannah L. Miller ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Lymphoblastic Leukemia ◽  
E3 Ligase ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Cyclin D2 ◽  
Phase Arrest ◽  
G0 Phase ◽  
F Box Protein ◽  
D2 Protein

AbstractHematologic maligancies exhibit a growth advantage by up-regulation of components within the molecular apparatus involved in cell-cycle progression. The SCF (Skip-Cullin1-F-box protein) E3 ligase family provides homeostatic feedback control of cell division by mediating ubiquitination and degradation of cell-cycle proteins. By screening several previously undescribed E3 ligase components, we describe the behavior of a relatively new SCF subunit, termed FBXL2, that ubiquitinates and destabilizes cyclin D2 protein leading to G0 phase arrest and apoptosis in leukemic and B-lymphoblastoid cell lines. FBXL2 expression was strongly suppressed, and yet cyclin D2 protein levels were robustly expressed in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) patient samples. Depletion of endogenous FBXL2 stabilized cyclin D2 levels, whereas ectopically expressed FBXL2 decreased cyclin D2 lifespan. FBXL2 did not bind a phosphodegron within its substrate, which is typical of other F-box proteins, but uniquely targeted a calmodulin-binding signature within cyclin D2 to facilitate its polyubiquitination. Calmodulin competes with the F-box protein for access to this motif where it bound and protected cyclin D2 from FBXL2. Calmodulin reversed FBXL2-induced G0 phase arrest and attenuated FBXL2-induced apoptosis of lymphoblastoid cells. These results suggest an antiproliferative effect of SCFFBXL2 in lymphoproliferative malignancies.

Low-intensity pulsed ultrasound promotes repair of 4-vinylcyclohexene diepoxide induced premature ovarian insufficiency in SD rats

2021 ◽  
Author(s):  
Juan Qin ◽  
Junlin Chen ◽  
Haopeng Xu ◽  
Yi Xia ◽  
Wentao Tang ◽  
...  
Keyword(s):  
Estrous Cycle ◽  
Premature Ovarian Insufficiency ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Pulsed Ultrasound ◽  
Ovarian Insufficiency ◽  
Vinylcyclohexene Diepoxide ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Sd Rats

Abstract Women with premature ovarian insufficiency (POI) may be more vulnerable to a variety of health risks. To seek a new method to treat the disease, the effects of low intensity pulsed ultrasound (LIPUS) on promoting repair of ovarian injury in female SD rats induced by 4-vinylcyclohexene diepoxide (VCD) were explored in this research. A total of 24 female SD rats were subjected to intraperitoneal injection of VCD to induce POI. Successful modeling was achieved in 22 rats, which were then randomized into VCD + LIPUS group (n=13) and VCD group (n=9). The control group (n=5) was injected with equal normal saline. Hematoxylin and eosin staining (H&E staining), enzyme-linked immunosorbent assay (ELISA), western-blot analysis, scanning electron microscope (SEM), immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay were applied to detect the results. The results indicated that rats in the VCD group showed disorder in the estrous cycle, the number of atresia follicles and apoptosis granulosa cells increased (P < 0.05). After the LIPUS treatment, the estrous cycle recovered, the number of follicles increased (P < 0.05), the level of E2 and AMH enhanced (P < 0.05) and the FSH decreased (P < 0.05). The expression of NF-κB p65, TNFα, Bax, ATF4 and caspase-3 in ovarian tissue significantly decreased (P < 0.05). These findings showed that LIPUS could promote the repair of the VCD induced ovarian damage in SD rats, which has the potential to be further applied in the clinic.

scholarly journals Concentrated exosomes from menstrual blood-derived stromal cells improves ovarian activity in a rat model of premature ovarian insufficiency

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Siwen Zhang ◽  
Boxian Huang ◽  
Peng Su ◽  
Qiyuan Chang ◽  
Pingping Li ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Rat Model ◽  
Stromal Cells ◽  
Premature Ovarian Insufficiency ◽  
Menstrual Blood ◽  
Follicle Development ◽  
Ovarian Insufficiency ◽  
Estrous Cyclicity

Abstract Background Premature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. Recent studies indicated that mesenchymal stem cell-derived exosomes were important components in tissue repair. In this study, we investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation. Methods Ovaries of 4.5-day-old Sprague Dawley rats (SD rats) were cultured in vitro to evaluate the effects of MenSCs-Exos exposure on early follicle development. Furthermore, POI in rats was induced by intraperitoneal administration of 4-vinylcyclohexene diepoxide (VCD). Forty-eight POI rats were randomly assigned to four groups, each receiving a different treatment: PBS, MenSCs, MenSCs-Exos, and Exo-free culture supernatant of MenSCs. Estrous cyclicity, ovarian morphology, follicle dynamics, serum hormones, pregnancy outcomes, and molecular changes were investigated. Results Exposure to MenSCs-Exos promoted the proliferation of granulosa cells in primordial and primary follicles in vitro and increased the expression of early follicle markers Deleted In Azoospermia Like (DAZL) and Forkhead Box L2 (FOXL2) while inhibiting follicle apoptosis. In vivo, MenSCs-Exos transplantation effectively promoted follicle development in the rat model of POI and restored the estrous cyclicity and serum sex hormone levels, followed by improving the live birth outcome. In addition, transplantation of MenSCs-Exos regulated the composition of the ovarian extracellular matrix and accelerated the recruitment of dormant follicles in the ovarian cortex and increased proliferation of granulosa cells in these follicles. Conclusion MenSCs-Exos markedly promoted follicle development in vitro and in vivo and restored fertility in POI rats, suggesting a restorative effect on ovarian functions. The therapeutic effect of MenSCs-Exos transplantation was sustainable, consistent with that of MenSCs transplantation. Our results suggested that MenSCs-Exos transplantation may be a promising cell-free bioresource in the treatment of POI.

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