Autophagy in hypoxic ovary

Yadav, Anil Kumar; Yadav, Pramod K.; Chaudhary, Govind R.; Tiwari, Meenakshi; Gupta, Akhil; Sharma, Alka; Pandey, Ashutosh; Pandey, Ajai Kumar; Chaube, Shail K.

doi:10.1007/s00018-019-03122-4

Cited by 63 publications

(40 citation statements)

References 165 publications

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“…The hypoxic microenvironment has been a focus of research in recent years. Some studies have shown that a hypoxic microenvironment is closely related to female fertility; for example, low O 2 might regulate placental development [17], and hypoxia might induce oocyte autophagy [18]. Thus far, no studies have reported the relationship between a hypoxic microenvironment and endometrial receptivity in AM.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and its possible relationship with endometrial receptivity in adenomyosis: a preliminary study

Guo

Zhang

et al. 2021

Reprod Biol Endocrinol

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Background Adenomyosis (AM) is an important cause of female infertility. However, the underlying mechanism remains unclear. This report describes a preliminary study of hypoxia and its possible association with endometrial receptivity in AM. Methods The study was divided into in vitro and in vivo experiments. In vitro, expression levels of the endometrial receptivity markers HOXA10 and HOXA11 in the implantation period were examined using real-time PCR and western blotting. Endometrial expression of hypoxia-inducible factor (HIF)-1α, HIF-2α, and HIF-3α was determined using immunohistochemistry. In vivo, using an AM mouse model established by oral administration of tamoxifen, we inhibited expression of HIF-2α using an HIF-2α antagonist (PT2399; 30 mg/kg body weight, twice daily by oral gavage for 2 days) and then examined expression levels of Hoxa10 and Hoxa11 using real-time PCR and western blotting. Results Endometrial mRNA and protein expression levels of HOXA10 and HOXA11 were significantly lower in patients with AM than in control patients. Expression of HIF-2α was significantly higher in the AM group than in the control group, whereas that of HIF-1α and HIF-3α was equivalent in both groups. In vivo analysis showed that administration of the HIF-2α antagonist resulted in increased expression of Hoxa10 and Hoxa11 at both the mRNA and protein levels in AM model mice. Conclusions HIF-2α overexpression may be one reason for decreased endometrial receptivity in AM. The current findings provide insight into HIF-2α-mediated AM-related infertility and suggest that PT2399 has potential as a treatment for AM. Trial registration This trial was retrospectively registered.

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Section: Discussionmentioning

confidence: 99%

Hypoxia and its possible relationship with endometrial receptivity in adenomyosis: a preliminary study

Guo

Zhang

et al. 2021

Reprod Biol Endocrinol

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“…For example, high levels of ROS-induced oxidative stress increase HCG-stimulated androgen secretion and contribute to polycystic ovary syndrome (PCOS) [29]. Besides, excess ROS induces autophagy in oocytes, which eventually leads to follicular atresia and premature ovarian failure [30, 31]. 3-NP has been used as an oxidant in several studies and proves that it causes excess ROS generation and induces mouse follicular atresia and mouse GC (mGC) apoptosis in vivo [32, 33].…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of miRNA-mRNA Interaction Network in Porcine Granulosa Cells Undergoing Oxidative Stress

Cao

Wang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Oxidative stress (OS), a common intracellular phenomenon induced by excess reactive oxygen species (ROS) generation, has been shown to be associated with mammalian ovarian follicular development blockage and granulosa cell (GC) impairment. However, the mechanism involved in these effects remains unknown, and the effect of OS on the transcriptome profiles in porcine GCs has not been fully characterized. In this study, we found that hydrogen peroxide-mediated oxidative stress induced porcine GC apoptosis and impaired cell viability. Moreover, RNA-seq analysis showed that oxidative stress induced dramatic changes in gene expression in porcine GCs. A total of 2025 differentially expressed genes (DEGs) were identified, including 1940 DEmRNAs and 55 DEmiRNAs. Functional annotation showed that the DEGs were mainly associated with cell states and function regulation. In addition, multiple hub genes (FOXO1, SOD2, BMP2, DICER1, BCL2L11, FZD4, ssc-miR-424, and ssc-miR-27b) were identified by constructing protein-protein interaction and DEmiRNA-DEmRNA regulatory networks. Furthermore, a gene-pathway-function coregulatory network was established and demonstrated that these hub genes were enriched in FoxO, TGF-β, Wnt, PIK3-Akt, MAPK, and cAMP signaling pathways, which play important roles in regulating cell apoptosis, cell proliferation, stress responses, and hormone secretion. The current research provides a comprehensive perspective of the effects of oxidative stress on porcine GCs and also identifies potential therapeutic targets for oxidative stress-induced female infertility.

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“…Given that oxidative stress is an inducer of pathological ovarian aging [32], we speculated that the fMSC-mediated improvement in ovarian activity might be attributed to the decreased ROS level. To test this hypothesis, POI hGCs were treated with fMSCs to measure the ROS rate by FACS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting MT1

et al. 2019

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Background: With the development of regenerative medicine and tissue engineering technology, almost all stem cell therapy is efficacious for the treatment of premature ovarian failure (POF) or premature ovarian insufficiency (POI) animal models, whereas little stem cell therapy has been practiced in clinical settings. The underlying molecular mechanism and safety of stem cell treatment in POI are not fully understood. In this study, we explored whether fetal mesenchymal stem cells (fMSCs) from the liver restore ovarian function and whether melatonin membrane receptor 1 (MT1) acts as a regulator for treating POI disease. Methods: We designed an in vivo model (chemotherapy-induced ovary damage) and an in vitro model (human ovarian granulosa cells (hGCs)) to understand the efficacy and molecular cues of fMSC treatment of POI. Follicle development was observed by H&E staining. The concentration of sex hormones in serum (E2, AMH, and FSH) and the concentration of oxidative and antioxidative metabolites and the enzymes MDA, SOD, CAT, LDH, GR, and GPx were measured by ELISA. Flow cytometry (FACS) was employed to detect the percentages of ROS and proliferation rates. mRNA and protein expression of antiapoptotic genes (SURVIVIN and BCL2), apoptotic genes (CASPASE-3 and CASPASE-9), and MT1 and its downstream genes (JNK1, PCNA, AMPK) were tested by qPCR and western blotting. MT1 siRNA and related antagonists were used to assess the mechanism. Results: fMSC treatment prevented cyclophosphamide (CTX)-induced follicle loss and recovered sex hormone levels. Additionally, fMSCs significantly decreased oxidative damage, increased oxidative protection, improved antiapoptotic effects, and inhibited apoptotic genes in vivo and in vitro. Furthermore, fMSCs also upregulated MT1, JNK1, PCNA, and AMPK at the mRNA and protein levels. With MT1 knockdown or antagonist treatment in normal hGCs, the protein expression of JNK1, PCNA, and AMPK and the percentage of proliferation were impaired. Conclusions: fMSCs might play a crucial role in mediating follicular development in the POI mouse model and stimulating the activity of POI hGCs by targeting MT1.

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Autophagy in hypoxic ovary

Cited by 63 publications

References 165 publications

Hypoxia and its possible relationship with endometrial receptivity in adenomyosis: a preliminary study

Hypoxia and its possible relationship with endometrial receptivity in adenomyosis: a preliminary study

Integrated Analysis of miRNA-mRNA Interaction Network in Porcine Granulosa Cells Undergoing Oxidative Stress

Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting MT1

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