Erythropoietin-producing hepatocellular A7 triggering ovulation indicates a potential beneficial role for polycystic ovary syndrome

Li, Shang; Zhai, Junyu; Liu, Jiansheng; Di, Fangfang; Sun, Yun; Li, Weiping; Chen, Zi‐Jiang; Du, Yanzhi

doi:10.1016/j.ebiom.2018.09.046

Cited by 12 publications

(16 citation statements)

References 68 publications

(94 reference statements)

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“…Indeed, after 1 week of modelling followed by superovulation, FHL2 overexpression rats displayed significantly decreased ovulation efficiency and MII oocyte rate. Following 3 weeks of modelling, we detected that FHL2 overexpression group displayed acyclicity and PCOM, which were similar to the phenotypes of PCOS rat models observed previously in our laboratory [19,68]. All of these clues indicate that FHL2 may play a role in the development of the ovarian features of PCOS.…”

Section: Discussionsupporting

confidence: 87%

“…Among these regulatory genes, four and a half LIM domain (FHL) 1 and 2 as well as C/EBPb were identified based on the high frequencies of their occurrence in the gene expression profiles. C/EBPb is an essential ERK1/2-mediated ovulation-related gene [15], and its lower expression in hGCs from patients with PCOS that involved in the pathogenesis of ovulatory dysfunction of PCOS has been demonstrated by our research group [19]. Therefore, we hypothesised that FHL1/2 plays a role in the development of PCOS and we examined whether FHL1/2 can regulate ovulation-related genes related to ovulatory disorder in PCOS.…”

Section: Introductionmentioning

confidence: 94%

“…The negative control was the corresponding empty lentiviral vector. The lentivirus vector protocol was modified from the published method [45À47] and combined with our previous experience [19,48]. In brief, we used 293T cells to confirm the transfection efficiency and determined the proper virus titre by examining the expression of FHL2 using qRT-PCR and immunoblotting.…”

Section: Injection Of Lentivirus-mediated Vectors Into Rat Ovariesmentioning

confidence: 99%

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Up-regulated FHL2 inhibits ovulation through interacting with androgen receptor and ERK1/2 in polycystic ovary syndrome

Zhou

Liu

et al. 2020

EBioMedicine

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Background: The ovulatory dysfunction mechanisms underlying polycystic ovary syndrome (PCOS) are not completely understood. There is no effective therapy for PCOS so far. Methods: We measured the expression of four and a half LIM domain 2 (FHL2) and other related-genes in human granulosa cells (hGCs) from patients with and without PCOS. To minimise the heterogeneity of patients with PCOS, we only included PCOS patients meeting all three criteria according to the revised Rotterdam consensus. The in vitro effects of FHL2 on ovulatory genes and the underlying mechanisms were examined in KGN cells. The role of FHL2 in ovulation was investigated in vivo by overexpressing FHL2 in rat ovaries via intrabursal lentivirus injection. Findings: Increased FHL2 and androgen receptor (AR) expression and decreased CCAAT/enhancer-binding protein b (C/EBPb) expression were observed in hGCs from patients with PCOS. FHL2 inhibited the expression of ovulation-related genes, including phosphorylated ERK1/2, C/EBPb, COX2 and HAS2 in KGN cells. It was partially by interacting with AR to act as its co-regulator to inhibit C/EBPb expression and by binding to ERK1/2 to inhibit its phosphorylation. Moreover, FHL2 abundance in hGCs was positively correlated with the basal serum testosterone concentration of patients with PCOS, and dihydrotestosterone (DHT)-induced FHL2 upregulation was mediated by AR signalling in KGN cells. Additionally, lentiviral-mediated functional FHL2 overexpression in rat ovaries for 1 week contributed to an impaired superovulatory response, displaying decreased numbers of retrieved oocytes and a lower MII oocyte rate. 3-week FHL2 overexpression rat models without superovulation led to acyclicity and polycystic ovary morphology. Interpretation: Our findings provide novel insights into the mechanisms underlying the pathogenesis of PCOS, suggesting that FHL2 could be a potential treatment target for ovulatory obstacles in PCOS.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 94%

Section: Injection Of Lentivirus-mediated Vectors Into Rat Ovariesmentioning

confidence: 99%

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Up-regulated FHL2 inhibits ovulation through interacting with androgen receptor and ERK1/2 in polycystic ovary syndrome

Zhou

Liu

et al. 2020

EBioMedicine

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“…Predominant proestrus stage was observed in the curcumin treated group whereas estrus phase was observed as the predominant phase (35.6±1.5) in the groups treated with nanoparticles. Previous research studies 77 , 78 also reported similar effects on the estrous cycle with different suggested protocol.…”

Section: Resultssupporting

confidence: 61%

Development and Evaluation of Curcumin Encapsulated Self-assembled Nanoparticles as Potential Remedial Treatment for PCOS in a Female Rat Model

Raja¹,

Maldonado²,

Chen³

et al. 2021

IJN

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Purpose Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age and leads to metabolic disorders and infertility. The present study was conducted to investigate the therapeutic effects of curcumin (Cur) encapsulated arginine (Arg) and N-acetyl histidine (NAcHis) modified chitosan (Arg-CS-NAcHis/Cur) nanoparticles (NPs). Methods In this study, amphiphilic chitosan (CS) conjugate was developed by modification with hydrophilic arginine (Arg) and hydrophobic N-acetyl histidine (NAcHis) group (Arg-CS-NAcHis). The synthesized conjugate was well characterized by FTIR and NMR studies. Self-assembled nanoparticles based on the synthesized conjugate were developed by simple sonication method and characterized for the physicochemical properties of zeta potential, particle size and drug encapsulation. Next, in vitro drug release, cytotoxicity, and cellular uptake studies of the NPs were evaluated. Finally, the developed nanoparticles were examined for their therapeutic potential against estradiol valerate (EV) induced PCOS rats by evaluating hormone level changes and ovarian morphology. Results The results showed that zeta potential of the nanoparticles was 39.8±2.52 mV and the average size was 200 nm. The in vitro drug release profile showed sustained release pattern. Cytotoxicity and cellular uptake studies also showed preferential effectiveness than free curcumin. Both the biochemical and histopathological studies showed positive effects in reverting the symptoms of PCOS rats to normalcy. Conclusion Curcumin encapsulated arginine and N-acetyl histidine modified chitosan (Arg-CS-NAcHis/Cur) nanoparticles have been successfully developed. The present study suggested that treatment of the nanoparticles might reverse many of the PCOS symptoms. Therefore, these nanoparticles might be used as promising new candidate for delivery of curcumin to treat PCOS.

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“…Unlike miRNA mimics, siRNAs and shRNAs exhibit higher specificity by binding specifically the targeted mRNA. siRNAs against EphA4 have been used to highlight the negative role of EphA4 in recovery after brain hemorrhages [104] while an shRNA against EphA7 was employed to demonstrate its implication in the ovulation process [105]. Despite their common higher specificity, siRNAs and shRNAs present several differences (for review see [106]).…”

Section: Interfering Rnasmentioning

confidence: 99%

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

2020

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Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

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Erythropoietin-producing hepatocellular A7 triggering ovulation indicates a potential beneficial role for polycystic ovary syndrome

Cited by 12 publications

References 68 publications

Up-regulated FHL2 inhibits ovulation through interacting with androgen receptor and ERK1/2 in polycystic ovary syndrome

Up-regulated FHL2 inhibits ovulation through interacting with androgen receptor and ERK1/2 in polycystic ovary syndrome

Development and Evaluation of Curcumin Encapsulated Self-assembled Nanoparticles as Potential Remedial Treatment for PCOS in a Female Rat Model

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

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