Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome

Wang, Meijiao; Zhao, Dan; Xu, Liangzhi; Guo, Wenjing; Nie, Lihong; Lei, Yi; Long, Yun; Liu, Min; Wang, Yichen; Zhang, Xueqin; Zhang, Li; Li, H.; Zhang, Jinhu; Yuan, Dongzhi; Liu, Yue

doi:10.1016/j.metabol.2019.02.002

Cited by 43 publications

(26 citation statements)

References 36 publications

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“…In line with present findings, the PCOS mice (PCOS mouse model induced by DHEA) also exhibited elevated T and estradiol levels, elevated LH levels and LH/FSH ratio, and decreased ovarian follicular development, increased follicle atresia and cystic follicles, which were consistent with features exhibited in PCOS patients 14 . In addition, serum levels of E2, T and LH were increased, and levels of FSH were reduced, the proliferation of GCs was reduced and apoptosis was promoted in PCOS‐modelled rat serum 15 .…”

Section: Discussionsupporting

confidence: 91%

Oxidized high‐density lipoprotein enhances endocrine disorders and ovarian damage in rats

Wang

Tang

et al. 2021

J Cellular Molecular Medi

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Previous findings have highlighted the association between oxidized high‐density lipoprotein (ox‐HDL) and polycystic ovary syndrome (PCOS) development; however, the underlying mechanism remains unclear. Under such context, the present study aimed to investigate the mechanism underlying the involvement of ox‐HDL in PCOS in relation to the p65/micro‐RNA‐34a (miR‐34a)/FOS axis. PCOS rat models were established with the injection of dehydroepiandrosterone (6 mg/100 g body weight). Both PCOS‐modelled rats and granulosa cells (GCs) were received treatment with ox‐HDL in order to identify its role in PCOS. Next, apoptosis and viability of GCs were detected with the application of TdT‐mediated dUTP Nick‐End Labeling and flow cytometry and Cell counting kit‐8, respectively. A series of assays were performed to determine the interaction among ox‐HDL, p65, miR‐34a, FOS and nuclear factor‐κB (NF‐κB). The results revealed high expression of ox‐HDL in PCOS, and enhanced endocrine disorders and ovarian damage in rats. ox‐HDL promoted apoptosis of GCs and decreased its viability. ox‐HDL activated NF‐κB pathway and induced p65 phosphorylation to promote miR‐34a expression. miR‐34a targeted and inhibited FOS expression. In conclusion, our findings suggested that ox‐HDL promoted the activation of p65 and transcription of miR‐34a, which stimulated apoptosis of GCs and inhibited expression of FOS, resulting in the overall acceleration of PCOS development.

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Section: Discussionsupporting

confidence: 91%

Oxidized high‐density lipoprotein enhances endocrine disorders and ovarian damage in rats

Wang

Tang

et al. 2021

J Cellular Molecular Medi

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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: 62%

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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“…It can be applied to identify metabolites in samples under normal conditions compared with disease-induced altered states and is considered as a powerful phenotyping tool [ 24 ]. Early studies have validated the reliability of metabolic changes for assessing oocyte quality and studying ovarian diseases, such as polycystic ovary syndrome (PCOS) [ 25 – 27 ], suggesting that metabolic variation may offer a suitable strategy for POI study.…”

Section: Introductionmentioning

confidence: 99%

Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice

Zhao

et al. 2020

Stem Cell Res Ther

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Background Premature ovarian insufficiency (POI) is an ovarian dysfunction that seriously affects a woman’s physiological health and reproduction. Mesenchymal stem cell (MSC) transplantation offers a promising treatment option for ovarian restoration in rodent POI models. However, the efficacy and mechanism of it remain unclear. Methods POI mice model was generated by cyclophosphamide and busulfan, followed with the treatment of tail-vein injection of the human umbilical cord mesenchymal stem cells (hUCMSCs). Maternal physiological changes and offspring behavior were detected. To reveal the pathogenesis and therapeutic mechanisms of POI, we first compared the metabolite profiles of healthy and POI ovarian tissues using untargeted metabolomics analyses. After stem cell therapy, we then collected the ovaries from control, POI, and hUCMSC-treated POI groups for lipid metabolomics and pseudotargeted metabolomics analysis. Results Our results revealed remarkable changes of multiple metabolites, especially lipids, in ovarian tissues after POI generation. Following the transplantation of clinical-grade hUCMSCs, POI mice exhibited significant improvements in body weight, sex hormone levels, estrous cycles, and reproductive capacity. Lipid metabolomics and pseudotargeted metabolomics analyses for the ovaries showed that the metabolite levels in the POI group, mainly lipids, glycerophospholipids, steroids, and amino acids changed significantly compared with the controls’, and most of them returned to near-healthy levels after receiving hUCMSC treatment. Meanwhile, we also observed an increase of monosaccharide levels in the ovaries from POI mice and a decrease after stem cell treatment. Conclusions hUCMSCs restore ovarian function through activating the PI3K pathway by promoting the level of free amino acids, consequently improving lipid metabolism and reducing the concentration of monosaccharides. These findings provide potential targets for the clinical diagnosis and treatment of POI.

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Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome

Cited by 43 publications

References 36 publications

Oxidized high‐density lipoprotein enhances endocrine disorders and ovarian damage in rats

Oxidized high‐density lipoprotein enhances endocrine disorders and ovarian damage in rats

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

Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice

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