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Uterine receptivity to the embryo is crucial for successful implantation. The establishment of uterine receptivity requires a large amount of energy, and abnormal energy regulation causes implantation failure. Glucose metabolism in the endometrium is tissue specific. Glucose is largely stored in the form of glycogen, which is the main energy source for the endometrium. AMP-activated protein kinase (AMPK), an important energy-sensing molecule, is a key player in the regulation of glucose metabolism and its regulation is also tissue specific. However, the mechanism of energy regulation in the endometrium for the establishment of uterine receptivity remains to be elucidated. In this study, we aimed to investigate the energy regulation mechanism of mouse uterine receptivity and its significance in embryo implantation. The results showed that the AMPK, p-AMPK, glycogen synthase 1, and glycogen phosphorylase M levels and the glycogen content in mouse endometrial epithelium varied in a periodic manner under regulation by the ovarian hormone. Specifically, progesterone significantly activated AMPK, promoted glycogenolysis, and upregulated glycogen phosphorylase M expression. AMPK regulated glycogen phosphorylase M expression and promoted glycogenolysis. AMPK was also found to be activated by changes in the energy or glycogen of the endometrial epithelial cells. The inhibition of AMPK activity or glycogenolysis altered the uterine receptivity markers during the window of implantation and ultimately interfered with implantation. In summary, consistency and synchronization of AMPK and glycogen metabolism constitute the core regulatory mechanism in mouse endometrial epithelial cells involved in the establishment of uterine receptivity.

The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.

Many functional activities of endometrium epithelium are energy consuming which are very important for maintaining intrauterine environment needed by early embryonic development and establishment of implantation window. Glucose is a main energy supplier and one of the main components of intrauterine fluid. Obviously, glucose transports in endometrium epithelium involve in for these activities but their functions have not been elucidated. In this research, we observed a spatiotemporal pattern of sodium glucose transporter 1 (SGLT1) expression in the mouse endometrium. We also determined that progesterone can promote the expression of SGLT1 in the mouse endometrial epithelium in response to the action of oestrogen. Treatment with the SGLT1 inhibitor phlorizin or small interfering RNA specific for SGLT1 (SGLT1-siRNA) altered glucose uptake in primary cultured endometrial epithelial cells, which exhibited reduced ATP levels and AMPK activation. The injection of phlorizin or SGLT1-siRNA into one uterine horn of each mouse on day 2 of pregnancy led to an increased glucose concentration in the uterine fluid and decreased number of harvested normal blastocysts and decreased expression of integrin αVβ3 in endometrial epithelium and increased expression of mucin 1 and lactoferrin in endometrial epithelium and the uterine homogenates exhibited activated AMPK, a decreased ATP level on day 4, and a decreased number of implantation sites on day 5. In embryo transfer experiments, pre-treatment of the uterine horn with phlorizin or SGLT1-siRNA during the implantation window led to a decreased embryo implantation rate on day 5 of pregnancy, even when embryos from normal donor mice were used. In conclusion, SGLT1, which participates in glucose transport in the mouse endometrial epithelium, inhibition and/or reduced expression of SGLT1 affects early embryo development by altering the glucose concentration in the uterine fluid. Inhibition and/or reduced expression of SGLT1 also affects embryo implantation by influencing energy metabolism in epithelial cells, which consequently influences implantation-related functional activities.

Type 2 diabetes mellitus (T2DM) is a disease characterized by hyperglycemia resulting from insulin resistance. In recent years, the incidence of T2DM has been increasing. Women with T2DM often suffer from infertility and early miscarriage; however, the underlying mechanisms remain unclear. Insulin is the most important regulatory hormone of glycogen metabolism. In addition, 5' adenosine monophosphate-activated protein kinase (AMPK) is an important regulator of glycogen metabolism. Patients with T2DM have inhibited AMPK expression in the liver, which leads to impaired glucose metabolism. However, the role of AMPK in endometrial glycogen metabolism has not been reported. In this study, a mouse model of T2DM was established to investigate whether altered endometrial glucose metabolism affects early embryo implantation. Metformin and insulin were used for therapy; the resulting changes to glycogen metabolism and embryo implantation were examined. The results indicate that the concentrations of glycogen decreased significantly in T2DM mice, resulting in insufficient energy supplies for proper endometrial function, and thereby impeding embryonic implantation. Interestingly, endometrial AMPK was not found to be overactivated. Insulin treatment was found to partially resolve the embryo implantation defects in T2DM mice. Metformin improved blood glucose but did not have a significant effect on local endometrial glucose metabolism. This study explored the changes in endometrial glucose metabolism in T2DM mouse, and the effects of these changes on embryo implantation. We found that insulin, but not metformin, significantly resolved embryo implantation problems. These findings will help to increase our understanding of the pathomechanisms of infertility and early miscarriage in women with T2DM.

To study the protective effect of cerebrospinal fluid containing Qingxin Kaiqiao Fang on sodium dithionite (Na2S2O4)-induced PC12 cell injury, in order to provide basis for clinical application of the prescription.SD rats were orally administered with water decoction of Qingxin Kaiqiao Fang (7. 9 g . kg-1) once every 12 h, for a total of 7 times, in order to prepare cerebrospinal fluid containing Qingxin Kaiqiao Fang. The neurocyte injury model was established by adding Na2S2O4 with the final concentration of 8 m mol . L-1 into PC12 cells. With nimodipine (1 x 10(7)mol . L-1 ) as the positive control group, MTT method test was adopted to detect the impact of cerebrospinal fluid containing Qingxin Kaiqiao Fang on the activity of PC12 cells. The expression of Bax, Bel-2 and Caspase-3 mRNA was detected by RT-PCR.The cerebrospinal fluid containing Qingxin Kaiqiao Fang groups showed a significantly higher activity in PC12 cells than the model group, with decrease in expressions of Bax mRNA and Caspase-3 mRNA and increase in expression of Bel-2 mRNA. There were significant differences compared with the model group (P0. 05,P0. 01).Qingxin Kaiqiao Fang shows a notable protective effect on Na2S2 04-induced neurocyte injury.