Friend leukemia integration 1 overexpression decreases endometrial receptivity and induces embryo implantation failure by promoting PART1 transcription in the endometrial epithelial cells.

Background: In vitro fertilization-embryo transfer (IVF-ET) is a crucial assisted reproductive technology for treating infertility. However, recurrent implantation failure (RIF), a significant challenge in IVF-ET success, remains unresolved. This study aimed to explore the role and mechanism of FLI1 in endometrial receptivity and RIF. Methods: Differential endometrial cell proportions between patients with RIF and control subjects were assessed using single-cell RNA sequencing (scRNA-seq) analysis. The chromatin accessibility of FLI1 in the luteal endometrial tissue of patients with RIF and control subjects was examined using the single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq). FLI1 mRNA and protein levels were gauged by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Cell viability and migration were examined via cell counting kit (CCK)-8 and scratch healing assays. Epithelial-mesenchymal transition markers were analyzed using western blotting. Mechanisms underlying FLI1's regulation of PART1 transcription and expression in endometrial epithelial cells were explored using chromatin immunoprecipitation and dual-luciferase reporter assays. Adeno-associated virus (AAV) carrying epithelial cell-specific FLI1/PART1 overexpression sequences was uterinely injected in mice to assess FLI1/PART1 effects. Results: scRNA-seq revealed diminished endometrial epithelial cell proportions in RIF patients. Meanwhile, scATAC-seq indicated enhanced chromatin accessibility of FLI1 in these cells. FLI1 exhibited specific expression in RIF patients' endometrial epithelial cells. Specific FLI1 overexpression inhibited embryo implantation, while knockdown enhanced it. Pregnant mice injected with AAV encoding FLI1 overexpression had significantly lower implantation than AAV-negative controls. FLI1 binding to PART1 promoter heightened PART1 transcription and expression in endometrial epithelial cells. Rescue experiments illustrated FLI1's role in embryo implantation by boosting PART1 expression. PART1 was notably elevated in RIF patients' luteal endometrial tissue and non-receptive endometrial epithelial cells (HEC-1-A). Specific PART1 overexpression dampened embryo implantation, whereas knockdown promoted it. Pregnant mice injected with AAV encoding PART1 had lower implantation than negative controls. PART1 knockdown mitigated FLI1's inhibitory impact on HEC-1-A cell viability and migration. Conclusions: FLI1 overexpression in the endometrial epithelial cells of patients with RIF inhibited embryo implantation by binding to the PART1 promoter region to promote PART1 expression. These findings can aid in the development of novel therapeutic targets for RIF.

Resveratrol inhibits the formation and accumulation of lipid droplets through AdipoQ signal pathway and lipid metabolism lncRNAs.

Resveratrol (RES) is one of the best-known bioactive polyphenols that has received much attention in recent years because of its importance to anti-obesity. However, the exact mechanism underlying this effect and whether it can improve lipid metabolism by regulating the long-chain noncoding RNA (lncRNA) remains unclear. In this study, 24 healthy crossbred castrated boars were fed a basal diet (control) and a basal diet supplemented with 200 mg, 400 mg or 600 mg RES per Kilogram (kg) of feed for 41 d, respectively. We found that 400 mg/kg and 600 mg/kg RES-supplemented diet did not affect growth rate, but reduced significantly subcutaneous adipose thickness, carcass fat rate, greater dramatically the serum concentration of adiponectin and high-density lipoprotein in pigs. Further, we verified that RES could inhibit the formation and accumulation of lipid droplets by AdipoQ-AdipoR1-AMPKα and AdipoQ-AdipoR2-PPARα signal pathway in vivo and vitro (3T3-L1 preadipocytes). Transcriptome analyses found that 5 differently expressed (DE) lncRNAs and 77 mRNAs in subcutaneous adipose between control group and 400 mg/kg RES group, which mainly involved in "adipocytokine signaling pathway," "Wnt signaling pathway," "PI3K-Akt signaling pathway" and "MAPK signaling pathway." In conclusion, RES can inhibit the formation and accumulation of lipid droplets through AdipoQ signal pathway and lipid metabolism-related lncRNAs. Our results provide a new insight on the molecular mechanism of RES as a nutritional agents to the prevention and treatment for obesity.

Effects of trigger-day progesterone in the preimplantation genetic testing cycle on the embryo quality and pregnancy outcomes of the subsequent first frozen-thawed blastocyst transfer.

Objective: To assess whether progesterone (P) levels on the trigger day during preimplantation genetic testing (PGT) cycles are associated with embryo quality and pregnancy outcomes in the subsequent first frozen-thawed blastocyst transfer (FET) cycle. Methods: In this retrospective analysis, 504 eligible patients who underwent ICSI followed by frozen-thawed embryo transfer (FET) with preimplantation genetic test (PGT) between December 2014 and December 2019 were recruited. All patients adopted the same protocol, namely, the midluteal, short-acting, gonadotropin-releasing hormone agonist long protocol. The cutoff P values were 0.5 and 1.5 ng/ml when serum P was measured on the day of human chorionic gonadotropin (HCG) administration, and cycles were grouped according to P level on the day of HCG administration. Furthermore, the effect of trigger-day progesterone on embryo quality and the subsequent clinical outcome of FET in this PGT population was evaluated. Results: In total, 504 PGT cycles were analyzed. There was no significant difference in the number of euploid blastocysts, top-quality blastocysts, euploidy rate, or miscarriage rate among the three groups (P>0.05). The 2PN fertilization rate (80.32% vs. 80.17% vs. 79.07%) and the top-quality blastocyst rate (8.71% vs. 8.24% vs. 7.94%) showed a downward trend with increasing P, and the between-group comparisons showed no significant differences (P>0.05). The clinical pregnancy rate (41.25% vs. 64.79%; P<0.05) and live birth rate (35.00% vs. 54.93%; P<0.05) in subsequent FET cycles were substantially lower in the high-P group than in the P ≤ 0.5 ng/ml group. After adjustments were made for confounding variables, multivariate logistic regression analysis revealed that the high-P group had a lower clinical pregnancy rate (adjusted OR, 0.317; 95% CI, 0.145-0.692; P=0.004) and live birth rate (adjusted OR, 0.352; 95% CI, 0.160-0.773; P=0.009) than the low-P group in subsequent FET cycles, and the differences were significant. Conclusions: This study demonstrates that in the PGT population, elevated P on the trigger day may diminish the top-quality blastocyst rate (although there is no difference in the euploidy rate). Trigger-day P is an important factor influencing clinical outcomes in subsequent FET cycles.

Comparing Day 5 versus Day 6 euploid blastocyst in frozen embryo transfer and developing a predictive model for optimizing outcomes: a retrospective cohort study.

Background: Optimal protocols for frozen-thawed embryo transfer (FET) after preimplantation genetic testing (PGT) remain unclear. This study compared Day 5 (D5) and Day 6 (D6) blastocysts and evaluated predictors of FET success. Methods: A total of 870 patients with genetic diseases or chromosomal translocations who received PGT at the First Affiliated Hospital of Zhengzhou University from January 2015 to December 2019 were recruited. All patients underwent at least one year of follow-up. Patients were divided into groups according to the blastocyst development days and quality. Univariate and multivariate logistic regression were applied to identify risk factors that affect clinical outcomes and to construct a predictive nomogram model. Area under the curve (AUC) of the subject's operating characteristic curve and GiViTI calibration belt were conducted to determine the discrimination and fit of the model. Results: D5 blastocysts, especially high-quality D5, resulted in significantly higher clinical pregnancy (58.4% vs 49.2%) and live birth rates (52.5% vs 45%) compared to D6. Multivariate regression demonstrated the number of blastocysts, endometrial preparation protocol, days of embryonic development and the quality of blastocysts independently affected live birth rates (P<0.05). A nomogram integrating these factors indicated favorable predictive accuracy (AUC=0.598) and fit (GiViTI, P=0.192). Conclusions: Transferring high-quality D5 euploid blastocysts after PGT maximizes pregnancy outcomes. Blastocyst quality, blastocyst development days, endometrial preparation protocols, and number of blastocysts, independently predicted outcomes. An individualized predictive model integrating these factors displayed favorable accuracy for counseling patients and optimizing clinical management.

Resveratrol regulates skeletal muscle fibers switching through the AdipoR1-AMPK-PGC-1α pathway.

This study was conducted to investigate the effect and underlying mechanism of Resveratrol (RES) in regulating skeletal muscle fiber-type switching. We found that RES had no effect on the body weight and food intake of Kunming mice (KM mice) that were orally administered with 400 mg kg-1 d-1 RES for 12 weeks. Notably, the RES administration significantly increased the expression of myosin heavy chain (MyHC) 1, MyHC2a, and MyHC2x in the extensor digitorum longus (EDL) and soleus (SOL) muscles. Furthermore, the muscle immunostaining of the results showed that the RES treatment led to the myofiber type transition from glycolytic to oxidative in muscles. The mRNA and protein levels of the adiponectin receptor (AdipoR), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in EDL and SOL were drastically increased after RES treatment. Moreover, the plasma Adiponectin (AdipoQ) protein levels were higher in the RES-treated mice compared to the control mice. Moreover, the in vitro results further demonstrated that the 20 µM RES treatment increased the expression of AdipoR1, AdipoR2, AMPK, PGC-1α and MyHC1, but decreased the expression of MyHC2b in C2C12 myoblasts. Furthermore, mechanistic studies revealed that silencing the AdiopR1, not the AdiopR2, abolished the effect of RES on the expression of AMPK and PGC-1α in the C2C12 cells. These results indicated that RES could regulate skeletal fiber switching through the AdiopR1-AMPK-PGC-1α pathway. This work may provide a new strategy for enhancing endurance and relieving muscle diseases caused by oxidative muscle fiber deficiency.