N6-methyladenosine RNA methylation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, and hyperglycemic memory associated with diabetes carries the risk of disease occurrence, even after the termination of blood glucose injury. The existence of hyperglycemic memory supports the concept of an epigenetic mechanism involving n6-methyladenosine (m6A) modification. Several studies have shown that m6A plays a key role in the pathogenesis of DKD. This review addresses the role and mechanism of m6A RNA modification in the progression of DKD, including the regulatory role of m6A modification in pathological processes, such as inflammation, oxidative stress, fibrosis, and non-coding (nc) RNA. This reveals the importance of m6A in the occurrence and development of DKD, suggesting that m6A may play a role in hyperglycemic memory phenomenon. This review also discusses how some gray areas, such as m6A modified multiple enzymes, interact to affect the development of DKD and provides countermeasures. In conclusion, this review enhances our understanding of DKD from the perspective of m6A modifications and provides new targets for future therapeutic strategies. In addition, the insights discussed here support the existence of hyperglycemic memory effects in DKD, which may have far-reaching implications for the development of novel treatments. We hypothesize that m6A RNA modification, as a key factor regulating the development of DKD, provides a new perspective for the in-depth exploration of DKD and provides a novel option for the clinical management of patients with DKD.

The effect of peak serum estradiol level during ovarian stimulation on cumulative live birth and obstetric outcomes in freeze-all cycles.

Objective: To determine whether the peak serum estradiol (E2) level during ovarian stimulation affects the cumulative live birth rate (CLBR) and obstetric outcomes in freeze-all cycles. Methods: This retrospective cohort study involved patients who underwent their first cycle of in vitro fertilization followed by a freeze-all strategy and frozen embryo transfer cycles between January 2014 and June 2019 at a tertiary care center. Patients were categorized into four groups according to quartiles of peak serum E2 levels during ovarian stimulation (Q1-Q4). The primary outcome was CLBR. Secondary outcomes included obstetric and neonatal outcomes of singleton and twin pregnancies. Poisson or logistic regression was applied to control for potential confounders for outcome measures, as appropriate. Generalized estimating equations were used to account for multiple cycles from the same patient for the outcome of CLBR. Results: A total of 11237 patients were included in the analysis. Cumulatively, live births occurred in 8410 women (74.8%). The live birth rate (LBR) and CLBR improved as quartiles of peak E2 levels increased (49.7%, 52.1%, 54.9%, and 56.4% for LBR; 65.1%, 74.3%, 78.4%, and 81.6% for CLBR, from the lowest to the highest quartile of estradiol levels, respectively, P<0.001). Such association remained significant for CLBR after accounting for potential confounders in multivariable regression models, whereas the relationship between LBR and peak E2 levels did not reach statistical significance. In addition, no significant differences were noticed in adverse obstetric and neonatal outcomes (gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, placental disorders, preterm birth, low birthweight, and small for gestational age) amongst E2 quartiles for either singleton or twin live births, both before and after adjustment. Conclusion: In freeze-all cycles, higher peak serum E2 levels during ovarian stimulation were associated with increased CLBR, without increasing the risks of adverse obstetric and neonatal outcomes.

Elevated SAA1 promotes the development of insulin resistance in ovarian granulosa cells in polycystic ovary syndrome.

BACKGROUND: Insulin resistance (IR) contributes to ovarian dysfunctions in polycystic ovarian syndrome (PCOS) patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive. METHODS: Follicular fluid, granulosa cells and peripheral venous blood were collected from PCOS and non-PCOS patients with and without IR to measure SAA1 abundance for analysis of its correlation with IR status. The effects of SAA1 on its own expression and insulin signaling pathway were investigated in cultured primary granulosa cells. RESULTS: Ovarian granulosa cells were capable of producing SAA1, which could be induced by SAA1 per se. Moreover, the abundance of SAA1 significantly increased in granulosa cells and follicular fluid in PCOS patients with IR. SAA1 treatment significantly attenuated insulin-stimulated membrane translocation of glucose transporter 4 and glucose uptake in granulosa cells through induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with subsequent inhibition of Akt phosphorylation. These effects of SAA1 could be blocked by inhibitors for toll-like receptors 2/4 (TLR 2/4) and nuclear factor kappa light chain enhancer of activated B (NF-κB). CONCLUSIONS: Human granulosa cells are capable of feedforward production of SAA1, which significantly increased in PCOS patients with IR. Excessive SAA1 reduces insulin sensitivity in granulosa cells via induction of PTEN and subsequent inhibition of Akt phosphorylation upon activation of TLR2/4 and NF-κB pathway. These findings highlight that elevation of SAA1 in the ovary promotes the development of IR in granulosa cells of PCOS patients.

Association between the number of oocytes retrieved and neonatal outcomes after freeze-all IVF cycles.

STUDY QUESTION: Is there any association between the number of oocytes retrieved and neonatal outcomes following IVF/ICSI treatment for patients using a freeze-all strategy? SUMMARY ANSWER: There was no increased risk of adverse neonatal outcomes in cycles with high number of oocytes retrieved (≥ 16) compared to those with 10-15 oocytes retrieved in freeze-all cycles. WHAT IS KNOWN ALREADY: Recent studies have found that there is an increased risk of preterm birth (PTB, <37 weeks gestation) and low birth weight (LBW, <2500 g) following IVF in women with a high number (>20) of oocytes retrieved in fresh embryo transfer (ET) cycles. Other studies have found that there is an association between the number of oocytes retrieved and placenta praevia. However, the association between the number of oocytes retrieved and neonatal outcomes when using a freeze-all strategy is unknown. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 14 170 women with singleton deliveries achieved by a freeze-all strategy performed between November 2006 and December 2017 in China. Only the first delivery from one episode of ovarian stimulation was included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Only cycles using a freeze-all strategy performed during the study period and resulting in singleton live births were included. Patients were categorized into five groups according to the number of oocytes retrieved: 1-3, 4-9, 10-15, 16-20 or >20 oocytes. In univariate and multivariate logistic regression analysis of the association between ovarian response and the outcomes of PTB, early PTB, LBW and other neonatal outcomes, the 10 to 15 oocyte category was used as a reference and other four groups were analysed as dummy variables. Multiple linear regression analysis was used to evaluate possible associations of birth weight z-scores and the number of oocytes retrieved (analysed as a continuous variable) with other confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusted for confounding factors, no significant differences were observed in the risk of PTB (P = 0.837), LBW (P = 0.974), early PTB (P = 0.341), very LBW (P = 0.848), congenital malformation (P = 0.916) and other adverse neonatal outcome among patients with different number of oocytes retrieved. There was a higher risk of early PTB among women with a poor ovarian response (1-3 oocytes) compared with women with a normal response (10-15 oocytes) (1.5% vs 0.8%), crude odds ratio (OR): 2.001, 95% CI: 1.159-3.465, P = 0.013. However, the difference was not significant after adjusting for confounders, adjusted OR: 1.753, 95% CI: 0.997-3.081, P = 0.051. LIMITATIONS, REASONS FOR CAUTION: Data on some known confounders such as smoking and medical history of gestational diabetes mellitus and preeclampsia were lacking. As with any retrospective study, unknown confounders may affect outcomes. WIDER IMPLICATIONS OF THE FINDINGS: In the freeze-all cycles, there was no association between number of oocytes retrieved and adverse neonatal outcomes. This is a reassuring finding for both clinicians and patients who are planning to use freeze-all cycles for a variety of indications. STUDY FUNDING/COMPETING INTEREST(S): Grants from the National Natural Science Foundation of China (NSFC) (31770989 to Y.W.) and the Shanghai Ninth People's Hospital Foundation of China (JYLJ030 to Y.W.). None of the authors have any conflicts of interest to declare.