An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation.

Deficiency of decidual NK (dNK) cell number and function has been widely regarded as an important cause of spontaneous abortion. However, the metabolic mechanism underlying the crosstalk between dNK cells and embryonic trophoblasts during early pregnancy remains largely unknown. Here, we observed that enriched glutamine and activated glutaminolysis in dNK cells contribute to trophoblast invasion and embryo growth by insulin-like growth factor-1 (IGF-1) and growth differentiation factor-15 (GDF-15) secretion. Mechanistically, these processes are dependent on the downregulation of EGLN1-HIF-1α mediated by α-ketoglutarate (α-KG). Blocking glutaminolysis with the GLS inhibitor BPTES or the glutamate dehydrogenase inhibitor EGCG leads to early embryo implantation failure, spontaneous abortion and/or fetal growth restriction in pregnant mice with impaired trophoblast invasion. Additionally, α-KG supplementation significantly alleviated pregnancy loss mediated by defective glutaminolysis in vivo, suggesting that inactivated glutamine/α-ketoglutarate metabolism in dNK cells impaired trophoblast invasion and induced pregnancy loss.

Protopanaxadiol improves endometriosis associated infertility and miscarriage in sex hormones receptors-dependent and independent manners.

Background: Patients with endometriosis (EMs) have high risks of infertility and spontaneous abortion. How to remodel the fertility of patients with EMs has always been the hot spot and difficulty in the field of reproductive medicine. As an aglycone of ginsenosides, protopanaxadiol (PPD) possesses pleiotropic biological functions and has high medicinal values. We aimed to investigate the effect and potential mechanism of PPD in the treatment of EMs-associated infertility and spontaneous abortion. Methods: The EMs mice models were constructed by allotransplantation. The pregnancy rates, embryo implantation numbers and embryo resorption rates of control and EMs were counted. RNA sequencing, qRT-PCR, enzyme linked immunosorbent assay (ELISA) and FCM analysis were performed to screen and confirm the expression of endometrial receptivity/decidualization-related molecules, inflammation cytokines and NK cell function-related molecules in vitro and/or in vivo. The SWISS Target Prediction, STRING and Cytoscape were carried out to predict the potential cellular sensory proteins, the protein-protein interaction (PPI) network between sensory proteins and fertility-related molecules, respectively. Micro-CT detection, liver and kidney function tests were used to evaluate the safety. Results: Here, we observe that PPD significantly up-regulates endometrial receptivity-related molecules (e.g., Lif, Igfbp1, Mmps, collagens) and restricts pelvic inflammatory response (low levels of IL-12 and IFN-γ) of macrophage, and further remodel and improve the fertility of EMs mice. Additionally, PPD increases the expression of decidualization-related genes and Collagens, and promotes the proliferation, residence, immune tolerance and anagogic functions of decidual NK cells (low levels of CD16 and NKp30, high levels of Ki67, VEGF, TGF-ß) in pregnant EMs mice, and further triggers decidualization, decidual NK cell-mediated maternal-fetal immune tolerance and angiogenesis, preventing pregnant EMs mice from miscarriage. Mechanically, these effects should be dependent on ESRs, PGR and other sensory proteins (e.g., AR). Compared with GnRHa (the clinic first-line drug for EMs), PPD does not lead to the decline of serum estrogen and bone loss. Conclusion: These data suggest that PPD prevents EMs-associated infertility and miscarriage in sex hormones receptors-dependent and independent manners possibly, and provides a potential therapeutic strategy with high efficiency and low side effects to remodels the fertility of patients with EMs.

The Role of Dietary Fiber Supplementation in Regulating Uremic Toxins in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: The results of previously published meta-analyses showed that dietary fiber could reduce the levels of p-cresyl sulfate, blood urea nitrogen, and creatinine in patients with chronic kidney disease (CKD). However, these results were based on some trials with pre-post design and randomized controlled trials of low quality. Additionally, it has been suggested that the dosage and duration of fiber supplementation and patients' characteristics potentially influence the effect of dietary fiber in reducing uremic toxins, but it would appear that no research has provided reliable evidence. DESIGN AND METHODS: We searched PubMed, Web of Science, and Cochrane Library. Data were pooled by the generic inverse variance method using random effects models and expressed as standardized mean difference (SMD) with 95% confidence interval (CI). Heterogeneity was quantified by I2. Publication bias was evaluated by Egger's test. RESULTS: Ten randomized controlled trials involving 292 patients with CKD were identified. Dietary fiber supplementation can significantly reduce the levels of indoxyl sulfate (SMD = -0.55, 95% CI = -1.04, -0.07, P = .03), p-cresyl sulfate (SMD = -0.47, 95% CI = -0.82, -0.13, P < .01), blood urea nitrogen (SMD = -0.31, 95% CI = -0.58, -0.03, P = .03), and uric acid (SMD = -0.60, 95% CI = -1.02, -0.18, P < .01), but not on reducing creatinine (SMD = -0.31, 95% CI = -0.73, 0.11, P = .14). In subgroup analyses, the reduction of indoxyl sulfate was more obvious among patients on dialysis than patients not on dialysis (P for interaction = .03); the reduction of creatinine was more obvious among patients without diabetes than those with diabetes (P for interaction <.01). CONCLUSIONS: This meta-analysis indicates that dietary fiber supplementation can significantly reduce the levels of uremic toxins in patients with CKD, with evidence for a more obvious effect of patients on dialysis and without diabetes. These findings inform recommendations for using dietary fiber to reducing the uremic toxin among CKD patients in clinical practice.