Systems Biology in Reproductive Medicine最新文献

Neurotrophins (NT) are a closely related family of growth factors, which regulate the nervous system's development, maintenance, and function. Although NTs have been well studied in neuronal cells, they are also expressed in the placenta. Despite their suggested role in regulating fetoplacental development, their precise functional significance in the placenta remains elusive. NT activate two different classes of receptors. These include the Trk, tropomyosin-related kinase family of high-affinity tropomyosin-related kinase receptors, which induces cell survival, and the p75NTR, p75 neurotrophin receptor, a member of the tumor necrosis factor(TNF) receptor superfamily, which induces apoptosis in neuronal cells. Mature NT molecule results from proteolysis of a biologically active precursor form called pro-neurotrophins (pro-NT) by the intracellular proprotein convertase or furin. Pro-NTs have a regulatory role in determining cell survival and apoptosis. Here, we review the literature on the expression and functions of NTs and their receptors in the placenta and discuss their possible role in placental tissue development and apoptosis. The possible implications of imbalance in pro-NT and mature-NT levels for fetoplacental development are also discussed.Abbreviations AGE/ALEs: Advanced glycation/lipoxidation end products; Bax: Bcl 2 Associated X; Bcl-2: B-cell lymphoma 2; BDNF: Brain-derived neurotrophic factor; FAS/FASL: Fas cell surface death receptor/ ligand; IUGR: Intrauterine growth restriction; JNK: c-Jun amino-terminal kinase; MAP: mitogen-activated protein k; mRNA: Messenger ribonucleic acid; NGF: Nerve growth factor; NT: Neurotrophins; NRAGE: Neurotrophin receptor-interacting MAGE homolog; NRIF: Neurotrophin receptor interacting factor; PE: Preeclampsia; PI3k: Phosphoinositide 3- kinase; PLC: Phospholipase C; p75NTR: p75 neurotrophin receptor; Pro-NT: Pro-neurotrophins; PTB: Preterm birth; p53: Tumor protein p53; TNF: Tumor necrosis factor; TRAF: TNFR-associated factors; Trk: Tropomyosin-related kinase; siRNA: small interfering ribonucleic acid.

Cumulus cell (CC) clumps that associate with oocytes provide the oocytes with growth and signaling factors. Thus, the metabolism of the CCs may influence oocyte function, and CC metabolism may be predictive of oocyte competence for in vitro fertilization. CCs are thought to be highly glycolytic, but data on the use of other potential carbon substrates are lacking in humans. This prospective and blinded cohort study was designed to examine the substrate utilization of CCs by age and oocyte competence. Individual sets of CC clumps from participants were removed after oocyte retrieval procedure then, incubated with stable isotope labeled substrates, and analyzed using liquid chromatography-high resolution mass spectrometry (LC-HRMS) for isotopologue enrichment of major metabolic intermediates, including acetyl-CoA. The acyl-chain of acetyl-CoA contains 2 carbons that can be derived from ¹³C-labeled substrates resulting in an M + 2 isotopologue that contains 2 ¹³C atoms. Comparing the fate of three major carbon sources, mean enrichment of M + 2 acetyl-CoA (mean, standard deviation) was for glucose (3.6, 7.7), for glutamine (9.4, 6.2), and for acetate (20.7, 13.9). Due to this unexpected high and variable labeling from acetate, we then examined acetyl-CoA mean % enrichment from acetate in 278 CCs from 21 women ≤34 (49.06, 12.73) decreased with age compared to 124 CCs from 10 women >34 (43.48, 16.20) (p = 0.0004, t-test). The CCs associated with the immature prophase I oocytes had significantly lower enrichment in M + 2 acetyl CoA compared to the CCs associated with the metaphase I and metaphase II oocytes (difference: -6.02, CI: -1.74,-13.79, p = 0.013). Acetate metabolism in individual CC clumps was positively correlated with oocyte maturity and decreased with maternal age. These findings indicate that CC metabolism of non-glucose substrates should be investigated relative to oocyte function and age-related fertility.Abbreviations: CCs: cumulus cells; COC: cumulus-oocyte complex; LC-MS: liquid chromatography-mass spectrometry; acetyl-CoA: acetyl-Coenzyme A; CoA: Coenzyme A.

Androgen and AR are essential for maintaining spermatogenesis and male fertility. Previous studies have shown that the phosphatidyl ethanolamine binding protein 1 (Pebp1) gene is down-regulated in the selective ablation of the AR in the Sertoli cells of mouse testes compared with wild-type mice, indicating that Pebp1 is a candidate target of AR. The ChIP-PCR data and ChIP-sequencing results of this study verified that Pebp1 is a target gene regulated by AR. Real-time PCR, Western blot analysis, and immunofluorescence data showed that Pebp1 is expressed at all stages of testicular development, with an increasing trend from 1 to 8 weeks of postnatal development. PEBP1 was principally located in the cytoplasm, and high-intensity fluorescence revealed PEBP in the lumen of the testicular tubules. Bioinformatics analysis indicated effective androgen-responsive elements (AREs) located in the promotor of Pepb1 gene. Dual fluorescence assay data showed that androgens and AR could bind to the AREs of Pebp1 and induce an increase of gene expression. These data suggest that Pepb1 is a newfound target gene regulated by androgens and AR in mouse Sertoli cells. However, the detailed molecular mechanism of their role in spermatogenesis still needs to be further studied.Abbreviations: AR: androgen receptor; Pebp1: phosphatidyl ethanolamine binding protein 1; ARKO: androgen receptor knockout; WT: wild type; SCARKO: Sertoli cell-selective androgen receptor knockout; ChIP: chromatin immunoprecipitation; RKIP: Raf kinase inhibitory protein; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; GSK-3: glycogen synthase kinase-3; RT-PCR: reverse transcriptase polymerase chain reaction; SEM: standard error of the mean.

Annually, approximately 2 million assisted reproductive technology (ART) procedures are performed worldwide, of which, only ~25% lead to successful delivery. There are two major factors contributing to successful implantation: embryo quality and endometrial receptivity (ER). Although embryo quality might be assessed through morphological and genetic testing, no clinically approved techniques are available to evaluate ER. Mucus in different parts of the female reproductive tract contains many cytokines, chemokines, growth factors, and nucleic acids, which influence and reflect various implantation-related processes. Therefore, the aim of the present review was to summarize available data regarding noninvasively obtained mucosal biomarkers for ER and to investigate their ability to predict the outcome of ART procedures. A broad literature search was performed to define studies related to noninvasive ER assessments. More than 50 biomarkers detectable in endometrial fluid, embryo transfer cannula leftover cells and mucus, menstrual blood, cervicovaginal washings are discussed herein. The remarkable methodological heterogeneity of the reviewed studies complicates the comparison of their results. Nevertheless, certain promising analytical targets may already be identified, such as urocortin, activin A, IL-1β, TNF-α, IP-10, MCP-1, and several oxidative stress biomarkers. The present review contains a collection of currently available mucosal biomarker-related data, which may provide insights for future studies.Abbreviations: ART: assisted reproductive technology; ER: endometrial receptivity; IVF: in vitro fertilization; ICSI: intracytoplasmic sperm injection; IUI: intrauterine insemination; MeSH: Medical Subject Headings; hDP 200: human decidua-associated protein 200; ET: embryo transfer; IL-18: Interleukin-18; LRG: leucine-rich α2-glycoprotein; ROC: receiver operating characteristic; AUC: area under the ROC-curve; LH: luteinizing hormone; LIF: leukemia inhibitory factor; TNF-α: tumor necrosis factor alpha; IFN-γ: interferon γ; MCP-1: monocyte chemoattractant protein-1; VEGF: vascular endothelial growth factor; SOD: superoxide dismutase; CAT: catalase; LPO: lipid peroxidation; TTG: total thiol groups; TAP: total antioxidant power; CE: chronic endometritis.

This study describes a successful case of preimplantation genetic testing for the monogenic disease (PGT-M) of methylmalonic acidemia (MMA). To avoid the transmission of pathogenic mutations and unnecessary pregnancy termination we applied next-generation sequencing (NGS)-based haplotyping on a couple with a previously deceased MMA offspring. After embryo preparation, all samples were amplified successfully by whole genome amplification. We performed preimplantation genetic testing for aneuploidy (PGT-A) to determine the copy number of embryos' chromosomes. PGT-A results showed five blastocysts (2, 11, 14, 15 and 16) with balanced chromosomes (46, XN). Two techniques were used for PGT-M. Sanger sequencing was used to detect the mutations of MMUT gene directly, and NGS-based single nucleotide polymorphism (SNP) haplotyping was used to distinguish the chromosomes that carried the mutation. Sanger sequencing and NGS-based SNP haplotyping confirmed that samples 2 and 15 carried c.730insTT, samples 11 and 15 carried c.1105 C > T and samples 14 and 16 did not carry any mutation. Thus, blastocyst 14 was transferred into the mother's uterus. After prenatal diagnosis at 18 weeks of gestation, a healthy infant without MMUT mutation was born at full term. This study highlights the efficiency of NGS-based SNP haplotyping for PGT-M of MMA.Abbreviations: MMA: methylmalonic acidemia; MMUT: methylmalonyl-CoA mutase; PGT-M: preimplantation genetic testing for monogenic disease; PGD: preimplantation genetic diagnosis; IVF: in vitro fertilization; ADO: allele dropout; WGA: whole genome amplification; SNP: single nucleotide polymorphism; NGS: next-generation sequencing; PND: prenatal diagnosis; ICSI: intracytoplasmic sperm injection; TE: trophectoderm; DOP-PCR: degenerate oligonucleotide primed polymerase chain reaction; PGT-A: preimplantation genetic testing for aneuploidy; PCR: polymerase chain reaction.