In pregnancy, trophoblast proliferation, migration and invasion are important for the establishment and maintenance of a successful pregnancy. Impaired trophoblast function has been implicated in recurrent spontaneous abortion (RSA), a major complication of pregnancy, but the underlying mechanisms remain unclear. Indoleamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan along the kynurenine pathway, is highly expressed in the placenta and serum during pregnancy. Here, we identified a novel function of IDO in regulating trophoblast cell proliferation and migration. We showed that IDO expression and activity were decreased in unexplained recurrent spontaneous abortion (URSA) compared to normal pregnancy. Furthermore, blocking IDO in human trophoblast cells led to reduced proliferation and migration, along with decreased STAT3 phosphorylation and MMP9 expression. Increased STAT3 phosphorylation reversed the IDO knockdown-suppressed trophoblast cell proliferation and migration. In addition, the overexpression of IDO promoted cell proliferation and migration, which could be abolished by the STAT3 signaling inhibitor (AG490). Finally, we observed similar reductions of STAT3 phosphorylation and MMP9 expression in URSA patients. These results indicate that the level of IDO expression may be associated with pregnancy-related complications, such as URSA, by affecting trophoblast cell proliferation and migration via the STAT3 signaling pathway.
Aberrant gene expression during placental development may affect fetal growth and contribute to preeclampsia. The high‑temperature requirement A (HTRA) family of proteins are serine proteases that may serve in the quality control of misfolded or mislocalized proteins. Recently, the potential involvement of HTRA1 and HTRA4 in the normal development of the placenta and in the pathogenesis of preeclampsia has been reported. The present study collected placental tissues from patients with severe preeclampsia and gestational age‑matched control samples. The expression of HTRA1 and HTRA4 was analyzed using reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry. The human trophoblast line HTR‑8 was transfected with HTRA1 or HTRA4, and cell function was assessed. The present study also detected the expression of HTRA1 and HTRA4 in HTR‑8/SVneo transfected cells under hypoxia (1% O2) and further studied the effects of hypoxia on HTR‑8 cell migration. HTRA1 and HTRA4 were mainly localized to the cytoplasm of syncytiotrophoblasts. The expression levels of the two genes were elevated in the placental tissues of patients with severe preeclampsia. Finally, it was determined in vitro that ectopic expression of HTRA1 and HTRA4 significantly attenuated HTR‑8 cell migration, and elevated HTRA1 limited HTR‑8 cell growth. Under hypoxic conditions, the expression levels of HTRA1 and HTRA4 improved significantly. It was hypothesized that the aberrant expression of HTRA1 or HTRA4 may be involved in the onset of preeclampsia, and increased HTRA1 or HTRA4 expression may affect trophoblast functions.
Human amniotic fluid stem cells (hAFSCs) can be readily isolated from human amniotic fluid and display multi-differentiation potential and immunomodulatory properties. The mechanism of hAFSCs immunoregulation has not been defined. Here, we explore the immunomodulatory effects of hAFSCs derived from human amniotic fluid and evaluate the role of IL-10 and the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in mediating the immunosuppressive actions of hAFSCs. Flow cytometry showed that hAFSCs were positive for the mesenchymal stem cell markers CD29, CD44, CD105, HLA-ABC, and more than 84% of the hAFSCs were positive for SSEA-4, which is a typical marker of embryonic stem cell (ESCs), and negative for HLA-DR. The RT-PCR and immunostaining results revealed that the multipotent stem cells expressed OCT-4, Nanog, CD44, SOX2 and SSEA-1. In vitro differentiation assays demonstrated that hAFSCs underwent osteogenic differentiation. We examined the immunomodulatory function of hAFSCs using a co-culture system with phorbol 12-myristate 13-acetate (PMA) stimulated peripheral blood mononuclear cells (PBMCs). PBMC proliferation was suppressed by the hAFSCs in a dose-dependent manner. The inhibitory effect was caused by increased IL-10 and IDO induction after co-culture. Neutralizing the IL-10 activity or blocking the function of IDO partially abolished the immunosuppressive action of the hAFSCs. In conclusion, these results suggest that the hAFSCs possess immunomodulatory properties, and IL-10 and IDO are involved in immunosuppression by hAFSCs.
SummaryThe objective of this retrospective study was to determine an optimal time point for vitrification of cleavage-stage human embryos. This study included patients who were undergoing day 2 or day 3 vitrified–warmed cleavage-stage embryo transfer at the In Vitro Fertilization (IVF) Programme of the Shanghai First Maternity and Infant Hospital, China, affiliated to the Tongji University School of Medicine, from April 2010 to March 2012. Intervention was made for the entire cohort of vitrified embryos for poor responder patients so as to avoid severe ovarian hyperstimulation syndrome. Embryo survival rate (SR) after vitrification–warming, implantation rate (IR), and clinical pregnancy rate (CPR) were the main outcome measurements. In total, 380 vitrified–warmed cleavage-stage embryo transfer (VWT) cycles were included. We found that the SR after vitrification and warming for day 2 embryos and day 3 embryos were 92.7% and 92.8%, respectively. For poor ovarian responders, the IR of day 2 and day 3 vitrified–warmed embryos was 6.4% and 13.2%, respectively (P = 0.186). The CPR for day 3 vitrified–warmed embryos was significantly higher than that of day 2 vitrified–warmed embryos (17.6 vs. 4.0 % per transfer cycle, P = 0.036). For patients who had their entire cohort of embryos vitrified to prevent severe ovarian hyperstimulation syndrome (OHSS), the IR and CPR were not significantly different for day 2 and day 3 vitrified–warmed embryo transfer. In conclusion, for vitrified–warmed embryo transfer, cryopreservation of the entire cohort of embryos on day 3 resulted in better clinical outcomes compared with cryopreservation on day 2. Therefore, it is highly recommended that cleavage-stage embryos should be vitrified on day 3, but not on day 2, particularly for poor ovarian responder patients.
Background: Primary open-angle glaucoma (POAG) is the commonest form of glaucoma which is estimated to cause bilaterally blind within 11.1 million people by 2020.Therefore, the primary objectives of this study were to investigate the clinical significance of single-nucleotide polymorphisms (SNPs) in the lncRNAs MALAT1 and ANRIL in a Chinese Han POAG cohort.Methods: Three hundred and forty-six glaucoma patients and 263 healthy controls were recruited, and totally 14 SNPs in MALAT1 and ANRIL were genotyped between the two populations. Results:The MALAT1 SNPs rs619586 (A>G), rs3200401 (C>T), and rs664589 (C>G) were associated with POAG risk, and the ANRIL SNPs rs2383207 (A>G), rs564398 (A>G), rs2157719 (A>G), rs7865618 (G>A), and rs4977574 (A>G) were associated with POAG (p < 0.05). The MALAT1 haplotypes ACG and ATC, comprised rs619586, rs3200401, and rs664589, increased POAG risk, and the ANRIL haplotype AAGAA, made up of rs2383207, rs7865618, rs4977574, rs564398, and rs2157719, show a significantly increased risk of POAG. In addition, rs619586 (A>G) of MALAT1 and rs564398/rs2157719 of ANRIL were associated with a smaller vertical cup-to-disc ratio, while rs619586 of MALAT1 and rs2383207/rs4977574 of ANRIL were associated with higher intraocular pressure in the POAG population. Conclusion: Single-nucleotide polymorphisms and haplotypes in ANRIL and MALAT1were associated with POAG onset in our study population, which provide more possibilities to POAG diagnosis and treatment.
Previous evidence suggested that puerarin may attenuate cardiac hypertrophy; however, the potential mechanisms were undetermined. Moreover, the use of puerarin is limited by severe adverse events, including intravascular hemolysis. This study used a rat model of abdominal aortic constriction (AAC) -induced cardiac hypertrophy to evaluate the potential mechanisms underlying the attenuating efficacy of puerarin on cardiac hypertrophy as well as the metabolic mechanisms of puerarin involved. We confirmed that puerarin (50 mg/kg/d) significantly attenuated cardiac hypertrophy, upregulated Nrf2 and decreased Keap1 in the myocardium. Moreover, puerarin significantly promoted Nrf2 translocation to the nucleus in parallel with the upregulated downstream proteins including heme oxygenase-1, glutathione s-transferase p-1 and NAD(P)H: quinone oxidoreductase-1. Similar results were obtained in neonatal rat cardiomyocytes (NRCMs) treated with angiotensin II (1 μM) and puerarin (100 μM), while the silencing of Nrf2 abolished the antihypertrophic effects of puerarin. The mRNA and protein levels of UGT1A1 and UGT1A9, enzymes for puerarin metabolism, were significantly increased in the liver and heart tissues of AAC rats and angiotensin II-treated NRCMs. Interestingly, the silencing of Nrf2 attenuated the puerarin-induced upregulation of UGT1A1 and UGT1A9. The results of chromatin immunoprecipitation-qPCR indicated that the binding of Nrf2 to the promoter region of UGT1A1 or UGT1A9 was significantly enhanced in puerarin-treated cardiomyocytes. These results suggest that Nrf2 is the key regulator of antihypertrophic effects and the upregulation of the metabolic enzymes UGT1A1 and UGT1A9 of puerarin. This autoregulatory circuits between puerarin and Nrf2-induced UGT1A1/1A9 are beneficial to attenuate adverse effects and maintain the pharmacological effects of puerarin.
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