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Eldecalcitol is an active vitamin D

8-methylene-tert-butylamine-3',5,7-trihydroxy-4'-methoxyflavanone (MTBH), a novel hesperidin derivative, has potential in the prevention of hepatic disease, however, its effects on cytochrome P450 isoforms (P450s) remains unexplored. The purpose was to investigate the effects of MTBH on the mRNA, protein levels and activities of six P450s (1A2, 2C11/9, 2D2/6, 3A1/4, 2C13/19 and 2E1) in vitro and in vivo.In vitro study, rat and human liver microsomes were adopted to elucidate the inhibitory effect of MTBH on six P450s using probe drugs. In vivo study, Sprague-Dawley male rats were treated with MTBH (25, 50 or 100 mg/kg for 28 consecutive days), phenobarbital (80 mg/kg for 12 consecutive days) or 0.5% CMC-Na solution (control group) by intragastric administration, then, the mRNA, protein levels and activities of liver P450s were analyzed by real-time PCR, western blotting and probe-drug incubation systems, respectively.The in vitro study indicated that MTBH inhibits the activities of CYP3A1/4 and CYP2E1 in rat and human liver microsomes. In vivo data showed that MTBH inhibits mRNA, protein levels and activities of CYP3A1 and CYP2E1 in medium- and high-dose MTBH groups.MTBH has the potential to cause drug-drug interactions when co-administered with drugs that are metabolized by CYP3A1/4 and CYP2E1.

We aimed to estimate the risk of preeclampsia (PE) associated with in vitro fertilization (IVF) and potential predisposing factors responsible for the observed association.This retrospective cohort study included 114485 pregnant women who delivered at the Nanjing Maternity and Child Health Care Hospital between 2013 and 2018. Of the 114485 women, 4601 (4%) conceived through IVF (IVF group) and 109884 (96%) conceived spontaneously (SC group). We performed logistic regression analysis to evaluate the risk of PE following IVF compared to spontaneous conception (SC). Then, we used propensity score matching analysis to compare the clinical characteristics and pregnancy outcomes between IVF patients with and without PE.There were 1339 PE cases in the total study population, with a significantly higher incidence of PE in IVF relative to spontaneous pregnancies (6.1% vs. 1.0%, p 0.01). Severe PE was more prevalent in singleton IVF-PE group than in singleton SC-PE group (40% vs. 24.1%, p = 0.025). Placenta accreta was more common in singleton preeclamptic patients with IVF than without IVF (12.5vs.2.6%, p = 0.003). Placental hypoxia was more prevalent in twin IVF pregnancies with PE than without PE (6% vs. 12.2%, p = 0.045). Moreover, the IVF-PE group showed more frequent first-trimester bleeding (31.6% vs. 10.5%, p = 0.024) compared to the control group.IVF is associated with the onset and progression of PE. Defective placentation and placental insufficiency may predispose IVF patients to PE and may manifest as first-trimester bleeding.

Purpose Eldecalcitol is an active vitamin D3 derivative for preventing and treating osteoporosis. The objectives of this study was to evaluate the bioequivalence and safety of two formulations of eldecalcitol capsule (0.75 µg) in healthy Chinese male and female volunteers, as well as to investigate the food effect on the pharmacokinetics. Methods An open-label, randomized, three-period, three-sequence, reference-replicated crossover clinical study was performed in 27 healthy Chinese volunteers under fasting condition. Meanwhile, a two-way crossover study was performed in 28 healthy Chinese volunteers under fed condition. Subjects were administered with a single oral dose of 0.75 µg eldecalcitol after an overnight fast. The washout time between each period was 25 days. Blood samples were collected with scheduled time points from 0 to168 h. Results The 90% confidence intervals (CI) of test/reference AUC ratio and Cmax ratio of the eldecalcitol were within the acceptance criteria based on average bioequivalence method. Tmax of test and reference formulation were 3.987 h and 3.489 h under the fasting conditions. While Tmax was prolonged to 9.006 h and 6.007 h in test and reference formulation after a high-fat meal. Only mild and transient, but not severe adverse events were detected in the study. Conclusion Two formulations of eldecalcitol was bioequivalent under both fasting and fed conditions. Whereas, food intake prolonged the oral absorption of eldecalcitol, but did not significantly influence the system exposure.

1. 8-methylene-tert-butylamine-3',5,7-trihydroxy-4'-methoxyflavanone (MTBH), a novel hesperidin derivative, has potential in the prevention of hepatic disease, however, its effects on cytochrome P450 isoforms (CYP450s) remains unexplored. The purpose was to investigate the effects of MTBH on the mRNA, protein levels, and activities of six CYP450s (1A2, 2C11/9, 2D2/6, 3A1/4, 2C13/19, and 2E1)

Vulvovaginal candidiasis (VVC) is considered the second most common cause of vaginitis after bacterial vaginosis and the most common lower genital tract infection during pregnancy.

Background: Gestational diabetes mellitus (GDM) has significant short and long-term health consequences for both the mother and child. There is limited but suggestive evidence that inulin could improve glucose tolerance during pregnancy. This study assessed the effect of inulin on glucose homeostasis and elucidated the molecular mechanisms underlying the inulin-induced antidiabetic effects during pregnancy. Method: Female C57BL/6 mice were randomized to receive either no treatment, high-dose inulin and low-dose inulin for 7 weeks with measurement of biochemical profiles. A real-time2 (RT2) profiler polymerase chain reaction (PCR) array involved in glycolipid metabolism was measured. Results: Inulin treatment facilitated glucose homeostasis in a dose-dependent manner by decreasing fasting blood glucose and total cholesterol, and improving glucose tolerance. Suppressing resistin (RETN) expression was observed in the inulin treatment group and the expression was significantly correlated with fasting blood glucose levels. The ratios of p-IRS to IRS and p-Akt to Akt in liver tissue and the ratio of p-Akt to Akt in adipose tissue increased significantly after inulin treatment. Conclusions: Our findings indicated the observed decreased glucose level may be due to insulin signaling pathway repairment due to decreased expression of RETN and enhanced phosphorylation of IRS and Akt in GDM mice.

Background Maternal intrapartum fever has a serious impact on mother and child. However, the corresponding study seems to be in short. Methods The role of inflammatory cells in patients who were diagnosed with intrapartum fever lived in part of Eastern China was evaluated. The obstetrics outcomes, complete blood cell count (CBC) and thereby converted neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio, monocyte to lymphocyte ratio (MLR), and vaginal secretion were compared in different groups. Results Prepartum values of white blood cell (WBC), red blood cell (RBC), and hemoglobin (Hb) were all a little higher in the febrile group than in the afebrile group, and postpartum WBC in the afebrile group was still higher while postpartum RBC and Hb were inferior to non‐fever maternity. Postpartum NLR and MLR were all higher in the fever group but not preferred overtly difference before delivery. Additionally, the comparison of WBC, RBC, Hb, platelets, neutrophils, and monocytes in prepartum and postpartum all showed significant differences. Conclusion The parturition could bring about the value change of CBC and intrapartum fever might aggravate or alleviate this change. Besides, the intrapartum fever might not be caused mainly by infection and the difference between bacteria and fungus could reflect in the CBC., Maternal intrapartum fever is a common obstetric disease during birth process and has a serious impact on mother and child. However, corresponding study seems to be in short. A retrospective cohort study was designed to evaluate the role of inflammatory cell in patients who diagnosed with intrapartum fever (defined as temperature over 37.5℃) lived in part of Eastern China. Prepartum value of white blood cell (WBC), red blood cell (RBC), and hemoglobin (Hb) were all a little higher in febrile group than afebrile group, and postpartum WBC in afebrile group still higher while postpartum RBC and Hb were inferior to non‐fever maternity. Postpartum neutrophil to lymphocyte ratio and monocyte to lymphocyte ratio were all higher in fever group but not preferred overtly difference before delivery. Additionally, the comparison of WBC, RBC, Hb, platelets, neutrophils, and monocytes in prepartum and postpartum all showed significant difference. The parturition could bring about the value change of CBC and intrapartum fever might aggravate or alleviate this change. Besides, the intrapartum fever might not be caused mainly by infection and the difference between bacteria and fungus could reflect in the CBC.

Preterm birth (PTB) is a major cause of neonatal mortality, with a poorly understood etiology. The regular contraction of the myometrium was considered as contributing to the etiology of the onset of labor, especially PTB. Thus, studying the mechanism of myometrium contraction is very important for understanding the initiation of labor and also for preventing PTB. Using liquid chromatography-mass spectrometry, we found 322 significantly differential peptides in myometrium tissues between term nonlabor and term labor groups (absolute fold change ≥ 2 and P < .05). We next analyzed length, molecular weights, isoelectric point, and cleavage site of all the different peptides. We, next, analyzed the functions of different peptides through their precursor proteins by Gene Ontology, enrichment and canonical pathway analysis. The results indicated that the extracellular matrix (ECM) played a major role in biological process, the cellular component, and molecular function categories, and revealed that ECM remodeling played a vital role in myometrial contraction. In addition, some known signaling, such as corticotropin-releasing hormone signaling and calcium signaling were proven to be involved in this process. Ingenuity Pathways Analysis upstream regulator analysis suggested that some of the known molecules, which reportedly were very important in labor onset, were included, for example, nuclear factor κB, tubulin, and phosphoinositide 3-kinase. We also identified 23 peptides derived from the precursor protein TITIN, of which 21 peptides sequences from TITIN were located in functional domains. These results suggested that peptides play an important role in labor onset and provide further insight into PTB therapy.

To evaluate whether programmed intermittent epidural bolus (PIEB) reduces the incidence of maternal intra-partum fever compared with continuous epidural infusion (CEI) during labor. Parturients were randomized to receive CEI (CEI group) or PIEB (PIEB group) with 10 ml per hour for epidural labor analgesia with 1500 subjects in each group. The maintaining dose of two groups is 0.08% ropivacaine with 0.4 μg/ml sufentanil, with patient-controlled epidural analgesia (PCEA) dose of 5 ml and lockout interval of 30 min. The incidence of maternal fever, pain score, epidural sensory levels, the number and proportion of PCEA demand, anesthetics consumption, satisfaction score, neonatal Apgar scale, and maternal and neonatal side effects were recorded. It was significantly lower of the incidence of maternal fever beginning at 4 h post-analgesia and continuing until delivery in the PIEB group than the CEI group (4 h: 2.6% vs. 4.2%; 5 h: 7.3% vs. 10.2%; delivery: 5.6% vs. 7.9%; 1 h post-delivery: 3.9% vs. 6.2%; 2 h post-delivery: 2.1 vs. 3.5%; total: 5.8% vs. 8.4% in PIEB and CEI, respectively). Compared with CEI group, pain scores at 3, 4, 5 h post-analgesia and delivery (3 h: 2 [1, 2] vs. 2 [1–3]; 4 h: 2 [2, 3] vs. 3 [2–4]; 5 h: 2 [2, 3] vs. 3 [2–4]; delivery: 3 [2–4] vs. 4 [3, 4] in PIEB and CEI, respectively), the number and proportion of PCEA demand (number: 0.7 ± 0.9 vs. 2.2 ± 1.9; proportion: 42.0% vs. 80.3% in PIEB and CEI, respectively), and anesthetics consumption significantly decreased in the PIEB group (Ropivacaine: 60 ± 13 mg vs. 76 ± 17 mg; Sufentanil: 26 ± 4 mg vs. 32 ± 6 mg in PIEB and CEI, respectively), without severe maternal and neonatal side effects and any difference in neonatal Apgar scale. The epidural sensory levels 2 h post-analgesia (2 h: 8[8, 9] vs. 9[8, 9] in PIEB and CEI) and satisfaction score (9 [9, 10] vs. 7 [6, 7] in PIEB and CEI) were significantly higher in the PIEB group compared with those in the CEI group. PIEB with 10 ml of 0.08% ropivacaine and 0.4 μg/ml sufentanil hourly provided a lower incidence of intra-partum fever with a better analgesic effect compared with CEI, without any severe maternal and neonatal adverse reactions.

Aerobic vaginitis (AV) can occur if normal vaginal microflora are dominated by aerobic bacteria, seriously affects not only female health, but also fetal health while they are pregnant. Besides, pregnant status also aggravates the symptoms and consequences of the infection. Here, we infected pregnant BALB/c mice with Escherichia coli on embryonic day 4.5 (E4.5) (study group), and administered an equivalent volume of phosphate-buffered saline in another cohort of pregnant mice (control group). We recorded the weight of pregnant mice and their fetuses. The maternal and fetal weight of the study group decreased in comparison with that of the control group, whereas the weight of placenta increased in the study group. Then, five genes with significant upregulation and 15 genes with downregulation were screened. Expression of interleukin 4 (IL-4) mRNA in the study group decreased to 18.5%. Enzyme-linked immunosorbent assay results showed IL-4 expression in mouse plasma declined in the study group at E11.5 and E18.5. mRNA expression of chemokine (c-c motif) ligand (CCL)-17, CCL-22, CCL-24, IL-4, Janus Kinase (JAK)-1, signal transducer and activator of transcription (STAT)-6, and GATA-3 showed significant downregulation in placental and uterine tissues. Flow cytometry of primary decidual macrophages (DMs) revealed more M1-like macrophages in the study group. And after addition of IL-4 to DMs, more M1 macrophages polarized to M2 type macrophages. We did not discover bacteria existed in mouse placentas. Our study affords a feasible method for exploring and managing AV during pregnancy.

Vulvovaginal candidiasis (VVC), a major gynecological disease with high recurrence rate, increases the risk of abortion, intrauterine infection, premature rupture of membranes, and premature birth in pregnancy. However, the exact pathogenesis of this disease has yet to be elucidated. To facilitate understanding of the pathogenesis of VVC in pregnancy, this study sought to establish an animal model of vaginal infection with Candida albicans in pregnant mice. Female mice were mated with male mice, and female mice were infected with C. albicans at E4.5 (embryonic day 4.5). The weight and abortion rate of pregnant mice at E0.5, E4.5, E8.5, E11.5, and E18.5 were recorded, respectively, as well as the weights of fetus and placenta on E18.5. Fetal weight at E18.5 and the weight growth rate in the experimental mice was lower than those in the control mice, but the placenta weight at E18.5 and the abortion rate in the experimental mice were increased with those of the control mice. Hematoxylin-eosin (HE) staining, Gomori-Grocott staining and vaginal lavage culturing were conducted to verify that the experimental mice were infected with C. albicans. Differentially expressed gene IL-15 was screened out by polymerase chain reaction (PCR) array between the two groups. Enzyme-linked immunosorbent assay (ELISA) showed that IL-15 expression in plasma of the mice was decreased in the experimental group compared with the control group. RT-qPCR confirmed that IL-15 mRNA expression was increased in placental tissues, while mRNA expression of IL-15R/JAK1-JAK3/PI3K/PDK1/AKT/P70S6K-mTOR was decreased in placental tissues. In conclusion, this study demonstrated that VVC in BALB/c pregnant mice led to a series of adverse pregnancy outcomes that were related to changes in IL-15 and its downstream signaling pathways, which may indicate a potential therapy for VVC during pregnancy in humans.

Objective To investigate the impact of intrapartum fever on maternity and fetus. Design Retrospective cohort study. Setting Women’s Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China Population We studied intrapartum fever, as well as non-fever parturients, between January 1, 2018 and December 31, 2018. Methods We collected pregnancy outcomes of intrapartum fever and non-fever mother and neonatal data. Main outcomes and measures The obstetrics outcomes, complete blood cell count (CBC) and thereby converted neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR), as well as vaginal secretion were observed in women with and without intrapartum fever. Results Prepartum white blood cell (WBC), red blood cell (RBC), and hemoglobin (Hb) were all higher in febrile group, and WBC still higher but RBC and Hb lower after birth. Postpartum NLR and MLR were all higher in fever group but not preferred overtly difference before delivery. Additionally, the comparison of WBC, RBC, Hb, platelets (PLT), neutrophils, and monocytes in prepartum and postpartum all showed significant difference. Conclusions The differences of the prepartum WBC, RBC, Hb, and monocytes existed in the intrapartum fever and afebrile groups. Besides, the parturition could bring about the change of the value of CBC and intrapartum fever might aggravate or alleviate this change. Additionally, the intrapartum fever might not be caused mainly by infection and the difference between bacteria and fungus could reflect in the CBC. Keywords: Intrapartum fever, perinatal period, vaginal discharge examination

Preterm birth is a complex syndrome and remains a substantial public health problem globally. Its common complications include periventricular leukomalacia (PVL), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP). Despite great advances in the comprehension of the pathogenesis and improvements in neonatal intensive care and associated medicine, preterm birth-related diseases remain essentially without adequate treatment and can lead to high morbidity and mortality. The therapeutic potential of mesenchymal stem/stromal cells (MSCs) appears promising as evidenced by their efficacy in preclinical models of pathologies relevant to premature infant complications. MSC-based therapeutic efficacy is closely associated with MSC secretomes and a subsequent paracrine action response to tissue injuries, which are complex and abundant in response to the local microenvironment. In the current review, we summarize the paracrine mechanisms of MSC secretomes underlying diverse preterm birth-related diseases, including PVL, BPD, NEC and ROP, are summarized, and focus is placed on MSC-conditioned media (CM) and MSC-derived extracellular vesicles (EVs) as key mediators of modulatory action, thereby providing new insights for future therapies in newborn medicine.

Objective We aimed to explore the expression level and biological function of lncRNA PVT1 in human trophoblast cells. Methods The expression levels of PVT1 in cancer cell lines, HTR8/SVneo cell, HUVEC cell, the maternal placenta of GDM patients, PE patients and normal pregnancy were detected by qRT-PCR. The cell culture, cell transfection, CCK-8 assay, flow cytometry, wound scratch assay and transwell were carried out to determine the effects of silencing and overexpression of PVT1 on the HTR8/SVneo trophoblast cell line. Nuclear and chromatin RNA fraction assay, RNA-sequencing, western blot and qRT-PCR were conducted to preliminarily explore possible mechanisms. Results The relative PVT1 expression level in HTR-8/Svneo cells was higher compared to other cancer cells and HUVEC, and was lower in the GDM and PE placentas than in the normal placentas. The results showed that PVT1 knockdown notably inhibited the proliferation, migration and invasiveness abilities of trophoblast cells, and significantly promoted the apoptosis. Furthermore, overexpression of PVT1 showed the opposite results. We identified 105 differentially expressed genes after PVT1 knockdown, 23 were up-regulated and 82 were down-regulated. GO enrichment analysis and pathway enrichment analysis showed that the DEGs were closely related to the functional changes of trophoblast cells. Because of the enrichment of 7 DEGs and less Q value, PI3K/AKT pathway was prominent and attracted our attention. More importantly, we confirmed that knockdown of PVT1 obviously decreased AKT phosphorylation and decreased the expression of DEGs (GDPD3, ITGAV and ITGB8) while overexpression of PVT1 promoted the AKT phosphorylation and increased the expression of DEGs (GDPD3, ITGAV and ITGB8). PVT1 was primarily distributed in the nuclear compartment and also distributed in the cytoplasmic of HTR-8/Svneo cells. Conclusions This study provided the evidence that PVT1 played a vital role in trophoblast cells, and it is important for maintaining the normal physiological function of trophoblast cells. The PVT1 expression was lower in the GDM and PE placentas than the normal placentas, which might disrupt the function of trophoblast cells through PI3K/AKT pathway.

Objective We aimed to explore the expression level and biological function of miR-145–5p in preeclampsia (PE). Methods The differentially expressed miRNA/mRNA between normal placentas and PE placentas were screened using the GSE84260 and GSE73374 datasets from the Gene Expression Omnibus Database. The expression of miR-145–5p in PE placentas was detected by qRT-PCR. The CCK-8 assay, wound healing and transwell were carried out to determine the cell growth, migration and invasion when miR-145–5p was overexpressed or inhibited. The real-time quantitative PCR (qRT-PCR), Western Blot and dual-luciferase reporter assays were conducted to preliminarily explore possible mechanisms. Results A total of 33 miRNAs were found significantly differentially expressed in PE patients, 19 were significantly upregulated and 14 were significantly downregulated. The relative miR-145–5p expression was lower in PE placentas than normal placentas. The viability and invasion were suppressed when miR-145–5p was inhibited in trophoblasts cells, while miR-145–5p overexpression promoted the effectiveness. In addition, mRNA and protein expression of FLT1 in HTR-8/SVneo cell was also downregulated with miR-145–5p overexpression, suggesting that FLT1 is the target gene of miR-145–5p. Consistent with miR-145–5p overexpression, the mRNA and protein expression of FLT1 also were upregulated with miR-145–5p interference. Furthermore, the expression of miR-145–5p was regulated by the Hypoxic conditions. Conclusions In conclusion, the results showed miR-145–5p may participate in PE development by affecting the proliferation and invasion of trophoblast cells. This is a new perspective to understand the etiology and pathogenesis of PE, which may provide a new breakthrough for the early prediction and diagnosis of PE.