Analysis of risk factors related to extremely and very preterm birth: a retrospective study.

BACKGROUND: Preterm birth is one of the main causes of perinatal morbidity and mortality and imposes a heavy burden on families and society. The aim of this study was to identify risk factors and analyze birth conditions and complications of newborns born at < 32 gestational weeks for extremely preterm (EP) and very preterm (VP) birth in the clinic to further extend the gestational period. METHODS: We performed a retrospective cohort study and collected data from 1598 pregnant women and 1660 premature newborns (excluding 229 premature babies who died due to severe illness and abandonment) admitted to the Obstetrics and Gynecology Hospital Affiliated with Nanjing Medical University in China from 2016 to 2020. We compared women's and newborns' characteristics by t-tests and Chi-square tests for continuous and categorical variables, respectively. Multivariable logistic regression was performed to estimate the effects of risk factors on EP and VP birth. RESULTS: We identified 3 independent risk factors for EP birth: cervical incompetency (P < 0.001); multiple pregnancy (P < 0.01), primipara (P < 0.001). Additionally, we identified 4 independent risk factors for VP birth: gestational diabetes mellitus (GDM) (P < 0.05), preterm premature rupture of membrane (PPROM) (P < 0.01), fetal intrauterine distress (P < 0.001), and hypertensive disorder complicating pregnancy (HDCP) (P < 0.001). In addition, pairwise comparisons revealed statistically significant differences in the incidence rates of neonatal pneumonia, bronchopulmonary dysplasia (BPD) and sepsis between the 28-28 + 6 and 29-29 + 6 weeks of gestation groups (P < 0.05). Compared with 28-28 + 6 weeks of gestation, neonatal complications were significantly more common at < 26 weeks of gestation (P < 0.05). The incidence rates of neonatal intracranial hemorrhage(NICH), patent ductus arteriosus(PDA), patent foramen ovale(PFO), pneumonia, BPD and sepsis were significantly higher in the 26-26 + 6 and 27-27 + 6 gestational weeks than in the 28-28 + 6 gestational weeks (P < 0.05). CONCLUSION: PPROM, is the most common risk factor for EP and VP birth, and cervical insufficiency, multiple pregnancy, and primipara are independent risk factors for EP birth. Therefore, during pregnancy, attention should be devoted to the risk factors for PPROM, and reproductive tract infection should be actively prevented to reduce the occurrence of PPROM. Identifying the risk factors for cervical insufficiency, actively intervening before pregnancy, and cervical cervix ligation may be considered to reduce the occurrence of EP labor. For iatrogenic preterm birth, the advantages and disadvantages should be carefully weighed, and the gestational period should be extended beyond 28 weeks to enhance the safety of the mother and child and to improve the outcomes of preterm birth.

The COL-4A1 polypeptide destroy endothelial cells through the TGF-ß/PI3K/AKT pathway.

Preeclampsia (PE) is commonly considered as a placental disorder in pregnancy. Until now, the etiology and pathological mechanism of PE have remained ambiguous. Although PE can lead to a variety of maternal and infant complications, there are still no effective treatments. This study aimed to explore the correlation between the novel polypeptide COL-4A1 and PE, and to identify the underlying mechanism by which this polypeptide may function and to explore new therapeutic targets for PE. A rat model of PE was established and used to verify the function of the polypeptide COL-4A1 in vivo. Additionally, human umbilical vascular endothelial cells (HUVECs) were cultured with or without COL-4A1 and TNF-α (20 ng/ml). Cell Counting Kit-8 (CCK-8), wound-healing, Transwell and tube formation assays were used to evaluate cell proliferation, migration and angiopoiesis. RNA sequencing and mass spectrometry were conducted to explore the underlying downstream mechanism of COL-4A1. In vivo, COL-4A1 increased blood pressure and elevated the risk of fetal growth restriction (FGR) which was induced by lipopolysaccharide (LPS) in the rat model. In vitro, COL-4A1 significantly inhibited the proliferation and migration of HUVECs. After culture with COL-4A1, compared to control group the adhesive ability and level of reactive oxygen species (ROS) were enhanced and tube formation ability was decreased. Furthermore, Western blotting (WB) and pull-down assays were conducted to explore the underlying mechanism by which COL-4A1 functions, and the TGF-ß/PI3K/AKT pathway was identified as the potential pathway involved in its effects. In summary, these results revealed that the polypeptide COL-4A1 caused PE-like symptoms in cells and a rat model. Through the TGF-ß/PI3K/AKT pathway, COL-4A1 interferes with the pathogenesis of PE. Thus COL-4A1 is expected to become a potential target of PE, providing a basis for exploring the treatment of PE.

A Novel Peptide Ameliorates TNFα- and LPS-Induced Endothelia Dysfunction in Preeclampsia.

BACKGROUND: To investigate the protective effects of the novel peptide antiendothelial dysfunction peptide in preeclampsia (AEDPPE) on tumor necrosis factor α (TNFα)- and lipopolysaccharide (LPS)-induced injury in the vascular endothelium in preeclampsia. METHODS: The effects of AEDPPE on TNFα-induced vascular endothelial injury were assessed by enzyme-linked immunosorbent assay, quantitative real-time PCR, mitochondrial membrane potential assay, Cell Counting Kit-8 assay, THP-1 monocyte-human umbilical vein endothelial cell (HUVEC) adhesion assay, endothelial tube-forming assay, transcriptomic analysis, preeclamptic symptom analysis, and histological analysis in preeclampsia-like rat models induced by LPS. RESULTS: AEDPPE alleviated the upregulation of antiangiogenic factors including soluble fms-like tyrosine kinase-1, endothelin-1, and tissue plasminogen activator and attenuated the reduction in mitochondrial potential induced by TNFα in HUVECs. In addition, AEDPPE treatment counteracted the decrease in tube formation and decreased the numbers of THP-1 monocytes attached to HUVECs caused by TNFα. Mechanistically, cytokine-cytokine receptor interactions enriched many genes and the TNF signaling pathway may be involved in this phenomenon. Moreover, cotreatment with LPS and AEDPPE significantly reversed the preeclampsia-like phenotype including hypertension and proteinuria and improved the functions of the kidney and placenta. CONCLUSIONS: AEDPPE effectively ameliorated the vascular endothelial injury induced by TNFα and LPS in preeclampsia. We suggest that AEDPPE may be a novel therapeutic candidate for preeclampsia treatment. These findings demonstrate that AEDPPE may play an effective role in ameliorating vascular endothelial dysfunction and be a potential therapeutic agent for preeclampsia.

Integrated microarray analysis of key genes and a miRNA­mRNA regulatory network of early­onset preeclampsia.

Early­onset preeclampsia (EOPE) is a serious threat to maternal and foetal health. The present study aimed to identify potential biomarkers and targets for the treatment of EOPE. Expression profiles of placenta from patients with EOPE and healthy controls (GSE103542, GSE74341 and GSE44711) were downloaded from the Gene Expression Omnibus database. Integrated analysis revealed 246 genes and 28 microRNAs (miRNAs) that were differentially expressed between patients with EOPE and healthy controls. Differentially expressed genes (DEGs) were primarily enriched in 'biological processes', such as 'cell adhesion', 'female pregnancy', 'extracellular matrix organization' and 'response to hypoxia'. Significant pathways associated with DEGs primarily included 'focal adhesion', 'ECM­receptor interaction', 'PI3K­Akt signaling' and 'ovarian steroidogenesis'. A Protein­Protein Interaction network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database, and epidermal growth factor receptor, collagen α­1(I) chain, secreted phosphoprotein 1, leptin (LEP), collagen α­2(I) chain (COL1A2), plasminogen activator inhibitor 1 (SERPINE1), Thy­1 membrane glycoprotein, bone morphogenetic protein 4, vascular cell adhesion protein 1 and matrix metallopeptidase 1 were identified as hub genes. The alterations of hsa­miR­937, hsa­miR­148b*, hsa­miR­3907, hsa­miR­367*, COL1A2, LEP and SERPINE1 in placenta were validated using our local samples. Our research showed that the expression of hsa­miR­937, hsa­miR­1486*, hsa­miR­3907, hsa­miR­367* and hub genes in the placenta were closely associated with the pathophysiology of EOPE. hsa­miR­937, hsa­miR­1486*, hsa­miR­3907, hsa­miR­367* and hub genes could serve as biomarkers for diagnosis and as potential targets for the treatment of EOPE.

Down-regulated expressed protein HMGB3 inhibits proliferation and migration, promotes apoptosis in the placentas of fetal growth restriction.

Fetal growth restriction (FGR) is one of the major complications of pregnancy, which can lead to serious short-term and long-term diseases. High-mobility group box 3 (HMGB3) has been found to contribute to the development of many cancers. However, the role of HMGB3 in the pathogenesis of FGR is blank. Here, we measured the expression level of HMGB3 in the placenta tissues of six normal pregnancies and five FGR patients by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). CCK8 assay, transwell assay and flow cytometry were used to detect the functional effects of overexpression and silencing of HMGB3 on the HTR8/SVneo trophoblast cell line. The results showed that the protein levels of HMGB3 were significantly decreased in FGR placentas compared to normal controls, while mRNA levels of HMGB3 were not significantly altered. Furthermore, when overexpressed of protein HMGB3 of the trophoblast cells, the proliferation and migration abilities were significantly promoted, and the apoptosis abilities of these cells were statistically inhibited. Cell functional experiments showed the opposite results when the expression of HMGB3 was silent. And the expression of cell function-related genes PCNA, Ki67, Tp53, Bax, MMP-2 and E-cadherin was observed to show corresponding changes by qRT-PCR. The results of mass spectrometry showed that HMGB3 may directly or indirectly interact with 71 proteins. In summary, our results indicated that HMGB3 might be of very great significance to the pathogenesis of FGR and might play the role by leading the dysfunction of placental villous trophoblast cells and through the interaction with some other proteins.

Comparative proteomics of umbilical vein blood plasma from normal and gestational diabetes mellitus patients reveals differentially expressed proteins associated with childhood obesity.

PURPOSE: Offspring obesity is one of long-term complications of gestational diabetes mellitus (GDM). The aim of this study is to identify proteins differentially expressed in the umbilical vein blood plasma, which could become markers for early diagnosis of childhood obesity. EXPERIMENTAL DESIGN: Umbilical vein plasma samples were collected from 30 control and 30 GDM patients in 2007-2008 whose offspring were suffering from obesity at 6-7 years old. Multiplexed isobaric tandem mass tag labeling combined with LC-MS/MS was used to identify differentially expressed proteins. Ingenuity pathway analysis was performed to identify canonical pathways, biological functions, and networks of interacting proteins. Western blotting was used to verify the expression of three selected proteins. RESULTS: A total of 318 proteins were identified, of which 12 proteins were upregulated in GDM group while 24 downregulated. Lipid metabolism was the top category identified by ingenuity pathway analysis. Three randomly chosen proteins were validated by Western blotting, which were consistent with LC-MS. CONCLUSION: There are significant differences of protein profile in the umbilical vein blood plasma between normal and GDM patients with obese offspring. The results indicate that a variety of proteins and biological mechanisms may contribute to childhood obesity.