Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia

Liu, Xiru; Deng, Qinyin; Luo, Xin; Chen, Ying; Shan, Nan; Qi, Hongbo

doi:10.3109/14767058.2016.1144744

Cited by 34 publications

(26 citation statements)

References 47 publications

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“…Our results demonstrated that p38 MAPK was upregulated by knockdown of HPSE, and when pretreated with BMS582949, SB203580, or BIRB796, the invasiveness of HTR8/SVneo cells with knockdown of HPSE was recovered. This revealed that the underlying mechanism by which knockdown of HPSE suppressed HTR8/SVneo cell invasion was by activating the p38 MAPK pathway, which was consistent with a previous report [ 25 ]. Proper phosphorylated p38 is necessary for the normal physiological function of the cells.…”

Section: Discussionsupporting

confidence: 92%

Knockdown of Heparanase Suppresses Invasion of Human Trophoblasts by Activating p38 MAPK Signaling Pathway

et al. 2018

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Preeclampsia is a pregnancy-related disease with increasing maternal and perinatal morbidity and mortality worldwide. Defective trophoblast invasion is considered to be a major factor in the pathophysiological mechanism of preeclampsia. Heparanase, the only endo-β-glucuronidase in mammalian cells, has been shown to be abnormally expressed in the placenta of preeclampsia patients in our previous study. The biological role and potential mechanism of heparanase in trophoblasts remain unclear. In the present study, stably transfected HTR8/SVneo cell lines with heparanase overexpression or knockdown were constructed. The effect of heparanase on cellular proliferation, apoptosis, invasion, tube formation, and potential pathways in trophoblasts was explored. Our results showed that overexpression of heparanase promoted proliferation and invasion. Knockdown of heparanase suppressed proliferation, invasion, and tube formation but induced apoptosis. These findings reveal that downregulation of heparanase may contribute to defective placentation and plays a crucial role in the pathogenesis of preeclampsia. Furthermore, increased activation of p38 MAPK in heparanase-knockdown HTR8/SVneo cell was shown by MAPK pathway phosphorylation array and Western blotting assay. After pretreatment with 3 specific p38 MAPK inhibitors (BMS582949, SB203580, or BIRB796), inadequate invasion in heparanase-knockdown HTR8/SVneo cell was rescued. That indicates that knockdown of heparanase decreases HTR8/SVneo cell invasion through excessive activation of the p38 MAPK signaling pathway. Our study suggests that heparanase can be a potential predictive biomarker for preeclampsia at an early stage of pregnancy and represents a promising therapeutic target for the treatment of preeclampsia.

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Section: Discussionsupporting

confidence: 92%

Knockdown of Heparanase Suppresses Invasion of Human Trophoblasts by Activating p38 MAPK Signaling Pathway

et al. 2018

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“…Gadd45α(DNA damage-inducible 45 alpha) is an oxidative stress-induced factor with high levels in PE. Gadd45αinhibits trophoblast invasion and regulates anti-angiogenesis factor secretion via the p38 MAPK signalling pathway[ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of key microRNAs and genes in preeclampsia by bioinformatics analysis

et al. 2017

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Preeclampsia is a leading cause of perinatal maternal–foetal mortality and morbidity. The aim of this study is to identify the key microRNAs and genes in preeclampsia and uncover their potential functions. We downloaded the miRNA expression profile of GSE84260 and the gene expression profile of GSE73374 from the Gene Expression Omnibus database. Differentially expressed miRNAs and genes were identified and compared to miRNA-target information from MiRWalk 2.0, and a total of 65 differentially expressed miRNAs (DEMIs), including 32 up-regulated miRNAs and 33 down-regulated miRNAs, and 91 differentially expressed genes (DEGs), including 83 up-regulated genes and 8 down-regulated genes, were identified. The pathway enrichment analyses of the DEMIs showed that the up-regulated DEMIs were enriched in the Hippo signalling pathway and MAPK signalling pathway, and the down-regulated DEMIs were enriched in HTLV-I infection and miRNAs in cancers. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses of the DEGs were performed using Multifaceted Analysis Tool for Human Transcriptome. The up-regulated DEGs were enriched in biological processes (BPs), including the response to cAMP, response to hydrogen peroxide and cell-cell adhesion mediated by integrin; no enrichment of down-regulated DEGs was identified. KEGG analysis showed that the up-regulated DEGs were enriched in the Hippo signalling pathway and pathways in cancer. A PPI network of the DEGs was constructed by using Cytoscape software, and FOS, STAT1, MMP14, ITGB1, VCAN, DUSP1, LDHA, MCL1, MET, and ZFP36 were identified as the hub genes. The current study illustrates a characteristic microRNA profile and gene profile in preeclampsia, which may contribute to the interpretation of the progression of preeclampsia and provide novel biomarkers and therapeutic targets for preeclampsia.

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“…Indeed, concentrations of the antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFLT-1) e15a and soluble endoglin were increased in the placenta as well as in the circulation of PE patients [109][110][111].…”

Section: Immunological Backgroundmentioning

confidence: 99%

Immunology of hepatic diseases during pregnancy

2016

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The mother's immune system has to adapt to pregnancy accepting the semi-allograft fetus and preventing harmful effects to the developing child. Aberrations in feto-maternal immune adaptation may result in disease of the mother, such as liver injury. Five pregnancy-associated liver disorders have been described so far, however, little is known concerning immune alterations promoting the respective disease. These liver disorders are pre-eclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy. On the other hand, pre-existing autoimmune liver injury of the mother can be affected by pregnancy. This review intends to summarize current knowledge linking feto-maternal immunology and liver inflammation with a special emphasis on novel potential biomarkers.

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Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia

Abstract: Oxidative stress-induced overexpression of Gadd45α might influence the activity of MMPs through activation of p38 MAPK signaling to affect the invasion of trophoblast cells, and increase the secretions of sFlt-1/sEng, which then participate in the pathogenesis of pre-eclampsia.

Cited by 34 publications

References 47 publications

Knockdown of Heparanase Suppresses Invasion of Human Trophoblasts by Activating p38 MAPK Signaling Pathway

Knockdown of Heparanase Suppresses Invasion of Human Trophoblasts by Activating p38 MAPK Signaling Pathway

Identification of key microRNAs and genes in preeclampsia by bioinformatics analysis

Immunology of hepatic diseases during pregnancy

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