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      Potential urine biomarkers for gestational hypertension and preeclampsia

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          Abstract

          Differential proteomic technology was used to identify urine proteomic profile of gestational hypertension and preeclampsia. Urine samples were collected from 10 patients with gestational hypertension, 10 patients with mild preeclampsia, 10 patients with severe preeclampsia and 10 normal pregnancies and analyzed by 2-D difference gel electrophoresis, then matrix assisted laser desorption ionization mass spectrometry was used to identify differential proteins. Subsequently, ELISA was used to verify the content variation of the identified proteins in 200 urine samples. In total, 30 differential proteins were identified. For prostaglandin-H2 D-isomerase (L-PGDS), perlecan and other 15 proteins, the contents in patients with gestational hypertension were higher than that of normal pregnancies, but lower in mild and severe preeclampsia. By contrast, serum albumin and α-1-antitrypsin was lower in samples from patients with gestational hypertension and higher in patients with mild and severe preeclampsia compared with normal pregnancies. ELISA verified that the urinary concentration of L-PGDS and perlecan were significantly lower in patients with preeclampsia than in normal pregnancies (P<0.05). Urine proteomics is a useful tool to identify potential biomarkers to distinguish between different types of hypertensive disorders in pregnancy. L-PGDS and perlecan could potentially be used as markers to reflect the state of renal function, and may participate in the genesis and development of renal injury during preeclampsia.

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          Most cited references18

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          A novel experimental design for comparative two-dimensional gel analysis: two-dimensional difference gel electrophoresis incorporating a pooled internal standard.

          The comparison of two-dimensional (2-D) gel images from different samples is an established method used to study differences in protein expression. Conventional methods rely on comparing images from at least 2 different gels. Due to the high variation between gels, detection and quantification of protein differences can be problematic. Two-dimensional difference gel electrophoresis (Ettan trade mark DIGE) is an emerging technique for comparative proteomics, which improves the reproducibility and reliability of differential protein expression analysis between samples. In the application of DIGE different samples are labelled with mass and charge matched spectrally resolvable fluorescent dyes and are then separated on the same 2-D gel. Using an Escherichia coli lysate "spiked" with varying amounts of four different known proteins, we have tested a novel experimental design that exploits the sample multiplexing capabilities of DIGE, by including a standard sample in each gel. The standard sample comprises equal amounts of each sample to be compared and was found to improve the accuracy of protein quantification between samples from different gels allowing accurate detection of small differences in protein levels between samples.
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            A current view of perlecan in physiology and pathology: A mosaic of functions

            Perlecan, a large basement membrane heparan sulfate proteoglycan, is expressed in a wide array of tissues where it regulates diverse cellular processes including bone formation, inflammation, cardiac development, and angiogenesis. Here we provide a contemporary review germane to the biology of perlecan encompassing its genetic regulation as well as an analysis of its modular protein structure as it pertains to function. As perlecan signaling from the extracellular matrix converges on master regulators of autophagy, including AMPK and mTOR, via a specific interaction with vascular endothelial growth factor receptor 2, we specifically focus on the mechanism of action of perlecan in autophagy and angiogenesis and contrast the role of endorepellin, the C-terminal fragment of perlecan, in these cellular and morphogenic events.
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              Urinary proteomics for prediction of preeclampsia.

              Preeclampsia is a major determinant of fetal and maternal morbidity and mortality. We used a proteomic strategy to identify urinary biomarkers that predict preeclampsia before the onset of disease. We prospectively collected urine samples from women throughout pregnancy. Samples from gestational weeks 12 to 16 (n=45), 20 (n=50), and 28 (n=18) from women who subsequently had preeclampsia develop were matched to controls (n=86, n=49, and n=17, respectively). We performed capillary electrophoresis online coupled to micro-time-of-flight mass spectrometry. Disease-specific peptide patterns were generated using support vector machine-based software. Candidate biomarkers were sequenced by liquid chromatography-tandem mass spectrometry. From comparison with nonpregnant controls, we defined a panel of 284 pregnancy-specific proteomic biomarkers. Subsequently, we developed a model of 50 biomarkers from specimens obtained at week 28 that was associated with future preeclampsia (classification factor in cases, 1.032 ± 0.411 vs controls, -1.038 ± 0.432; P<0.001). Classification factor increased markedly from week 12 to 16 to 28 in women who subsequently had preeclampsia develop (n=16; from -0.392 ± 0.383 to 1.070 ± 0.383; P<0.001) and decreased slightly in controls (n=16; from -0.647 ± 0.437 to -1.024 ± 0.433; P=0.043). Among the biomarkers are fibrinogen alpha chain, collagen alpha chain, and uromodulin fragments. The markers appear to predict preeclampsia at gestational week 28 with good confidence but not reliably at earlier time points (weeks 12-16 and 20). After prospective validation in other cohorts, these markers may contribute to better prediction, monitoring, and accurate diagnosis of preeclampsia.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                April 2019
                30 January 2019
                30 January 2019
                : 19
                : 4
                : 2463-2470
                Affiliations
                [1 ]Department of Obstetrics, Baoan Maternal and Child Health Hospital, Jinan University, Shenzhen, Guangdong 518102, P.R. China
                [2 ]Department of Obstetrics and Gynecology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518100, P.R. China
                [3 ]Department of Obstetrics and Gynecology, Nan Fang Hospital of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
                [4 ]Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
                Author notes
                Correspondence to: Professor Hong-Xia Guo, Department of Obstetrics, Baoan Maternal and Child Health Hospital, Jinan University, 56 Yulv Road, Shenzhen, Guangdong 518102, P.R. China, E-mail: doctorghx@ 123456163.com
                Article
                mmr-19-04-2463
                10.3892/mmr.2019.9911
                6423646
                30720087
                875f587c-fe3f-4670-8e35-7979fba08e97
                Copyright: © Guo et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 22 April 2018
                : 17 December 2018
                Categories
                Articles

                preeclampsia,body fluid,two-dimensional difference gel electrophoresis,matrix assisted laser desorption ionization-time of flight-mass spectrometry,l-prostaglandin-h2 d-isomerase,perlecan

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