{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:08:33Z","timestamp":1740146913180,"version":"3.37.3"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T00:00:00Z","timestamp":1715126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gansu Provincial Hospital Internal Research Fund","award":["23GSSYF-1"],"award-info":[{"award-number":["23GSSYF-1"]}]},{"name":"Lanzhou Petrochemical General Hospital Internal Research Projects","award":["LZSHZYY2023-03"],"award-info":[{"award-number":["LZSHZYY2023-03"]}]},{"DOI":"10.13039\/501100004775","name":"Natural Science Foundation of Gansu Province","doi-asserted-by":"publisher","award":["21JR7RA608"],"award-info":[{"award-number":["21JR7RA608"]}],"id":[{"id":"10.13039\/501100004775","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>Preeclampsia (PE) is a severe complication of unclear pathogenesis associated with pregnancy. This research aimed to elucidate the properties of immune cell infiltration and potential biomarkers of PE based on bioinformatics analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\" sec-type=\"materials|methods\">\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>Two PE datasets were imported from the Gene ExpressioOmnibus (GEO) and screened to identify differentially expressed genes (DEGs). Significant module genes were identified by weighted gene co-expression network analysis (WGCNA). DEGs that interacted with key module genes (GLu-DEGs) were analyzed further by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. The diagnostic value of the genes was assessed using receiver operating characteristic (ROC) curves and protein-protein interaction (PPI) networks were constructed using GeneMANIA, and GSVA analysis was performed using the MSigDB database. Immune cell infiltration was analyzed using the TISIDB database, and StarBase and Cytoscape were used to construct an RBP-mRNA network. The identified hub genes were validated in two independent datasets. For further confirmation, placental tissue from healthy pregnant women and women with PE were collected and analyzed using both RT-qPCR and immunohistochemistry.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>A total of seven GLu-DEGs were obtained and were found to be involved in pathways associated with the transport of sulfur compounds, PPAR signaling, and energy metabolism, shown by GO and KEGG analyses. GSVA indicated significant increases in adipocytokine signaling. Furthermore, single-sample Gene Set Enrichment Analysis (ssGSEA) indicated that the levels of activated B cells and T follicular helper cells were significantly increased in the PE group and were negatively correlated with GLu-DEGs, suggesting their potential importance.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>In summary, the results showed a correlation between glutamine metabolism and immune cells, providing new insights into the understandingPE pathogenesis and furnishing evidence for future advances in the treatment of this disease.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0303471","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T17:34:34Z","timestamp":1715189674000},"page":"e0303471","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of hub glutamine metabolism-associated genes and immune characteristics in pre-eclampsia"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2059-5160","authenticated-orcid":true,"given":"Yan","family":"Mao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinye","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuehong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,5,8]]},"reference":[{"issue":"2S","key":"pone.0303471.ref001","doi-asserted-by":"crossref","first-page":"S844","DOI":"10.1016\/j.ajog.2021.11.1356","article-title":"The etiology of preeclampsia.","volume":"226","author":"E Jung","year":"2022","journal-title":"Am J Obstet Gynecol"},{"issue":"2S","key":"pone.0303471.ref002","doi-asserted-by":"crossref","first-page":"S835","DOI":"10.1016\/j.ajog.2021.11.1371","article-title":"The evolution of the diagnostic criteria of preeclampsia-eclampsia","volume":"226","author":"MS Tanner","year":"2022","journal-title":"Am J Obstet Gynecol"},{"issue":"5","key":"pone.0303471.ref003","doi-asserted-by":"crossref","first-page":"e12756","DOI":"10.1111\/sji.12756","article-title":"The role of immunity in the pathogenesis and development of pre-eclampsia","volume":"90","author":"HQ Lu","year":"2019","journal-title":"Scand J Immunol"},{"issue":"6","key":"pone.0303471.ref004","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/j.1600-0897.2010.00836.x","article-title":"The immune system in pregnancy: A unique complexity","volume":"63","author":"G Mor","year":"2010","journal-title":"Am J Reprod Immunol"},{"issue":"8","key":"pone.0303471.ref005","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/cac2.12459","article-title":"Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2-positive gastric cancer","volume":"43","author":"XB Hu","year":"2023","journal-title":"Cancer Commun (Lond)."},{"key":"pone.0303471.ref006","doi-asserted-by":"crossref","first-page":"115767","DOI":"10.1016\/j.bcp.2023.115767","article-title":"ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus","volume":"216","author":"W Li","year":"2023","journal-title":"Biochem Pharmacol"},{"key":"pone.0303471.ref007","doi-asserted-by":"crossref","first-page":"1251643","DOI":"10.3389\/fimmu.2023.1251643","article-title":"Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer","volume":"14","author":"RH Huang","year":"2023","journal-title":"Front Immunol"},{"issue":"6","key":"pone.0303471.ref008","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"JT Leek","year":"2012","journal-title":"Bioinformatics"},{"issue":"12","key":"pone.0303471.ref009","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0.","volume":"27","author":"A Liberzon","year":"2011","journal-title":"Bioinformatics"},{"issue":"43","key":"pone.0303471.ref010","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"A Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pone.0303471.ref011","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pone.0303471.ref012","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: An R package for weighted correlation network analysis","volume":"9","author":"P Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"pone.0303471.ref013","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"M Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pone.0303471.ref014","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"GC Yu","year":"2012","journal-title":"OMICS"},{"issue":"Web Server issue","key":"pone.0303471.ref015","doi-asserted-by":"crossref","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function","volume":"38","author":"D Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"pone.0303471.ref016","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1471-2105-12-77","article-title":"pROC: An open-source package for R and S+ to analyze and compare ROC curves","volume":"12","author":"X Robin","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"pone.0303471.ref017","first-page":"3140263","article-title":"Integrated machine learning and single-sample gene set enrichment analysis identifies a TGF-beta signaling pathway derived score in headneck squamous cell carcinoma","volume":"2022","author":"S Wu","year":"2022","journal-title":"J Oncol"},{"issue":"20","key":"pone.0303471.ref018","doi-asserted-by":"crossref","first-page":"4200","DOI":"10.1093\/bioinformatics\/btz210","article-title":"TISIDB: An integrated repository portal for tumor-immune system interactions","volume":"35","author":"BB Ru","year":"2019","journal-title":"Bioinformatics"},{"issue":"10","key":"pone.0303471.ref019","first-page":"e79","article-title":"Application of ggplot2 to pharmacometric graphics.","volume":"2","author":"K Ito","year":"2013","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"issue":"8","key":"pone.0303471.ref020","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.3390\/biomedicines11082328","article-title":"Single-cell RNA sequencing and microarray analysis reveal the role of lipid-metabolism-related genes and cellular immune infiltration in pre-eclampsia and identify novel biomarkers for pre-eclampsia","volume":"11","author":"YJ Liu","year":"2023","journal-title":"Biomedicines"},{"key":"pone.0303471.ref021","doi-asserted-by":"crossref","first-page":"1209144","DOI":"10.3389\/fmolb.2023.1209144","article-title":"Association of the LEP gene with immune infiltration as a diagnostic biomarker in preeclampsia","volume":"10","author":"SR Chen","year":"2023","journal-title":"Front Mol Biosci"},{"issue":"7","key":"pone.0303471.ref022","doi-asserted-by":"crossref","first-page":"4554","DOI":"10.1007\/s00330-023-09454-x","article-title":"Magnetic resonance spectroscopy and liquid chromatography-mass spectrometry metabolomics study may differentiate pre-eclampsia from gestational hypertension","volume":"33","author":"XF Liu","year":"2023","journal-title":"Eur Radiol"},{"issue":"18","key":"pone.0303471.ref023","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.3390\/nu15183877","article-title":"Decreased fatty acid oxidation gene expression in pre-eclampsia according to the onset and presence of intrauterine growth restriction","volume":"15","author":"A Abascal-Saiz","year":"2023","journal-title":"Nutrients"},{"issue":"31","key":"pone.0303471.ref024","doi-asserted-by":"crossref","first-page":"4900","DOI":"10.1021\/acs.biochem.5b00388","article-title":"Structure-based identification of inhibitors for the SLC13 family of Na+\/dicarboxylate cotransporters","volume":"54","author":"C Colas","year":"2015","journal-title":"Biochemistry"},{"key":"pone.0303471.ref025","doi-asserted-by":"crossref","first-page":"11960","DOI":"10.1038\/ncomms11960","article-title":"Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia.","volume":"7","author":"X Gao","year":"2016","journal-title":"Nat Commun"},{"issue":"12","key":"pone.0303471.ref026","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1016\/j.placenta.2015.10.014","article-title":"Correlation of long-chain fatty acid oxidation with oxidative stress and inflammation in pre-eclampsia-like mouse models","volume":"36","author":"XY Ding","year":"2015","journal-title":"Placenta"},{"issue":"4","key":"pone.0303471.ref027","doi-asserted-by":"crossref","first-page":"e054697","DOI":"10.1136\/bmjopen-2021-054697","article-title":"Prediction of pregnancy-related hypertensive disorders using metabolomics: A systematic review","volume":"12","author":"J Mayrink","year":"2022","journal-title":"BMJ Open"},{"issue":"6","key":"pone.0303471.ref028","doi-asserted-by":"crossref","first-page":"e0270329","DOI":"10.1371\/journal.pone.0270329","article-title":"Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia","volume":"17","author":"R Chandra","year":"2022","journal-title":"PLoS One"},{"issue":"11","key":"pone.0303471.ref029","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1038\/cr.2015.100","article-title":"Loss of the sulfate transporter Slc13a4 in placenta causes severe fetal abnormalities and death in mice","volume":"25","author":"J Rakoczy","year":"2015","journal-title":"Cell Res"},{"key":"pone.0303471.ref030","first-page":"44","article-title":"ADAMTS proteases and cancer","author":"S Cal","year":"2015","journal-title":"Matrix Biol"},{"issue":"3","key":"pone.0303471.ref031","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.3390\/nu7031594","article-title":"Sulphate in pregnancy.","volume":"7","author":"PA Dawson","year":"2015","journal-title":"Nutrients."},{"issue":"3","key":"pone.0303471.ref032","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1042\/CS20220644","article-title":"Targeted bisulfite resequencing of differentially methylated cytosines in pre-eclampsia reveals a skewed dynamic balance in the DNA methylation of enhancers","volume":"137","author":"XG Zheng","year":"2023","journal-title":"Clin Sci (Lond)."},{"issue":"8","key":"pone.0303471.ref033","doi-asserted-by":"crossref","first-page":"BSR20231076","DOI":"10.1042\/BSR20231076","article-title":"Dose-related relationship between ergothioneine concentrations and risk of preeclampsia","volume":"43","author":"KM Ho","year":"2023","journal-title":"Biosci Rep"},{"key":"pone.0303471.ref034","doi-asserted-by":"crossref","first-page":"113018","DOI":"10.1016\/j.biopha.2022.113018","article-title":"Hydrogen sulfide ameliorated preeclampsia via suppression of toll-like receptor 4-activated inflammation in the rostral ventrolateral medulla of rats","volume":"150","author":"JX Du","year":"2022","journal-title":"Biomed Pharmacother"},{"issue":"2","key":"pone.0303471.ref035","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nri2922","article-title":"Immunometabolism: An emerging frontier","volume":"11","author":"D Mathis","year":"2011","journal-title":"Nat Rev Immunol"},{"issue":"8","key":"pone.0303471.ref036","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nri.2017.64","article-title":"The unique immunological and microbial aspects of pregnancy","volume":"17","author":"G Mor","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"pone.0303471.ref037","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.3389\/fimmu.2018.03142","article-title":"Galectin-9 alleviates LPS-induced preeclampsia-like impairment in rats via switching decidual macrophage polarization to M2 subtype.","volume":"9","author":"ZH Li","year":"2019","journal-title":"Front Immunol"},{"issue":"1","key":"pone.0303471.ref038","doi-asserted-by":"crossref","first-page":"11573","DOI":"10.1038\/s41598-023-38700-x","article-title":"Medium-chain fatty acids modify macrophage expression of metabolic and inflammatory genes in a PPAR \u03b2\/\u03b4-dependent manner.","volume":"13","author":"PV Gaete","year":"2023","journal-title":"Sci Rep"},{"issue":"4","key":"pone.0303471.ref039","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1161\/HYPERTENSIONAHA.110.157297","article-title":"Robust early pregnancy prediction of later preeclampsia using metabolomic biomarkers","volume":"56","author":"LC Kenny","year":"2010","journal-title":"Hypertension"},{"key":"pone.0303471.ref040","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.prostaglandins.2018.09.006","article-title":"Role of dyslipidemia in preeclampsia-A review of lipidomic analysis of blood, placenta, syncytiotrophoblast microvesicles and umbilical cord artery from women with preeclampsia","volume":"139","author":"D Wojcik-Baszko","year":"2018","journal-title":"Prostaglandins Other Lipid Mediat"},{"key":"pone.0303471.ref041","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.placenta.2022.05.015","article-title":"Fenofibrate mediated activation of PPAR\u03b1 negatively regulates trophoblast invasion","volume":"126","author":"S Singh","year":"2022","journal-title":"Placenta"},{"issue":"1","key":"pone.0303471.ref042","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3892\/etm.2022.11386","article-title":"CTRP9 overexpression attenuates palmitic acid-induced inflammation, apoptosis and impaired migration in HTR8\/SVneo cells through AMPK\/SREBP1c signaling.","volume":"24","author":"L Li","year":"2022","journal-title":"Exp Ther Med."},{"key":"pone.0303471.ref043","doi-asserted-by":"crossref","first-page":"e11110","DOI":"10.7717\/peerj.11110","article-title":"Ameliorative effect of apelin-13 against renal complications in L-NAME-induced preeclampsia in rats.","volume":"9","author":"RZ Hamza","year":"2021","journal-title":"PeerJ."},{"key":"pone.0303471.ref044","doi-asserted-by":"crossref","first-page":"1031950","DOI":"10.3389\/fphys.2022.1031950","article-title":"Bioinformatics analysis combined with clinical sample screening reveals that leptin may be a biomarker of preeclampsia","volume":"13","author":"YJ Wang","year":"2023","journal-title":"Front Physiol"},{"issue":"6","key":"pone.0303471.ref045","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1042\/CS20150702","article-title":"The role of inflammation in the pathology of preeclampsia","volume":"130","author":"AC Harmon","year":"2016","journal-title":"Clin Sci (Lond)."},{"issue":"5","key":"pone.0303471.ref046","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1600-0897.2009.00697.x","article-title":"Functional changes of human peripheral B-lymphocytes in pre-eclampsia","volume":"61","author":"AH Liao","year":"2009","journal-title":"Am J Reprod Immunol"},{"issue":"6","key":"pone.0303471.ref047","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/aji.12154","article-title":"Treg cells are negatively correlated with increased memory B cells in pre-eclampsia while maintaining suppressive function on autologous B-cell proliferation","volume":"70","author":"B Zeng","year":"2013","journal-title":"Am J Reprod Immunol"},{"key":"pone.0303471.ref048","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fimmu.2014.00006","article-title":"B-1a B cells regulate T cell differentiation associated with pregnancy disturbances","volume":"5","author":"DO Muzzio","year":"2014","journal-title":"Front Immunol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0303471","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T17:35:07Z","timestamp":1715189707000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0303471"}},"subtitle":[],"editor":[{"given":"Jinhui","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,5,8]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0303471","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2024,5,8]]}}}