{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:13:47Z","timestamp":1791000827020,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,9,17]],"date-time":"2014-09-17T00:00:00Z","timestamp":1410912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health","award":["R01HD076245"],"award-info":[{"award-number":["R01HD076245"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Diabetes mellitus in pregnancy causes defects in infant heart, including the outflow tracts (OFTs). Development of the aorta and pulmonary artery, which are derived from the common OFT in the embryo, is regulated by the transforming growth factor \u03b2 (TGF\u03b2) and Wnt families, and can be perturbed by hyperglycemia\u2010generated intracellular stress conditions. However, the underlying cellular and molecular mechanisms remain to be delineated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Female mice were induced diabetic with streptozotocin. Embryonic and fetal OFTs were examined morphologically and histologically. Cell proliferation was assessed using 5\u2019\u2010bromo\u20102\u2019\u2010deoxyuridine incorporation assay. Oxidative and endoplasmic reticulum (ER) stress markers and TGF\u03b2 factors were detected using immunohistochemistry. The expression of genes in the Wnt\u2010signaling system was assessed using real\u2010time reverse transcription polymerase chain reaction array. The role of activin\u2010A in cell proliferation was addressed by treating embryos cultured in high glucose with activin\u2010A.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Maternal diabetes caused complex abnormalities in the OFTs, including aortic and pulmonary stenosis and persistent truncus arteriosus. The development of the endocardial cushions was suppressed, manifested with insufficient cellularization of the tissues. Cell proliferation was significantly decreased under oxidative and ER stress conditions. The expression of genes in the Wnt signaling was significantly altered. Activin\u2010A and Smad3 were found to be expressed in the OFT. Treatment with activin\u2010A rescued cell proliferation in the endocardial cushions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Maternal diabetes generates oxidative and ER stress conditions, suppresses TGF\u03b2 and Wnt signaling, inhibits cell proliferation and cellularization of the endocardial cushions, leading to OFT septal defects. Activin\u2010A plays a role in hyperglycemia\u2010suppressed proliferation of the endocardial cells<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bdrb.21120","type":"journal-article","created":{"date-parts":[[2014,9,17]],"date-time":"2014-09-17T21:29:29Z","timestamp":1410989369000},"page":"364-370","source":"Crossref","is-referenced-by-count":14,"title":["TGF\u03b2 and Wnt in Cardiac Outflow Tract Defects in Offspring of Diabetic Pregnancies"],"prefix":"10.1002","volume":"101","author":[{"given":"Zhiyong","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Obstetrics Gynecology and Reproductive Sciences University of Maryland School of Medicine  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,9,17]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.89.9.1110"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-46954-6_8"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.016865"},{"issue":"3","key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2008.06.028","article-title":"Diabetes mellitus and birth defects","volume":"199","author":"Correa A","year":"2008","journal-title":"Am J Obstet Gynecol"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20567"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a015081"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(01)02004-6"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420410309"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.221531"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2002.67.57"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7123245"},{"key":"e_1_2_6_13_1","volume-title":"Basic histology","author":"Junqueira LC","year":"2003"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2012.04.003"},{"issue":"34","key":"e_1_2_6_15_1","first-page":"1","article-title":"Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development","volume":"6","author":"Kumar SD","year":"2007","journal-title":"Cardiovasc Diabetol"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.753"},{"issue":"6","key":"e_1_2_6_17_1","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1101\/gad.14.6.627","article-title":"Controlling TGF\u2010\u03b2 signaling","volume":"14","author":"Massague J","year":"2000","journal-title":"Genes Dev"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420250316"},{"issue":"46","key":"e_1_2_6_19_1","first-page":"1","article-title":"N\u2010Acetylcysteine prevents congenital heart defects induced by pregestational diabetes","volume":"13","author":"Moazzen H","year":"2014","journal-title":"Cardiovasc Diabetol"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20101"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0177(199808)212:4<548::AID-AJA8>3.0.CO;2-H"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2008.07.003"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20457"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/wdev.98"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7290260"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20495"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(05)43005-3"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.2337\/db07-1016"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9926(200005)61:5<355::AID-TERA7>3.0.CO;2-W"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2005.06.004"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(93)25013-R"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1995.1102"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.033910"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-7580.2003.00168.x"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.89.10.1217"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2007.06.070"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20225"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20330"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.21060"}],"container-title":["Birth Defects Research Part B: Developmental and Reproductive Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdrb.21120","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdrb.21120","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdrb.21120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T09:21:43Z","timestamp":1696584103000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdrb.21120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,17]]},"references-count":39,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,10]]}},"alternative-id":["10.1002\/bdrb.21120"],"URL":"https:\/\/doi.org\/10.1002\/bdrb.21120","archive":["Portico"],"relation":{},"ISSN":["1542-9733","1542-9741"],"issn-type":[{"value":"1542-9733","type":"print"},{"value":"1542-9741","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,9,17]]}}}