{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T02:12:13Z","timestamp":1775182333927,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2015,3,13]],"date-time":"2015-03-13T00:00:00Z","timestamp":1426204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Nature Science Foundation of China","award":["31271246"],"award-info":[{"award-number":["31271246"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>It is well known that maternal folate deficiency results in adverse pregnancy outcomes. In addition to aspects in embryonic development, maternal uterine receptivity and the decidualization of stromal cells is also very important for a successful pregnancy. In this study, we focused on endometrium decidualization and investigated whether apoptosis, which is essential for decidualization, was impaired. Flow cytometry and TUNEL detection revealed that apoptosis of mouse endometrium decidual cells was suppressed in the dietary folate-deficient group on Days 7 and 8 of pregnancy (Day 1 = vaginal plug) when decidua regression is initiated. The endometrium decidual tissue of the folate deficiency group expressed less Bax compared to the normal diet group while they had nearly equal expression of Bcl2 protein. Further examination revealed that the mitochondrial transmembrane potential (\u0394\u03a8m) decreased, and the fluorescence of diffuse cytoplasmic cytochrome c protein was detected using laser confocal microscopy in normal decidual cells. However, no corresponding changes were observed in the folate-deficient group. Western blotting analyses confirmed that more cytochrome c was released from mitochondria in normal decidual cells. Taken together, these results demonstrated that folate deficiency could inhibit apoptosis of decidual cells via the mitochondrial apoptosis pathway, thereby restraining decidualization of the endometrium and further impairing pregnancy.   <\/jats:p>","DOI":"10.3390\/nu7031916","type":"journal-article","created":{"date-parts":[[2015,3,13]],"date-time":"2015-03-13T11:51:52Z","timestamp":1426247512000},"page":"1916-1932","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Folate Deficiency Decreases Apoptosis of Endometrium Decidual Cells in Pregnant Mice via the Mitochondrial Pathway"],"prefix":"10.3390","volume":"7","author":[{"given":"Xing","family":"Liao","sequence":"first","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ru","family":"Gao","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Geng","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Ding","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Mu","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"He","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"MRC Vitamin Study Research Group (1991). Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet, 338, 131\u2013137.","DOI":"10.1016\/0140-6736(91)90133-A"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1056\/NEJM200405203502120","article-title":"Folic acid and the prevention of neural-tube defects","volume":"350","author":"Mills","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1016\/S0140-6736(01)07105-7","article-title":"Short interpregnancy intervals and unfavourable pregnancy outcome: Role of folate depletion","volume":"358","author":"Smits","year":"2001","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.1093\/humrep\/des187","article-title":"Effect of folate deficiency on promoter methylation and gene expression of Esr1, Cdh1 and Pgr, and its influence on endometrial receptivity and embryo implantation","volume":"27","author":"Gao","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e26774","DOI":"10.1371\/journal.pone.0026774","article-title":"Decidual cell polyploidization necessitates mitochondrial activity","volume":"6","author":"Ma","year":"2011","journal-title":"PLoS One"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0925-4773(01)00614-1","article-title":"Evidence for coordinated interaction of cyclin D3 with p21 and CDK6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation","volume":"111","author":"Tan","year":"2002","journal-title":"Mech. Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/BF00310059","article-title":"Involution of the antimesometrial decidua in the mouse. An ultrastructural study","volume":"176","author":"Katz","year":"1987","journal-title":"Anat. Embryol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/sj.cdd.4400516","article-title":"Apoptosis at the time of embryo implantation in mouse and rat","volume":"6","author":"Pampfer","year":"1999","journal-title":"Cell Death Differ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/BF00305087","article-title":"Ultrastructural study of the mouse antimesometrial decidua","volume":"166","author":"Abrahamsohn","year":"1983","journal-title":"Anat. Embryol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1095\/biolreprod63.1.188","article-title":"Regression of the decidualized mesometrium and decidual cell apoptosis are associated with a shift in expression of Bcl2 family members","volume":"63","author":"Dai","year":"2000","journal-title":"Biol. Reprod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1530\/eje.0.1490069","article-title":"The involvement of apoptotic regulators during in vitro decidualization","volume":"149","author":"Akcali","year":"2003","journal-title":"Eur. J. Endocrinol.\/Eur. Fed. Endocr. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1210\/endo.137.7.8770938","article-title":"Effect of decidualization on the expression of Bax and Bcl-2 in the rat uterine endometrium","volume":"137","author":"Akcali","year":"1996","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0753-3322(01)00095-6","article-title":"Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-kappaB in human Hep G2 cells","volume":"55","author":"Chern","year":"2001","journal-title":"Biomed. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e77931","DOI":"10.1371\/journal.pone.0077931","article-title":"Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet beta-cells: Relevant to the pathogenesis of diabetes","volume":"8","author":"Hsu","year":"2013","journal-title":"PLoS One"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3945\/jn.108.095661","article-title":"Intestinal neoplasia induced by low dietary folate is associated with altered tumor expression profiles and decreased apoptosis in mouse normal intestine","volume":"139","author":"Knock","year":"2009","journal-title":"J. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/j.biocel.2012.07.014","article-title":"Mechanism of folate deficiency-induced apoptosis in mouse embryonic stem cells: Cell cycle arrest\/apoptosis in G1\/G0 mediated by microRNA-302a and tumor suppressor gene Lats2","volume":"44","author":"Liang","year":"2012","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/S0955-2863(03)00115-3","article-title":"Folate deficiency, mismatch repair-dependent apoptosis, and human disease","volume":"14","author":"Li","year":"2003","journal-title":"J. Nutr. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.chroma.2005.11.052","article-title":"Determination of folic acid by capillary electrophoresis with chemiluminescence detection","volume":"1107","author":"Zhao","year":"2006","journal-title":"J Chromatogr. A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12542","DOI":"10.1073\/pnas.0901647106","article-title":"de Novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis","volume":"106","author":"Das","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5575","DOI":"10.1210\/en.2012-1528","article-title":"Overexpression of cyclin D3 improves decidualization defects in Hoxa-10-\/- mice","volume":"153","author":"Sroga","year":"2012","journal-title":"Endocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/301192b0","article-title":"Folic acid deficiency","volume":"301","author":"Jukes","year":"1983","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1161\/01.CIR.98.16.1657","article-title":"Apoptosis and cell proliferation after porcine coronary angioplasty","volume":"98","author":"Malik","year":"1998","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1146\/annurev-genet-102108-134850","article-title":"The role of mitochondria in apoptosis","volume":"43","author":"Wang","year":"2009","journal-title":"Ann. Rev. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/jcb.24709","article-title":"Apoptosis regulation at the mitochondrial outer membrane","volume":"115","author":"Gillies","year":"2014","journal-title":"J. Cell. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3332","DOI":"10.1529\/biophysj.106.100362","article-title":"Response to bistability in apoptosis: Roles of Bax, Bcl-2, and mitochondrial permeability transition pores","volume":"92","author":"Eissing","year":"2007","journal-title":"Biophys. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1529\/biophysj.105.068122","article-title":"Bistability in apoptosis: Roles of Bax, Bcl-2, and mitochondrial permeability transition pores","volume":"90","author":"Bagci","year":"2006","journal-title":"Biophys. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.toxlet.2012.10.008","article-title":"Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway","volume":"215","author":"Elumalai","year":"2012","journal-title":"Toxicol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e47351","DOI":"10.1371\/journal.pone.0047351","article-title":"Berberine inhibits doxorubicin-triggered cardiomyocyte apoptosis via attenuating mitochondrial dysfunction and increasing Bcl-2 expression","volume":"7","author":"Lv","year":"2012","journal-title":"PLoS One"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1079\/BJN20051579","article-title":"In vitro folate deficiency induces apoptosis by a p53, Fas (Apo-1, CD95) independent, Bcl-2 related mechanism in phytohaemagglutinin-stimulated human peripheral blood lymphocytes","volume":"95","author":"Lin","year":"2006","journal-title":"Br. J. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1093\/carcin\/bgi312","article-title":"Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells","volume":"27","author":"Novakovic","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1093\/jn\/138.4.653","article-title":"Strain differences in mice highlight the role of DNA damage in neoplasia induced by low dietary folate","volume":"138","author":"Knock","year":"2008","journal-title":"J. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1093\/humrep\/deu202","article-title":"Human decidual stromal cells secrete soluble pro-apoptotic factors during decidualization in a cAMP-dependent manner","volume":"29","author":"Requena","year":"2014","journal-title":"J. Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1159\/000143431","article-title":"Influences of reduced expression of maternal bone morphogenetic protein 2 on mouse embryonic development","volume":"2","author":"Singh","year":"2008","journal-title":"Sex. Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/dvdy.21829","article-title":"Bmp2 is required for cephalic neural tube closure in the mouse","volume":"238","author":"Castranio","year":"2009","journal-title":"Dev. Dyn."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/7\/3\/1916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:43:29Z","timestamp":1760215409000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/7\/3\/1916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,13]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2015,3]]}},"alternative-id":["nu7031916"],"URL":"https:\/\/doi.org\/10.3390\/nu7031916","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,13]]}}}