{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:59:15Z","timestamp":1764053955859,"version":"3.41.2"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the efficacy of the Er Zhi Tian Gui Formula (EZTGF) in diminished ovarian reserve (DOR) patients undergoing <jats:italic>in vitro<\/jats:italic> fertilization-embryo transfer (IVF-ET); to examine the pharmacological mechanism of EZTGF in inhibiting ovarian granulosa cell (OGC) apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 120 DOR patients undergoing IVF-ET in the Affiliated Hospital of Shandong University of TCM from March to December 2021 were randomly assigned to the EZTGF (n = 60) or Placebo (n = 60) groups. All participants followed a gonadotropin-releasing hormone antagonist protocol for controlled ovarian stimulation, with interventions starting on days 2\u20133 of the preceding menstrual cycle and continuing until the trigger day. IVF-ET outcomes measured included the number of oocytes retrieved, embryo quality, and pregnancy rates. NEAT1, miR-10b-3p, and FOXO3a OGCs expression was analyzed via qRT-PCR. Mechanistic studies were conducted using KGN cells, with dual-luciferase reporter assays confirming regulatory relationship between NEAT1, miR-10b-3p, and FOXO3a.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 116 patients completed the trial (58 in each group). The EZTGF group showed a significant increase in both the number (especially at the cleavage stage) and rate of high-quality embryos, compared with the Placebo group (P &amp;lt; 0.05). No statistically significant differences in pregnancy outcomes were observed (P &amp;gt; 0.05). Cellular experiments showed that miR-10b-3p inhibits proliferation and promotes apoptosis in oocyte granulosa cells (OGCs). Dual luciferase reporter gene assay confirms target-regulatory relationship of NEAT1 with miR-10b-3p, miR-10b-3p and FOXO3a. EZTGF treatment partially reversed the low expression of NEAT1 and FOXO3a, and the high expression of miR-10b-3p in OGCs from DOR patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Treatment with EZTGF enhances embryo quality in women with DOR undergoing IVF-ET, which can be partially attributed to modulation of the NEAT1\/miR-10b-3p\/FOXO3a pathway. Trial registration: ChiCTR2100052522.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1552581","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T15:07:24Z","timestamp":1742569644000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical efficacy and pharmacological mechanism of Er Zhi Tian Gui formula in enhancing IVF-ET outcomes for diminished ovarian reserve"],"prefix":"10.3389","volume":"16","author":[{"given":"Wen","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Lian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyan","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengyong","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haicui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3160","DOI":"10.3390\/ijms19103160","article-title":"Hormone replacement therapy: would it be possible to replicate a functional ovary?","volume":"19","author":"Agarwal","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.ogc.2024.10.005","article-title":"The mental health traumas of infertility: impact and consequences","volume":"52","author":"Bindeman","year":"2025","journal-title":"Obstet. Gynecol. Clin. North Am."},{"key":"B3","doi-asserted-by":"publisher","first-page":"8855","DOI":"10.3390\/ijms21228855","article-title":"LncRNAs in ovarian cancer progression, metastasis, and main pathways: ceRNA and alternative mechanisms","volume":"21","author":"Braga","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1007\/s10815-022-02422-2","article-title":"Expression of pro-apoptotic and anti-apoptotic proteins in granulosa cells of women with diminished ovarian reserve","volume":"39","author":"Bulgurcuoglu Kuran","year":"2022","journal-title":"J. Assist. Reprod. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/s10815-024-03301-8","article-title":"Role of epigenetic regulation in diminished ovarian reserve","volume":"42","author":"Chen","year":"2024","journal-title":"J. Assist. Reprod. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"635370","DOI":"10.3389\/fendo.2021.635370","article-title":"Prospects of germline nuclear transfer in women with diminished ovarian reserve","volume":"12","author":"Christodoulaki","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"hoz025","DOI":"10.1093\/hropen\/hoz025","article-title":"Recommendations for good practice in ultrasound: oocyte pick up(\u2020)","volume":"2019","author":"D'Angelo","year":"2019","journal-title":"Hum. Reprod. Open"},{"key":"B8","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1186\/s12889-025-21790-9","article-title":"The effect of job stress on fertility, its intention, and infertility treatment among the workers: a systematic review","volume":"25","author":"Dehkordi","year":"2025","journal-title":"BMC Public Health"},{"key":"B9","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1477-7827-10-26","article-title":"GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF\/ET)","volume":"10","author":"Depalo","year":"2012","journal-title":"Reprod. Biol. Endocrinol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"4905","DOI":"10.2147\/ott.S142446","article-title":"NEAT1 regulates cell proliferation and apoptosis of ovarian cancer by miR-34a-5p\/BCL2","volume":"10","author":"Ding","year":"2017","journal-title":"Onco Targets Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"123473","DOI":"10.1016\/j.lfs.2025.123473","article-title":"Targeting autophagy in premature ovarian failure: therapeutic strategies from molecular pathways to clinical applications","author":"Ding","year":"2025","journal-title":"Life Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/s13048-022-01053-6","article-title":"Expression of long noncoding RNAs in the ovarian granulosa cells of women with diminished ovarian reserve using high-throughput sequencing","volume":"15","author":"Dong","year":"2022","journal-title":"J. Ovarian Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1162725","DOI":"10.3389\/fendo.2023.1162725","article-title":"Visual analytics identifies key miRNAs for differentiating peripancreatic paraganglioma and pancreatic neuroendocrine tumors","volume":"14","author":"Enguita","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1007\/s10815-019-01446-5","article-title":"Apoptosis of mural granulosa cells is increased in women with diminished ovarian reserve","volume":"36","author":"Fan","year":"2019","journal-title":"J. Assist. Reprod. Genet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1093\/molehr\/gay035","article-title":"Does the molecular and metabolic profile of human granulosa cells correlate with oocyte fate? New insights by Fourier transform infrared microspectroscopy analysis","volume":"24","author":"Gioacchini","year":"2018","journal-title":"Mol. Hum. Reprod."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1007\/s10815-022-02650-6","article-title":"Association between oocyte retrieval technique and number of oocytes retrieved","volume":"39","author":"Gordon","year":"2022","journal-title":"J. Assist. Reprod. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e2300069","DOI":"10.1002\/bies.202300069","article-title":"Epigenetic programming in the ovarian reserve","volume":"45","author":"Hu","year":"2023","journal-title":"Bioessays"},{"key":"B18","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1093\/humupd\/dmv016","article-title":"Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century","volume":"21","author":"Inhorn","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"B19","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s12031-013-0208-0","article-title":"EPO-dependent activation of PI3K\/Akt\/FoxO3a signalling mediates neuroprotection in in vitro and in vivo models of Parkinson's disease","volume":"53","author":"Jia","year":"2014","journal-title":"J. Mol. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.bbi.2023.10.005","article-title":"Paternal immune activation by Poly I:C modulates sperm noncoding RNA profiles and causes transgenerational changes in offspring behavior","volume":"115","author":"Kleeman","year":"2024","journal-title":"Brain Behav. Immun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/s0015-0282(01)02017-9","article-title":"Reproductive outcome in patients with diminished ovarian reserve","volume":"76","author":"Levi","year":"2001","journal-title":"Fertil. Steril."},{"key":"B22","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1007\/s12015-024-10679-6","article-title":"Exploring the protective effect of total flavonoids from semen cuscutae on ovarian germline stem cells based on Notch signaling pathway","volume":"20","author":"Li","year":"2024","journal-title":"Stem Cell. Rev. Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.7661\/j.cjim.20171018.393","article-title":"Effect of Erzhitiangui formula on apoptosis of granulosa cells in IVF-ET patients","volume":"37","author":"Lian","year":"2017","journal-title":"Chin. J. Integr. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1136121","DOI":"10.3389\/fendo.2023.1136121","article-title":"Clinical efficacy of acupuncture for diminished ovarian reserve: a systematic review and meta-analysis of randomized controlled trials","volume":"14","author":"Lin","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1073274819897977","DOI":"10.1177\/1073274819897977","article-title":"Long noncoding RNA NEAT1 suppresses proliferation and promotes apoptosis of glioma cells via downregulating MiR-92b","volume":"27","author":"Liu","year":"2020","journal-title":"Cancer control."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e33652","DOI":"10.1097\/MD.0000000000033652","article-title":"MicroRNA profiling reveals effects of Erzhi Tiangui granules on kidney deficiency diminished ovarian reserve: a randomized trial","volume":"102","author":"Liu","year":"2023","journal-title":"Med. Baltim."},{"key":"B27","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.bbrc.2009.02.138","article-title":"FOXO3a is involved in the apoptosis of naked oocytes and oocytes of primordial follicles from neonatal rat ovaries","volume":"381","author":"Liu","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"10401","DOI":"10.2147\/ott.S217763","article-title":"Long non-coding RNA NEAT1 promoted hepatocellular carcinoma cell proliferation and reduced apoptosis through the regulation of let-7b-IGF-1R Axis","volume":"12","author":"Liu","year":"2019","journal-title":"Onco Targets Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"0","DOI":"10.14336\/ad.2024.1468","article-title":"Ovarian aging: the silent catalyst of age-related disorders in female body","author":"Liu","year":"2025","journal-title":"Aging Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s12943-018-0856-3","article-title":"Critical role of FOXO3a in carcinogenesis","volume":"17","author":"Liu","year":"2018","journal-title":"Mol. Cancer"},{"key":"B31","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1186\/s13046-018-0966-1","article-title":"Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC)","volume":"37","author":"Lu","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.theriogenology.2023.04.009","article-title":"Oocyte-cumulus cells crosstalk: new comparative insights","volume":"205","author":"Martinez","year":"2023","journal-title":"Theriogenology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.3390\/life13122247","article-title":"Stem-cell-derived extracellular vesicles: unlocking new possibilities for treating diminished ovarian reserve and premature ovarian insufficiency","volume":"13","author":"Martirosyan","year":"2023","journal-title":"Life (Basel)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1210\/endo.142.1.7862","article-title":"Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor","volume":"142","author":"Nishi","year":"2001","journal-title":"Endocrinology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.3390\/genes14101831","article-title":"CeRNA network reveals the circular RNA characterization in goat ear fibroblasts reprogramming into mammary epithelial cells","volume":"14","author":"Sahito","year":"2023","journal-title":"Genes. (Basel)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1038\/s41416-022-01759-w","article-title":"Low miR-10b-3p associated with sorafenib resistance in hepatocellular carcinoma","volume":"126","author":"Shao","year":"2022","journal-title":"Br. J. Cancer"},{"key":"B37","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1080\/10409238.2018.1447542","article-title":"Complexities of post-transcriptional regulation and the modeling of ceRNA crosstalk","volume":"53","author":"Smillie","year":"2018","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1136\/acupmed-2015-011014","article-title":"Electroacupuncture for reproductive hormone levels in patients with diminished ovarian reserve: a prospective observational study","volume":"34","author":"Wang","year":"2016","journal-title":"Acupunct. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"100","DOI":"10.4103\/aja.aja_35_19","article-title":"Altered microRNA profiles of testicular biopsies from patients with nonobstructive azoospermia","volume":"22","author":"Zhang","year":"","journal-title":"Asian J. Androl."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1007\/s43032-020-00237-z","article-title":"Adiponectin reduces embryonic loss rate and ameliorates trophoblast apoptosis in early pregnancy of mice with polycystic ovary syndrome by affecting the AMPK\/PI3K\/Akt\/FoxO3a signaling pathway","volume":"27","author":"Zhang","year":"","journal-title":"Reprod. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1111\/jphp.12668","article-title":"Oleanolic acid rejuvenates testicular function through attenuating germ cell DNA damage and apoptosis via deactivation of NF-\u03baB, p53 and p38 signalling pathways","volume":"69","author":"Zhao","year":"2017","journal-title":"J. Pharm. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s11655-020-3484-x","article-title":"Effects of bushen yiqi huoxue decoction in treatment of patients with diminished ovarian reserve: a randomized controlled trial","volume":"28","author":"Zhou","year":"2022","journal-title":"Chin. J. Integr. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1552581\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T15:07:30Z","timestamp":1742569650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1552581\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,21]]},"references-count":42,"alternative-id":["10.3389\/fphar.2025.1552581"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1552581","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2025,3,21]]},"article-number":"1552581"}}