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Wuzi Yanzong Pill (WYP) is an herbal formula of traditional Chinese medicine (TCM) that has been shown to have a protective effect against NTDs in a rodent model induced by all\u2010trans retinoic acid (atRA), but the mechanism remains unclear. In this study, the neuroprotective effect and mechanism of WYP on NTDs were investigated in vivo using an atRA\u2010induced mouse model and in vitro using cell injury model induced by atRA in Chinese hamster ovary (CHO) cells and Chinese hamster dihydrofolate reductase\u2010deficient (CHO\/dhFr) cells. Our findings suggest that WYP has an excellent preventive effect on atRA\u2010induced NTDs in mouse embryos, which may be related to the activation of the PI3K\/Akt signaling pathway, improved embryonic antioxidant capacity, and anti\u2010apoptotic effects, and this effect is not dependent on folic acid (FA). Our results demonstrated that WYP significantly reduced the incidence of NTDs induced by atRA; increased the activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH\u2010Px), and content of glutathione (GSH); decreased the apoptosis of neural tube cells; up\u2010regulated the expression of phosphatidylinositol 3 kinase (PI3K), phospho protein kinase B (p\u2010Akt), nuclear factor erythroid\u20102 related factor (Nrf2), and b\u2010cell lymphoma\u20102 (Bcl\u20102); and down\u2010regulated the expression of bcl\u20102\u2010associated X protein (Bax). Our in vitro studies suggested that the preventive effect of WYP on atRA\u2010treated NTDs was independent of FA, which might be attributed to the herbal ingredients of WYP. The results suggest that WYP had an excellent prevention effect on atRA\u2010induced NTDs mouse embryos, which may be independent of FA but related to the activation of the PI3K\/Akt signaling pathway and improvement of embryonic antioxidant capacity and anti\u2010apoptosis.<\/jats:p>","DOI":"10.1002\/jdn.10267","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T05:00:25Z","timestamp":1684731625000},"page":"417-430","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Wuzi Yanzong Pill protects neural tube defects by activating PI3K\/Akt signaling pathway"],"prefix":"10.1002","volume":"83","author":[{"given":"Xinliang","family":"Wang","sequence":"first","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanjuan","family":"Yang","sequence":"additional","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanrong","family":"Li","sequence":"additional","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Gong","sequence":"additional","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Ru","sequence":"additional","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangqi","family":"Xie","sequence":"additional","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Chai","sequence":"additional","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8543-1368","authenticated-orcid":false,"given":"Huijie","family":"Fan","sequence":"additional","affiliation":[{"name":"The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine\/Neurobiology Research Center Shanxi University of Chinese medicine  Jinzhong 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