PMID- 35960485 OWN - NLM STAT- MEDLINE DCOM- 20221209 LR - 20221209 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 47 IP - 12 DP - 2022 Dec TI - Unraveling the Mechanisms of Clinical Drugs-Induced Neural Tube Defects Based on Network Pharmacology and Molecular Docking Analysis. PG - 3709-3722 LID - 10.1007/s11064-022-03717-7 [doi] AB - Chemotherapeutic agents such as methotrexate (MTX), raltitrexed (RTX), 5-fluorouracil (5-FU), hydroxyurea (HU), and retinoic acid (RA), and valproic acid (VPA), an antiepileptic drug, all can cause malformations in the developing central nervous system (CNS), such as neural tube defects (NTDs). However, the common pathogenic mechanisms remain unclear. This study aimed to explore the mechanisms of NTDs caused by MTX, RTX, 5-FU, HU, RA, and VPA (MRFHRV), based on network pharmacology and molecular biology experiments. The MRFHRV targets were integrated with disease targets, to find the potential molecules related to MRFHRV-induced NTDs. Protein-protein interaction analysis and molecular docking were performed to analyze these common targets. Utilizing the kyoto encyclopedia of genes and genomes (KEGG) signaling pathways, we analyzed and searched the possible causative pathogenic mechanisms by crucial targets and the signaling pathway. Results showed that MRFHRV induced NTDs through several key targets (including TP53, MAPK1, HSP90AA1, ESR1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN) and multiple signaling pathways such as PI3K/Akt pathway, suggesting that abnormal proliferation and differentiation could be critical pathogenic contributors in NTDs induced by MRFHRV. These results were further validated by CCK8 assay in mouse embryonic stem cells and GFAP staining in embryonic brain tissue. This study indicated that chemotherapeutic and antiepileptic agents induced NTDs might through predicted targets TP53, MAPK1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN and multiple signaling pathways. More caution was required for the clinical administration for women with childbearing potential and pregnant. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Guan, Zhen AU - Guan Z AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. FAU - Liang, Yingchao AU - Liang Y AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. FAU - Wang, Xiuwei AU - Wang X AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. FAU - Zhu, Zhiqiang AU - Zhu Z AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. FAU - Yang, Aiyun AU - Yang A AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. FAU - Li, Shen AU - Li S AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. FAU - Yu, Jialu AU - Yu J AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. FAU - Niu, Bo AU - Niu B AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. niub2004@126.com. FAU - Wang, Jianhua AU - Wang J AD - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China. fywjh@163.com. LA - eng GR - No. 81700777/National Natural Science Foundation of China/ GR - No.7222016/Beijing Municipal Natural Science Foundation/ GR - CXYJ-2021-03/Research Foundation of Capital Institute of Pediatricsx/ PT - Journal Article DEP - 20220812 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 0 (Anticonvulsants) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.10.1 (ErbB Receptors) RN - U3P01618RT (Fluorouracil) RN - X6Q56QN5QC (Hydroxyurea) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - FCB9EGG971 (raltitrexed) RN - 5688UTC01R (Tretinoin) RN - 614OI1Z5WI (Valproic Acid) RN - YL5FZ2Y5U1 (Methotrexate) RN - 0 (Antineoplastic Agents) SB - IM MH - Animals MH - Female MH - Mice MH - Pregnancy MH - Anticonvulsants/adverse effects MH - Class I Phosphatidylinositol 3-Kinases MH - ErbB Receptors MH - Fluorouracil/adverse effects MH - Hydroxyurea/adverse effects MH - Molecular Docking Simulation MH - Network Pharmacology MH - *Neural Tube Defects/chemically induced MH - Phosphatidylinositol 3-Kinases MH - Tretinoin/adverse effects MH - Valproic Acid/adverse effects MH - Methotrexate/adverse effects MH - *Antineoplastic Agents/adverse effects OTO - NOTNLM OT - Antiepileptic drugs OT - Cell differentiation OT - Chemotherapeutic agents OT - Network pharmacology OT - Neural tube defects OT - PI3K/Akt signaling pathway EDAT- 2022/08/13 06:00 MHDA- 2022/12/07 06:00 CRDT- 2022/08/12 11:25 PHST- 2022/06/24 00:00 [received] PHST- 2022/07/31 00:00 [accepted] PHST- 2022/07/23 00:00 [revised] PHST- 2022/08/13 06:00 [pubmed] PHST- 2022/12/07 06:00 [medline] PHST- 2022/08/12 11:25 [entrez] AID - 10.1007/s11064-022-03717-7 [pii] AID - 10.1007/s11064-022-03717-7 [doi] PST - ppublish SO - Neurochem Res. 2022 Dec;47(12):3709-3722. doi: 10.1007/s11064-022-03717-7. Epub 2022 Aug 12.