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Unraveling the Mechanisms of Clinical Drugs-Induced Neural Tube Defects Based on Network Pharmacology and Molecular Docking Analysis

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Abstract

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.

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Data availability

The data used to support the finding of this study are available from the corresponding author upon request.

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Acknowledgements

We appreciate the help offered by Prof. Jing Pan during the process. This study was supported by Beijing Natural Science Foundation (No.7222016), National Natural Science Foundation of China (No. 81700777); Research Foundation of Capital Institute of Pediatrics (CXYJ-2021-03).

Funding

National Natural Science Foundation of China, No. 81700777, Beijing Municipal Natural Science Foundation, No.7222016, Research Foundation of Capital Institute of Pediatrics, CXYJ-2021-03.

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  1. Zhen Guan and Yingchao Liang have contributed equally to this paper.

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  1. Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China

    Zhen Guan, Yingchao Liang, Xiuwei Wang, Zhiqiang Zhu, Aiyun Yang, Shen Li, Jialu Yu, Bo Niu & Jianhua Wang

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Contributions

Conceptualization: ZG, YL, XW, BN, JW. Data curation: ZG, JW. Formal analysis: ZG, YL, XW, ZZ, JY. Funding acquisition: ZG, JW. Methodology: ZG, YL. Supervision: JW. Writing – original draft: ZG, YL. Writing – review & editing: ZG, YL, XW, JW, BN, SL, ZZ, AY, JY.

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Correspondence to Bo Niu or Jianhua Wang.

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All animal experiment procedures were approved by the Animal Ethics Committee of Capital Institute of Pediatrics.

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Guan, Z., Liang, Y., Wang, X. et al. Unraveling the Mechanisms of Clinical Drugs-Induced Neural Tube Defects Based on Network Pharmacology and Molecular Docking Analysis. Neurochem Res 47, 3709–3722 (2022). https://doi.org/10.1007/s11064-022-03717-7

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