Molecular Mechanisms of Medicinal Plant Securinega suffruticosa-derived Compound Securinine against Spinal Muscular Atrophy based on Network Pharmacology and Experimental Verification-Reference-Cited by-同舟云学术

Molecular Mechanisms of Medicinal Plant Securinega suffruticosa-derived Compound Securinine against Spinal Muscular Atrophy based on Network Pharmacology and Experimental Verification

Published:2024-04 Issue:15 Volume:30 Page:1178-1193
ISSN:1381-6128
Container-title:Current Pharmaceutical Design
language:en
Short-container-title:CPD

Author:

Zhang Yinhong¹²³,He Jing¹²³,Xiang Lifeng²³⁴,Tang Xinhua¹²³,Wang Shiyu³,Li Aoyu³,Wang Chaoyan³,Li Li²³⁵,Zhu Baosheng¹²³

Affiliation:

1. NHC Key Laboratory of Preconception Health Birth in Western China, Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, Department of Medical Genetics, Yunnan Provincial Clinical Research Center for Birth Defects and Rare Diseases, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan, China

2. The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China

3. School of Medical, Kunming University of Science and Technology, Kunming 650500, Yunnan, China

4. NHC Key Laboratory of Periconception Health Birth in Western China, Department of Reproductive Medicine, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan, China

5. Department of Pediatrics, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan, China

Abstract

Background: Spinal Muscular Atrophy (SMA) is a severe motor neuronal disorder with high morbidity and mortality. Securinine has shown the potential to treat SMA; however, its anti-SMA role remains unclear. Objective: This study aims to reveal the anti-SMA mechanisms of securinine. Methods: Securinine-associated targets were acquired from Herbal Ingredients' Targets (HIT), Similarity Ensemble Approach (SEA), and SuperPred. SMA-associated targets were obtained from GeneCards and Dis- GeNET. Protein-protein interaction (PPI) network was constructed using GeneMANIA, and hug targets were screened using cytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfifiler. Molecular docking was conducted using Pymol and Auto- Dock. In vitro assays were used to verify the anti-SMA effects of securinine. Results: Twenty-six intersection targets of securinine and SMA were obtained. HDAC1, HDAC2, TOP2A, PIK3R1, PRMT5, JAK2, HSP90AB1, TERT, PTGS2, and PAX8 were the core targets in PPI network. GO analysis demonstrated that the intersecting targets were implicated in the regulation of proteins, steroid hormones, histone deacetylases, and DNA transcription. KEGG analysis, pathway-pathway, and hub target-pathway networks revealed that securinine might treat SMA through TNF, JAK-STAT, Ras, and PI3K-Akt pathways. Securinine had a favorable binding affinity with HDAC1, HSP90AB, JAK2, PRMT5, PTGS2, and TERT. Securinine rescued viability suppression, mitochondria damage, and SMN loss in the SMA cell model. Furthermore, securinine increased HDAC1 and PRMT5 expression, decreased PTGS2 expression, suppressed the JAK2-STAT3 pathway, and promoted the PI3K-Akt pathway. Conclusion: Securinine might alleviate SMA by elevating HDAC1 and PRMT5 expression and reducing PTGS2 via JAK2-STAT3 suppression and PI3K-Akt activation.

Funder

Fund of Yunnan Provincial Clinical Research Center for Birth Defects and Rare Diseases

“Famous Doctor” special project of the Ten Thousand People Program of Yunnan Province

Co-operation Fund of Kunming Medical University and the Science and Technology Department of Yunnan Province

Open Fund of Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases

Innovation Research Project of Human Assisted Reproductive Technology of Yunnan Province

Open Fund of Reproductive Obstetrics and Gynecology Clinical Center of Yunnan Province

National Key Research and Development Program of China

Kunming University of Science and Technology & the First People's Hospital of Yunnan Province

Yunnan Provincial Young and Middle-aged Academic and Technical Leaders Reserve Talents Program

Publisher

Bentham Science Publishers Ltd.

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