Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation
<b>Background/Objectives:</b> Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic...
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MDPI AG
2025-04-01
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| author | Jiaxin Chu Jianqiang Song Zhuolin Fan Ruijun Zhang Qiwei Wang Kexin Yi Quan Gong Benju Liu |
| author_facet | Jiaxin Chu Jianqiang Song Zhuolin Fan Ruijun Zhang Qiwei Wang Kexin Yi Quan Gong Benju Liu |
| author_sort | Jiaxin Chu |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic and neuroprotective properties. However, the pharmacological mechanisms underlying 3-MA’s therapeutic effects on diabetic microvascular complications remain incompletely understood, owing to the intricate and multifactorial pathogenesis of DE. <b>Methods</b>: This study employed network pharmacology and molecular docking techniques to predict potential targets and signaling pathways of 3-MA against DE, with subsequent validation through animal experiments to elucidate the molecular mechanisms of 3-MA in DE treatment. <b>Results</b>: Network pharmacological analysis identified two key targets of 3-MA in DE modulation: AKT and GSK3β. Molecular docking confirmed a strong binding affinity between 3-MA and AKT/GSK3β. In animal experiments, 3-MA significantly reduced blood glucose levels in diabetic mice, ameliorated learning and memory deficits, and preserved hippocampal neuronal integrity. Furthermore, we found that 3-MA inhibited apoptosis by regulating the expression of Bax and BCL-2. Notably, 3-MA also downregulated the expression of amyloid precursor protein (APP) and Tau while enhancing the expression of phosphorylated AKT and GSK-3β. <b>Conclusions</b>: Our findings may contribute to elucidating the therapeutic mechanisms of 3-MA in diabetic microangiopathy and provide potential therapeutic targets through activation of the AKT/GSK-3β pathway. |
| format | Article |
| id | doaj-art-8d5bf32a90244d2891e70efcea8ee2db |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-8d5bf32a90244d2891e70efcea8ee2db2025-08-20T03:14:36ZengMDPI AGPharmaceuticals1424-82472025-04-0118560510.3390/ph18050605Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental ValidationJiaxin Chu0Jianqiang Song1Zhuolin Fan2Ruijun Zhang3Qiwei Wang4Kexin Yi5Quan Gong6Benju Liu7Department of Medcine, Yangtze University, Jingzhou 434023, ChinaDepartment of Medcine, Yangtze University, Jingzhou 434023, ChinaDepartment of Medcine, Yangtze University, Jingzhou 434023, ChinaDepartment of Medcine, Yangtze University, Jingzhou 434023, ChinaDepartment of Medcine, Yangtze University, Jingzhou 434023, ChinaDepartment of Medcine, Yangtze University, Jingzhou 434023, ChinaDepartment of Medcine, Yangtze University, Jingzhou 434023, ChinaDepartment of Medcine, Yangtze University, Jingzhou 434023, China<b>Background/Objectives:</b> Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic and neuroprotective properties. However, the pharmacological mechanisms underlying 3-MA’s therapeutic effects on diabetic microvascular complications remain incompletely understood, owing to the intricate and multifactorial pathogenesis of DE. <b>Methods</b>: This study employed network pharmacology and molecular docking techniques to predict potential targets and signaling pathways of 3-MA against DE, with subsequent validation through animal experiments to elucidate the molecular mechanisms of 3-MA in DE treatment. <b>Results</b>: Network pharmacological analysis identified two key targets of 3-MA in DE modulation: AKT and GSK3β. Molecular docking confirmed a strong binding affinity between 3-MA and AKT/GSK3β. In animal experiments, 3-MA significantly reduced blood glucose levels in diabetic mice, ameliorated learning and memory deficits, and preserved hippocampal neuronal integrity. Furthermore, we found that 3-MA inhibited apoptosis by regulating the expression of Bax and BCL-2. Notably, 3-MA also downregulated the expression of amyloid precursor protein (APP) and Tau while enhancing the expression of phosphorylated AKT and GSK-3β. <b>Conclusions</b>: Our findings may contribute to elucidating the therapeutic mechanisms of 3-MA in diabetic microangiopathy and provide potential therapeutic targets through activation of the AKT/GSK-3β pathway.https://www.mdpi.com/1424-8247/18/5/6053-methyladeninediabetic encephalopathynetwork pharmacologymolecular dockingAKT/GSK-3βmechanism |
| spellingShingle | Jiaxin Chu Jianqiang Song Zhuolin Fan Ruijun Zhang Qiwei Wang Kexin Yi Quan Gong Benju Liu Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation Pharmaceuticals 3-methyladenine diabetic encephalopathy network pharmacology molecular docking AKT/GSK-3β mechanism |
| title | Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation |
| title_full | Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation |
| title_fullStr | Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation |
| title_full_unstemmed | Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation |
| title_short | Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation |
| title_sort | investigating the effect and mechanism of 3 methyladenine against diabetic encephalopathy by network pharmacology molecular docking and experimental validation |
| topic | 3-methyladenine diabetic encephalopathy network pharmacology molecular docking AKT/GSK-3β mechanism |
| url | https://www.mdpi.com/1424-8247/18/5/605 |
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