靶向IDO1治疗亨廷顿舞蹈病:网络药理学和来自阿拉比卡咖啡的临床前证据

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Vishnu Kumar Malakar, Dhritiman Roy, Chandi C. Malakar, Yogesh Mahadu Khetmalis, Pratap Chand Mali, Nitesh Kumar Poddar
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引用次数: 0

摘要

亨廷顿氏病(HD)是一种遗传性神经退行性疾病,以不自主运动功能障碍和进行性认知障碍为特征。本研究旨在利用基于网络药理学的药物再利用方法探索阿拉比卡咖啡(CA)植物成分的治疗潜力。ca相关的植物成分从公共数据库中鉴定,而hd相关的目标则从DisGeNET数据库中检索。利用Venny 2.1鉴定吲哚胺2,3-双加氧酶(IDO1)和亨廷顿蛋白(HTT)是两个常见的重叠靶点。利用CytoScape软件构建蛋白-蛋白相互作用(PPI)网络。基因本体(GO)和KEGG通路富集分析,以及MCODE和ClueGO软件发现IDO1、HTT、PPAR-γ、ESR1和CASP3是HD发病机制的关键靶点。在CA植物成分中,香叶醇因其与IDO1的高结合亲和力(PDB: 6V52)而被选中,其对接评分为8.01 kcal/mol,而参考抑制剂的对接评分为4.39 kcal/mol。密度泛函理论(DFT)分析表明偶极矩为2.50德拜。分子动力学模拟证实了ido1 -香叶醇复合物的稳定性,其关键相互作用涉及Ser167。在3-硝基丙酸(3-NP)诱导的HD动物模型中,香叶醇(15 mg/kg)可显著改善运动功能和认知能力,降低脂质过氧化和亚硝酸盐水平,恢复抗氧化酶(SOD、GSH、过氧化氢酶)活性。神经递质改变(GABA, DA,谷氨酸,乙酰胆碱酯酶)也受到调节。组织学研究显示纹状体神经元保存完好。这些发现表明,香叶醇通过调节IDO1活性、氧化应激和神经递质平衡,在HD中发挥神经保护作用。本研究将网络药理学、计算机建模和体内分析相结合,探索阿拉比卡咖啡的关键代谢物香叶醇作为亨廷顿病(HD)的多靶点药物。在HD大鼠模型中,香叶醇显示出与IDO1的强结合,恢复认知和运动功能,平衡氧化应激,并保存纹状体神经元。我们的研究结果表明,香叶醇通过调节IDO1、氧化还原平衡和神经递质,是一种有希望的治疗候选者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting IDO1 in Huntington’s Disease: Network Pharmacology and Preclinical Evidence from Coffea arabica

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary motor dysfunction and progressive cognitive impairment. This study aimed to explore the therapeutic potential of Coffea arabica (CA) phytoconstituents using a network pharmacology-based drug repurposing approach. CA-related Phytoconstituents were identified from public databases, while HD-related targets were retrieved from the DisGeNET database. Indoleamine 2,3-dioxygenase (IDO1) and huntingtin (HTT) were identified as two common overlapping targets using Venny 2.1. Protein–protein interaction (PPI) networks were constructed by CytoScape software. Gene ontology (GO) and KEGG pathway enrichment analysis, followed by MCODE and ClueGO software, revealed IDO1, HTT, PPAR-γ, ESR1, and CASP3 as key targets in HD pathogenesis. Among CA phytoconstituents, geraniol was selected based on its high binding affinity to IDO1 (PDB: 6V52), with a docking score of–8.01 kcal/mol compared to–4.39 kcal/mol for the reference inhibitor. Density functional theory (DFT) analysis showed a dipole moment of 2.50 Debye. Molecular dynamics simulations confirmed the stability of the IDO1–geraniol complex, with key interactions involving Ser167. In a 3-nitropropionic acid (3-NP)-induced HD animal model, geraniol (15 mg/kg) significantly improved motor function and cognitive performance, reduced lipid peroxidation and nitrite levels, and restored the activities of antioxidant enzymes (SOD, GSH, catalase). Neurotransmitter alterations (GABA, DA, glutamate, AChE) were also regulated. Histological studies revealed preservation of striatal neurons. These findings suggest that geraniol exerts neuroprotective effects in HD via modulation of IDO1 activity, oxidative stress, and neurotransmitter balance.

This study integrates network pharmacology, in silico modeling, and in vivo analysis to explore geraniol, a key metabolite of Coffea arabica, as a multi-target agent for Huntington’s disease (HD). Geraniol showed strong binding to IDO1, restored cognitive and motor functions, balanced oxidative stress, and preserved striatal neurons in an HD rat model. Our findings suggest geraniol as a promising therapeutic candidate through modulation of IDO1, redox balance, and neurotransmitters.

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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