Gao Jian, Yuan Linjie, Jiang Huanyu, Li Ganggang, Zhang Yuwei, Zhou Ruijun, Xian Wenjia, Zou Yutong, Du Quanyu, Zhou Xianhua
Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
Traditional Chinese Medicine Hospital of Meishan, Chengdu, China.
Front Pharmacol. 2024 Oct 15;15:1448308. doi: 10.3389/fphar.2024.1448308. eCollection 2024.
Previous studies have demonstrated that naringenin possesses lipid-lowering effects; however, the underlying mechanisms, particularly its specific molecular targets, remain uncertain.
Using bioinformatics, three traditional Chinese medicine databases and one human disease database were integrated to establish two naringenin-target-hyperlipidemia modules: naringenin-oxidative stress (OS) and naringenin-lipid metabolism (LM). Data on 1,850 proteins from 1,871 genetic instruments were sourced from seven previous studies. Using Mendelian randomization based on data from the Integrative Epidemiology Unit genome-wide association study (case, n = 5,153; control, n = 344,069), we identified potential drug targets that were subsequently validated in the UK Biobank (396,565 individuals) and FinnGen (412,181 individuals) cohorts. Using molecular docking and molecular dynamics simulation to verify the binding ability of naringenin and causal protein.
In plasma, every standard deviation increase in apolipoprotein B (APOB) was associated with an increased risk of hyperlipidemia (odds ratio [OR] = 9.37, 95% confidence interval [CI], 5.12-17.12; = 3.58e-13; posterior probability of hypothesis 4 [PPH4] = 0.997), and the same was observed for proprotein convertase subtilisin/kexin type 9 (OR = 1.81, 95% CI, 1.51-2.16; = 6.87e-11; PPH4 = 1) and neurocan (OR = 2.34, 95% CI, 1.82-3.01; = 4.09e-11; PPH4 = 0.932). The intersection of two modules and Mendelian randomization result identified APOB as a key regulatory target of naringenin in the treatment of hyperlipidemia. The binding energy between naringenin and APOB was determined to be -7.7 kcal/mol. Additionally, protein-protein interactions and protein-disease networks were analyzed to uncover potential connections between proteins and hyperlipidemia.
This Mendelian randomization-based combined analysis offers a robust framework for elucidating the pharmacological effects of naringenin and identifying candidate proteins for further investigation in the context of hyperlipidemia treatment.
先前的研究表明柚皮素具有降血脂作用；然而，其潜在机制，尤其是其特定的分子靶点仍不明确。
利用生物信息学，整合三个中药数据库和一个人类疾病数据库，建立两个柚皮素-靶点-高脂血症模块：柚皮素-氧化应激（OS）和柚皮素-脂质代谢（LM）。来自七项先前研究的1871个遗传工具的1850种蛋白质的数据。基于综合流行病学单位全基因组关联研究的数据（病例，n = 5153；对照，n = 344069）进行孟德尔随机化，我们确定了潜在的药物靶点，随后在英国生物银行（396565人）和芬兰基因队列（412181人）中进行了验证。使用分子对接和分子动力学模拟来验证柚皮素与因果蛋白的结合能力。
在血浆中，载脂蛋白B（APOB）每增加一个标准差与高脂血症风险增加相关（优势比[OR] = 9.37，95%置信区间[CI]，5.12 - 17.12； = 3.58e - 13；假设4的后验概率[PPH4] = 0.997），前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（OR = 1.81，95% CI，1.51 - 2.16； = 6.87e - 11；PPH4 = 1）和神经蛋白聚糖（OR = 2.34，95% CI，1.82 - 3.01； = 4.09e - 11；PPH4 = 0.932）也是如此。两个模块与孟德尔随机化结果的交集确定APOB是柚皮素治疗高脂血症的关键调控靶点。柚皮素与APOB之间的结合能确定为 - 7.7千卡/摩尔。此外，分析蛋白质-蛋白质相互作用和蛋白质-疾病网络以揭示蛋白质与高脂血症之间的潜在联系。
这种基于孟德尔随机化的联合分析为阐明柚皮素的药理作用和识别在高脂血症治疗背景下进一步研究的候选蛋白质提供了一个强大的框架。
