Department of Critical Care Medicine, Maoming People's Hospital, Maoming, China; Center of Scientific Research, Maoming People's Hospital, Maoming, China.
Department of Intensive Care Unit of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Ann Palliat Med. 2021 Dec;10(12):12441-12455. doi: 10.21037/apm-21-3298.
With its complex pathogenesis and high mortality, acute lung injury (ALI) is closely associated with a poor prognosis in critically ill patients. The present study used network pharmacology to investigate the mass spectrometry (MS) behaviors and molecular mechanisms of Amadori compounds acting on ALI and diabetes.
Two typical Amadori compounds (Fru-Trp and Glc(α1,4)-Fru-Trp) were used to study the fragmentation mechanisms by tandem MS in negative and positive-ion modes. The potential targets of Amadori compounds on ALI were screened from a public database. R package was used for the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and the protein-protein interactions (PPIs) of the targets were evaluated by Search Tool for the Retrieval of Interacting Genes (STRING). Finally, molecular docking was implemented to analyze the binding energies and action modes of the target compounds through the online tool CB-Dock.
In relation the common precursor ions of the Amadori compounds, the sodium adducting cations provided the most abundant fragmentation information in c for analyzing their chemical structures. 103 and 109 intersecting targets of glucose-Amadori and maltose-Amadori, respectively, were separately identified in the ALI database, and significant overlaps between the GO terms and KEGG pathways were noted. Three shared hub targets (i.e., vascular endothelial growth factor A, caspase-3, and proto-oncogene tyrosine-protein kinase) were selected from the 2 PPI networks by STRING. The molecular docking results showed that the Amadori compounds had good binding potential to the hub target proteins, and that Amadori compounds had lower binding energies and more stable conformations than their corresponding carbohydrates.
As the endogenous compounds in diabetes, Amadori compounds may act on and activate a wide range of protein receptors, which may also produce bi-directional regulatory effects that influence ALI progression. Thus, the risk factors of diabetes in the progression of ALI should be carefully assessed, and the molecular mechanisms of Amadori compounds in animal models for ALI should be further verified.
急性肺损伤（ALI）的发病机制复杂，死亡率高，与危重病患者的预后密切相关。本研究采用网络药理学方法研究了美拉德化合物对 ALI 和糖尿病的质谱（MS）行为和分子机制。
采用两种典型的美拉德化合物（Fru-Trp 和 Glc（α1,4）-Fru-Trp），在正负离子模式下通过串联 MS 研究其裂解机制。从公共数据库中筛选美拉德化合物在 ALI 上的潜在靶点。R 包用于基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路分析，通过 Search Tool for the Retrieval of Interacting Genes（STRING）评估靶点的蛋白质-蛋白质相互作用（PPIs）。最后，通过在线工具 CB-Dock 进行分子对接，分析目标化合物的结合能和作用模式。
与美拉德化合物的常见前体离子有关，钠离子加合阳离子在 c 中提供了最丰富的裂解信息，用于分析其化学结构。在 ALI 数据库中分别鉴定出葡萄糖-美拉德和麦芽糖-美拉德的 103 个和 109 个相交靶点，GO 术语和 KEGG 通路之间存在显著重叠。通过 STRING 从 2 个 PPI 网络中选择了 3 个共享的枢纽靶点（即血管内皮生长因子 A、半胱天冬酶-3 和原癌基因酪氨酸蛋白激酶）。分子对接结果表明，美拉德化合物与枢纽靶蛋白具有良好的结合潜力，美拉德化合物的结合能较低，构象更稳定。
作为糖尿病的内源性化合物，美拉德化合物可能作用于并激活广泛的蛋白受体，也可能产生双向调节作用，影响 ALI 的进展。因此，应仔细评估糖尿病在 ALI 进展中的危险因素，并进一步验证美拉德化合物在 ALI 动物模型中的分子机制。
